Intervenciones para la prevención del herpes labial
Resumen
Antecedentes
El herpes simple labial (HSL), también conocido como herpes labial, es una enfermedad frecuente de los labios causada por el virus del herpes simple, que se encuentra en todo el mundo. Se presenta como una erupción vesicular dolorosa que forma costras desagradables que causan desfiguración estética y trastornos psicosociales. No existe una cura disponible, y se repite periódicamente.
Objetivos
Evaluar los efectos de las intervenciones para la prevención del HSL en pacientes de todas las edades.
Métodos de búsqueda
Se hicieron búsquedas en las siguientes bases de datos hasta el 19 de mayo de 2015: registro especializado del Grupo Cochrane de Piel (Cochrane Skin Group), registro especializado del Grupo Cochrane de Salud Oral (Oral Health Group), CENTRAL en the Cochrane Library (número 4, 2015), MEDLINE (desde 1946), EMBASE (desde 1974), LILACS (desde 1982), en la China National Knowledge Infrastructure (CNKI) database, Airiti Library y en cinco registros de ensayos. Para identificar más referencias a ensayos controlados aleatorizados relevantes, se examinaron las bibliografías de los estudios incluidos y se publicaron revisiones y también se estableció contacto con los investigadores originales de los estudios incluidos.
Criterios de selección
Ensayos controlados aleatorizados (ECA) de intervenciones para la prevención del HSL en pacientes inmunocompetentes.
Obtención y análisis de los datos
Dos autores de la revisión seleccionaron los ensayos de forma independiente, extrajeron los datos y evaluaron el riesgo de sesgo. Un tercer autor estaba disponible para resolver las diferencias de opinión.
Resultados principales
Esta revisión incluyó 32 ECA con 2640 participantes inmunocompetentes que analizaron 19 tratamientos. La calidad del conjunto de evidencia fue baja a moderada para la mayoría de los resultados, pero fue muy baja para algunos resultados. Los resultados primarios fueron "Incidencia del HSL" y "Efectos adversos durante la administración de la intervención preventiva".
La evidencia para la administración a corto plazo (≤ un mes) del aciclovir oral para prevenir el HSL recurrente fue inconsistente para las dosis utilizadas en los estudios: Dos ECA mostraron evidencia de baja calidad de una menor recurrencia del HSL con aciclovir 400 mg dos veces al día (riesgos relativos (RR) 0,26; intervalo de confianza (IC) del 95%: 0,13 a 0,51; n = 177), mientras que un ECA que evaluó el aciclovir 800 mg dos veces al día y dos ECA que evaluaron 200 mg cinco veces al día no encontraron efectos preventivos similares (RR 1,08; IC del 95%: 0,62 a 1,87; n = 237; evidencia de calidad moderada y RR 0,46; IC del 95%: 0,20 a 1,07; n = 66; evidencia de baja calidad, respectivamente). La dirección del efecto de la intervención no estaba relacionada con el riesgo de sesgo. La evidencia de un ECA sobre el efecto del uso a corto plazo del valaciclovir para reducir la recurrencia del HSL mediante la evaluación clínica fue incierta (RR 0,55; IC del 95%: 0,23 a 1,28; n = 125; evidencia de calidad moderada), al igual que la evidencia de un ECA que probaba el uso a corto plazo del famciclovir.
La administración a largo plazo (> un mes) de los agentes antivirales orales redujo la recurrencia del HSL. Hubo evidencia de baja calidad de un ECA de que la administración a largo plazo de aciclovir oral redujo las recurrencias clínicas (1,80 versus 0,85 episodios por participante por un período de cuatro meses, p = 0,009) y la recurrencia virológica (1,40 versus 0,40 episodios por participante por un período de cuatro meses, p = 0,003). Un ECA encontró que la administración a largo plazo de valaciclovir fue efectiva para reducir la incidencia del HSL (con una disminución de 0,09 episodios por participante por mes; n = 95). Un ECA encontró que un régimen supresivo a largo plazo de valaciclovir tuvo una incidencia inferior del HSL que un régimen episódico de valaciclovir (diferencia de medias [DM] ‐0,10 episodios por participante por mes; IC del 95%: ‐0,16 a ‐0,05; n = 120).
Estos ensayos no encontraron un aumento de los eventos adversos asociados con la administración de agentes antivirales orales (evidencia de calidad moderada).
No hubo evidencia que indicara que la administración a corto plazo de agentes antivirales tópicos previniera el HSL recurrente. Hubo evidencia de calidad moderada de dos ECA de que la crema tópica de aciclovir al 5% probablemente tiene poco efecto sobre la prevención de la recurrencia del HSL (RR agrupado 0,91; IC del 95%: 0,48 a 1,72; n = 271). Hubo evidencia de calidad moderada de un ECA único de que la crema tópica de foscarnet al 3% tiene poco efecto para prevenir el HSL (RR 1,08; IC del 95%: 0,82 a 1,40; n = 295).
La eficacia de la administración a largo plazo de la crema tópica de aciclovir fue incierta. Un ECA encontró significativamente menos recurrencias diagnosticadas por investigación del HSL con el tratamiento con crema de aciclovir que con placebo (p < 0,05), pero no encontró diferencias significativas en el número medio de recurrencias informadas por participante entre los dos grupos (P ≥ 0,05). Un ECA no encontró un efecto preventivo de la aplicación tópica del gel de 1,5‐pentanediol durante 26 semanas (P > 0,05). Otro ECA encontró que el grupo que utilizó el gel de 2‐hidroxipropilo‐β‐ciclo dextrina al 20% durante seis meses tuvo significativamente más recurrencias que el grupo placebo (P = 0,003).
Estos estudios no encontraron un aumento de los eventos adversos relacionados con la administración de los agentes antivirales tópicos.
Dos ECA encontraron que la aplicación del filtro solar previno significativamente el HSL recurrente inducido por la luz ultravioleta experimental (RR agrupado 0,07; IC del 95%: 0,01 a 0,33; n = 111), pero otro ECA encontró que el protector solar no previno el HSL inducido por la luz solar (RR 1,13, IC del 95%: 0,25 a 5,06; n = 51). Estos ECA no informaron eventos adversos.
Hubo datos muy escasos que indicaron que la timopentina, el tratamiento con láser de bajo nivel y la hipnoterapia fueron eficaces para prevenir el HSL recurrente, con uno a dos ECA para cada intervención. No fue posible encontrar evidencia de la eficacia de la lisina, la administración del suplemento LongoVital®, la gammaglobulina, la vacuna de la subunidad tipo I del virus del herpes simple (HSV) y la vacuna antifiebre amarilla para prevenir el HSL. No hubo datos consistentes que apoyaran la eficacia de levamisol e interferón, que también se asociaron con un mayor riesgo de efectos adversos como la fiebre.
Conclusiones de los autores
La evidencia actual demuestra que la administración a largo plazo de agentes antivirales orales puede prevenir el HSL, pero el efecto beneficioso clínico es pequeño. No se encontró evidencia de un mayor riesgo de eventos adversos. Por otro lado, la evidencia sobre los agentes antivirales tópicos y otras intervenciones no mostraron eficacia o no pudieron confirmar su eficacia para prevenir el HSL.
PICO
Resumen en términos sencillos
Medidas para prevenir el herpes labial
Pregunta de la revisión
¿Qué medidas son efectivas para prevenir la recurrencia del herpes labial?
Antecedentes
Un herpes labial es una infección viral recurrente e irritante sin una cura comprobada. Da lugar a vesículas dolorosas en los labios que forman costras desagradables y causan una apariencia desagradable y trastornos psicológicos. Se intentó examinar los efectos de las medidas disponibles para prevenir la recurrencia del herpes labial en los pacientes con inmunidad normal.
Características de los estudios
Se examinó la investigación publicada hasta el 19 de mayo 2015. Se planificó incluir los estudios solo si la administración de una u otra medida preventiva se decidía por azar. Este método de investigación, denominado ensayo controlado aleatorizado (ECA), es la mejor manera de probar que un efecto preventivo es causado por la medida que se prueba. Se encontraron 32 ECA que incluyeron a 2640 pacientes y examinaron 19 medidas preventivas. El fabricante del fármaco financió 18 de los 32 estudios, las organizaciones sin fines de lucro financiaron cuatro y no se conoce cómo se financiaron los otros diez.
Resultados clave
La administración a largo plazo de fármacos antivirales tomados por vía oral previno el herpes labial, aunque con una disminución muy pequeña de 0,09 episodios por persona por mes. El efecto preventivo de la administración a largo plazo de la crema de aciclovir aplicada a los labios fue incierto. La administración a largo plazo del gel de 1,5‐pentanediol y el gel de 2‐hidroxipropilo‐β‐ciclo dextrina al 20% aplicado a los labios no previno el herpes labial.
La administración a corto plazo de fármacos o cremas antivirales no previno el herpes labial. Ni la administración a corto plazo ni la administración a largo plazo de estos fármacos o cremas antivirales parecieron causar efectos secundarios.
Los efectos preventivos del filtro solar fueron inciertos. La aplicación del filtro solar previno el herpes labial inducido por la luz ultravioleta experimental, pero no previno el herpes labial inducido por la luz solar.
Se encontró muy poca evidencia acerca de los efectos preventivos de la timopentina, el láser de baja energía y la hipnoterapia para el herpes labial. La evidencia disponible no encontró un efecto preventivo de la lisina, la administración del suplemento LongoVital®, la gammaglobulina, la vacuna del herpes virus y la vacuna antifiebre amarilla. No hubo datos consistentes para confirmar que el levamisol y el interferón previenen el herpes labial.
Estos estudios no encontraron un aumento de los eventos adversos relacionados con la administración de los agentes antivirales tópicos.
Calidad de la evidencia
La calidad de la evidencia fue de baja a moderada para la mayoría de los resultados, pero fue muy baja para algunos resultados.
Authors' conclusions
Summary of findings
| Oral aciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis (cold sores on the lips) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Oral aciclovir (short‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 800 mg twice daily | Study population | RR 1.08 | 237 | ⊕⊕⊕⊝ | ‐ | |
| 171 per 1000 | 184 per 1000 | |||||
| Moderate | ||||||
| 171 per 1000 | 185 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 400 mg twice daily | Study population | RR 0.26 | 177 | ⊕⊕⊝⊝ | ‐ | |
| 364 per 1000 | 95 per 1000 | |||||
| Moderate | ||||||
| 538 per 1000 | 140 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 200 mg 5 times/day | Study population | RR 0.46 | 66 | ⊕⊕⊝⊝ | ‐ | |
| 394 per 1000 | 181 per 1000 | |||||
| Moderate | ||||||
| 394 per 1000 | 181 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) ‐ aciclovir 400 mg twice daily | Study population | RR 0.05 | 30 | ⊕⊕⊝⊝ | ‐ | |
| 750 per 1000 | 38 per 1000 | |||||
| Moderate | ||||||
| 750 per 1000 | 38 per 1000 | |||||
| Adverse effects during use of the preventative intervention ‐ aciclovir 800 mg twice daily | Study population | RR 0.98 | 239 | ⊕⊕⊕⊝ | ‐ | |
| 363 per 1000 | 356 per 1000 | |||||
| Moderate | ||||||
| 363 per 1000 | 356 per 1000 | |||||
| Adverse effects during use of the preventative intervention ‐ aciclovir 400 mg twice daily | Study population | RR 2.3 | 183 | ⊕⊕⊝⊝ | ‐ | |
| 33 per 1000 | 75 per 1000 | |||||
| Moderate | ||||||
| 20 per 1000 | 46 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Oral aciclovir (long‐term) compared with placebo for prevention of herpes simplex labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| placebo | Oral aciclovir (long‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) | 1.40 episodes per participant per a 4‐month period | 0.40 episodes per participant per a 4‐month period | Not estimable | 40 | ⊕⊕⊝⊝ | ‐ |
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) | 1.80 episodes per participant per a 4‐month period | 0.85 episodes per participant per a 4‐month period | Not estimable | 40 | ⊕⊕⊝⊝ | ‐ |
| Duration of attack of herpes labialis during use of the preventative intervention | ‐ | The mean duration of attack of herpes labialis during use of the preventative intervention in the intervention groups was 3.6 lower (7.2 lower to 0 higher) | ‐ | 40 | ⊕⊕⊝⊝ | ‐ |
| Rate of adherence to the regimen of the preventative intervention | 99% of the prescribed study medication | 99% of the prescribed study medication | ‐ | 40 | ⊕⊕⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded two levels due to risk of bias and imprecision: the available evidence is limited to one single randomised trial with a high risk of reporting bias. | ||||||
| Valaciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Valaciclovir (short‐term) | |||||
| Incidence of HSL during use of the preventative intervention (by clinical evaluation) | Study population | RR 0.55 | 125 | ⊕⊕⊕⊝ | ‐ | |
| 206 per 1000 | 113 per 1000 | |||||
| Moderate | ||||||
| 206 per 1000 | 113 per 1000 | |||||
| Incidence of HSL during use of the preventative intervention (by culture) | Study population | RR 0.47 | 125 | ⊕⊕⊕⊝ | ‐ | |
| 238 per 1000 | 112 per 1000 | |||||
| Moderate | ||||||
| 238 per 1000 | 112 per 1000 | |||||
| Adverse effects during use of the preventative intervention | Study population | RR 1.33 | 125 | ⊕⊕⊕⊝ | ‐ | |
| 206 per 1000 | 274 per 1000 | |||||
| Moderate | ||||||
| 206 per 1000 | 274 per 1000 | |||||
| Viral load (shedding) in saliva | Study population | RR 0.16 | 120 | ⊕⊕⊕⊝ | ‐ | |
| 103 per 1000 | 17 per 1000 | |||||
| Moderate | ||||||
| 103 per 1000 | 16 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Valaciclovir (long‐term) compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Valaciclovir (long‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention | 0.21 episodes per participant per month | 0.12 episodes per participant per month | Not estimable | 95 | ⊕⊕⊕⊝ | ‐ |
| Adverse effects during use of the preventative intervention | Study population | RR 0.86 | 95 | ⊕⊕⊕⊝ | ‐ | |
| 396 per 1000 | 340 per 1000 | |||||
| Moderate | ||||||
| 396 per 1000 | 341 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Valaciclovir (suppressive regimen compared with episodic regimen) for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Episodic regimen | Suppressive regimen | |||||
| Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month) | 0.1775 ± 0.1975 | 0.075 ± 0.1025 | The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 0.1 lower (0.16 to 0.05 lower) | 120 | ⊕⊝⊝⊝ | ‐ |
| Adverse effects during use of the preventative intervention | Study population | RR 1.21 (0.78 to 1.87) | 152 | ⊕⊝⊝⊝ | ‐ | |
| 316 per 1000 | 382 per 1000 | |||||
| Moderate | ||||||
| 316 per 1000 | 382 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | 2.86 ± 3.10 days | 1.78 ± 2.92 days | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 1.08 days shorter (2.16 lower to 0 higher) | 120 | ⊕⊝⊝⊝ | ‐ |
| Severity (pain) of attack of recurrent herpes labialis during use of the preventative intervention | 0.23 ± 0.32 | 0.14 ± 0.27 | The mean severity (pain) of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.09 lower (0.2 lower to 0.02 higher) | 120 | ⊕⊝⊝⊝ | ‐ |
| Severity (maximum total lesion area) of attack of recurrent herpes labialis during use of the preventative intervention | 10.52 ± 19.45 mm² | 5.14 ± 9.98 mm² | The mean severity (maximum total lesion area) of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 5.38 smaller (10.91 lower to 0.15 higher) | 120 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and multiple risk of biases in performance, detection, attrition, and other sources: the available evidence is limited to one single randomised trial with a high risk of biases. | ||||||
| Famciclovir compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Famciclovir | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 125 mg | Study population | RR 0.74 | 120 | ⊕⊕⊕⊝ | ‐ | |
| 517 per 1000 | 382 per 1000 | |||||
| Moderate | ||||||
| 517 per 1000 | 383 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 250 mg | Study population | RR 0.69 | 122 | ⊕⊕⊕⊝ | ‐ | |
| 517 per 1000 | 357 per 1000 | |||||
| Moderate | ||||||
| 517 per 1000 | 357 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 500 mg | Study population | RR 0.82 | 121 | ⊕⊕⊕⊝ | ‐ | |
| 517 per 1000 | 424 per 1000 | |||||
| Moderate | ||||||
| 517 per 1000 | 424 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 125 mg | Study population | HR 1.63 | 47 | ⊕⊕⊕⊝ | ‐ | |
| See comment² | See comment² | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 250 mg | Study population | HR 1.59 | 45 | ⊕⊕⊕⊝ | ‐ | |
| See comment² | See comment² | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 500 mg | Study population | HR 2.39 | 51 | ⊕⊕⊕⊝ | ‐ | |
| See comment² | Shortened by 2.8 days | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Levamisole compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Levamisole | |||||
| Incidence of herpes labialis during use of the preventative intervention | 2.7 ± 2.3 recurrences during a 6‐month period | The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 2 lower (2.24 to 1.76 lower) during a 6‐month period | ‐ | 72 | ⊕⊝⊝⊝ | Of the 99 participants randomised, 27 (27.2%) did not complete the trial and were excluded from the analysis, with 19 (39.6%) in the levamisole group and 8 (15.7%) in the placebo group |
| Adverse effects during use of the preventative intervention (leading to withdrawal) | Study population | See comment | 99 | ⊕⊝⊝⊝ | Risks were calculated from pooled risk differences | |
| 157 per 1000 | 395 per 1000 | |||||
| Moderate | ||||||
| 157 per 1000 | 396 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | 8.2 ± 2.8 days | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.7 days longer (0.22 to 1.18 longer) | ‐ | 72 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and attrition and other biases: the available evidence is limited to a single study with a high risk of attrition and other biases. | ||||||
| Lysine compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis (cold sores on the lips) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Lysine | |||||
| Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month) | ‐ | The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 0.04 lower (0.37 lower to 0.29 higher) | ‐ | 26 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and reporting and other biases: the available evidence is limited to a single study with a high risk of reporting and other biases. | ||||||
| Topical aciclovir (short‐term) compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical aciclovir (short‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention | Study population | RR 0.91 | 271 | ⊕⊕⊕⊝ | ‐ | |
| 304 per 1000 | 276 per 1000 | |||||
| Moderate | ||||||
| 328 per 1000 | 298 per 1000 | |||||
| Adverse effects during use of the preventative intervention | Study population | RR 1.17 | 191 | ⊕⊕⊝⊝ | ‐ | |
| 135 per 1000 | 158 per 1000 | |||||
| Moderate | ||||||
| 135 per 1000 | 158 per 1000 | |||||
| Severity (aborted lesions) of attack of recurrent herpes labialis during use of the preventative intervention | Study population | RR 1.02 | 52 | ⊕⊕⊝⊝ | ‐ | |
| 95 per 1000 | 97 per 1000 | |||||
| Moderate | ||||||
| 95 per 1000 | 97 per 1000 | |||||
| Incidence of herpes labialis after use of the preventative intervention | Study population | RR 0.35 | 181 | ⊕⊕⊝⊝ | ‐ | |
| 156 per 1000 | 54 per 1000 | |||||
| Moderate | ||||||
| 156 per 1000 | 55 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to risk of bias: the evidence is from two trials with a high risk of reporting bias. | ||||||
| Topical aciclovir and 348U87 cream (short‐term) compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical aciclovir and 348U87 cream (short‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) | Study population | RR 0.78 | 51 | ⊕⊝⊝⊝ | ‐ | |
| 154 per 1000 | 120 per 1000 | |||||
| Moderate | ||||||
| 154 per 1000 | 120 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) | Study population | RR 1.46 | 51 | ⊕⊝⊝⊝ | ‐ | |
| 192 per 1000 | 281 per 1000 | |||||
| Moderate | ||||||
| 192 per 1000 | 280 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | ‐ | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 2.5 days longer (1.39 shorter to 6.39 longer) | ‐ | 9 | ⊕⊝⊝⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) in the intervention groups was 73 larger (42.22 smaller to 188.22 larger) | ‐ | 9 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and reporting and other biases: the available evidence is from a single trial with a high risk of reporting and other biases. | ||||||
| Topical foscarnet compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical foscarnet | |||||
| Incidence of herpes labialis during use of the preventative intervention | Study population | RR 1.08 | 295 | ⊕⊕⊕⊝ | ‐ | |
| 408 per 1000 | 441 per 1000 | |||||
| Moderate | ||||||
| 408 per 1000 | 441 per 1000 | |||||
| Adverse effects during use of the preventative intervention (leading to discontinuation) | Study population | RR 2.96 | 302 | ⊕⊕⊕⊝ | ‐ | |
| 0 per 1000 | 0 per 1000 | |||||
| Moderate | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| Adverse effects during use of the preventative intervention (application site reactions) | Study population | RR 2.47 | 302 | ⊕⊕⊕⊝ | ‐ | |
| 27 per 1000 | 66 per 1000 | |||||
| Moderate | ||||||
| 27 per 1000 | 67 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention (healing time) | ‐ | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention (healing time) in the intervention groups was 0.21 days shorter (1.68 shorter to 1.26 longer) | ‐ | 125 | ⊕⊕⊕⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (mean lesion area) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (mean lesion area) in the intervention groups was 16 lower (38.96 lower to 6.96 higher) | ‐ | 124 | ⊕⊕⊕⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) in the intervention groups was 30 lower (72.64 lower to 12.64 higher) | ‐ | 124 | ⊕⊕⊕⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (duration of pain) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (duration of pain) in the intervention groups was 0.1 higher (1.11 lower to 1.31 higher) | ‐ | 113 | ⊕⊕⊕⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| Topical 1,5‐pentanediol compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical 1,5‐pentanediol | |||||
| Incidence of herpes labialis during use of the preventative intervention | Study population | Not estimable | 102 | ⊕⊕⊕⊝ | P > 0.05 calculated using the Mann‐Whitney test by the trialists | |
| 109 episodes out of 50 | 120 episodes out of 52 | |||||
| Moderate | ||||||
| ‐ | ‐ | |||||
| Adverse effects during use of the preventative intervention | Study population | Not estimable | 102 | ⊕⊕⊕⊝ | ‐ | |
| See comment | See comment | |||||
| Moderate | ||||||
| ‐ | ‐ | |||||
| Severity (blistering, swelling, or pain) of recurrence | Study population | RR 1.05 | 224 | ⊕⊕⊕⊝ | ‐ | |
| 756 per 1000 | 794 per 1000 | |||||
| Moderate | ||||||
| 756 per 1000 | 794 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single study. | ||||||
| Sunscreen compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Sunscreen | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ solar radiation | Study population | RR 1.12 | 51 | ⊕⊕⊝⊝ | ‐ | |
| 111 per 1000 | 124 per 1000 | |||||
| Moderate | ||||||
| 111 per 1000 | 124 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ experimental ultraviolet light | Study population | RR 0.07 | 111 | ⊕⊝⊝⊝ | ‐ | |
| 456 per 1000 | 32 per 1000 | |||||
| Moderate | ||||||
| 487 per 1000 | 34 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) | Study population | See comment | 73 | ⊕⊝⊝⊝ | Risks were calculated from pooled risk differences | |
| 658 per 1000 | 26 per 1000 | |||||
| Moderate | ||||||
| 658 per 1000 | 26 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded two levels due to risk of bias and imprecision: the available evidence is limited to a single study with a high risk of reporting bias. | ||||||
| Interferon compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Interferon | |||||
| Incidence of herpes labialis during use of the preventative intervention ‐ presurgical | Study population | RR 1.59 | 32 | ⊕⊕⊝⊝ | ‐ | |
| 571 per 1000 | 909 per 1000 | |||||
| Moderate | ||||||
| 571 per 1000 | 908 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention ‐ postsurgical | Study population | RR 0.99 | 44 | ⊕⊕⊝⊝ | ‐ | |
| 571 per 1000 | 566 per 1000 | |||||
| Moderate | ||||||
| 571 per 1000 | 565 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention ‐ pre‐ and postsurgical | Study population | RR 0.57 | 37 | ⊕⊕⊝⊝ | ‐ | |
| 833 per 1000 | 475 per 1000 | |||||
| Moderate | ||||||
| 833 per 1000 | 475 per 1000 | |||||
| Adverse effects during use of the preventative intervention (fever) ‐ presurgical | Study population | RR 2.45 | 32 | ⊕⊕⊕⊝ | ‐ | |
| 333 per 1000 | 817 per 1000 | |||||
| Moderate | ||||||
| 333 per 1000 | 816 per 1000 | |||||
| Adverse effects during use of the preventative intervention (fever) ‐ postsurgical | Study population | RR 1.96 | 44 | ⊕⊕⊕⊝ | ‐ | |
| 333 per 1000 | 653 per 1000 | |||||
| Moderate | ||||||
| 333 per 1000 | 653 per 1000 | |||||
| Adverse effects during use of the preventative intervention (fever) ‐ pre‐ and postsurgical | Study population | RR 11.76 | 38 | ⊕⊕⊕⊝ | ‐ | |
| 0 per 1000 | 0 per 1000 | |||||
| Moderate | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to inconsistency: the effects of presurgical, postsurgical, and continuous pre‐ and postsurgical administration of interferon were inconsistent. | ||||||
| Gamma globulin compared with histamine (control) for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Histamine (control) | Gamma globulin | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | ‐ | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.7 higher (0.55 lower to 1.95 higher) | ‐ | 72 | ⊕⊕⊝⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (less severe recurrences than usual) | Study population | RR 0.97 | 73 | ⊕⊕⊝⊝ | ‐ | |
| 750 per 1000 | 728 per 1000 | |||||
| Moderate | ||||||
| 750 per 1000 | 728 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded two levels due to risk of bias and imprecision: the available evidence is from a single trial with a high risk of reporting bias. | ||||||
| Thymopentin compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Thymopentin | |||||
| Incidence of herpes labialis during use of the preventative intervention | 0.9 (range 0.1 to 2.0) | Median 0.2 (range 0.0 to 2.7) | ‐ | 36 | ⊕⊕⊕⊝ | P = 0.0027 using the Mann‐Whitney test by the trialists |
| Adverse effects during use of the preventative intervention | 111 per 1000 | 222 per 1000 | RR 2 | 36 | ⊕⊕⊕⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| HSV vaccination compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | HSV vaccination | |||||
| Incidence of herpes labialis during use of the preventative intervention | 1.3 recurrences in a 4‐month period | 1.6 recurrences in a 4‐month period | P = 0.10 calculated by the trialists | 64 | ⊕⊕⊕⊝ | ‐ |
| Adverse effects during use of the preventative intervention | 13 adverse events per 100 injections | 22 adverse events per 100 injections | RR 0.33 | 64 | ⊕⊕⊕⊝ | Several adverse events might have occurred in the same participant; no statistical tests were conducted by the trialists |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| Yellow fever vaccination compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Yellow fever vaccination | |||||
| Incidence of herpes labialis during use of the preventative intervention | See comment | See comment | ‐ | 1 | ⊕⊕⊕⊝ | ‐ |
| Adverse effects during use of the preventative intervention | 83 per 1000 | 28 per 1000 | RR 0.33 | 24 | ⊕⊕⊕⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| Laser compared with no interventions for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No interventions | Laser | |||||
| Incidence of herpes labialis during use of the preventative intervention | 0.116 recurrences per month | 0.076 recurrences per month | Not estimable | 71 | ⊕⊝⊝⊝ | P = 0.076, calculated using the Mann‐Whitney U test by the trialists |
| Adverse effects during use of the preventative intervention | 0 | 0 | Not estimable | 119 | ⊕⊕⊝⊝ | No adverse events were observed in either group |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision: the evidence is from a single trial with a high risk of performance and detection biases. | ||||||
| Hypnotherapy compared with control for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Hypnotherapy | |||||
| Incidence of herpes labialis during use of the preventative intervention (change in frequency of recurrence) | ‐ | The mean incidence of herpes labialis during use of the preventative intervention (change in frequency of recurrence) in the intervention groups was 6.5 lower (8.76 to 4.24 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (change in intensity) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (change in intensity) in the intervention groups was 9.7 lower (12.46 to 6.94 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| Change in severity (pain) of herpes labialis | ‐ | The mean change in severity (pain) of herpes labialis in the intervention groups was 2.2 lower (3.14 to 1.26 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| Change in severity (impairment of appearance) of herpes labialis | ‐ | The mean change in severity (impairment of appearance) of herpes labialis in the intervention groups was 1.6 lower (2.5 to 0.7 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision (the evidence is from a single trial) with a high risk of performance and detection biases. | ||||||
Background
Description of the condition
A virus that resides in the skin of the lips causes herpes simplex labialis (HSL) (Higgins 1993). Its manifestation on the skin is also known as a 'cold sore' or 'fever blister'. The initial infection with the virus, which is called herpes simplex virus (HSV), is by direct contact between the mucous membranes or abraded skin of the lips or mouth and the saliva or other secretions of a person with active primary or recurrent infection (Higgins 1993). Primary infection with HSV typically occurs in early childhood, often with no symptoms, but primary HSV infection may also present as herpetic gingivostomatitis, which is characterised by oral and perioral vesicles (tiny blisters) and ulcers (Higgins 1993). It has been reported that when clinical disease is not present, the virus spreads through respiratory droplets or through interaction with the mucocutaneous releases of an asymptomatic person shedding the virus (Fatahzadeh 2007). Following the primary infection, the virus resides in the sensory ganglia (nerve endings) in a latent form (Higgins 1993). After reactivation, HSV migrates from these sensory ganglia to the outer layer of the skin of the lips or mouth to cause recurrent HSL (Fatahzadeh 2007). Herpes simplex virus type 1 (HSV‐1) causes recurrent HSL. Although herpes simplex virus type 2 (HSV‐2) may occasionally cause primary oral infection, it rarely causes recurrent HSL (Fatahzadeh 2007).
Herpes simplex labialis affects the lips, with the outer third of the lower lip being most frequently affected (Marques 2003). In up to 60% of affected people, HSL is preceded by warning signs, which are known as 'prodromal symptoms'; these are feelings of pain, burning, itching, or tingling at the site of subsequent vesicle development. Headache may also occur in the prodromal stage (Joseph 1985). Within 24 hours of the prodrome, multiple grouped vesicles appear and then weep until they finally form crusts (Fatahzadeh 2007). Such crusts can often bleed quite easily, forming unsightly blackish crusts due to dried blood, which can bleed again when the skin is stretched, e.g., when smiling (Fatahzadeh 2007). These usually heal without scarring within 5 to 15 days (Marques 2003). Herpes simplex labialis may cause pain, discomfort, inconvenience, and some amount of psychological and social distress as a result of cosmetic disfigurement (Fatahzadeh 2007).
Herpes simplex labialis occurs worldwide and is a very common disease (Higgins 1993). The lifetime prevalence of recurrent herpes labialis is 20% to 52.5% (Celik 2013; Higgins 1993). It has been estimated that there are 98 million cases of HSL each year in the US alone (Higgins 1993). Most people with recurrent HSL have fewer than 2 episodes per year, but 5% to 10% of affected people have a minimum of 6 recurrences per annum (Celik 2013; Rooney 1993). Recurrences of HSL seem to be precipitated by a number of factors, including ultraviolet light (UVL); illness; stress; premenstrual tension; severe drug eruptions; and surgical procedures, such as dental surgery, neural surgery, and dermabrasion (a cosmetic procedure used to smooth scars) (Celik 2013; Higgins 1993; Shiohara 2013). People with atopic dermatitis who carry filaggrin mutations are prone to recurrent HSL, which may be attributed to their deficient antiviral immune response (Leung 2014; Rystedt 1986).
Description of the intervention
To date, there has been no proven way of eradicating HSV from the body completely. A number of interventions have been proposed for the prevention of recurrent HSL, including oral antivirals, topical antivirals, and sunscreens (Worrall 2009).
Antiviral agents, including aciclovir, famciclovir, penciclovir, and valaciclovir, inhibit DNA polymerase and viral replications. Before converting to the active antiviral triphosphate form, these drugs need to be phosphorylated by enzymes, such as viral thymidine kinase (TK) or host cellular kinases. Compared with aciclovir, famciclovir and valaciclovir have greater bioavailability and need less frequent dosing. Foscarnet inhibits viral DNA polymerase independent of phosphorylation and is thus used in aciclovir‐resistant HSV infections (Fatahzadeh 2007).
The active ingredients of sunscreens are generally classified into inorganic and organic UVL filters. Inorganic filters, such as titanium oxide, reflect or scatter UVL, while organic filters absorb UVL and convert the energy into heat. The most frequently‐used efficacy index of sunscreen in preventing sunburns is the sun protection factor (SPF), which is measured after application of 2 mg/cm² of product (Kullavanijaya 2005).
How the intervention might work
Long‐term prophylactic administration of oral antivirals (e.g., aciclovir, famciclovir, and valaciclovir) is expected to prevent reactivation of HSV (Worrall 2009). However, continuous daily intake of antivirals is not only costly but also requires the person to adhere to such a programme consistently (Fatahzadeh 2007). Therefore, it is important to design an optimal regimen, balancing known effectiveness of any preventative intervention with the inconvenience and possible side‐effects of continuous medication.
When topical aciclovir cream is used as a treatment for HSL, the frequency of application is five times daily (four hours apart except for sleep) (GSK 2008). However, the efficacy and frequency of application when used as a preventative intervention is unclear.
Based on the fact that ultraviolet light induces the recurrence of HSL (Higgins 1993), sunscreens, theoretically, can prevent recurrence of HSL. However, commercially available sunscreens vary greatly in their active ingredients and the effectiveness of their photoprotection. The effectiveness of photoprotection also depends on the appropriate application of sunscreens; frequency of re‐application after sweating or water sports (Kullavanijaya 2005); and in the case of lips, eating or drinking (Rooney 1991). In actual use, most people apply less than the amounts used in testing SPF, which compromises the efficacy of the sunscreen (Kullavanijaya 2005). Photoprotective lipscreens often contain less UVL‐absorbing ingredients than skin sunscreens (Wahie 2007).
Why it is important to do this review
There has been a Cochrane review on the effects of systemic aciclovir for primary herpetic gingivostomatitis (Nasser 2008) and another on the interventions for the prevention and treatment of HSV in people being treated for cancer (Glenny 2009). However, a systematic review on interventions for preventing HSL in those who are immunocompetent is lacking. We aimed to conduct such a review in order to find out the best evidence on the effects of those interventions currently available for the prevention of recurrent HSL.
The plans for this review were published as a protocol 'Interventions for prevention of herpes simplex labialis (cold sores on the lips)' (Chi 2012).
Objectives
To assess the effects of interventions for the prevention of HSL in people of all ages.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) of systemic, topical, and physical interventions for the prevention of herpes simplex labialis (HSL).
Types of participants
Anyone who was immunocompetent and had been initially diagnosed with recurrent HSL by a healthcare professional or trained researcher.
Types of interventions
Any systemic, topical, or physical intervention used for the prevention of HSL. The interventions could be either a single intervention or a combination of interventions. When there were different lengths of use of the intervention, we regarded those of ≤ 1 month as short‐term use and those of > 1 month as long‐term use. The controls might be a placebo, no intervention, or another active intervention.
Types of outcome measures
Primary outcomes
-
Incidence of HSL during use of the preventative intervention. We accepted both researcher‐diagnosed and participant‐reported recurrences.
-
Adverse effects during use of the preventative intervention.
Secondary outcomes
-
Duration of attack of recurrent HSL during use of the preventative intervention.
-
Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention.
-
Viral load in saliva.
-
Rate of adherence to the regimen of the preventative intervention.
-
Incidence of HSL after use of the preventative intervention. We accepted both researcher‐diagnosed and participant‐reported recurrences.
-
Duration of attack of recurrent HSL after use of the preventative intervention.
-
Severity (lesion area, stage, pain) of attack of recurrent HSL after use of the preventative intervention.
Search methods for identification of studies
We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
We searched the following databases up to 19 May 2015:
-
the Cochrane Skin Group Specialised Register using the search strategy in Appendix 1;
-
the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (Issue 4, 2015) using the strategy in Appendix 2;
-
MEDLINE via Ovid (from 1946) using the strategy in Appendix 3;
-
EMBASE via Ovid (from 1974) using the strategy in Appendix 4; and
-
LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 5.
We searched the Cochrane Oral Health Group Specialised Register using the search strategy in Appendix 1 up to 19 May 2015.
On 22 May 2015, we searched the China National Knowledge Infrastructure (CKNI) database (from 1994) using the strategy in Appendix 6 and Airiti Library (publications and theses from Taiwan, from 1991) using the strategy in Appendix 7.
Trials registers
We searched the following trials databases on 25 May 2015 using the strategy in Appendix 8.
-
The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).
-
The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
-
The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).
-
The EU Clinical Trials Register (www.clinicaltrialsregister.eu).
We searched the metaRegister of Controlled Trials (www.controlled‐trials.com) on 13 June 2014, but this was closed and under review when we updated our search on 25 May 2015.
Searching other resources
Reference lists
We scanned the bibliographies of the included studies and published reviews for further references to relevant trials.
Unpublished literature
We tried to identify further unpublished trials through correspondence with the original researchers of the included studies.
Adverse effects
We did not run separate searches for adverse effects of the target interventions. However, we did extract relevant data from the included trials that we identified.
Data collection and analysis
Some parts of this section uses text that was originally published in another Cochrane review (Chi 2011). We included 'Summary of findings' tables where we used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of the evidence for the primary outcomes for the treatment comparisons.
Selection of studies
Two authors (CC and SW) independently checked titles and abstracts identified from the searches. The authors were not blinded to the names of the original researchers, journals, or institutions. If it was clear from the abstract that the study did not refer to a RCT on interventions for prevention of HSL, we excluded it. The same two authors independently assessed the full text version of each remaining study to determine whether it met the predefined selection criteria. We resolved any disagreement by discussion with referral to a third author (FW), if necessary. We listed the studies that we could only exclude after reading the full text and reasons for exclusion in the 'Characteristics of excluded studies' tables.
Data extraction and management
Two authors (CC and SW) independently extracted the data using a specialised data extraction form. We resolved discrepancies by discussion with a third author (FW). One author (CC) entered the data into Review Manager (RevMan) (Review Manager 2014).
Assessment of risk of bias in included studies
We evaluated the following components since there is some evidence that these are associated with biased estimates of intervention effect (Higgins 2011):
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random sequence generation ‐ adequacy of the method of random sequence generation to produce comparable groups in every aspect except for the intervention;
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allocation concealment ‐ adequacy of the method used to conceal the allocation sequence to prevent anyone foreseeing the allocation sequence in advance of, or during, enrolment;
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blinding of participants and personnel ‐ adequacy of blinding study participants and researchers from knowledge of the allocated interventions;
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blinding of outcome assessment ‐ adequacy of blinding outcome assessors from knowledge of the allocated interventions;
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incomplete outcome data ‐ the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis, whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition/exclusions where reported, and any re‐inclusions in our analyses;
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selective reporting ‐ whether all prespecified outcomes were reported when the trial protocol was available; and
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other sources of bias ‐ any other important concerns about bias.
Measures of treatment effect
For dichotomous outcomes, we expressed the results as risk ratios (RR) with 95% confidence intervals (CI) and where appropriate as number needed to treat to benefit (NNTB) with 95% CI and the baseline risk to which it applies. For continuous outcomes, we expressed the results as difference in means (MD) with 95% CI or where different outcome scales were pooled as standardised mean differences (SMD) with 95% CI. For time‐to‐event outcomes, we expressed the results as hazard ratios (HRs). If Kaplan‐Meier curves were presented, we would have extracted the data from the graphs and calculated HRs according to the methods given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). However, time‐to‐event outcomes were treated as continuous data in a few included trials. We therefore could only present the original data reported.
With regard to our primary outcome 'Adverse effects during use of the preventative intervention', we measured this by assessing the proportion of participants who experienced adverse events.
With regard to our secondary outcome 'Rate of adherence to the regimen of the preventative intervention', we measured this by assessing either the proportion of participants who adhered to the interventions or the mean proportion of interventions participants received.
Unit of analysis issues
All randomised participants in the control and intervention groups were the unit of analysis. We did not pool the following types of studies with studies of other designs.
Cluster‐randomised trials
For cluster‐randomised trials, we would have used appropriate techniques described in section 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Cross‐over trials
For cross‐over trials, we used appropriate techniques described in section 16.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Studies with multiple treatment groups
Where there were multiple intervention groups within a trial, we made pair‐wise comparisons of an intervention versus no intervention, placebo, or another active intervention.
Dealing with missing data
We contacted the original researchers of studies less than 15 years old for missing data (Table 1). When the missing data were not available, we initially assumed those data were missing at random. If the missing data were caused by participants' dropout, we conducted intention‐to‐treat analyses. For dichotomous outcomes, we would have regarded participants with missing outcome data as treatment failures and included them in the analyses. For continuous outcomes, we would have carried forward the last recorded value for participants with missing outcome data. Where high levels of missing data were seen within the analyses, we would have conducted sensitivity analyses to assess the robustness of the results from the approach described above by comparing the results with those that exclude the missing data from the analyses. However, we failed to conduct the planned analyses because of lacking adequate data, for example, the respective number of randomised participants and those who were lost to follow up in each group.
| Study | Enquiries | Reply |
| We sent the following request on 13 February 2015: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) Could you please offer the details of how you achieved double blindness? (4) Did you use a person other than the physician to assess the outcomes? | No reply | |
| We sent the following request on 23 June 2014: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) Did you use a person other than the physician to assess the outcomes? (4) The number of dropouts or withdrawals in this trial (5) Did you assess any outcomes regarding adverse events? If you did, what were the results? | 4 August 2014 (1) Randomisation was down through sortition (2) No (3) No (4) 01 (5) Adverse events were evaluated, but there were no adverse events detected | |
| We sent the following request on 13 February 2015: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? | No reply | |
| We sent the following request on 23 June 2014: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) The number of dropouts or withdrawals in this trial (4) Did you assess any outcomes regarding adverse events? If you did, what were the results? | No reply | |
| This trial was identified from searching trial registers (NCT00914745). We sent the following request on 27 December 2013: "Dear Prof Kündig, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you have completed a trial (http://clinicaltrials.gov/show/NCT00914745) that assessed a topical ointment for prevention of herpes simplex labialis, and was wondering if you would like to share your results with us, thus we could include your trial in our review. Your assistance would be appreciated" | The trialists provided us with the full published article | |
| We sent the following request on 27 December 2013: "Dear Dr Cheras, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you completed a trial that used Sheabutter extract BSP110 for prevention of herpes simplex labialis (http://www.controlled‐trials.com/ISRCTN03397663#?close=1). I was wondering if you would like to share your results with us. Thus, we could include your trial in our review. Your assistance would be appreciated" | No reply | |
| We sent the following request on 27 December 2013: "Dear Dr Dayan, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you are conducting a trial that uses botulinum toxin A injections for prevention of herpes simplex labialis (http://clinicaltrials.gov/show/NCT01225341). I was wondering if you have completed the trial and would like to share your results with us. Thus, we could include your trial in our review. Your assistance would be appreciated" | No reply | |
| We sent the following request on 19 January 2014: "Dear Dr Kimball, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you are doing a trial (http://www.clinicaltrials.gov/ct2/show/NCT01971385) that assessed a topical ointment for prevention of herpes simplex labialis, and was wondering if you would like to share your results with us if you have completed the trial, thus we could include your trial in our review. Your assistance would be greatly appreciated" | No reply |
Assessment of heterogeneity
We assessed clinical heterogeneity inherent in the study design, interventions, participants, and outcome measures to determine whether a meta‐analysis was appropriate. The anticipated clinical heterogeneity included various lengths and regimens of the same intervention, presence of atopic dermatitis, and induction by UVL. We also determined the I² statistic to assess the statistical heterogeneity. When there was clinical heterogeneity or the I² statistic was greater than 80%, we did not perform a meta‐analysis.
Assessment of reporting biases
We would have tested publication bias for primary outcomes by using a funnel plot when at least 10 trials on an intervention were available. However, the limited number of trials for each intervention meant it was impossible to do this test.
Data synthesis
For trials on a particular intervention, we conducted a meta‐analysis using a random‐effects model (DerSimonian and Laird model) to calculate a weighted intervention effect across trials when the I² statistic was 80% or less with reasonable clinical homogeneity. We decided clinical homogeneity based on similar participants and intervention regimens. Where it was inappropriate or impossible to perform a meta‐analysis, we summarised the data narratively for each trial.
Subgroup analysis and investigation of heterogeneity
We discussed similarities and differences of included RCTs in terms of the study design, interventions, participants, and outcome measures. We would have conducted subgroup analyses of the following if adequate data were available:
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participants with atopic dermatitis: we found no data relevant to atopic dermatitis and thus did not conduct a subgroup analysis; and
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participants with UVL‐induced HSL: for sunscreen where relevant data were available, we conducted a subgroup analysis on HSL induced by natural and experimental UVL separately.
Sensitivity analysis
We would have performed a sensitivity analysis to examine the intervention effects after excluding those studies with lower methodological quality if appropriate. However, we did not do so because of a very limited number of trials for the same intervention.
Other
We involved a consumer coauthor (FD) throughout the review process to help improve the relevance and readability of the final review.
Results
Description of studies
Results of the search
As shown in Figure 1, our search identified 1387 citations. After removing duplicates, we assessed 1329 citations. We excluded 1252 citations because the title, abstract, or both did not meet our inclusion criteria. We sought the full texts of the remaining 77 citations. We excluded 38 citations, mostly because these were either non‐randomised studies or randomised controlled trials (RCTs) on interventions for treatments of herpes simplex labialis (HSL). Of the remaining 39 citations, we transferred 4 studies to the section 'Ongoing studies' as they were not yet completed. We included the remaining 35 citations, reporting 32 relevant trials, in this review. One included citation reported four trials, of which three met our inclusion criteria (Spruance 1991a; Spruance 1991b; Spruance 1991c). Five included trials, Miller 2004; Pazin 1979; Pedersen 2001; Russell 1978; Schindl 1999, had two citations.
Study flow diagram.
Included studies
This review included 32 trials, with a total of 2640 participants, covering 19 treatments. We describe the details of the included studies in the 'Characteristics of included studies' tables.
Design
All of the 32 included studies were RCTs, with 5 being cross‐over RCTs (Gibson 1986; Gilbert 2007; Rooney 1991; Rooney 1993; Thein 1984).
Sample sizes
The number of participants in the included studies ranged from 19 to 310. Seven of the included trials had a small sample size of less than 30 participants (Duteil 1998; Gibson 1986; Møller 1997; Pfitzer 2005; Rooney 1993; Thein 1984).
Setting
The setting was multicentre in 13 trials (Altmeyer 1991; Bernstein 1994; Bernstein 1997; Bolla 1985; Busch 2009; Gibson 1986; Mills 1987; Raborn 1997; Raborn 1998; Rooney 1991; Spruance 1988; Spruance 1991c; Spruance 1999) and single‐centre in 19 trials (Baker 2003; de Carvalho 2010; Duteil 1998; Gilbert 2007; Ho 1984; Miller 2004; Møller 1997; Pazin 1979; Pedersen 2001; Pfitzer 2005; Redman 1986; Rooney 1993; Russell 1978; Schädelin 1988; Schindl 1999; Senti 2013; Spruance 1991a; Spruance 1991b; Thein 1984). All of the included trials were conducted either in Europe or North America.
Participants
All of the included trials included adults aged 18 years or older, with 2 trials extending to persons aged 16 years or older, Bolla 1985; Gibson 1986, and 1 trial extending to persons aged at least 12 years (Miller 2004). Two trials, Russell 1978; Thein 1984, did not state the age limit of inclusion criteria but included participants aged seven and eight years, respectively.
Interventions
The included trials assessed the effects of 19 interventions for preventing HSL, including 6 oral treatments (aciclovir (Raborn 1998; Rooney 1993; Schädelin 1988; Spruance 1988; Spruance 1991a; Spruance 1991b), valaciclovir (Baker 2003; Gilbert 2007; Miller 2004), famciclovir (Spruance 1999), levamisole (Russell 1978), lysine (Thein 1984), and LongoVital® (a vitamin and herbs supplement) (Pedersen 2001)), 5 topical treatments (aciclovir cream (Gibson 1986; Raborn 1997; Spruance 1991c), aciclovir plus 348U87 cream (Bernstein 1994), topical foscarnet 3% (Bernstein 1997), 1,5‐pentanediol (a low‐toxicity molecule with an antiviral activity) gel (Busch 2009), 2‐hydroxypropyl‐β‐cyclo dextrin gel (Senti 2013)), sunscreens (Duteil 1998; Mills 1987; Rooney 1991), 3 immunomodulating treatments given by injection (interferon (Ho 1984; Pazin 1979), intradermal gamma globulin (Redman 1986), and thymopentin (Bolla 1985)), 2 vaccines (herpes simplex virus (HSV) type I subunit vaccine (Altmeyer 1991) and yellow fever vaccination (Møller 1997)), low‐intensity lasers (de Carvalho 2010; Schindl 1999), and hypnotherapy (Pfitzer 2005).
Outcomes
Of the 32 included trials, all reported either the incidence or frequency of HSL during use of the preventative intervention, and 17 trials (53%) reported adverse events. There were 12 and 20 trials reporting the duration and severity of recurrent HSL, respectively. Only one trial, Miller 2004, measured the shedding of HSV in the saliva, and only two trials, Rooney 1993; Spruance 1999, assessed participants' adherence to study medications.
Funding source
Of the included 32 trials, industry supported 18, and non‐profit organisations (such as government or academic institutions) supported 4; the other 10 trials did not report the funding source.
Excluded studies
We excluded 38 citations after examining the full text. We list the reasons for exclusion in the 'Characteristics of excluded studies' tables.
Ongoing Studies
We identified 4 ongoing trials that were on a sheabutter extract (BSP110), botulinum toxin A injection, an experimental drug (BTL‐TML‐HSV), and squaric acid dibutylester, respectively (ISRCTN03397663; NCT01225341; NCT01902303; NCT01971385). We contacted the four trialists, but none of them replied. We present the details of these trials in the 'Characteristics of ongoing studies' tables.
Risk of bias in included studies
We summarise our judgements about each 'Risk of bias' item presented as percentages across all of the included trials in Figure 2, and we summarise our judgements about each 'Risk of bias' item for each included trial in Figure 3. We present further details in the 'Risk of bias' tables in the 'Characteristics of included studies' section. The risk of bias of the included trials varied from low to high.
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
Allocation
Nine trials used an adequate method of generation of the randomisation sequence (Bernstein 1994; Busch 2009; de Carvalho 2010; Miller 2004; Mills 1987; Møller 1997; Pazin 1979; Rooney 1991; Schädelin 1988), but all the other 23 trials did not describe the process of randomisation.
Allocation could not be foreseen in 5 trials (Busch 2009; Miller 2004; Møller 1997; Schädelin 1988; Spruance 1999), while it was unclear if allocation was concealed in the other 27 trials.
Blinding
Twenty‐six trials blinded both the investigators and participants (Altmeyer 1991; Baker 2003; Bernstein 1994; Bernstein 1997; Bolla 1985; Busch 2009; Gibson 1986; Ho 1984; Miller 2004; Mills 1987; Møller 1997; Pazin 1979; Pedersen 2001; Raborn 1997; Raborn 1998; Redman 1986; Rooney 1993; Russell 1978; Schädelin 1988; Senti 2013; Spruance 1988; Spruance 1991a; Spruance 1991b; Spruance 1991c; Spruance 1999; Thein 1984), while 5 trials did not blind them (de Carvalho 2010; Gilbert 2007; Pfitzer 2005; Rooney 1991; Schindl 1999). The de Carvalho 2010 trial compared laser treatments with no interventions. The Schindl 1999 trial performed the placebo irradiation in the same manner as in the laser group except that the laser was not turned on. However, laser irradiation might produce the sensation of sound and heat that could have been sensed by the participants. The Gilbert 2007 trial compared episodic and suppressive valaciclovir regimens. The Pfitzer 2005 trial compared hypnotherapy with no hypnotherapy. The Rooney 1991 trial compared a sunscreen with placebo solution, but the placebo recipients had sunburn while none of the sunscreen recipients had sunburn. Thus, the participants and researchers might have known the assigned treatments. It was unclear if the investigators and participants were blinded in the Duteil 1998 trial.
Outcome assessment was blinded in 27 trials (Altmeyer 1991; Baker 2003; Bernstein 1994; Bernstein 1997; Bolla 1985; Busch 2009; Gibson 1986; Ho 1984; Miller 2004; Mills 1987; Møller 1997; Pazin 1979; Pedersen 2001; Raborn 1997; Raborn 1998; Redman 1986; Rooney 1993; Russell 1978; Schädelin 1988; Schindl 1999; Senti 2013; Spruance 1988; Spruance 1991a; Spruance 1991b; Spruance 1991c; Spruance 1999; Thein 1984) and unblinded in 4 trials (de Carvalho 2010; Gilbert 2007; Pfitzer 2005; Rooney 1991). It was unclear if the outcome assessors were blinded in the other trial (Duteil 1998).
Incomplete outcome data
The risk of attrition bias was low in 17 trials because of a low or null dropout rate (Baker 2003; Busch 2009; de Carvalho 2010; Miller 2004; Mills 1987; Møller 1997; Pazin 1979; Pedersen 2001; Raborn 1997; Raborn 1998; Rooney 1991; Rooney 1993; Schindl 1999; Schädelin 1988; Senti 2013; Spruance 1988; Spruance 1999). On the other hand, the risk of attrition bias was high in two trials because of a high dropout rate (Gilbert 2007; Russell 1978). No dropouts or withdrawals were mentioned in the other 13 trials.
Selective reporting
A total of 18 trials reported both the prespecified primary efficacy and adverse outcomes (Altmeyer 1991; Baker 2003; Bernstein 1997; Bolla 1985; Busch 2009; de Carvalho 2010; Gibson 1986; Gilbert 2007; Ho 1984; Miller 2004; Møller 1997; Pazin 1979; Pfitzer 2005; Raborn 1998; Russell 1978; Schädelin 1988; Spruance 1988; Spruance 1999). We judged these 18 trials to be at a low risk of reporting bias.
The Schindl 1999 trial reported the median recurrence‐free interval, which was not a prespecified outcome in our review protocol. The study protocol of the Senti 2013 trial is available on the US National Institutes of Health ongoing trials register (identifier: NCT00914745). The prespecified primary outcome (the number of herpes labialis relapse) has been reported. However, the exact numerical data were not provided; the authors only provided the data in plots. We therefore judged the two trials to be at an unclear risk of bias.
A total of 10 trials did not report adverse events (Bernstein 1994; Duteil 1998; Mills 1987; Redman 1986; Rooney 1991; Rooney 1993; Spruance 1991a; Spruance 1991b; Spruance 1991c; Thein 1984). The Pedersen 2001 and Raborn 1997 trials did not fully report the details of outcome data. All of these 12 trials were marked as high risk of bias for this domain.
Other potential sources of bias
A total of nine trials had a high risk of other potential bias for various reasons including early termination (Bernstein 1994), no washout period (Gibson 1986; Gilbert 2007; Rooney 1993; Thein 1984), different baseline frequency of recurrence of HSL (Pedersen 2001; Russell 1978), lack of standardised follow‐up plan (Schindl 1999), and a low percentage of participants having a history of HSL (Schädelin 1988). We judged Spruance 1988 at a low risk of other potential bias because of the trialists' advice to participants on frequent use of a standard sunscreen and no relation between the occurrence of herpes labialis and the potential confounding factors.
Effects of interventions
See: Summary of findings for the main comparison Oral aciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis; Summary of findings 2 Oral aciclovir (long‐term) compared with placebo for prevention of herpes simplex labialis; Summary of findings 3 Valaciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis; Summary of findings 4 Valaciclovir (long‐term) compared with placebo for prevention of herpes labialis; Summary of findings 5 Valaciclovir (suppressive regimen compared with episodic regimen) for prevention of herpes labialis; Summary of findings 6 Famciclovir compared with placebo for prevention of herpes labialis; Summary of findings 7 Levamisole compared with placebo for prevention of herpes labialis; Summary of findings 8 Lysine compared with placebo for prevention of herpes labialis; Summary of findings 9 Topical aciclovir (short‐term) compared with placebo for prevention of herpes labialis; Summary of findings 10 Topical aciclovir and 348U87 cream (short‐term) compared with placebo for prevention of herpes labialis; Summary of findings 11 Topical foscarnet compared with placebo for prevention of herpes labialis; Summary of findings 12 Topical 1,5‐pentanediol compared with placebo for prevention of herpes labialis; Summary of findings 13 Sunscreen compared with placebo for prevention of herpes labialis; Summary of findings 14 Interferon compared with placebo for prevention of herpes labialis; Summary of findings 15 Gamma globulin compared with histamine (control) for prevention of herpes labialis; Summary of findings 16 Thymopentin compared with placebo for prevention of herpes labialis; Summary of findings 17 HSV vaccination compared with placebo for prevention of herpes labialis; Summary of findings 18 Yellow fever vaccination compared with placebo for prevention of herpes labialis; Summary of findings 19 Laser compared with no interventions for prevention of herpes labialis; Summary of findings 20 Hypnotherapy compared with control for prevention of herpes labialis
Our prespecified outcomes were as follows:
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Primary outcomes
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Incidence of HSL during use of the preventative intervention. We accepted both researcher‐diagnosed and participant‐reported recurrences.
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Adverse effects during use of the preventative intervention.
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Secondary outcomes
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Duration of attack of recurrent HSL during use of the preventative intervention.
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Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention.
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Viral load in saliva.
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Rate of adherence to the regimen of the preventative intervention.
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Incidence of HSL after use of the preventative intervention. We accepted both researcher‐diagnosed and participant‐reported recurrences.
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Duration of attack of recurrent HSL after use of the preventative intervention.
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Severity (lesion area, stage, pain) of attack of recurrent HSL after use of the preventative intervention.
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Not all of the included studies addressed our prespecified outcomes. In which case, we indicated this at the bottom of the section for the specific comparison.
We only provided short‐term and long‐term subheadings when both short‐ and long‐term data were available. If only one kind of data were available, we described the length of trial in the text.
In general, the quality of the body of evidence is low to moderate, but very low for some outcomes of few interventions. We present the respective judgement of the quality of evidence for each intervention in the 'Summary of findings' tables.
Oral interventions
Oral aciclovir
Short‐term (≤ 1 month) use
A total of five trials tested the efficacy of short‐term use of oral aciclovir in preventing HSL (Raborn 1998; Schädelin 1988; Spruance 1988; Spruance 1991a; Spruance 1991b). Please see summary of findings Table for the main comparison where we judged the quality of the evidence for this comparison as low to moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
One trial on aciclovir 800 mg twice daily beginning 12 to 24 hours before sun exposure and continuing for the entire sun‐exposure period (3 to 7 days), Raborn 1998, found no significant evidence for the prevention of HSL (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.62 to 1.87; n = 237; see Analysis 1.1). Two trials tested the efficacy of 200 mg 5 times daily beginning immediately after, or 7 days before, ultraviolet radiation exposure and continuing for 7 days following the exposure (Spruance 1991a; Spruance 1991b). The trialists pooled the data from the two trials because of similar results. No significant effects in preventing HSL were found (RR 0.46, 95% CI 0.20 to 1.07; n = 66; see Analysis 1.1). However, aciclovir 400 mg twice daily (starting on the evening prior to surgery or 12 hours prior to the first anticipated sun exposure and continued for 5 to 7 days) significantly reduced the occurrence of HSL either by clinical evaluation (RR 0.26, 95% CI 0.13 to 0.51; n = 177; 2 trials (Schädelin 1988; Spruance 1988); see Analysis 1.1) or culture (RR 0.05, 95% CI 0.00 to 0.70; n = 30; 1 trial (Schädelin 1988); see Analysis 1.2).
Primary outcome 2. Adverse effects during use of the preventative intervention
Three trials, Raborn 1998; Schädelin 1988; Spruance 1988, found no significant differences in adverse events between placebo and aciclovir 800 mg or 400 mg twice daily (aciclovir 800 mg twice daily: RR 0.98, 95% CI 0.70 to 1.38; n = 239; 1 trial; aciclovir 400 mg twice daily: RR 2.30, 95% CI 0.62 to 8.58; n = 183; 2 trials) (see Analysis 1.3).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
The Raborn 1998 trial found a shorter length and width of the lesion in the placebo group when compared with the aciclovir 800 mg group (see Analysis 1.4), but found no differences in disease stage between the aciclovir 800 mg and placebo groups (see Analysis 1.5). The Spruance 1988 trial found no differences in lesional size and pain between the aciclovir 400 mg and placebo groups (see Analysis 1.4 and Analysis 1.6).
Secondary outcome 5. Incidence of HSL after use of the preventative intervention
The Spruance 1988 trial followed up the participants for 4 weeks after treatment and found no significant difference in the recurrence of HSL after use of the preventative intervention (RR 1.23, 95% CI 0.49 to 3.14; n = 147; see Analysis 1.7).
There were no relevant data for this intervention for our other outcomes.
Long‐term (> 1 month) use
Only one cross‐over trial assessed the efficacy of 4‐month use of oral aciclovir in preventing HSL (Rooney 1993). Please see summary of findings Table 2 where we judged the quality of the evidence for this comparison as low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
Aciclovir therapy when compared with placebo resulted in a reduced mean of clinically documented recurrences (0.85 versus 1.80 episodes per participant per a 4‐month period, P = 0.009) and culture‐positive recurrence (0.40 versus 1.40 episodes per participant per a 4‐month period, P = 0.003).
When comparing with placebo, Rooney 1993 also found a longer time to first recurrence (which was not a prespecified outcome in this review) during aciclovir treatment (clinically determined recurrence: 46 versus 118 days, P = 0.05; culture‐positive recurrence: > 118 versus 46 days, P = 0.002).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
The Rooney 1993 trial did not prespecify an analysis on the duration of recurrent HSL but did a posthoc comparison and found a marginally shorter duration of recurrent HSL during aciclovir treatment when compared with placebo (difference in means (MD) ‐3.60, 95% CI ‐7.20 to 0; n = 40; see Analysis 2.1).
Secondary outcome 4. Rate of adherence to the regimen of the preventative intervention
The rate of adherence to the preventative intervention was very high; the participants took 99% of the prescribed study medication during both aciclovir and placebo treatments.
There were no relevant data for this intervention for our other outcomes.
Valaciclovir
Short‐term (≤ 1 month) use
Only one trial, Miller 2004, investigated the effects of a two‐day valaciclovir treatment (on the day of dental procedure and the following day) in preventing recurrence of HSL during a one‐week observation period. Please see summary of findings Table 3 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
There was no reduction in the recurrence of HSL either by clinical evaluation (RR 0.55, 95% CI 0.23 to 1.28; n = 125; see Analysis 3.1) or culture confirmation (RR 0.47, 95% CI 0.21 to 1.08; n = 125; see Analysis 3.2).
Primary outcome 2. Adverse effects during use of the preventative intervention
There were no significant differences in adverse events found between the valaciclovir and placebo groups (RR 1.33, 95% CI 0.71 to 2.50; n = 125; see Analysis 3.3).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
The Miller 2004 trial found that valaciclovir treatment was associated with a significantly shorter time to cessation of pain in comparison with placebo (3.2 versus 6.2 days; P = 0.006; n = 125).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the clinical severity (1.7 versus 1.9; P = non‐significant; n = 125) between the valaciclovir and placebo groups.
Secondary outcome 3. Viral load in saliva
There were no significant differences in the viral load, i.e., HSV‐1 shedding in the saliva (RR 0.16, 95% CI 0.02 to 1.26; n = 120; see Analysis 3.4), between the valaciclovir and placebo groups.
There were no relevant data for this intervention for our other outcomes.
Long‐term (> 1 month) use
Please see summary of findings Table 4 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
Only 1 placebo‐controlled trial, Baker 2003, assessed the effects of valaciclovir 500 mg once daily for 16 weeks in preventing HSL and found a significantly lower incidence of HSL in the valaciclovir group (0.12 versus 0.21 episodes per participant per month; P = 0.042; n = 95).
Primary outcome 2. Adverse effects during use of the preventative intervention
No differences in adverse events existed between the 2 groups (RR 0.86, 95% CI 0.51 to 1.46; n = 95; see Analysis 4.1).
There were no relevant data for this comparison for our secondary outcomes.
Suppressive regimen versus episodic regimen
A cross‐over trial, Gilbert 2007, compared an 'episodic regimen' (two 2 gm doses of valaciclovir separated by 12 hours at the first sign of prodrome) and 'suppressive regimen' (valaciclovir 1 gm once daily) for 6 months, respectively. Please see summary of findings Table 5 where we judged the quality of the evidence for this comparison as very low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
Compared with the episodic regimen, the suppressive regimen had a significantly lower incidence of HSL (MD ‐0.10 episodes per participant per month, 95% CI ‐0.16 to ‐0.05; n = 120; see Analysis 5.1).
Primary outcome 2. Adverse effects during use of the preventative intervention
There were no significant differences in adverse events between the 2 regimens (RR 1.21, 95% CI 0.78 to 1.87; n = 152; see Analysis 5.2).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the duration of attack (MD ‐1.08, 95% CI ‐2.16 to 0.00; n = 120; see Analysis 5.3) between the 2 regimens.
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the pain (MD ‐0.09, 95% CI ‐0.20 to 0.02; n = 120; see Analysis 5.4) and maximal total lesion area (MD ‐5.38, 95% CI ‐10.91 to 0.15; n = 120; see Analysis 5.5) between the 2 regimens.
There were no relevant data for this intervention for our other outcomes.
Famciclovir
A placebo‐controlled trial, Spruance 1999, assessed the effects of various dosages of famciclovir (125 mg, 250 mg, and 500 mg) 3 times daily for 5 days, beginning 48 hours after ultraviolet radiation exposure in preventing HSL. Please see summary of findings Table 6 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The Spruance 1999 trial found no differences in recurrence of HSL between 3 different doses of famciclovir and placebo (n = 243; see Analysis 6.1).
Primary outcome 2. Adverse effects during use of the preventative intervention
No significant differences in adverse events were found between three different doses of famciclovir and placebo. (The trialists did not provide exact numerical data.)
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
The difference in time to healing compared with the placebo group was significantly shorter in the famciclovir 500 mg group (by 2.8 days: hazard ratio (HR) 2.39; 95% CI 1.23 to 4.63; P = 0.010), but not for the other 2 groups (n = 243; see Analysis 6.2).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no differences in pain between the 3 famciclovir groups and the placebo groups (RR 1.0, 95% CI 0.90 to 1.16; RR 0.92, 95% CI 0.76 to 1.12; and RR 0.90, 95% CI 0.75 to 1.09 for the famciclovir 125 mg, 250 mg, and 500 mg groups, respectively, when compared with the placebo group; n = 102; see Analysis 6.3).
Secondary outcome 4. Rate of adherence to the regimen of the preventative intervention
The rate of adherence was very high: 100% of the participants in all 3 famciclovir groups (n = 183) and 95% of those in the placebo group (n = 60) took all of the prescribed study medication.
There were no relevant data for this intervention for our other outcomes.
Levamisole
Only 1 trial with a high withdrawal rate (27.2%), Russell 1978, evaluated the effects of levamisole in preventing HSL. Please see summary of findings Table 7 where we judged the quality of the evidence for this comparison as very low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
Among the 72 participants who completed the trial, both the levamisole group and placebo group showed a reduction in the frequency of HSL, but there were no significant differences between the 2 groups (2.1 ± 1.2 versus 2.7 ± 2.3 episodes during a 6‐month period). When taking into account the different baseline frequency of HSL (4.8 ± 2.7 and 3.4 ± 1.8 episodes during a 6‐month period for the levamisole and placebo group, respectively), levamisole was associated with a greater reduction in the frequency of HSL (MD ‐2.00, 95% CI ‐2.24 to ‐1.76; n = 72; see Analysis 7.1).
Primary outcome 2. Adverse effects during use of the preventative intervention
Of the 99 randomised participants, 27 (27.2%) did not complete the trial because of either adverse events (such as nausea and fever) or lack of efficacy: the trialists' analysis excluded 19 (39.6%) in the levamisole group and 8 (15.7%) in the placebo group. The levamisole group had a significantly higher withdrawal rate than the placebo group (risk difference (RD) 0.24, 95% CI 0.07 to 0.41; n = 99; see Analysis 7.2).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
Compared with the placebo group, the levamisole group was associated with a lesser reduction in the duration of attack of HSL (MD 0.70, 95% CI 0.22 to 1.18; n = 72; see Analysis 7.3).
There were no relevant data for this intervention for our other outcomes.
Lysine
A placebo‐controlled cross‐over trial, Thein 1984, investigated the effects of L‐lysine monolysine monohydrochloride 1000 mg per day for 6 months in preventing recurrent HSL. Please see summary of findings Table 8 where we judged the quality of the evidence for this comparison as very low for the following outcome.
Primary outcomes 1. Incidence of HSL during use of the preventative intervention
Because the Thein 1984 trial lacked a washout period, we used only the data from the first period before cross‐over for analysis and found no significant difference in the incidence of recurrent HSL between lysine and placebo treatment (MD ‐0.04, 95% CI ‐0.37 to 0.29; n = 26; see Analysis 8.1).
There were no relevant data for this intervention for our other outcomes.
LongoVital®
A placebo‐controlled trial, Pedersen 2001, evaluated the effects of daily intake of LongoVital® (a vitamin and herbs supplement) in preventing recurrence of HSL. The treatment period was four months, and the participants were followed up for another four months after stopping the study medications.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
During the treatment period, there were no significant differences in the number of recurrent HSL episodes found between the LongoVital® (LV) and placebo groups (the median being 1.2 and 1.6 during the period 'days 0 to 60' and 0.7 and 1.0 during the period 'days 61 to 120' for the LV and placebo groups, respectively; n = 52).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the median duration of recurrent HSL episodes between the LongoVital® and placebo groups (the median being 5.0 days and 4.3 days during the period 'days 0 to 60' and 3.0 days and 4.2 days during the period 'days 61 to 120', respectively; n = 52).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
The maximal size of recurrent HSL lesions did not significantly differ between the LongoVital® and placebo groups (the median being 5.1 mm and 5.0 mm during the period 'days 0 to 60' and 2.5 mm and 5.2 mm during the period 'days 61 to 120', respectively; n = 52).
Secondary outcome 5. Incidence of HSL after use of the preventative intervention
During the post‐treatment follow‐up period, there were no significant differences in the number of recurrent HSL episodes between the LongoVital® and placebo groups (the median being 1.1 and 1.4 during the period 'days 121 to 180' and 0.9 and 0.8 during the period 'days 181 to 240', respectively; n = 52).
Secondary outcome 6. Duration of attack of recurrent HSL after use of the preventative intervention
During the post‐treatment follow‐up period, there were no significant differences in the median duration of recurrent HSL episodes between the LongoVital® and placebo groups (the median being 4.0 and 4.0 days during the period 'days 121 to 180' and 6.3 and 4.0 days during the period 'days 181 to 240', respectively; n = not reported).
Secondary outcome 7. Severity (lesion area, stage, pain) of attack of recurrent HSL after use of the preventative intervention
During the post‐treatment follow‐up period, there were no significant differences in the maximal size of recurrent HSL lesions between the LongoVital® and placebo groups (median = 2.9 and 5.0 mm during the period 'days 121 to 180' and 4.3 and 2.0 mm during the period 'days 181 to 240', respectively; n = not reported).
There were no relevant data for this intervention for our other outcomes.
Topical interventions
Topical aciclovir
Short‐term (≤ 1 month) use
Two trials assessed the effects of short‐term use of topical aciclovir 5% cream in preventing recurrence of HSL induced by sunlight or ultraviolet light (UVL) (Raborn 1997; Spruance 1991c). The Raborn 1997 trial assessed the effects of short‐term use of topical aciclovir 5% cream starting 12 hours before sunlight exposure and continuing for 72 to 168 hours in preventing recurrence of HSL. The Spruance 1991c trial assessed the effects of short‐term use of topical aciclovir 5% cream, beginning 5 minutes following experimental UVL exposure for 7 days. Please see summary of findings Table 9 where we judged the quality of the evidence for this comparison as low to moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
Neither of the 2 placebo‐controlled trials found significant differences in the recurrence of HSL between the aciclovir and placebo groups nor did the meta‐analysis of the 2 trials (pooled RR 0.91, 95% CI 0.48 to 1.72; n = 271; I² statistic = 66%; 2 trials; see Analysis 9.1).
Primary outcome 2. Adverse effects during use of the preventative intervention
Only the Raborn 1997 trial assessed the adverse events and found no differences between the 2 groups (RR 1.17, 95% CI 0.59 to 2.32; n = 191; see Analysis 9.2).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
Only the Spruance 1991c trial assessed this outcome and found no differences in the mean healing time to normal skin (6.8 days versus 7.4 days; P = 0.70; n = 52).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
Only the Spruance 1991c trial assessed the severity of recurrent HSL and found no differences in aborted lesions (RR 1.02, 95% CI 0.19 to 5.57; n = 52; see Analysis 9.3), mean maximal lesion area (110 mm² versus 72 mm²; P = 0.88; n = 52), and mean duration of pain (3.7 days versus 3.6 days; P > 0.10; n = 52).
Secondary outcome 5. Incidence of HSL after use of the preventative intervention
The Raborn 1997 trial also assessed the recurrences of HSL in a 4‐day post‐treatment follow‐up period and found fewer recurrences of HSL in the aciclovir group (RR 0.35, 95% CI 0.13 to 0.94; n = 181; Analysis 9.4).
There were no relevant data for this intervention for our other outcomes.
Topical aciclovir 5% plus 348U87 3%
Short‐term (≤ 1 month) use
A placebo‐controlled trial evaluated the effects of short‐term use of topical aciclovir 5% plus 348U87 3% (a ribonucleotide reductase inhibitor) cream, starting immediately after UVL exposure and continuing for 7 days (Bernstein 1994). Please see summary of findings Table 10 where we judged the quality of the evidence for this comparison as very low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
There were no significant differences in the development of HSV(+) lesions (RR 0.78, 95% CI 0.19 to 3.14; n = 51; Analysis 10.1) and development of lesions consistent with HSL (RR 1.46, 95% CI 0.53 to 3.99; n = 51; see Analysis 10.2) between the 2 groups.
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the healing time (MD 2.50 days, 95% CI ‐1.39 to 6.39; n = 9; see Analysis 10.3) between the 2 groups.
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the maximal lesion size (MD 73.00 cm², 95% CI ‐42.22 to 188.22; n = 9; see Analysis 10.4) between the 2 groups.
There were no relevant data for the comparison of these interventions for our other outcomes.
Long‐term (> 1 month) use
A placebo‐controlled cross‐over trial, Gibson 1986, evaluated the efficacy of aciclovir cream applied to all previously affected areas 4 times per day for 16 weeks.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The trial found significantly fewer research‐diagnosed recurrences of HSL during a 16‐week period when on aciclovir cream treatment than on placebo (the mean being 0.5 and 1.1, respectively; standard deviation (SD) not reported; P < 0.05 calculated by trialists; n = 23). However, no significant differences existed in the mean number of participant‐reported recurrences between aciclovir cream treatment and placebo (the mean being 1.6 and 2.4, respectively; SD not reported; P ≥ 0.05 calculated by trialists; n = 23).
Primary outcome 2. Adverse effects during use of the preventative intervention
There were no significant adverse events while on either aciclovir cream or placebo (n = 23).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
The trial found significantly fewer mean days with HSL present when on aciclovir cream treatment than on placebo (the mean being 9.5 and 12.4 days, respectively; SD not reported; P < 0.01 calculated by trialists). Also, the trial found significantly fewer mean days with any symptom or sign of HSL present when on aciclovir cream treatment than on placebo (the mean being 12.2 and 17.4 days, respectively; SD not reported; P < 0.001 calculated by trialists).
There were no relevant data for this intervention for our other outcomes.
Foscarnet
A placebo‐controlled trial, Bernstein 1997, examined the effects of topical application of foscarnet 3% cream 8 times daily (at least every 2 hours while awake) for 7 days in preventing experimental UVL‐induced HSL. Please see summary of findings Table 11 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
There were no significant differences in the researcher‐diagnosed recurrence of HSL (RR 1.08, 95% CI 0.82 to 1.40; n = 295; see Analysis 11.1) between the foscarnet and placebo groups.
Primary outcome 2. Adverse effects during use of the preventative intervention
No significant differences were found in adverse events either leading to withdrawals (RR 2.96, 95% CI 0.12 to 72.11; n = 302; see Analysis 11.2) or application site reactions (RR 2.47, 95% CI 0.79 to 7.69; n = 302; see Analysis 11.3) between the foscarnet and placebo groups.
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
The healing time did not significantly differ between the foscarnet and placebo groups (MD ‐0.21 days, 95% CI ‐1.68 to 1.26; n = 125; see Analysis 11.4).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the mean lesion area (MD ‐16.00, 95% CI ‐38.96 to 6.96; n = 124; see Analysis 11.5), maximum lesion area (MD ‐30.00, 95% CI ‐72.64 to 12.64; n = 124; see Analysis 11.6), and duration of pain (MD 0.10, 95% CI ‐1.11 to 1.31; n = 113; see Analysis 11.7) between the foscarnet and placebo groups.
There were no relevant data for this intervention for our other outcomes.
1,5‐pentanediol
A placebo‐controlled trial evaluated the effects of twice daily application of topical 1,5‐pentanediol (PD) gel for 26 weeks in preventing HSL (Busch 2009). Please see summary of findings Table 12 where we judged the quality of the evidence for this comparison as moderate to low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The trial found no significant differences in the number of recurrences between the PD and placebo groups (109 episodes out of 50 participants versus 120 episodes out of 52 participants; P > 0.05 calculated using the Mann‐Whitney test by trialists; n = 102).
Primary outcome 2. Adverse effects during use of the preventative intervention
No adverse events leading to discontinuation were observed in either group (n = 102).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no significant differences in the severity of attack of recurrent HSL between the 2 groups (RR 1.05, 95% CI 0.91 to 1.20; episodes = 224; see Analysis 12.1).
There were no relevant data for this intervention for our other outcomes.
2‐hydroxypropyl‐β‐cyclo dextrin
A placebo‐controlled trial, Senti 2013, examined the effects of twice daily application of topical 2‐hydroxypropyl‐β‐cyclo dextrin (2‐HPβCD) 20% gel for 6 months in preventing HSL.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The trialists did not provide the exact numerical data on recurrences but presented them in plots. The 2‐HPβCD group had significantly more recurrences than the placebo group (P = 0.003 calculated using the Mann‐Whitney test by the trialists; n = 33). Both groups had significantly fewer recurrences during than before the study (P < 0.001 calculated by the trialists; n = 33).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
There were no differences in the duration of the relapses between the 2‐HPβCD and placebo groups.
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
There were no differences in the maximal size of the relapses between the 2‐HPβCD and placebo groups. Although the 2‐HPβCD group experienced less pain than the placebo group, the cumulative burden of pain assessed using the area‐under‐curve (AUC) of the daily pain visual analogue scale level was not significantly different between the 2 groups (P = 0.101). However, the symptoms were more severe in the placebo than in the 2‐HPβCD group: the symptom scores were significantly higher in the former group for tingling (P = 0.040), burning (P = 0.028), and total symptoms (P = 0.048), but not for tension (P = 0.156), hypersensitivity (P = 0.119), and itching (P = 0.283).
There were no relevant data for this intervention for our other outcomes.
Sunscreen
A total of three placebo‐controlled trials assessed the efficacy of sunscreen in preventing HSL, with one parallel trial using solar radiation, Mills 1987, and two cross‐over trials using experimental UVL (Duteil 1998; Rooney 1991). Please see summary of findings Table 13 where we judged the quality of the evidence for this comparison as low to very low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
As shown in Analysis 13.1, application of sunscreen did not reduce the recurrences of HSL induced by sunlight (RR 1.13, 95% CI 0.25 to 5.06; n = 51; 1 trial), but significantly reduced the clinically diagnosed recurrences induced by experimental UVL (pooled RR 0.07, 95% CI 0.01 to 0.33; n = 111; I² statistic = 0%; 2 trials; number needed to treat to benefit (NNTB) = 3; 95% CI 2 to 4). The Rooney 1991 trial found sunscreen use significantly reduced virologically confirmed recurrences of HSL (RR 0.04, 95% CI 0.01 to 0.30; n = 73; 1 trial; NNTB = 2; 95% CI 2 to 3; see Analysis 13.2).
There were no relevant data for this intervention for our other outcomes.
Interventions given by injection
Three immunomodulating treatments were given by injection (interferon (Ho 1984; Pazin 1979), intradermal gamma globulin (Redman 1986), and thymopentin (Bolla 1985)).
Interferon
A placebo‐controlled trial, Ho 1984, investigated whether either presurgical or postsurgical intramuscular administration of interferon (3 and 7 doses of 3.5 x 10⁴ units/kg of body weight, respectively) could reduce recurrences of HSL in participants receiving microvascular decompression for trigeminal neuralgia. Another placebo‐controlled trial, Pazin 1979, evaluated the effects of interferon administered intramuscularly for 5 days (10 doses of 3.5 x 10⁴ units/kg of body weight), beginning on the day before receiving the same surgical procedure. Please see summary of findings Table 14 where we judged the quality of the evidence for this comparison as very low to moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
When assessing recurrences of HSL defined by the presence of clinical lesions, isolation of virus, or both (Analysis 14.1), the presurgical group was associated with a significant increase in recurrences (RR 1.59, 95% CI 1.05 to 2.41; n = 32), but no significant differences were found between the postsurgical and placebo groups (RR 0.99, 95% CI 0.59 to 1.66; n = 44). On the other hand, continuous pre‐ and postsurgical administration of interferon was associated with a significant decrease in the recurrences of HSL (RR 0.57, 95% CI 0.34 to 0.95; n = 37).
Primary outcome 2. Adverse effects during use of the preventative intervention
A significant increase in adverse events presenting as fever was found across the 3 interferon groups when compared with placebo (pooled RR 2.30, 95% CI 1.44 to 3.67; I² statistic = 0%; n = 114; 3 trials; see Analysis 14.2). One trial, Pazin 1979, found no significant differences in other adverse events including pain and tenderness at injection site (RR 0.95, 95% CI 0.06 to 14.04), malaise, nausea, or vomiting (RR 1.74, 95% CI 0.81 to 3.70) between the interferon and placebo groups (n = 37; see Analysis 14.3).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
In the Ho 1984 trial, the mean lesion area was 26, 135, and 30 mm² for the presurgical, postsurgical, and placebo groups, respectively (the trials did not report the SDs but stated no differences between them). The Pazin 1979 trial found no significant difference in the mean lesion area between the interferon and placebo groups (0.7 and 4.0 cm², respectively; SD not reported; P > 0.05 calculated by trialists).
There were no relevant data for this intervention for our other outcomes.
Gamma globulin
The Redman 1986 trial assessed the efficacy of intradermal administration of gamma globulin in preventing recurrence of HSL in a six‐month follow‐up period. Please see summary of findings Table 15 where we judged the quality of the evidence for this comparison as low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The gamma globulin and control groups did not significantly differ in the mean number of herpes lesions (2.65 and 2.76 days, respectively; SD not reported; no significant differences calculated by the trialists; n = 84).
Secondary outcome 1. Duration of attack of recurrent HSL during use of the preventative intervention
The gamma globulin and control groups did not significantly differ in the mean number of days to vesicle healing (MD 0.70 days, 95% CI ‐0.55 to 1.95; n = 72; see Analysis 15.1).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
The gamma globulin and control groups did not significantly differ when 'less severe recurrences than usual' were measured (RR 0.97, 95% CI 0.74 to 1.28; n = 73; see Analysis 15.2).
There were no relevant data for this intervention for our other outcomes.
Thymopentin
A placebo‐controlled trial, Bolla 1985, evaluated the effects of 6 weeks of treatment with subcutaneous administration of thymopentin in preventing recurrence of HSL in a 18‐week follow‐up period. Please see summary of findings Table 16 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
During the follow‐up period, the incidence of recurrent HSL was lower in the thymopentin group than the placebo group (median = 0.2 (range = 0.0 to 2.7) and 0.9 (range = 0.1 to 2.0) relapses/month, respectively; P = 0.0027 using the Mann‐Whitney test by trialists; n = 36).
Primary outcome 2. Adverse effects during use of the preventative intervention
The 2 groups did not significantly differ in adverse events (RR 2.00, 95% CI 0.42 to 9.58; n = 36; see Analysis 16.1).
There were no relevant data for this intervention for our secondary outcomes.
Interventions given by vaccination
HSV vaccine
A placebo‐controlled trial, Altmeyer 1991, tested the efficacy of a HSV type I subunit vaccine in preventing recurrences of HSL. Please see summary of findings Table 17 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The vaccine and placebo groups did not differ in the mean number of recurrences (1.6 versus 1.3 recurrences in a 4‐month period; P = 0.10 calculated by trialists; n = 58). Both groups had a significantly fewer number of recurrences when compared with baseline (vaccine group: from 2.2 to 1.6, P < 0.01 calculated by trialists; placebo group: from 2.6 to 1.3, P < 0.001 calculated by the trialists; n = 58).
Primary outcome 2. Adverse effects during use of the preventative intervention
The vaccine and placebo groups had 22 and 13 adverse events per 100 injections. (Several adverse events might have occurred in the same participant; the trialists conducted no statistical tests.)
There were no relevant data for this intervention for our secondary outcomes.
Yellow fever vaccination
A placebo‐controlled trial, Møller 1997, examined the efficacy of yellow fever vaccination in preventing recurrences of HSL in a 12‐month follow‐up period. Please see summary of findings Table 18 where we judged the quality of the evidence for this comparison as moderate for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The vaccine and placebo groups did not significantly differ in the mean number of recurrences (5 and 7, respectively; SD and P values not reported; n = 24) and the median number of recurrences (both being 5.5; P values not reported; n = 24).
Primary outcome 2. Adverse effects during use of the preventative intervention
The vaccine and placebo groups did not differ significantly in the number of participants with adverse events (RR 0.33, 95% CI 0.01 to 7.45; n = 24; see Analysis 17.1).
There were no relevant data for this intervention for our secondary outcomes.
Laser
Please see summary of findings Table 19 where we judged the quality of the evidence for these comparisons as low to very low for the following outcomes.
Low‐energy gallium‐aluminium‐arsenide laser
The de Carvalho 2010 trial evaluated the efficacy of a 10‐week low‐energy gallium‐aluminium‐arsenide laser phototherapy (3 to 4.5 J/cm²) in preventing recurrence of HSL during a 16‐month follow‐up period.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The number of recurrences per month did not differ significantly between the laser and control groups (0.076 and 0.116, respectively; P = 0.076 calculated using the Mann‐Whitney U test by the trialists; n = 71).
Primary outcome 2. Adverse effects during use of the preventative intervention
No adverse events were observed in either group (n = 71).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
The monthly average lesion size was significantly smaller in the laser group than in the control group (0.122 and 0.223 mm, respectively; P = 0.013 calculated using the Mann‐Whitney U test by the trialists; n = 71). The inflammatory oedema was significantly less in the laser group than in the control group (the monthly mean being 0.015 and 0.00196, respectively; P = 0.031 calculated using the Mann‐Whitney U test by the trialists; n = 71). There were no significant differences in the pain levels between the 2 groups (the monthly mean being 0.113 and 0.184; P = 0.051 calculated using the Mann‐Whitney U test by the trialists; n = 71).
There were no relevant data for this intervention for our other outcomes.
Low‐intensity diode laser therapy
The Schindl 1999 trial tested the effects of a 2‐week low‐intensity diode laser therapy (48 J/cm²) in preventing recurrence of HSL during a 52‐week follow‐up period. A significantly longer median recurrence‐free interval was found in the laser group (37.5 weeks; range = 2 to 52 weeks) than in the control group (3 weeks; range = 1 to 20 weeks) (P < 0.0001 calculated using the Wilcoxon rank‐sum test by trialists; MD 30.00, 95% CI 21.42 to 38.58; n = 48; see Analysis 18.1), although this measure was not a prespecified outcome in our protocol.
Primary outcome 2. Adverse effects during use of the preventative intervention
No adverse events were observed in either group (n = 48).
There were no relevant data for this intervention for our other outcomes.
Hypnotherapy
The Pfitzer 2005 trial assessed the efficacy of five weekly hypnotherapy sessions in preventing recurrence of HSL during a follow‐up period of six months in comparison with no hypnotherapy (control). Please see summary of findings Table 20 where we judged the quality of the evidence for this comparison as very low for the following outcomes.
Primary outcome 1. Incidence of HSL during use of the preventative intervention
The frequency of recurrences significantly decreased in the hypnotherapy group (from 10.4 ± 7.6 to 5.2 ± 3.3; MD ‐5.20, 95% CI ‐10.34 to ‐0.06), but did not change in the control group (from 7.2 ± 5.7 to 8.5 ± 6.8; MD 1.30, 95% CI ‐3.94 to 6.54) (mean change in frequency of recurrences: MD ‐6.50, 95% CI ‐8.76 to ‐4.24; n = 21; see Analysis 19.1).
Secondary outcome 2. Severity (lesion area, stage, pain) of attack of recurrent HSL during use of the preventative intervention
The intensity of symptoms significantly diminished in the hypnotherapy group (from 26.0 ± 10.3 to 15.0 ± 7.0; MD ‐11.00, 95% CI ‐18.72 to ‐3.28), while that of the control group did not change significantly (from 24.4 ± 6.1 to 23.1 ± 3.8; MD ‐1.30, 95% CI ‐5.55 to 2.95) (mean change in the intensity of symptoms: MD ‐9.70, 95% CI ‐12.46 to ‐6.94; n = 21; see Analysis 19.2). The levels of pain did not change significantly in either the hypnotherapy group (MD ‐2.10, 95% CI ‐4.46 to 0.26) or the control group (MD 0.10, 95% CI ‐1.78 to 1.98). However, the levels of pain decreased significantly greater in the hypnotherapy group than in the control group (mean change in pain: MD ‐2.20, 95% CI ‐3.14 to ‐1.26; n = 21; see Analysis 19.2). The subjective impairment of appearance also improved significantly greater in the hypnotherapy group than in the control group (mean change in subjective impairment of appearance: MD ‐1.60, 95% CI ‐2.50 to ‐0.70; n = 21; see Analysis 19.2).
There were no relevant data for this intervention for our other outcomes.
Discussion
Summary of main results
The evidence does not support the efficacy of short‐term use of oral antiviral agents in preventing recurrence of herpes simplex labialis (HSL). The efficacy of short‐term use of oral aciclovir in preventing recurrent HSL was inconsistent and lacked a dose‐response relationship: 2 trials testing aciclovir 400 mg twice daily showed a reduced risk of recurrence of HSL (Schädelin 1988; Spruance 1988), while 1 trial testing aciclovir 800 mg twice daily, Raborn 1998, and 2 trials testing 200 mg 5 times daily, Spruance 1991a; Spruance 1991b, found no similar preventative effects. The direction of intervention effect was unrelated to the risk of bias of the studies. One trial, Miller 2004, found no preventative effect of short‐term use of valaciclovir in reducing recurrence of HSL nor did a trial testing short‐term use of famciclovir (Spruance 1999). On the other hand, long‐term use of oral antiviral agents reduced the recurrence of HSL, but the clinical benefit was small. One trial found long‐term use of oral aciclovir resulted in a small but significant reduction in either clinical or virological recurrence (by one episode per participant over a four‐month period) (Rooney 1993). One trial found long‐term use of valaciclovir effective in reducing the incidence of HSL (Baker 2003), but the clinical significance of the difference was very small, with a decrease of 0.09 episodes per participant per month. One trial, Gilbert 2007, found that when compared with an episodic regimen, a long‐term suppressive regimen of valaciclovir had a lower incidence of HSL, but the difference was also very small, with a reduction of 0.10 episodes per participant per month.
One trial, Russell 1978, with a very high withdrawal rate (39.6% in the levamisole group and 15.7% in the placebo group) showed a reduced frequency of HSL in both the levamisole and placebo groups among those who completed the trial, but there were no significant differences between the 2 groups. Although the levamisole group was associated with a greater reduction in the frequency of HSL after taking into account the different baseline frequency of HSL (difference in means (MD) ‐2.00, 95% CI ‐2.24 to ‐1.76; see Analysis 7.1), the placebo group was associated with a greater reduction in the duration of attack of HSL (MD 0.70, 95% CI 0.22 to 1.18; see Analysis 7.3). Thus, there was no consistent evidence supporting the efficacy of levamisole in preventing HSL. Two other oral interventions, lysine and LongoVital® supplementation, did not prevent recurrence of HSL (Thein 1984; Pedersen 2001).
Similar to that for oral antiviral agents, the evidence shows no efficacy of short‐term use of topical antiviral agents in preventing recurrent HSL. Two trials found no effects of short‐term use of topical aciclovir 5% cream in preventing recurrence of HSL, Raborn 1997; Spruance 1991c, nor did another trial testing topical aciclovir 5% plus 348U87 3% cream (Bernstein 1994). One trial found no effects of short‐term use of topical foscarnet 3% cream in preventing recurrent HSL (Bernstein 1997). The efficacy of long‐term use of topical antiviral agents is uncertain. One trial, Gibson 1986, found long‐term use of aciclovir cream significantly reduced research‐diagnosed recurrences of HSL, but not participant‐reported recurrences. Another trial found no effects of long‐term use of topical 1,5‐pentanediol gel in preventing HSL (Busch 2009). One study, Senti 2013, found participants who applied topical 2‐hydroxypropyl‐β‐cyclo dextrin 20% gel had more recurrences than the placebo group, and the placebo group had milder symptoms of tingling and burning.
As shown in Analysis 13.1, application of sunscreen significantly prevented recurrent HSL induced by experimental ultraviolet light (UVL) (Duteil 1998; Rooney 1991), but did not reduce the recurrence of HSL induced by sunlight (Mills 1987). The efficacy of sunscreen under natural sunlight has not been confirmed.
The was a lack of consistent evidence supporting the efficacy of interferon in preventing recurrent HSL. Data from two trials, Ho 1984; Pazin 1979, showed an increased recurrence of HSL after presurgical administration of interferon, no difference in recurrence with postsurgical administration of interferon, but a decreased recurrence in those receiving continuous pre‐ and postsurgical administration of interferon. A trial, Redman 1986, found no efficacy of gamma globulin in preventing recurrent HSL, while another, Bolla 1985, found fewer incidences of recurrent HSL after six weeks of treatment with subcutaneous administration of thymopentin.
Both a HSV type I subunit vaccine and a yellow fever vaccine did not show a higher efficacy than placebo in preventing HSL (Altmeyer 1991; Møller 1997).
Two trials investigated the effects of low‐level laser therapy in preventing recurrent HSL. One trial, de Carvalho 2010, found no difference in the number of recurrences and pain, but found a significantly smaller average lesion size (with a very small difference of 0.1 mm) and a significantly lower monthly average inflammatory oedema (with a tiny difference of 0.0046 on a '0 to 3' oedema score) in the laser group. Although the latter two measures were statistically significant, the differences between the laser and control groups did not appear to be clinically significant. The other trial, Schindl 1999, found a significantly longer median recurrence‐free interval in the laser group (37.5 weeks versus 3 weeks in the control group), which was not a prespecified outcome in the present review.
One trial, Pfitzer 2005, found that hypnotherapy significantly reduced the frequency (MD ‐5.20, 95% CI ‐10.34 to ‐0.06 during a 6‐month follow‐up) and intensity of symptoms of HSL recurrences.
Overall completeness and applicability of evidence
The effects of oral and topical antiviral agents in preventing recurrent HSL have been extensively investigated. The body of evidence regarding oral and topical antiviral agents is adequate for us to conclude that long‐term use of oral aciclovir and valaciclovir are effective in preventing recurrent HSL, while short‐term use of either oral or topical antiviral agents is ineffective. On the other hand, there is a lack of evidence supporting the efficacy of long‐term use of topical antiviral agents in preventing recurrent HSL.
The available body of evidence regarding other interventions is scanty, with only one or two trials for each intervention. There is no consistent evidence supporting the efficacy of levamisole and interferon in preventing HSL. The current limited evidence found no efficacy of lysine, LongoVital® supplementation, gamma globulin, HSV type I subunit vaccine, and yellow fever vaccine in preventing HSL. There is very limited evidence suggesting that thymopentin, low‐level laser therapy, and hypnotherapy are effective in preventing HSL.
Quality of the evidence
Based on the following limitations, we rated the quality of the body of evidence low to moderate for most outcomes and very low for a few outcomes.
Limitations in the design and implementation of available studies suggesting high likelihood of bias
The risk of bias of the included trials varied from low to high (Figure 3). As shown in Figure 2, the high risk of bias most often appeared in the 'selective reporting' domain (12 (34%) out of 32 trials), followed by the 'other bias' domain (9 (28%) trials). The cause for a high risk of bias in 'selective reporting' was either a lack of data on adverse events or details on efficacy outcomes. The causes for a high risk of 'other bias' included early stopping of the trial (Bernstein 1994), no washout period in cross‐over trials (Gibson 1986; Gilbert 2007; Rooney 1993; Thein 1984), different baseline frequencies of HSL recurrences between the experimental and control groups (Pedersen 2001; Russell 1978), a low percentage of participants having a history of HSL (Schädelin 1988), and a lack of scheduled follow‐ups (Schindl 1999).
Over half of the included trials (17/32) were published before 1996 when the reporting guidelines for randomised controlled trials (RCTs), the CONsolidated Standards Of Reporting Trials (CONSORT) Statement, was first proposed. These trials often did not provide detailed reports on the methods of random sequence generation, allocation concealment, blinding, and withdrawal or dropout.
In five included trials (Altmeyer 1991; Bolla 1985; Russell 1978; Senti 2013; Thein 1984), the incidence of HSL decreased in both the experimental and placebo groups, which may be attributed to either the placebo effect or an overestimation of the baseline incidence of HSL.
Indirectness of evidence (indirect population, intervention, control, outcomes)
Direct evaluation under natural sunlight exposure in the de Carvalho 2010 trial did not confirm the indirect evidence of the preventative efficacy of sunscreen use under experimental UVL in the Schindl 1999 trial.
Unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses)
As stated previously (Analysis 1.1), the preventative efficacy of short‐term administration of oral aciclovir was inconsistent and lacked a dose‐response relationship (see summary of findings Table for the main comparison). Also, the efficacy of levamisole and interferon was inconsistent (see summary of findings Table 7; summary of findings Table 14). For other interventions, the direction of intervention effect was consistent.
Imprecision of results (wide confidence intervals)
For most interventions, there were only one or two relevant trials of limited sample size. We therefore downgraded the quality of evidence for imprecision.
High probability of publication bias
We were unable to detect publication bias because of the limited number of trials for each intervention.
Potential biases in the review process
We planned to conduct an intention‐to‐treat analysis by considering those with missing binary outcomes as treatment failures and carrying out a 'last observation carried forward' analysis for those with missing continuous or ordinal outcomes. However, many included trials did not report details of withdrawals or dropouts nor provided a participant flow chart (Bernstein 1994; Bolla 1985; de Carvalho 2010; Duteil 1998; Gibson 1986; Pfitzer 2005; Spruance 1991a; Spruance 1991b; Spruance 1991c; Thein 1984). We failed to conduct the planned analysis for missing data, and it is thus unclear whether the intervention effects were overestimated in these trials.
Agreements and disagreements with other studies or reviews
Three reviews, Opstelten 2008; Worrall 2009; Rahimi 2012, were published before we conducted this review, with Rahimi 2012 limited to antiviral agents and having a four‐year gap between the year of literature search and publication. They included RCTs from searching various databases up to April 2008, February 2009, and 2008, respectively. Two reviews, Opstelten 2008; Worrall 2009, found in line with our review that long‐term use of oral antiviral agents are effective in preventing HSL and found mixed results regarding the preventative efficacy of sunscreens.
The Opstelten 2008 review regarded short‐term use of topical antiviral agents effective in preventing HSL and interpreted Raborn 1997 as showing the efficacy of topical aciclovir cream in preventing HSL. However, in the Raborn 1997 trial, the proportion of participants presenting with recurrent HSL did not significantly differ between the aciclovir and placebo groups (15/91 versus 23/90). Only in the 'treatment period plus four days' follow‐up period' did the proportion of participants having recurrent HSL differ significantly between the two groups. The abstract of the Opstelten 2008 review stated short‐term use of oral antiviral agents would provide some protection against recurrent HSL, although its main text reported the inconsistent results from the Raborn 1998; Spruance 1988; Spruance 1991a; and Spruance 1991b trials.
The Worrall 2009 review could not conclude whether topical antiviral agents are effective in preventing HSL based on results from 2 trials on aciclovir 5% cream (Raborn 1997; Spruance 1991c). Our review included 2 more trials on aciclovir 5% plus 348U87 3% cream, Bernstein 1994, and foscarnet 3% cream, Bernstein 1997, and found no effects of short‐term use of topical antiviral agents in preventing recurrent HSL.
The Rahimi 2012 review was in agreement with us that topical aciclovir cream did not appear effective in preventing HSL. The Rahimi 2012 review examined the effects of various antivirals and found oral aciclovir and valaciclovir, but not famciclovir, effective in preventing HSL. However, the Rahimi 2012 review did not take into consideration the length of antiviral use.
Study flow diagram.
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 2 Incidence of HSL during use of the preventative intervention (by culture).
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 3 Adverse effects during use of the preventative intervention.
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 4 Severity (lesion size) of attack of herpes labialis during use of the preventative intervention.
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 5 Severity (stage) of attack of recurrent HSL during use of the preventative intervention.
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 6 Severity (pain) of attack of recurrent HSL during use of the preventative intervention.
Comparison 1 Oral aciclovir (short‐term) versus placebo, Outcome 7 Incidence of HSL after use of the preventative intervention.
Comparison 2 Oral aciclovir (long‐term) versus placebo, Outcome 1 Duration of attack of herpes labialis during use of the preventative intervention.
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 1 Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation).
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 2 Incidence of herpes labialis during use of the preventative intervention (by culture).
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 3 Adverse effects during use of the preventative intervention.
Comparison 3 Valaciclovir (short‐term) versus placebo, Outcome 4 Viral load (shedding) in saliva.
Comparison 4 Valaciclovir (long‐term) versus placebo, Outcome 1 Adverse effects during use of the preventative intervention.
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 1 Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month).
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 2 Adverse effects during use of the preventative intervention.
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 3 Duration of attack of recurrent HSL during use of the preventative intervention.
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 4 Severity (pain) of attack of recurrent HSL during use of the preventative intervention.
Comparison 5 Valaciclovir (suppressive regimen versus episodic regimen), Outcome 5 Severity (maximum total lesion area) of attack of recurrent HSL during use of the preventative intervention.
Comparison 6 Famciclovir versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
Comparison 6 Famciclovir versus placebo, Outcome 2 Duration of attack of recurrent HSL during use of the preventative intervention.
Comparison 6 Famciclovir versus placebo, Outcome 3 Severity (pain) of attack of recurrent HSL during use of the preventative intervention.
Comparison 7 Levamisole versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
Comparison 7 Levamisole versus placebo, Outcome 2 Adverse effects during use of the preventative intervention (leading to withdrawal).
Comparison 7 Levamisole versus placebo, Outcome 3 Duration of attack of recurrent HSL during use of the preventative intervention.
Comparison 8 Lysine versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (number of recurrences per participant per month).
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 2 Adverse effects during use of the preventative intervention.
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 3 Severity (aborted lesions) of attack of recurrent HSL during use of the preventative intervention.
Comparison 9 Topical aciclovir (short‐term) versus placebo, Outcome 4 Incidence of HSL after use of the preventative intervention.
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by culture).
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 2 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 3 Duration of attack of recurrent HSL during use of the preventative intervention.
Comparison 10 Topical aciclovir and 348U87 cream (short‐term) versus placebo, Outcome 4 Severity of attack of recurrent HSL during use of the preventative intervention (maximum lesion area).
Comparison 11 Topical foscarnet versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
Comparison 11 Topical foscarnet versus placebo, Outcome 2 Adverse effects during use of the preventative intervention (leading to discontinuation).
Comparison 11 Topical foscarnet versus placebo, Outcome 3 Adverse effects during use of the preventative intervention (application site reactions).
Comparison 11 Topical foscarnet versus placebo, Outcome 4 Duration of attack of recurrent HSL during use of the preventative intervention (healing time).
Comparison 11 Topical foscarnet versus placebo, Outcome 5 Severity of attack of recurrent HSL during use of the preventative intervention (mean lesion area).
Comparison 11 Topical foscarnet versus placebo, Outcome 6 Severity of attack of recurrent HSL during use of the preventative intervention (maximum lesion area).
Comparison 11 Topical foscarnet versus placebo, Outcome 7 Severity of attack of recurrent HSL during use of the preventative intervention (duration of pain).
Comparison 12 Topical 1,5‐pentanediol versus placebo, Outcome 1 Severity (blistering, swelling, or pain) of recurrence.
Comparison 13 Sunscreen versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation).
Comparison 13 Sunscreen versus placebo, Outcome 2 Incidence of HSL during use of the preventative intervention (by culture).
Comparison 14 Interferon versus placebo, Outcome 1 Incidence of HSL during use of the preventative intervention.
Comparison 14 Interferon versus placebo, Outcome 2 Adverse effects during use of the preventative intervention (fever).
Comparison 14 Interferon versus placebo, Outcome 3 Adverse effects during use of the preventative intervention (other).
Comparison 15 Gamma globulin versus histamine (control), Outcome 1 Duration of attack of recurrent HSL during use of the preventative intervention.
Comparison 15 Gamma globulin versus histamine (control), Outcome 2 Severity of attack of recurrent HSL during use of the preventative intervention (less severe recurrences than usual).
Comparison 16 Thymopentin versus placebo, Outcome 1 Adverse effects during use of the preventative intervention.
Comparison 17 Yellow fever vaccination versus placebo, Outcome 1 Adverse effects during use of the preventative intervention.
Comparison 18 Laser versus no interventions, Outcome 1 Time to first recurrence.
Comparison 19 Hypnotherapy versus control, Outcome 1 Incidence of HSL during use of the preventative intervention (change in frequency of recurrence).
Comparison 19 Hypnotherapy versus control, Outcome 2 Severity of attack of recurrent HSL during use of the preventative intervention.
| Oral aciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis (cold sores on the lips) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Oral aciclovir (short‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 800 mg twice daily | Study population | RR 1.08 | 237 | ⊕⊕⊕⊝ | ‐ | |
| 171 per 1000 | 184 per 1000 | |||||
| Moderate | ||||||
| 171 per 1000 | 185 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 400 mg twice daily | Study population | RR 0.26 | 177 | ⊕⊕⊝⊝ | ‐ | |
| 364 per 1000 | 95 per 1000 | |||||
| Moderate | ||||||
| 538 per 1000 | 140 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ aciclovir 200 mg 5 times/day | Study population | RR 0.46 | 66 | ⊕⊕⊝⊝ | ‐ | |
| 394 per 1000 | 181 per 1000 | |||||
| Moderate | ||||||
| 394 per 1000 | 181 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) ‐ aciclovir 400 mg twice daily | Study population | RR 0.05 | 30 | ⊕⊕⊝⊝ | ‐ | |
| 750 per 1000 | 38 per 1000 | |||||
| Moderate | ||||||
| 750 per 1000 | 38 per 1000 | |||||
| Adverse effects during use of the preventative intervention ‐ aciclovir 800 mg twice daily | Study population | RR 0.98 | 239 | ⊕⊕⊕⊝ | ‐ | |
| 363 per 1000 | 356 per 1000 | |||||
| Moderate | ||||||
| 363 per 1000 | 356 per 1000 | |||||
| Adverse effects during use of the preventative intervention ‐ aciclovir 400 mg twice daily | Study population | RR 2.3 | 183 | ⊕⊕⊝⊝ | ‐ | |
| 33 per 1000 | 75 per 1000 | |||||
| Moderate | ||||||
| 20 per 1000 | 46 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Oral aciclovir (long‐term) compared with placebo for prevention of herpes simplex labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| placebo | Oral aciclovir (long‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) | 1.40 episodes per participant per a 4‐month period | 0.40 episodes per participant per a 4‐month period | Not estimable | 40 | ⊕⊕⊝⊝ | ‐ |
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) | 1.80 episodes per participant per a 4‐month period | 0.85 episodes per participant per a 4‐month period | Not estimable | 40 | ⊕⊕⊝⊝ | ‐ |
| Duration of attack of herpes labialis during use of the preventative intervention | ‐ | The mean duration of attack of herpes labialis during use of the preventative intervention in the intervention groups was 3.6 lower (7.2 lower to 0 higher) | ‐ | 40 | ⊕⊕⊝⊝ | ‐ |
| Rate of adherence to the regimen of the preventative intervention | 99% of the prescribed study medication | 99% of the prescribed study medication | ‐ | 40 | ⊕⊕⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded two levels due to risk of bias and imprecision: the available evidence is limited to one single randomised trial with a high risk of reporting bias. | ||||||
| Valaciclovir (short‐term) compared with placebo for prevention of herpes simplex labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Valaciclovir (short‐term) | |||||
| Incidence of HSL during use of the preventative intervention (by clinical evaluation) | Study population | RR 0.55 | 125 | ⊕⊕⊕⊝ | ‐ | |
| 206 per 1000 | 113 per 1000 | |||||
| Moderate | ||||||
| 206 per 1000 | 113 per 1000 | |||||
| Incidence of HSL during use of the preventative intervention (by culture) | Study population | RR 0.47 | 125 | ⊕⊕⊕⊝ | ‐ | |
| 238 per 1000 | 112 per 1000 | |||||
| Moderate | ||||||
| 238 per 1000 | 112 per 1000 | |||||
| Adverse effects during use of the preventative intervention | Study population | RR 1.33 | 125 | ⊕⊕⊕⊝ | ‐ | |
| 206 per 1000 | 274 per 1000 | |||||
| Moderate | ||||||
| 206 per 1000 | 274 per 1000 | |||||
| Viral load (shedding) in saliva | Study population | RR 0.16 | 120 | ⊕⊕⊕⊝ | ‐ | |
| 103 per 1000 | 17 per 1000 | |||||
| Moderate | ||||||
| 103 per 1000 | 16 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Valaciclovir (long‐term) compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Valaciclovir (long‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention | 0.21 episodes per participant per month | 0.12 episodes per participant per month | Not estimable | 95 | ⊕⊕⊕⊝ | ‐ |
| Adverse effects during use of the preventative intervention | Study population | RR 0.86 | 95 | ⊕⊕⊕⊝ | ‐ | |
| 396 per 1000 | 340 per 1000 | |||||
| Moderate | ||||||
| 396 per 1000 | 341 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Valaciclovir (suppressive regimen compared with episodic regimen) for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Episodic regimen | Suppressive regimen | |||||
| Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month) | 0.1775 ± 0.1975 | 0.075 ± 0.1025 | The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 0.1 lower (0.16 to 0.05 lower) | 120 | ⊕⊝⊝⊝ | ‐ |
| Adverse effects during use of the preventative intervention | Study population | RR 1.21 (0.78 to 1.87) | 152 | ⊕⊝⊝⊝ | ‐ | |
| 316 per 1000 | 382 per 1000 | |||||
| Moderate | ||||||
| 316 per 1000 | 382 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | 2.86 ± 3.10 days | 1.78 ± 2.92 days | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 1.08 days shorter (2.16 lower to 0 higher) | 120 | ⊕⊝⊝⊝ | ‐ |
| Severity (pain) of attack of recurrent herpes labialis during use of the preventative intervention | 0.23 ± 0.32 | 0.14 ± 0.27 | The mean severity (pain) of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.09 lower (0.2 lower to 0.02 higher) | 120 | ⊕⊝⊝⊝ | ‐ |
| Severity (maximum total lesion area) of attack of recurrent herpes labialis during use of the preventative intervention | 10.52 ± 19.45 mm² | 5.14 ± 9.98 mm² | The mean severity (maximum total lesion area) of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 5.38 smaller (10.91 lower to 0.15 higher) | 120 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and multiple risk of biases in performance, detection, attrition, and other sources: the available evidence is limited to one single randomised trial with a high risk of biases. | ||||||
| Famciclovir compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Famciclovir | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 125 mg | Study population | RR 0.74 | 120 | ⊕⊕⊕⊝ | ‐ | |
| 517 per 1000 | 382 per 1000 | |||||
| Moderate | ||||||
| 517 per 1000 | 383 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 250 mg | Study population | RR 0.69 | 122 | ⊕⊕⊕⊝ | ‐ | |
| 517 per 1000 | 357 per 1000 | |||||
| Moderate | ||||||
| 517 per 1000 | 357 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ famciclovir 500 mg | Study population | RR 0.82 | 121 | ⊕⊕⊕⊝ | ‐ | |
| 517 per 1000 | 424 per 1000 | |||||
| Moderate | ||||||
| 517 per 1000 | 424 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 125 mg | Study population | HR 1.63 | 47 | ⊕⊕⊕⊝ | ‐ | |
| See comment² | See comment² | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 250 mg | Study population | HR 1.59 | 45 | ⊕⊕⊕⊝ | ‐ | |
| See comment² | See comment² | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention ‐ famciclovir 500 mg | Study population | HR 2.39 | 51 | ⊕⊕⊕⊝ | ‐ | |
| See comment² | Shortened by 2.8 days | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is limited to one single randomised trial. | ||||||
| Levamisole compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Levamisole | |||||
| Incidence of herpes labialis during use of the preventative intervention | 2.7 ± 2.3 recurrences during a 6‐month period | The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 2 lower (2.24 to 1.76 lower) during a 6‐month period | ‐ | 72 | ⊕⊝⊝⊝ | Of the 99 participants randomised, 27 (27.2%) did not complete the trial and were excluded from the analysis, with 19 (39.6%) in the levamisole group and 8 (15.7%) in the placebo group |
| Adverse effects during use of the preventative intervention (leading to withdrawal) | Study population | See comment | 99 | ⊕⊝⊝⊝ | Risks were calculated from pooled risk differences | |
| 157 per 1000 | 395 per 1000 | |||||
| Moderate | ||||||
| 157 per 1000 | 396 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | 8.2 ± 2.8 days | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.7 days longer (0.22 to 1.18 longer) | ‐ | 72 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and attrition and other biases: the available evidence is limited to a single study with a high risk of attrition and other biases. | ||||||
| Lysine compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes simplex labialis (cold sores on the lips) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Lysine | |||||
| Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month) | ‐ | The mean incidence of herpes labialis during use of the preventative intervention in the intervention groups was 0.04 lower (0.37 lower to 0.29 higher) | ‐ | 26 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and reporting and other biases: the available evidence is limited to a single study with a high risk of reporting and other biases. | ||||||
| Topical aciclovir (short‐term) compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical aciclovir (short‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention | Study population | RR 0.91 | 271 | ⊕⊕⊕⊝ | ‐ | |
| 304 per 1000 | 276 per 1000 | |||||
| Moderate | ||||||
| 328 per 1000 | 298 per 1000 | |||||
| Adverse effects during use of the preventative intervention | Study population | RR 1.17 | 191 | ⊕⊕⊝⊝ | ‐ | |
| 135 per 1000 | 158 per 1000 | |||||
| Moderate | ||||||
| 135 per 1000 | 158 per 1000 | |||||
| Severity (aborted lesions) of attack of recurrent herpes labialis during use of the preventative intervention | Study population | RR 1.02 | 52 | ⊕⊕⊝⊝ | ‐ | |
| 95 per 1000 | 97 per 1000 | |||||
| Moderate | ||||||
| 95 per 1000 | 97 per 1000 | |||||
| Incidence of herpes labialis after use of the preventative intervention | Study population | RR 0.35 | 181 | ⊕⊕⊝⊝ | ‐ | |
| 156 per 1000 | 54 per 1000 | |||||
| Moderate | ||||||
| 156 per 1000 | 55 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to risk of bias: the evidence is from two trials with a high risk of reporting bias. | ||||||
| Topical aciclovir and 348U87 cream (short‐term) compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical aciclovir and 348U87 cream (short‐term) | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) | Study population | RR 0.78 | 51 | ⊕⊝⊝⊝ | ‐ | |
| 154 per 1000 | 120 per 1000 | |||||
| Moderate | ||||||
| 154 per 1000 | 120 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) | Study population | RR 1.46 | 51 | ⊕⊝⊝⊝ | ‐ | |
| 192 per 1000 | 281 per 1000 | |||||
| Moderate | ||||||
| 192 per 1000 | 280 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | ‐ | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 2.5 days longer (1.39 shorter to 6.39 longer) | ‐ | 9 | ⊕⊝⊝⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) in the intervention groups was 73 larger (42.22 smaller to 188.22 larger) | ‐ | 9 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision and reporting and other biases: the available evidence is from a single trial with a high risk of reporting and other biases. | ||||||
| Topical foscarnet compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical foscarnet | |||||
| Incidence of herpes labialis during use of the preventative intervention | Study population | RR 1.08 | 295 | ⊕⊕⊕⊝ | ‐ | |
| 408 per 1000 | 441 per 1000 | |||||
| Moderate | ||||||
| 408 per 1000 | 441 per 1000 | |||||
| Adverse effects during use of the preventative intervention (leading to discontinuation) | Study population | RR 2.96 | 302 | ⊕⊕⊕⊝ | ‐ | |
| 0 per 1000 | 0 per 1000 | |||||
| Moderate | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| Adverse effects during use of the preventative intervention (application site reactions) | Study population | RR 2.47 | 302 | ⊕⊕⊕⊝ | ‐ | |
| 27 per 1000 | 66 per 1000 | |||||
| Moderate | ||||||
| 27 per 1000 | 67 per 1000 | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention (healing time) | ‐ | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention (healing time) in the intervention groups was 0.21 days shorter (1.68 shorter to 1.26 longer) | ‐ | 125 | ⊕⊕⊕⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (mean lesion area) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (mean lesion area) in the intervention groups was 16 lower (38.96 lower to 6.96 higher) | ‐ | 124 | ⊕⊕⊕⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (maximum lesion area) in the intervention groups was 30 lower (72.64 lower to 12.64 higher) | ‐ | 124 | ⊕⊕⊕⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (duration of pain) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (duration of pain) in the intervention groups was 0.1 higher (1.11 lower to 1.31 higher) | ‐ | 113 | ⊕⊕⊕⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| Topical 1,5‐pentanediol compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Topical 1,5‐pentanediol | |||||
| Incidence of herpes labialis during use of the preventative intervention | Study population | Not estimable | 102 | ⊕⊕⊕⊝ | P > 0.05 calculated using the Mann‐Whitney test by the trialists | |
| 109 episodes out of 50 | 120 episodes out of 52 | |||||
| Moderate | ||||||
| ‐ | ‐ | |||||
| Adverse effects during use of the preventative intervention | Study population | Not estimable | 102 | ⊕⊕⊕⊝ | ‐ | |
| See comment | See comment | |||||
| Moderate | ||||||
| ‐ | ‐ | |||||
| Severity (blistering, swelling, or pain) of recurrence | Study population | RR 1.05 | 224 | ⊕⊕⊕⊝ | ‐ | |
| 756 per 1000 | 794 per 1000 | |||||
| Moderate | ||||||
| 756 per 1000 | 794 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single study. | ||||||
| Sunscreen compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Sunscreen | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ solar radiation | Study population | RR 1.12 | 51 | ⊕⊕⊝⊝ | ‐ | |
| 111 per 1000 | 124 per 1000 | |||||
| Moderate | ||||||
| 111 per 1000 | 124 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) ‐ experimental ultraviolet light | Study population | RR 0.07 | 111 | ⊕⊝⊝⊝ | ‐ | |
| 456 per 1000 | 32 per 1000 | |||||
| Moderate | ||||||
| 487 per 1000 | 34 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention (by culture) | Study population | See comment | 73 | ⊕⊝⊝⊝ | Risks were calculated from pooled risk differences | |
| 658 per 1000 | 26 per 1000 | |||||
| Moderate | ||||||
| 658 per 1000 | 26 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded two levels due to risk of bias and imprecision: the available evidence is limited to a single study with a high risk of reporting bias. | ||||||
| Interferon compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Interferon | |||||
| Incidence of herpes labialis during use of the preventative intervention ‐ presurgical | Study population | RR 1.59 | 32 | ⊕⊕⊝⊝ | ‐ | |
| 571 per 1000 | 909 per 1000 | |||||
| Moderate | ||||||
| 571 per 1000 | 908 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention ‐ postsurgical | Study population | RR 0.99 | 44 | ⊕⊕⊝⊝ | ‐ | |
| 571 per 1000 | 566 per 1000 | |||||
| Moderate | ||||||
| 571 per 1000 | 565 per 1000 | |||||
| Incidence of herpes labialis during use of the preventative intervention ‐ pre‐ and postsurgical | Study population | RR 0.57 | 37 | ⊕⊕⊝⊝ | ‐ | |
| 833 per 1000 | 475 per 1000 | |||||
| Moderate | ||||||
| 833 per 1000 | 475 per 1000 | |||||
| Adverse effects during use of the preventative intervention (fever) ‐ presurgical | Study population | RR 2.45 | 32 | ⊕⊕⊕⊝ | ‐ | |
| 333 per 1000 | 817 per 1000 | |||||
| Moderate | ||||||
| 333 per 1000 | 816 per 1000 | |||||
| Adverse effects during use of the preventative intervention (fever) ‐ postsurgical | Study population | RR 1.96 | 44 | ⊕⊕⊕⊝ | ‐ | |
| 333 per 1000 | 653 per 1000 | |||||
| Moderate | ||||||
| 333 per 1000 | 653 per 1000 | |||||
| Adverse effects during use of the preventative intervention (fever) ‐ pre‐ and postsurgical | Study population | RR 11.76 | 38 | ⊕⊕⊕⊝ | ‐ | |
| 0 per 1000 | 0 per 1000 | |||||
| Moderate | ||||||
| 0 per 1000 | 0 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to inconsistency: the effects of presurgical, postsurgical, and continuous pre‐ and postsurgical administration of interferon were inconsistent. | ||||||
| Gamma globulin compared with histamine (control) for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Histamine (control) | Gamma globulin | |||||
| Duration of attack of recurrent herpes labialis during use of the preventative intervention | ‐ | The mean duration of attack of recurrent herpes labialis during use of the preventative intervention in the intervention groups was 0.7 higher (0.55 lower to 1.95 higher) | ‐ | 72 | ⊕⊕⊝⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (less severe recurrences than usual) | Study population | RR 0.97 | 73 | ⊕⊕⊝⊝ | ‐ | |
| 750 per 1000 | 728 per 1000 | |||||
| Moderate | ||||||
| 750 per 1000 | 728 per 1000 | |||||
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded two levels due to risk of bias and imprecision: the available evidence is from a single trial with a high risk of reporting bias. | ||||||
| Thymopentin compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Thymopentin | |||||
| Incidence of herpes labialis during use of the preventative intervention | 0.9 (range 0.1 to 2.0) | Median 0.2 (range 0.0 to 2.7) | ‐ | 36 | ⊕⊕⊕⊝ | P = 0.0027 using the Mann‐Whitney test by the trialists |
| Adverse effects during use of the preventative intervention | 111 per 1000 | 222 per 1000 | RR 2 | 36 | ⊕⊕⊕⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| HSV vaccination compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | HSV vaccination | |||||
| Incidence of herpes labialis during use of the preventative intervention | 1.3 recurrences in a 4‐month period | 1.6 recurrences in a 4‐month period | P = 0.10 calculated by the trialists | 64 | ⊕⊕⊕⊝ | ‐ |
| Adverse effects during use of the preventative intervention | 13 adverse events per 100 injections | 22 adverse events per 100 injections | RR 0.33 | 64 | ⊕⊕⊕⊝ | Several adverse events might have occurred in the same participant; no statistical tests were conducted by the trialists |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| Yellow fever vaccination compared with placebo for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Yellow fever vaccination | |||||
| Incidence of herpes labialis during use of the preventative intervention | See comment | See comment | ‐ | 1 | ⊕⊕⊕⊝ | ‐ |
| Adverse effects during use of the preventative intervention | 83 per 1000 | 28 per 1000 | RR 0.33 | 24 | ⊕⊕⊕⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded one level due to imprecision: the available evidence is from a single trial. | ||||||
| Laser compared with no interventions for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No interventions | Laser | |||||
| Incidence of herpes labialis during use of the preventative intervention | 0.116 recurrences per month | 0.076 recurrences per month | Not estimable | 71 | ⊕⊝⊝⊝ | P = 0.076, calculated using the Mann‐Whitney U test by the trialists |
| Adverse effects during use of the preventative intervention | 0 | 0 | Not estimable | 119 | ⊕⊕⊝⊝ | No adverse events were observed in either group |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision: the evidence is from a single trial with a high risk of performance and detection biases. | ||||||
| Hypnotherapy compared with control for prevention of herpes labialis | ||||||
| Patient or population: participants with recurrent herpes labialis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Hypnotherapy | |||||
| Incidence of herpes labialis during use of the preventative intervention (change in frequency of recurrence) | ‐ | The mean incidence of herpes labialis during use of the preventative intervention (change in frequency of recurrence) in the intervention groups was 6.5 lower (8.76 to 4.24 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| Severity of attack of recurrent herpes labialis during use of the preventative intervention (change in intensity) | ‐ | The mean severity of attack of recurrent herpes labialis during use of the preventative intervention (change in intensity) in the intervention groups was 9.7 lower (12.46 to 6.94 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| Change in severity (pain) of herpes labialis | ‐ | The mean change in severity (pain) of herpes labialis in the intervention groups was 2.2 lower (3.14 to 1.26 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| Change in severity (impairment of appearance) of herpes labialis | ‐ | The mean change in severity (impairment of appearance) of herpes labialis in the intervention groups was 1.6 lower (2.5 to 0.7 lower) | ‐ | 21 | ⊕⊝⊝⊝ | ‐ |
| *The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ¹Downgraded three levels due to imprecision (the evidence is from a single trial) with a high risk of performance and detection biases. | ||||||
| Study | Enquiries | Reply |
| We sent the following request on 13 February 2015: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) Could you please offer the details of how you achieved double blindness? (4) Did you use a person other than the physician to assess the outcomes? | No reply | |
| We sent the following request on 23 June 2014: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) Did you use a person other than the physician to assess the outcomes? (4) The number of dropouts or withdrawals in this trial (5) Did you assess any outcomes regarding adverse events? If you did, what were the results? | 4 August 2014 (1) Randomisation was down through sortition (2) No (3) No (4) 01 (5) Adverse events were evaluated, but there were no adverse events detected | |
| We sent the following request on 13 February 2015: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? | No reply | |
| We sent the following request on 23 June 2014: (1) How did you randomise the participants? (2) Did you do any measures for allocation concealment? (3) The number of dropouts or withdrawals in this trial (4) Did you assess any outcomes regarding adverse events? If you did, what were the results? | No reply | |
| This trial was identified from searching trial registers (NCT00914745). We sent the following request on 27 December 2013: "Dear Prof Kündig, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you have completed a trial (http://clinicaltrials.gov/show/NCT00914745) that assessed a topical ointment for prevention of herpes simplex labialis, and was wondering if you would like to share your results with us, thus we could include your trial in our review. Your assistance would be appreciated" | The trialists provided us with the full published article | |
| We sent the following request on 27 December 2013: "Dear Dr Cheras, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you completed a trial that used Sheabutter extract BSP110 for prevention of herpes simplex labialis (http://www.controlled‐trials.com/ISRCTN03397663#?close=1). I was wondering if you would like to share your results with us. Thus, we could include your trial in our review. Your assistance would be appreciated" | No reply | |
| We sent the following request on 27 December 2013: "Dear Dr Dayan, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you are conducting a trial that uses botulinum toxin A injections for prevention of herpes simplex labialis (http://clinicaltrials.gov/show/NCT01225341). I was wondering if you have completed the trial and would like to share your results with us. Thus, we could include your trial in our review. Your assistance would be appreciated" | No reply | |
| We sent the following request on 19 January 2014: "Dear Dr Kimball, I am conducting a Cochrane review on interventions for prevention of herpes simplex labialis (see http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010095/abstract). I have noticed that you are doing a trial (http://www.clinicaltrials.gov/ct2/show/NCT01971385) that assessed a topical ointment for prevention of herpes simplex labialis, and was wondering if you would like to share your results with us if you have completed the trial, thus we could include your trial in our review. Your assistance would be greatly appreciated" | No reply |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation) Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Aciclovir 800 mg twice daily | 1 | 237 | Risk Ratio (M‐H, Random, 95% CI) | 1.08 [0.62, 1.87] |
| 1.2 Aciclovir 400 mg twice daily | 2 | 177 | Risk Ratio (M‐H, Random, 95% CI) | 0.26 [0.13, 0.51] |
| 1.3 Aciclovir 200 mg 5 times/day | 1 | 66 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.20, 1.07] |
| 2 Incidence of HSL during use of the preventative intervention (by culture) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Adverse effects during use of the preventative intervention Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Aciclovir 800 mg twice daily | 1 | 239 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.70, 1.38] |
| 3.2 Aciclovir 400 mg twice daily | 2 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.30 [0.62, 8.58] |
| 4 Severity (lesion size) of attack of herpes labialis during use of the preventative intervention Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Length | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 Width | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 Area | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Severity (stage) of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 5.1 Prodrome | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Erythema | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 Papule | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6 Severity (pain) of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 7 Incidence of HSL after use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of attack of herpes labialis during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of herpes labialis during use of the preventative intervention (by clinical evaluation) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2 Incidence of herpes labialis during use of the preventative intervention (by culture) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Adverse effects during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4 Viral load (shedding) in saliva Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse effects during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of herpes labialis during use of the preventative intervention (number of recurrences per participant per month) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Adverse effects during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Duration of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 Severity (pain) of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5 Severity (maximum total lesion area) of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Famciclovir 125 mg | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Famciclovir 250 mg | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Famciclovir 500 mg | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Duration of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Hazard Ratio (Random, 95% CI) | Totals not selected | |
| 2.1 Famciclovir 125 mg | 1 | Hazard Ratio (Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Famciclovir 250 mg | 1 | Hazard Ratio (Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Famciclovir 500 mg | 1 | Hazard Ratio (Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Severity (pain) of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Famciclovir 125 mg | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Famciclovir 250 mg | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Famciclovir 500 mg | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Adverse effects during use of the preventative intervention (leading to withdrawal) Show forest plot | 1 | Risk Difference (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Duration of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention (number of recurrences per participant per month) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention Show forest plot | 2 | 271 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.48, 1.72] |
| 2 Adverse effects during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Severity (aborted lesions) of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Incidence of HSL after use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention (by culture) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Incidence of HSL during use of the preventative intervention (by clinical evaluation) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Duration of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4 Severity of attack of recurrent HSL during use of the preventative intervention (maximum lesion area) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Adverse effects during use of the preventative intervention (leading to discontinuation) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Adverse effects during use of the preventative intervention (application site reactions) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4 Duration of attack of recurrent HSL during use of the preventative intervention (healing time) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5 Severity of attack of recurrent HSL during use of the preventative intervention (mean lesion area) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 6 Severity of attack of recurrent HSL during use of the preventative intervention (maximum lesion area) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 7 Severity of attack of recurrent HSL during use of the preventative intervention (duration of pain) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Severity (blistering, swelling, or pain) of recurrence Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention (by clinical evaluation) Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Solar radiation | 1 | 51 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.25, 5.06] |
| 1.2 Experimental ultraviolet light | 2 | 111 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.01, 0.33] |
| 2 Incidence of HSL during use of the preventative intervention (by culture) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.1 Presurgical | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Postsurgical | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Pre‐ & postsurgical | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Adverse effects during use of the preventative intervention (fever) Show forest plot | 2 | 114 | Risk Ratio (M‐H, Random, 95% CI) | 2.30 [1.44, 3.67] |
| 2.1 Presurgical | 1 | 32 | Risk Ratio (M‐H, Random, 95% CI) | 2.45 [1.26, 4.78] |
| 2.2 Postsurgical | 1 | 44 | Risk Ratio (M‐H, Random, 95% CI) | 1.96 [1.00, 3.84] |
| 2.3 Pre‐ & postsurgical | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 11.76 [0.71, 195.11] |
| 3 Adverse effects during use of the preventative intervention (other) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.1 Pain & tenderness at injection site | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Malaise, nausea or vomiting | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Duration of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Severity of attack of recurrent HSL during use of the preventative intervention (less severe recurrences than usual) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse effects during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Adverse effects during use of the preventative intervention Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Time to first recurrence Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of HSL during use of the preventative intervention (change in frequency of recurrence) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Severity of attack of recurrent HSL during use of the preventative intervention Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.1 Intensity | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Pain | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Impairment of appearance | 1 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] | |
