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Intervenciones para pacientes sujetos a diálisis con infección por el virus de la hepatitis C (HCV)

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Antecedentes

La infección por el virus de la hepatitis C (HCV) es frecuente en pacientes con nefropatía crónica sujetos a diálisis, causa hepatopatía crónica, puede aumentar el riesgo de muerte e influye en los desenlaces de los trasplantes renales. Los antivirales de acción directa han sustituido a los interferones debido a su mayor eficacia y tolerabilidad. Esta es una actualización de una revisión publicada por primera vez en 2015.

Objetivos

El objetivo fue analizar los efectos beneficiosos y perjudiciales de las intervenciones para el HCV en pacientes con hepatopatía crónica sujetos a diálisis: muerte, recurrencia de la enfermedad, respuesta/interrupción del tratamiento, tiempo hasta la recuperación, calidad de vida (CdV), coste‐efectividad y eventos adversos. Se pretendió estudiar comparaciones de las intervenciones disponibles, comparadas con placebo, control, entre sí y con tratamientos más nuevos.

Métodos de búsqueda

Se realizaron búsquedas en el registro especializado del Grupo Cochrane de Riñón y Trasplante (Cochrane Kidney and Transplant) hasta el 23 de febrero de 2023, mediante contacto con el documentalista, utilizando los términos de búsqueda relevantes para esta revisión. Los estudios incluidos en el Registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, búsquedas manuales en resúmenes de congresos y búsquedas en la Plataforma de registros internacionales de ensayos clínicos (ICTRP) y en ClinicalTrials.gov.

Criterios de selección

Se consideraron los ensayos controlados aleatorizados (ECA), los ensayos controlados cuasialeatorizados, y el primer período de los estudios aleatorizados cruzados (cross‐over) sobre las intervenciones para la infección por HCV en pacientes con hepatopatía crónica sujetos a diálisis.

Obtención y análisis de los datos

Las estimaciones globales del efecto se obtuvieron mediante un modelo de efectos aleatorios y los resultados se expresaron como razones de riesgos (RR) y sus intervalos de confianza (IC) del 95%. La confianza en la evidencia se evaluó mediante el método GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Resultados principales

En esta actualización se incluyeron tres estudios, por lo que 13 estudios (997 participantes aleatorizados) cumplieron los criterios de inclusión. En general, el riesgo de sesgo se consideró bajo en siete estudios, incierto en cuatro, de bajo a incierto en uno y alto en un estudio. Las intervenciones incluyeron interferón estándar, interferón pegilado (PEG), interferón estándar o PEG más ribavirina, antivirales de acción directa, y antivirales de acción directa más interferón PEG más ribavirina.

Comparado con placebo o control, el interferón estándar podría suponer poca o ninguna diferencia con respecto a la muerte (cinco estudios, 134 participantes: RR 0,89; IC del 95%: 0,06 a 13,23) o recurrencia (evidencia de certeza baja), probablemente mejora la respuesta al final del tratamiento (RFT) (cinco estudios, 132 participantes: RR 8,62; IC del 95%: 3,03 a 24,55; I² = 0%) (evidencia de certeza moderada), y probablemente da lugar a poca o ninguna diferencia en la respuesta virológica sostenida (RVS) (cuatro estudios, 98 participantes: RR 3,25; IC del 95%: 0,81 a 13,07; I² = 53%), interrupción del tratamiento (cuatro estudios, 116 participantes: RR 4,59; IC del 95%: 0,49 a 42,69; I² = 63%) y eventos adversos (cinco estudios, 143 participantes: RR 3,56; IC del 95%: 0,98 a 13,01; I² = 25%) (evidencia de certeza moderada).

En la evidencia de certeza baja, el interferón PEG (un estudio, 50 participantes) podría mejorar la RFT (RR 1,53; IC del 95%: 1,09 a 2,15) pero podría dar lugar a poca o ninguna diferencia con respecto a la muerte (RR 0,33; IC del 95%: 0,01 a 7,81), la RVS (RR 2,40; IC del 95%: 0,99 a 5,81), la interrupción del tratamiento (RR 0,11; IC del 95%: 0,01 a 1,96), los eventos adversos (RR 0,11; IC del 95%: 0,01 a 1,96) y la recurrencia (21/38 tuvieron una recurrencia) (RR 0,72; IC del 95%: 0,41 a 1,25) en comparación con el interferón estándar.

En evidencia de certeza moderada, el interferón PEG en dosis altas (alfa‐2a y alfa‐2b) podría dar lugar a una diferencia escasa o nula con respecto a la muerte (dos estudios, 97 participantes: RR 4,30; IC del 95%: 0,76 a 24,33; I² = 0%), RFT (RR 1,42; IC del 95%: 0,51 a 3,90; I² = 20%), RVS (RR 1,19; IC del 95%: 0,68 a 2,07; I² = 0%), la interrupción del tratamiento (RR 1,20; IC del 95%: 0,63 a 2,28; I² = 0%) o los eventos adversos (RR 1,05; IC del 95%: 0,61 a 1,83; I² = 27%) en comparación con el interferón PEG a dosis bajas. Las dosis altas de interferón PEG podrían dar lugar a una diferencia escasa o nula en la recurrencia (un estudio, 43 participantes: RR 1,11; IC del 95%: 0,45 a 2,77; evidencia de certeza baja). No hubo diferencias significativas entre subgrupos.

El interferón estándar más ribavirina podría conducir a una mayor interrupción del tratamiento (un estudio, 52 participantes: RR 2,97; IC del 95%: 1,19 a 7,36; evidencia de certeza baja) en comparación con el interferón estándar solo.

Según evidencia de certeza baja, el interferón PEG más ribavirina (un estudio, 377 participantes) podría mejorar la RVS (RR 1,80; IC del 95%: 1,46 a 2,21), reducir la recurrencia (RR 0,33; IC del 95%: 0,23 a 0,48), aumentar ligeramente el número de eventos adversos (RR 1,10; IC del 95%: 1,01 a 1,19) y podría dar lugar a una diferencia escasa o nula en la RFT (RR 1,01; IC del 95%: 0,94 a 1,09) en comparación con el interferón PEG solo. La evidencia es muy incierta en relación al efecto del interferón PEG más ribavirina en la interrupción del tratamiento (RR 1,71; IC del 95%: 0,69 a 4,24) en comparación con el interferón PEG solo.

Un estudio informó que grazoprevir más elbasvir mejoraba la RFT (173 participantes: RR 174,99; IC del 95%: 11,03 a 2775,78; evidencia de certeza baja) en comparación con placebo.

No se sabe con certeza si telaprevir más ribavirina (dosis inicial alta versus dosis inicial baja) más interferón PEG durante 24 versus 48 semanas (un estudio, 35 participantes) mejora la RFT (RR 1,02; IC del 95%: 0,67 a 1,56) o la RVS (RR 1,02; IC del 95%: 0,67 a 1,56) porque la certeza de la evidencia es muy baja.

No se dispuso de datos sobre CdV, la coste‐efectividad, los desenlaces cardiovasculares ni la diálisis peritoneal.

Conclusiones de los autores

En pacientes sujetos a diálisis con infección por el HCV, el grazoprevir más el elbasvir probablemente mejore la RFT. No hay diferencias en la RFT o la RVS para las combinaciones de telaprevir, ribavirina e interferón PEG administradas durante diferentes duraciones y dosis. Aunque ya no se administra, el interferón PEG fue más eficaz que el interferón estándar para la RFT, pero no para la RVS. El aumento de las dosis de interferón PEG no mejoró las respuestas. El agregado de ribavirina al interferón PEG podría disminuir la recurrencia, dar lugar a una mayor RVS y a un mayor número de eventos adversos.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Intervenciones para pacientes sujetos a diálisis con infección por el virus de la hepatitis C (HCV)

¿Cuál es el problema?

La hepatitis C es una enfermedad del hígado causada por el virus de la hepatitis C (HCV) que se transmite de persona a persona por contacto sanguíneo, como resultado de compartir agujas para drogas y otros objetos contaminados con sangre. Este virus permanece en el organismo durante mucho tiempo, y en algunos puede afectar al hígado, provocando su lenta destrucción o cirrosis y cáncer de hígado. Las personas con esta infección pueden presentar debilidad, náuseas, ictericia y pérdida de peso, y pueden tener aumentadas las enzimas hepáticas y la bilirrubina.

El HCV está presente en todo el mundo y varía según los países, con un total aproximado de 70 millones de personas que padecen una infección crónica, y constituye el 40% de los pacientes con enfermedad hepática crónica. Las personas sometidas a hemodiálisis durante largos periodos tienen más probabilidades de contraer esta infección. Los medicamentos antivirales de acción directa, que pueden tomarse por vía oral, han sustituido a los interferones utilizados anteriormente para el tratamiento de la infección por el VHC. Los antivirales de acción directa tienen mejor eficacia y tolerabilidad y son eficaces en casi todos los pacientes. Los interferones deben administrarse en forma de inyecciones bajo la piel y tienen menos eficacia y más efectos secundarios. El tratamiento con antivirales de acción directa debe administrarse durante 12 semanas, en comparación con los interferones, que debían administrarse durante al menos 24 a 48 semanas con o sin comprimidos de ribavirina para mejorar su eficacia. Sin embargo, la ribavirina puede acumularse en los pacientes con enfermedades renales y provocar la destrucción de los glóbulos rojos y anemia.

¿Qué se hizo?

Desde la publicación de la revisión anterior en 2015, se dispone de nuevos medicamentos (antivirales de acción directa) para el tratamiento de la infección por el HCV, por lo que ahora se ha actualizado la evidencia para incluir la eficacia de los antivirales de acción directa. En esta actualización se buscó nueva evidencia procedente de estudios controlados aleatorizados para el tratamiento del HCV en pacientes sujetos a diálisis.

¿Qué se encontró?

La actualización encontró tres estudios con unos 600 pacientes que podían incluirse, además de la revisión anterior que tenía 10 estudios, todos en hemodiálisis. La administración de los antivirales de acción directa grazoprevir y elbasvir en combinación produce una respuesta del 100% al final del tratamiento, pero no se dispone de datos de seguimiento y la evidencia no es de calidad alta. El agregado de ribavirina al interferón dio lugar a una mejor respuesta sostenida (estar libre del virus en sangre después de interrumpir el tratamiento), disminuyó las probabilidades de recurrencia de la enfermedad, pero provocó más episodios adversos. Telaprevir junto con ribavirina en diferentes dosis combinado con interferón pegilado (PEG) en diferentes dosis y duraciones producen una respuesta al final del tratamiento y una respuesta sostenida casi similares, pero la evidencia no fue de calidad alta. El interferón PEG fue más eficaz que el interferón estándar a la hora de producir una respuesta a corto plazo, pero no sostenida, y ambos fueron tolerados de igual forma. El aumento de la dosis de interferón PEG no mejoró la respuesta, pero fue tolerado. Las limitaciones de esta revisión son que solo se dispuso de unos pocos estudios con escasos participantes, y que se excluyó a los pacientes con enfermedades graves de los estudios anteriores en previsión de efectos secundarios. Por lo tanto, la evidencia disponible no fue de calidad alta. La evidencia para los medicamentos más nuevos, es decir, los antivirales de acción directa, que ahora han sustituido la administración de interferones en la población general, fue limitada y no es de calidad alta.

Conclusiones

Esto ha sido una actualización de una revisión de los tratamientos disponibles para pacientes sujetos a diálisis infectados por el HCV. En la actualidad, los antivirales de acción directa han sustituido a los interferones en el tratamiento. Grazoprevir y elbasvir producen una respuesta al final del tratamiento en casi todos los pacientes, pero no se dispone de datos sobre una respuesta sostenida durante el seguimiento, y la evidencia no es de calidad alta. Las combinaciones de telaprevir, ribavirina e interferón PEG administradas en diferentes dosis y duraciones tienen una eficacia casi similar y la evidencia no es de calidad alta. El interferón PEG es más eficaz que el interferón estándar para producir una respuesta al final del tratamiento que no es sostenida, siendo ambos tolerados de igual forma. El aumento de las dosis de interferón PEG no mejora las respuestas, pero las dosis altas y bajas se toleran por igual. El agregado de ribavirina produce una mejor respuesta incluso después de interrumpir el tratamiento, pero presenta mayores episodios adversos.

Authors' conclusions

Implications for practice

Hepatitis C causes morbidity and death in CKD patients on dialysis and has implications for kidney transplant candidates. This review highlights the small number of studies with only a small number of participants available in most studies. There is a lack of high‐quality evidence in this area, though direct‐acting antivirals are the current preferred choice of therapy over interferons.

A combination of direct‐acting antivirals grazoprevir and elbasvir produces end‐of‐treatment responses in nearly all patients and was well tolerated, although the certainty of the evidence is low. 

A combination of PEG interferon and ribavirin produces an SVR, with lesser relapses with higher adverse events; the addition of telaprevir produced an end‐of‐treatment response and SVR irrespective of the dose of ribavirin or the duration of therapy. 

Standard interferon produces an end‐of‐treatment response which is not sustained but is relatively well tolerated. PEG interferon is better than standard interferon in producing end‐of‐treatment but not SVR. Both are equally tolerated. Increasing doses of PEG interferon does not improve responses but is tolerated. 

Implications for research

This review identifies the potential for conducting further RCTs using direct‐acting antivirals in dialysis patients and testing SVR as a surrogate for long‐term outcomes.

Summary of findings

Open in table viewer
Summary of findings 1. Standard interferon versus placebo or control for haemodialysis patients with hepatitis C virus infection

Standard interferon versus placebo or control for HD patients with HCV infection

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention: standard interferon
Comparison: placebo or control

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of evidence
(GRADE)

Comments

Risk with placebo or control

Risk with standard interferon

Death
Follow‐up: 6 to 52 months

17 per 1000

15 per 1000
(1 to 224)

RR 0.89 
(0.06 to 13.23)

134 (5)

⊕⊕⊝⊝
Low1

Standard interferon may make little or no difference to death compared to a placebo or control 

Out of 5 studies only 1 reported death. This evidence should be read with caution due to the low certainty of the evidence

In 2 studies data was not available for 18 participants total. Hence, 134/152 were analysed

Relapse
(recurrence after stopping intervention)
Follow‐up: 46 months

1000 per 1000

720 per 1000
(280 to 1000)

RR 0.72 
(0.28 to 1.88)

12 (1)

⊕⊕⊝⊝
Low1,2

Standard interferon may make little or no difference to the number of relapses compared to placebo or control. This evidence should be read with caution due to the low certainty of the evidence

Out of 5 studies only 1 reported relapse. Data was not available in 1 study; 2 studies had no responses in the placebo/control group and could not be analysed, and 1 study did not report follow‐up data

End‐of‐treatment response
Follow‐up: 6 to 12 months

Study population3

RR 8.62 
(3.03 to 24.55)

132 (5)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably leads to more end‐of‐treatment response compared to the placebo or control

Two studies had events in the control group hence second highest and lowest control group risks also expressed to represent varying levels of risk

In 2 studies data was not available for 20 participants

34 per 1000

292 per 1000
(103 to 832)

Moderate3

59 per 1000

507 per 1000
(178 to 1000)

High3

62 per 1000

539 per 1000
(189 to 1000)

Sustained virological response 6 months after stopping treatment
Follow‐up: 6 to 12 months

Study population3

RR 3.25 
(0.81 to 13.07)

98 (4)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably makes little or no difference to sustained virological response compared to placebo or control

This outcome could not be assessed in 1 study as there was no follow‐up data and data was not available for 18 participants in 2 studies

Two studies had events in the control group hence absolute effects for the second highest and lowest control group risks also expressed to represent varying levels of risk

116 per 1000

378 per 1000
(94 to 1000)

Low3

59 per 1000

192 per 1000
(48 to 771)

Treatment discontinuation
Follow‐up: 6 to 12 months

Study population3

RR 4.59 
(0.49 to 42.69)

116 (4)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably makes 

little or no difference in the number of patients discontinuing treatment compared to placebo or control

The control group had events in 1 study hence absolute effects at 2 levels of risk were given to represent varying control group risks

Data was not available for 1 study and for 18 participants in 2 studies

38 per 1000

177 per 1000
(19 to 1000)

High3

222 per 1000

1000 per 1000
(109 to 1000)

Adverse events
Follow‐up: 24 to 52 months

Study population3

RR 3.56 
(0.98 to 13.01)

143 (5)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably makes little or no difference to the number of patients experiencing adverse events compared to placebo or control

The control group had events in 1 study hence absolute effects at 2 levels of risk were given to represent varying control group risks. Data was not available for 9 participants in 1 study

31 per 1000

110 per 1000
(30 to 400)

High3

222 per 1000

790 per 1000
(218 to 1000)

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1  Number of events is low
2  One study
3 Based on the second lowest and highest control group risks; events occurred in the control group in some studies for some outcomes hence absolute effects are presented for varying levels of risk

4 Risk of bias for random sequence generation was unclear, and allocation concealment was unclear to high

Open in table viewer
Summary of findings 2. Pegylated interferon alpha‐2a versus standard interferon for haemodialysis patients with hepatitis C virus infection

PEG interferon alpha‐2a versus standard interferon for HD patients with HCV infection

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention: PEG interferon alpha‐2a 
Comparison: standard interferon alpha‐2a

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with standard interferon

Risk with PEG interferon

Death
Follow‐up: mean 24 weeks

40 per 1000

13 per 1000
(1 to 312)

RR 0.33 
(0.01 to 7.81)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to death compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Relapse
(recurrence after stopping)
Follow‐up: 72 weeks

667 per 1000

480 per 1000
(273 to 833)

RR 0.72 
(0.41 to 1.25)

38 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of relapses compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

End‐of‐treatment response
Follow‐up: 24 weeks

600 per 1000

918 per 1000
(654 to 1000)

RR 1.53 
(1.09 to 2.15)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may lead to more end‐of‐treatment response compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Sustained virological response 6 months after stopping treatment
Follow‐up: 48 weeks

200 per 1000

480 per 1000
(198 to 1000)

RR 2.4 
(0.99 to 5.81)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of patients having sustained virological response compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Treatment discontinuation
Follow‐up: 24 weeks

160 per 1000

18 per 1000
(2 to 314)

RR 0.11 
(0.01 to 1.96)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of patients discontinuing treatment compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Adverse events 
Follow‐up: 24 months

160 per 1000

18 per 1000
(2 to 314)

RR 0.11 
(0.01 to 1.96)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of patients having major adverse events requiring treatment withdrawal compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; PEG: pegylated; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1 Number of events is low

2 One study 

Zero events in the PEG interferon group for death, treatment discontinuation, and number of participants having adverse events

Open in table viewer
Summary of findings 3. High versus low dose pegylated interferon alpha‐2a or alpha‐2b for haemodialysis patients with hepatitis C virus infection

High versus low dose PEG interferon for HD patients with HCV infection
(separate and combined results of two preparations: alpha‐2a and alpha‐2b)

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention 1: high dose PEG interferon alpha‐2a (135 µg/week)
Comparison 1: low dose PEG interferon alpha‐2a (90 µg/week)

Intervention 2: high dose PEG interferon alpha‐2b (1 µg/kg/week)

Comparison 2: low dose PEG interferon alpha‐2b (0.5 µg/kg/week)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with low dose PEG interferon 

Risk with high dose PEG interferon 

Death

PEG interferon alpha‐2a
Follow‐up: 24 week

23 per 10001

132 per 1000
(16 to 1000)

RR 5.66 
(0.69 to 46.31)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to death compared to a low dose of PEG interferon 

PEG interferon alpha‐2b

Follow‐up: 72 weeks

0 per 1000

0 per 1000

(0 to 0)

RR 2.40 (0.11 to 51.32)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

20 per 1000

86 per 1000
(15 to 487)

RR 4.30 (0.76 to 24.33)

97 (2)

⊕⊕⊕⊝
Moderate1,3

Relapse (recurrence after stopping treatment)

PEG interferon alpha‐2a

Follow‐up: 24 weeks

286 per 10001

320 per 1000
(114 to 631)

RR 1.12 
(0.4 to 2.21)

43 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon may make little or no difference to the number of patients having a disease relapse compared to a low dose of PEG interferon. In one study there were no events in the control group and could not be analysed

This should be viewed with caution due to the low certainty of the evidence

PEG interferon alpha‐2b 

Follow‐up: 72 weeks

No data

 ‐‐

 ‐‐

 ‐‐

 ‐‐

PEG interferon (combined)

Follow‐up; 24 to 72 weeks

286 per 1000

320 per 1000
(114 to 631)

RR 1.12 
(0.4 to 2.21)

43 (1)

⊕⊕⊝⊝
Low1,2,3

End‐of‐treatment response

PEG interferon alpha‐2a
Follow‐up: 24 weeks

488 per 10001

581 per 1000
(386 to 869)

RR 1.19 
(0.79 to 1.78)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to end‐of‐treatment virological response compared to a low dose of PEG interferon

PEG interferon (alpha‐2b)

Follow‐up: 72 weeks

0 per 1000

0 per 1000

RR 5.60
(0.34 to 93.35)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

20 per 1000

28 per 1000

(10 to 78)

RR 1.42 (0.51 to 3.90)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Sustained virological response after stopping treatment

PEG interferon alpha‐2a
Follow‐up: 72 weeks

349 per 10001

394 per 1000
(223 to 698)

RR 1.13 
(0.64 to 2)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to sustained virological response compared to a low dose of PEG interferon 

PEG interferon alpha‐2b

Follow‐up: 72 weeks

0 per 1000

0 per 1000

RR 4.00
(0.22 to 72.01)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

300 per 1000

357 per 1000

(204 to 621)

RR 1.19

(0.68 to 2.07)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Treatment discontinuation

PEG interferon alpha‐2a
Follow‐up: 24 weeks

256 per 10001

263 per 1000
(125 to 550)

RR 1.03 
(0.49 to 2.15)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to the number of patients discontinuing treatment compared to a low dose of PEG interferon

PEG interferon alpha‐2b

Follow‐up: 72 weeks

286 per 1000

554 per 1000
(151 to 1000)

RR 1.94
(0.53 to 7.2)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

260 per 1000

3112 per 1000

(164 to 593)

RR 1.20

(0.63 to 2.28)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Adverse events

PEG interferon alpha‐2a
Follow‐up: 24 weeks

860 per 10001

817 per 1000
(671 to 990)

RR 0.95 
(0.78 to 1.15)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to the number of patients with adverse events compared to a low dose of PEG interferon

PEG interferon alpha‐2b

Follow‐up: 72 weeks

286 per 1000

554 per 1000
(151 to 1000)

RR 1.94
(0.53 to 7.20)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up 24 to 72 weeks

780 per 1000

819 per 1000

(476 to 1000)

RR 1.05 (0.61 to 1.83)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Serious adverse events

PEG interferon alpha‐2a
Follow‐up: 24 weeks

326 per 10001

368 per 1000
(202 to 671)

RR 1.13 
(0.62 to 2.06)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to the number of patients with serious adverse events compared to a low dose of PEG interferon

PEG interferon alpha‐2b

Follow‐up: 72 weeks

286 per 1000

554 per 1000
(151 to 1000)

RR 1.94
(0.53 to 7.2)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

320 per 1000

397 per 1000

(230 to 685)

RR 1.24

(0.72 to 2.14)

97 (2)

⊕⊕⊕⊝
Moderate2,3

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; PEG: pegylated; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1 One study

2 Number of events low

3 Risk of bias high for blinding of participants and personnel

Two studies compared different preparations of PEG interferon. Hence, each outcome is presented as three entries with results of each RCT and combined analysis result

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Summary of findings 4. Standard interferon plus ribavirin versus standard interferon alone for haemodialysis patients with hepatitis C virus infection

Standard interferon plus ribavirin versus standard interferon alone for HD patients with HCV infection

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention: standard interferon plus ribavirin
Comparison: standard interferon 

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with standard interferon

Risk with standard interferon plus ribavirin

Death

No data

‐‐

‐‐

‐‐

‐‐

Relapse
(recurrence after stopping)

No data

‐‐

‐‐

‐‐

‐‐

End‐of‐treatment response

No data

‐‐

‐‐

‐‐

‐‐

Sustained virological response

No data

‐‐

‐‐

‐‐

‐‐

Treatment discontinuation
Follow‐up: 16 weeks

163 per 1000
(67 to 402)

484 per 1000

(194 to 1000)

RR 2.97 
(1.19 to 7.36)

52 (1)

⊕⊕⊝⊝
Low1,2

Adverse events

No data

‐‐

‐‐

‐‐

‐‐

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1 One study

2 Risk of bias unclear

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Summary of findings 5. Pegylated interferon plus ribavirin versus pegylated interferon alone for haemodialysis patients with hepatitis C infection

PEG interferon plus ribavirin versus PEG interferon alone for HD patients with HCV infection

Patient or population: HD patients with HCV infection 
Setting: outpatients 
Intervention: PEG interferon alpha‐2a (135 μg/week) plus ribavirin (200 mg/day) for 48 weeks
Comparison: PEG interferon alpha‐2a (135 μg/week) for 48 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with PEG interferon

Risk with PEG interferon plus ribavirin

Death

No data

‐‐

‐‐

‐‐

‐‐

‐‐

Relapse
(recurrence after stopping)

Follow‐up: mean 18 months

463 per 1,000

153 per 1,000
(106 to 222)

RR 0.33
(0.23 to 0.48)

377 (1)

⊕⊕⊝⊝
Low1,2

The number of relapses of HCV infection was low in HD patients on PEG interferon with ribavirin therapy. This evidence was reported for HCV 1 and HCV 2 genotypes at 24 weeks and 48 weeks after intervention respectively. This effect should be read with caution because of the low certainty of the evidence

End‐of‐treatment response
Follow‐up: mean 18 months

867 per 1,000

876 per 1,000
(815 to 945)

RR 1.01
(0.94 to 1.09)

377 (1)

⊕⊕⊝⊝
Low1,2,3

The end‐of‐treatment response was more likely in patients treated with PEG interferon with ribavirin, with some limitations for the certainty of the evidence

Sustained virological response
Follow‐up: mean 18 months

383 per 1,000

689 per 1,000
(559 to 846)

RR 1.80
(1.46 to 2.21)

377 (1)

⊕⊕⊝⊝
Low2

Patients on PEG interferon with ribavirin were more likely to have sustained virologic response after treatment. The evidence reported is for both HCV genotype 1 and HCV genotype 2 with 24 weeks and 48 weeks of treatment, respectively

Treatment discontinuation
Follow‐up: mean 18 months

37 per 1,000

64 per 1,000
(26 to 158)

RR 1.71
(0.69 to 4.24)

377 (1)

⊕⊕⊝⊝
Low1,2,3,4

HD patients with HCV infection on PEG interferon with ribavirin were more likely to discontinue the treatment than patients on PEG interferon monotherapy. However, this evidence should be read with caution, due to the low certainty of the evidence

Adverse events
Follow‐up: mean 18 months

819 per 1,000

901 per 1,000
(827 to 975)

RR 1.10
(1.01 to 1.19)

377 (1)

⊕⊕⊝⊝
Low2

HD patients with HCV on PEG interferon with ribavirin therapy had a slightly higher risk of experiencing adverse events when compared to patients on PEG interferon alone. However, this evidence should be read with caution, due to the low certainty of the evidence

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; PEG: pegylated; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Less number of events

2 Only one study was available for analysis; Luxon 2005 reported pooled outcomes for both groups and could not be meta‐analysed

3 Risk estimate includes the null effect

4 High risk for blinding of participants 

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Summary of findings 6. Direct antivirals (grazoprevir and elbasvir) versus placebo for haemodialysis patients with hepatitis C infection

Direct antivirals (grazoprevir and elbasvir) versus placebo for HD patients with HCV infection

Patient or population: HD patients with HCV infection 
Setting: outpatients, international, multicentre 
Intervention: Direct antivirals (grazoprevir 100 mg/day and elbasvir 50 mg/day) 
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with direct‐acting antivirals

Death

No data

‐‐

‐‐

‐‐

‐‐

Relapse

No data

‐‐

‐‐

‐‐

‐‐

End‐of‐treatment response

Follow‐up: mean 28 weeks

6 per 1,000

1000 per 1,000
(63 to 1000)

RR 174.99
(11.03 to 2775.78)

173 (1)

⊕⊕⊝⊝
Low 1,2

Patients on direct‐acting antivirals were more likely to report an end‐of‐treatment response when compared to patients on placebo Evidence should be considered with caution as the certainty of the evidence is low.

Out of 235 participants, those on dialysis (173) were analysed

Sustained virological response

No data

‐‐

‐‐

‐‐

‐‐

Treatment discontinuation

No data

‐‐

‐‐

‐‐

‐‐

Adverse events

No data

‐‐

‐‐

‐‐

‐‐

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Placebo group also received the treatment after 4 weeks of study. Difficult to determine the directness of evidence for end‐of‐treatment response

2 Number of events low; wide 95% CI

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Summary of findings 7. Pegylated interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus pegylated interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) for haemodialysis patients with hepatitis C infection

PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) for HD patients with HCV infection

Patient or population: HD patients with HCV infection 
Setting: outpatients 
Intervention: PEG interferon + ribavirin (24 weeks) + initial telaprevir (12 weeks)
Comparison: PEG interferon (48 weeks) + initial telaprevir (12 weeks) + initial low dose ribavirin (12 + 36 weeks)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with PEG interferon + teleprevir + initial low dose ribavirin (12 + 48 weeks)

Risk with PEG interferon + telaprevir + ribavirin (36 weeks)

Death

No data

‐‐

‐‐

‐‐

‐‐

Relapse

No data

‐‐

‐‐

‐‐

‐‐

Sustained virological response

706 per 1,000

720 per 1,000
(473 to 1,000)

RR 1.02
(0.67 to 1.56)

35 (1)

⊕⊝⊝⊝
Very low1,2,3

HD patients with HCV in the intervention group were more likely to have sustained virological response when compared to control.

Evidence should be read with caution due to the very low certainty of the evidence

End‐of‐treatment response

706 per 1,000

720 per 1,000
(473 to 1,000)

RR 1.02
(0.67 to 1.56)

35 (1)

⊕⊝⊝⊝
Very low1.2.3

HD patients with HCV in the intervention groups were more likely to report end‐of‐treatment response when compared to the control group. Evidence should be read with caution due to the very low certainty of the evidence

Treatment discontinuation

No data

‐‐

‐‐

‐‐

‐‐

Adverse events

No data

‐‐

‐‐

‐‐

‐‐

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; PEG: pegylated; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Unclear risk of bias for allocation random sequence generation, allocation concealment, blinding of participants and personnel

2 Evidence is reported from a single study for which only an abstract is available

3 Low number of events and low sample size. CI including no effect

Background

Hepatitis C virus (HCV) infection is common in chronic kidney disease (CKD) patients on dialysis, causes chronic liver disease, increases death and impacts kidney transplant outcomes. Direct‐acting antivirals have replaced interferons as the standard of care for HCV treatment due to their higher efficacy and tolerability. We collated evidence for the benefits and harms of interventions for HCV infection in dialysis. This is an update of a review first published in 2015.

Description of the condition

HCV, identified in 1989 (Choo 1989), is a single‐strand RNA virus with a very high replication rate (1010 to 1012 virus/day) (Neumann 1998) and a relatively high mutation rate that impairs an effective immune response (Gomez 1999). HCV is found worldwide and is transmitted primarily through intravenous drug use, contaminated blood products, sexual transmission, perinatal, and needle stick injury (Dienstag 2012aDienstag 2012b). The global prevalence of HCV infection is estimated to be 1%, affecting over 70 million people worldwide and continues to have significant morbidity and death. Genotypes 1 and 3 were the most common cause of infections accounting for 44% and 25%, respectively. The prevalence of infection varies in different regions of the world. The top six countries with the highest burden are China (9.795 million), Pakistan (7.172 million), India (6.245 million), Egypt (5.625 million), Russia (4.748 million) and the USA (2.936 million) (Polaris Observatory HCV Collaborators 2017) because of their higher populations. The 69th World Health Assembly by WHO approved a global strategy of a "90% reduction in new cases, 65% reduction in deaths, and treatment of 80% of eligible chronic HCV patients" (WHO 2016).

Males are more affected than females (2.1:1.1) probably because of behavioural risk factors and hormonal influences (Dienstag 2012aDienstag 2012b). HCV is known to be prevalent (Bergman 2005) ranging from 8% to 20% in CKD patients on dialysis (Fabrizi 2003) with a wide variation of 1.9% in the USA compared to 59% in Egypt (Hassan 2000Rahnavardi 2008). The DOPPS study reported a prevalence of 9.9% in dialysis compared to 3% in the general population with regional variation (Jadoul 2019). Chandra 2004 conducted a study in 256 Indian patients with CKD and with a history of either a kidney transplant or haemodialysis (HD) and found that the prevalence was 46%. The implicated routes of transmission of HCV infection in the dialysis population include blood transfusions, cross‐contamination from supplies and surfaces within the dialysis unit, and direct contact with infected patients (Bravo 2016). Several studies have shown that HCV infection adversely affects survival in patients with CKD stage 5 (Fabrizi 2004). A 2019 meta‐analysis found that in the dialysis population, HCV infection was associated with an adjusted all‐cause death risk of 1.26 (95% CI 1.18 to 1.34), an adjusted risk of liver‐disease associated death of 5.05 (95% CI 2.53 to 10.0), and cardiovascular death risk of 1.18 (95% CI 1.09 to 1.29) (Fabrizi 2019). The DOPPS study also found that HCV‐infected dialysis patients had a higher risk of death, hospitalisation, anaemia‐related complications, and worse quality of life (QoL) scores (Goodkin 2017). 

HCV infection is an independent risk factor for death in dialysis patients and adversely affects patient and graft survival after kidney transplantation (Fabrizi 2014Nakayama 2000Rostami 2011), is associated with the development of new‐onset diabetes mellitus (DM) (Fabrizi 2005), de novo (Cruzado 2001) and recurrent (Hammoud 1996) glomerulonephritis, and post‐transplant lymphoproliferative disorder (Burra 2006). Observational studies have shown that sustained virological response (SVR), defined as the absence of detectable HCV RNA in the blood 12 to 24 weeks after the end of treatment, is associated with improved outcomes. A 2015 meta‐analysis found that the hazard ratio of death in patients achieving SVR was 0.50 (95% confidence interval (CI) 0.37 to 0.67) in the general population, 0.26 (95% CI 0.18 to 0.74) in those with cirrhosis, and 0.21 (95% CI 0.10 to 0.45) in those with HIV co‐infection (Simmons 2015). Large cohort studies have reported a reduction in death in patients being treated with direct‐acting antivirals (Carrat 2019Kalidindi 2020). Other reported benefits associated with achieving SVR based on observational studies include a reduction in the development of liver‐related complications, including hepatocellular carcinoma and liver‐related death (Nahon 2017), insulin resistance (Adinolfi 2018), and DM risk (Arase 2009). Based on this evidence, the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) guidelines recommend treatment with antivirals for all patients with acute or chronic HCV infection, except for those with a short life expectancy that cannot be remedied by HCV therapy, liver transplantation, or another directed therapy (AASLD/IDSA HCV Guidance Panel 2020). However, data that demonstrates that SVR at 12 weeks is associated with a reduction in death in CKD is lacking and those with advanced liver fibrosis or cirrhosis at the time of treatment are at risk of decompensation and hepatocellular carcinoma irrespective of SVR. Based on the evidence extrapolated from the general population and the favourable risk‐benefit profile of newer antivirals, the 2018 KDIGO guidelines recommend that all HCV‐positive CKD patients be evaluated for antiviral treatment. HCV‐infected kidney transplant candidates may be considered for antiviral treatment before or after transplantation. In advanced CKD, interferons are poorly tolerated, and ribavirin is associated with adverse events. Hence, interferon‐free therapy is recommended by KDIGO. Direct‐acting antiviral‐based regimen is preferred with a choice of drugs to be based on HCV genotype (and subtype), viral load, prior treatment, drug–drug interactions, glomerular filtration rate (GFR), degree of hepatic fibrosis, candidacy for a liver transplant, and co‐morbidities (KDIGO 2018).

Description of the intervention

The preferred antiviral therapy for HCV currently is a combination of direct‐acting antivirals. The HCV genome encodes for a polyprotein which requires cleaving by a host or virus‐coded proteases which are nonstructural proteins. Direct‐acting antivirals belong to three classes: NS3/4 protease inhibitors drug name ending with “previr”, NS5B nucleoside and nonnucleoside polymerase inhibitors drug name ending in “buvir” and NS5A inhibitors drug name ending in “asvir” (Dienstag 2022). Grazoprevir, asunaprevir, simeprevir and paritaprevir inhibit NS3/4A, while elbasvir, daclatasvir, ledipasvir, velpatasvir and ombitasvir inhibit NS5A. Sofosbuvir and dasabuvir are NS5B inhibitors (Jakobsen 2017Poordad 2012). The preferred drug combination varies based on the genotype of the HCV virus, CKD stage and availability (KDIGO 2018). Telaprevir, a protease inhibitor, induces and requires CYP3A4 for elimination and cannot be used with other drugs which induce or are eliminated by this enzyme. Certain combinations such as glecaprevir‐pibrentasvir, sofosbuvir‐daclatasvir and sofosbuvir‐velpatasvir are pangenotypic (Zoratti 2020). Grazoprevir‐elbasvir combination is recommended in advanced CKD (Bruchfeld 2017) in HCV genotypes 1 and 4. Both these are metabolised by the enzyme cytochrome P450 subfamily 3A (CYP3A) and concurrent administration of drugs which induce CYP3A such as rifampicin and phenytoin is to be avoided. Grazoprevir is a substrate for organic ion transporter B1 (OATB1) and concurrent administration of drugs which inhibit this protein, such as enalapril, angiotensin receptor blockers, statins and digoxin, are to be avoided. Other drugs recommended are paritaprevir‐ritonavir‐ombitasvir with or without dasabuvir, simeprevir and daclatasvir. Glecaprevir‐pibrentasvir combination can be used for all HCV genotypes (Gane 2017Lawitz 2019) with some reports of sofosbuvir‐ledipasvir or daclatasvir‐simeprevir, especially after kidney transplantation. Sofosbuvir can cause severe bradycardia if given with amiodarone and has drug‐drug interactions with p‐glycoprotein inducers like rifampin and proton‐pump inhibitors and decrease their concentrations. Protease inhibitors have drug‐drug interactions with CYP3A4 inducers. Daclatasvir levels are reduced by CYP3A inducers and inhibitors. Daclatasvir inhibits p‐glycoprotein OATP1B1, OATP1B3, breast cancer resistance protein and levels of drugs which are substrates for these proteins are increased. Elbasvir and grazoprevir can cause elevation of aminotransferases and are both metabolized through CYP3A. They both have multiple drug‐drug interactions and cannot be used with CYP3A inducers and CYP3A, OATP1B1 inhibitors can cause an increase in elbasvir‐grazoprevir concentrations. Glecaprevir‐pibrentasvir is avoided in decompensated cirrhosis (Dienstag 2022). The recommended duration of therapy is usually 12 weeks, and common adverse events include fatigue, malaise, nausea, diarrhoea, vomiting and headache (Hayes 2021). In severe kidney impairment, including those on HD, recommended medications are combinations are elbasvir‐grazoprevir for genotypes 1 and 4, glecaprevir‐pibrentasvir for all genotypes without dose adjustment, and those containing sofosbuvir (Dienstag 2022).

Interferons are proteins produced by nucleated cells available as recombinant standard or pegylated (PEG) forms. Standard interferons alpha‐2a and alpha‐2b are short‐acting, metabolised in the kidney, with doses being 1.5 to 3 million units subcutaneously (SC) 3 times/week for up to one year and no dose adjustment for kidney failure (Wills 1990). PEG interferons alpha‐2a and alpha‐2b are conjugates of interferons with polyethylene glycol, with differing molecular weights, smaller alpha‐2b requires differential dosing 1.0 to 1.5 µg/kg/week, larger alpha‐2a uniform dosing 135 to 180 µg/week both once weekly up to 48 weeks. Pegylation protects from degradation, renal clearance and maintains stable concentrations, but increases toxicity on dialysis (Ayaz 2008Dienstag 2012aDienstag 2012b).

Adverse events of interferons include flu‐like symptoms, marrow suppression, emotional lability, autoimmune reactions, alopecia, rash, diarrhoea, tingling, and numbness of extremities with most being reversible but contraindicated in pregnancy (Dienstag 2012aDienstag 2012bNeumann 1998Vial 1994), increased kidney allograft rejection (Magone 1995), and drug‐drug interactions with telbivudine (Zhang 2008) and theophylline (Williams 1987).

Ribavirin is a nucleoside analogue used with interferons, with a dose of 800 to 1200 mg/day, reduced in kidney failure (Baden 2012Bruchfeld 2001). Adverse events are haemolytic anaemia, teratogenicity, and interactions with abacavir, lamivudine, zidovudine, interferon alpha‐2b (USP 2006), azathioprine (Chaparro 2009), and didanosine (Moreno 2004).

How the intervention might work

Direct‐acting antivirals target specific nonstructural proteins of HCV causing disruption of viral replication and infection. Direct‐acting antivirals are classified by their mechanism of action and therapeutic target into four classes i.e. nonstructural proteins 3/4A (NS3/4A) protease inhibitors which cleave the HCV polyprotein into structural and nonstructural proteins, NS5B nucleoside/non‐nucleoside polymerase inhibitors (NPIs/NNPIs) which inhibit the RNA‐dependent RNA polymerase required in viral RNA synthesis, and NS5A inhibitors which inhibit a membrane‐associated phosphoprotein required for HVC RNA replication (Poordad 2012).

Interferons bind cell receptors, inhibit viral replication and cell proliferation, enhance macrophage phagocytic activity, natural killer cell and leukocyte antibody‐dependant cellular cytotoxicity, and cellular enzymes (Houglum 1983) by stimulation of JAK‐STAT signal transduction of antiviral genes (Dienstag 2012aDienstag 2012b). Ribavirin inhibits host inosine monophosphate dehydrogenase, reduces guanine nucleosides and viral replication, and induces virological mutational catastrophe and interferon‐stimulated gene expression (Dienstag 2012aDienstag 2012bThomas 2011).

Why it is important to do this review

Most studies on interventions in this area are of uncontrolled design, having small numbers of patients. Previous systematic reviews have included both controlled and uncontrolled studies. Previously, in non‐CKD patients, PEG interferon with ribavirin was preferred (Dienstag 2012aDienstag 2012b). Considering the reduced clearance and toxicity of these drugs in CKD on dialysis, and the present preferred use of direct‐acting antivirals due to their reported safety and efficacy (Iliescu 2020), we updated this review to collate evidence for these and other interventions.

Objectives

We aimed to look at the benefits and harms of various interventions for HCV infection in CKD patients on HD or peritoneal dialysis (PD), specifically on death, disease relapse, response to treatment, treatment discontinuation, time to recovery, QoL, cost‐effectiveness, adverse events, and other outcomes. We aimed to study comparisons of available interventions with a placebo or control group, combinations of interventions with a placebo or control group, interventions with each other singly and in combination, and available standard interventions with newer treatment modalities.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at interventions for HCV infection in CKD patients on HD or PD were considered. The first period of randomised cross‐over studies was also considered. There were no language restrictions.

Types of participants

Inclusion criteria

  • Studies on patients with CKD stage 5 as diagnosed by National Kidney Foundation criteria on HD or PD with HCV infection (NKF‐K/DOQI 2002)

  • HCV infection was established based on either a positive anti‐HCV antibody or detectable HCV RNA (i.e. > 50 IU/mL).

Exclusion criteria

  • Studies which included patients with HIV/HBsAg co‐infection

  • Studies which included patients with HCV‐related manifestations (e.g. cryoglobulinaemia, arthritis, thyroid disease) other than liver disease

  • Studies which analysed HCV as non‐A non‐B hepatitis.

Types of interventions

  • No treatment or placebo versus interferon therapy

  • No treatment or placebo versus PEG interferon

  • No treatment or placebo versus ribavirin

  • No treatment or placebo versus interferon plus ribavirin

  • No treatment or placebo versus PEG interferon plus ribavirin

  • Interferon versus PEG interferon therapy

  • Interferon versus ribavirin

  • PEG interferon versus ribavirin

  • Interferon monotherapy versus ribavirin plus PEG interferon

  • PEG interferon monotherapy versus ribavirin plus interferon

  • Interferon versus other newer treatment modalities

  • PEG interferon versus other newer treatment modalities

  • PEG interferon plus ribavirin versus other newer treatment modalities

  • Interferons versus other antivirals

  • Comparison of two antivirals other than interferons

  • Antivirals other than interferons versus placebo to no treatment

Types of outcome measures

Primary outcomes

  • Death at maximum follow‐up of individual studies

  • Relapse of disease: the reappearance of HCV RNA in patients who were HCV RNA negative at the end of treatment.

Secondary outcomes

  • End‐of‐treatment response: HCV RNA undetectable at the end of treatment

  • SVR: HCV RNA undetectable 24 weeks after stopping treatment

  • Time to recovery

  • Treatment discontinuation

  • Number and type of adverse events

  • Cost‐effectiveness

  • QoL issues

  • Other outcomes, e.g. cardiovascular (myocardial infarction).

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies to 22 February 2023 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Searches of kidney and transplant journals and the proceedings and abstracts from major kidney and transplant conferences

  4. Searching the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected kidney and transplant journals

  6. Searches of the International Clinical Trials Register Portal (ICTRP) and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of hand‐searched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website under CKT Register of Studies.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  • Reference lists of clinical practice guidelines, review articles and relevant studies.

  • Information about unpublished data, incomplete studies or availability of other RCTs was sought through electronic mail from the contact authors of RCTs.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies that were relevant to the review. The titles and abstracts were screened independently by three authors, who discarded studies that were not applicable. However, studies and reviews that included relevant data or information on studies were retained initially. Three authors independently assessed and retrieved abstracts and, if necessary the full text of these studies to determine which studies satisfied the inclusion criteria. Disagreements were resolved in consultation with a fourth author. Attempts were made to identify duplicate publications based on author names, study location, setting, date, duration, number of participants, baseline data and details of interventions.

Data extraction and management

Data extraction was carried out independently using standard pre‐structured data extraction forms. Studies reported in a non‐English language were translated before assessment with one study in Spanish requiring translation. Where more than one publication of a study exists, reports were grouped together using clinical trial registry entries and the most recent or most complete data set was used.  Authors independently applied the inclusion criteria, assessed study quality and extracted data. Disagreements were resolved by consensus or with a third author.

The following information was obtained.

  • Publication type and source, including the language of publication, year of publication, way of retrieval of the report

  • Sources of support

  • Study design, including method of generation and concealment of allocation, and type of control intervention

  • Setting including country and level of care

  • Patients: age, sex, CKD status along with hepatitis C infection, co‐morbidities, co‐intervention

  • Intervention, criteria for choosing patients, chronic disease stage, timing of initiation of therapy, kidney transplantation status, number of withdrawals and dropouts/groups, modalities and duration of treatment

  • Outcome measures included death, relapse and recovery as assessed by the end‐of‐treatment response and SVR

  • Analysis, including whether analysis was done according to the intention‐to‐treat principle

  • Results, including averages and variations of individual outcome assessments and different comparisons, test statistics and P values for comparisons within and between groups.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2022) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study?

    • Participants and personnel (performance bias)

    • Outcome assessors (detection bias)

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. death, remission or no remission), results were expressed as risk ratio (RR) with 95% CI. Data were pooled using the random‐effects model. None of the outcomes measured had continuous scales of measurement. Adverse events were tabulated and assessed with descriptive techniques, and the analysis was done for the number of patients having adverse events. Where data were available, serious adverse events were analysed separately.

Unit of analysis issues

The search did not find any cluster RCTs, cross‐over studies or studies with multiple interventions. This review included studies of parallel design comparing two interventions, two doses of the same intervention and an intervention versus a control or placebo group. One RCT crossed over the placebo group to the intervention arm at end of the treatment; hence analysis was only done for the end‐of‐treatment response.

Dealing with missing data

Studies were assessed for data with intention‐to‐treat principle and implication of missing outcome data discussed.

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows.

  • 0% to 40%: might not be important

  • 30% to 60%: may represent moderate heterogeneity

  • 50% to 90%: may represent substantial heterogeneity

  • 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity e.g. P value from the Chi² test or a CI for I² (Higgins 2022).

Assessment of reporting biases

Reporting bias was planned to be assessed using funnel plots with plotting of effect estimates against study size where data permitted. There were insufficient studies to assess reporting biases.

Data synthesis

Data were pooled using the random‐effects model, but the fixed‐effect model was also analysed to ensure the robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was planned for studies comparing different preparations of the same intervention or different doses of medications. Heterogeneity amongst participants could be related to age and kidney pathology, duration of disease, viral load, genotype, population and genetic differences. Heterogeneity in treatments could be related to prior agents used and the agent dose and duration of therapy. Heterogeneity in outcomes could be due to varying follow‐ups. There were too few studies to undertake meaningful subgroup analyses.

Sensitivity analysis

Sensitivity analysis was planned by removing studies available in abstract form only, according to language, risk of bias, studies where smaller doses of the study drug were used, and where the drug was used for a longer duration. There were no large, long or unpublished studies. However, this was not undertaken due to the small number of studies available.

Summary of findings and assessment of the certainty of the evidence

We have presented the main results of the review in Summary of Findings (SOF) tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2022a). The SOF tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2022b). We presented the following outcomes in the SOF tables.

  • Death

  • Relapse of disease

  • End‐of‐treatment response

  • SVR

  • Treatment discontinuation

  • Adverse events/serious adverse events.

Results

Description of studies

Results of the search

In our 2015 review, 322 records were identified. After screening titles and abstracts, 34 reports underwent full‐text review. Ten studies (17 reports) were included, and six studies (eight reports) were excluded. In addition, three studies (nine reports) were completed prior to publication; however, no results were available.

For this 2023 update, we last searched the Cochrane Kidney and Transplant Register of Studies on 22 February 2023 and identified nine reports. One new study (eight reports) was included. One study was recently completed and will be assessed in a future update (Muzammil 2022). We also reassessed and reclassified seven studies. Three studies (nine reports) were moved from awaiting classification to included studies, and four excluded studies were deleted as they were not randomised.

A total of 13 studies were included (34 reports, 997 randomised participants), two studies were excluded, and there is one study awaiting classification (Figure 1).


PRISMA flow diagram including previous review and update

PRISMA flow diagram including previous review and update

Included studies

Thirteen studies (997 randomised participants) met our inclusion criteria (Alfurayh 2000Campistol 1996Campistol 1999aC‐SURFER 2015Fernandez 1997HELPER 2013HELPS 2011Huraib 2001Liu 2008aLuxon 2005Russo 2006TARGET C 2013Tuglular 2001).

See Characteristics of included studies.

Design

Interventions

  • Standard recombinant interferon versus placebo or control: five studies (Alfurayh 2000Campistol 1996Campistol 1999aFernandez 1997Huraib 2001)

  • Standard recombinant interferon versus PEG interferon: one study (Liu 2008a)

    • Standard interferon (SC) was given 3 million units 3 times/week and PEG interferon 135 µg once/week for six months.

  • High versus low dose PEG interferon: two studies (HELPS 2011Russo 2006)

    • The doses used were 135 µg/week (SC) versus 90 µg/week (SC) of alpha‐2a preparation in (HELPS 2011) and 1.0 µg/kg/week versus 0.5 µg/kg/week of alpha‐2b preparation in (Russo 2006), for 48 weeks in both

  • Standard (Tuglular 2001) or PEG interferon (Luxon 2005HELPER 2013) alone or in combination with ribavirin

    • Standard interferon dose was 3 million units, 3 times/week and PEG interferon alpha‐2b 1 µg/kg/week, alpha‐2a 135 µg/week

    • Ribavirin dose was 200 mg/week increasing to 2 or 3 times/week as tolerated in Luxon 2005, 400 mg/day reducing to 200 mg/day as per tolerance in Tuglular 2001 and 200 mg/day in HELPER 2013.

  • Direct‐acting antivirals

    • Grazoprevir 100 mg and elbasvir 50 mg both once/day (C‐SURFER 2015)

    • Telaprevir 4500 mg/day for 3 days, PEG interferon alpha‐2a 135 µg once/week and ribavirin 400 mg (TARGET C 2013) for 24 and 48 weeks.

Outcomes

Excluded studies

Hepatitis C was not specifically mentioned in two studies (reported as non‐A non‐B hepatitis) (Ellis 1993; Simon 1984).

See Characteristics of excluded studies.

Risk of bias in included studies

Overall, there was a low risk of bias in seven studies (Campistol 1999a; C‐SURFER 2015Fernandez 1997; HELPER 2013Liu 2008aHELPS 2011Russo 2006), unclear in four studies (Alfurayh 2000Luxon 2005; TARGET C 2013Tuglular 2001), low to unclear in Huraib 2001, and high in Campistol 1996 

See Figure 2 and Figure 3.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

Random sequence generation

Random sequence generation was judged to be at low risk of bias in five studies (C‐SURFER 2015HELPER 2013HELPS 2011Liu 2008aRusso 2006); randomisation was done by computer‐generated table or permuted block in four studies (HELPER 2013HELPS 2011Liu 2008aRusso 2006), and centralised in three (C‐SURFER 2015HELPS 2011Russo 2006). The remaining eight studies were judged to have an unclear risk of bias (Alfurayh 2000Campistol 1996Campistol 1999aFernandez 1997Huraib 2001Luxon 2005TARGET C 2013Tuglular 2001).

Allocation concealment

Allocation concealment was judged to be at high risk of bias in two studies (Campistol 1996Campistol 1999a), low in four studies (C‐SURFER 2015HELPS 2011HELPER 2013Russo 2006), and unclear in the remaining seven studies (Alfurayh 2000Fernandez 1997Huraib 2001Liu 2008aLuxon 2005TARGET C 2013Tuglular 2001).

Blinding

Performance bias

Five studies were open‐label and were judged to be at high risk of bias (Campistol 1996Campistol 1999aHELPER 2013HELPS 2011Russo 2006). Three studies were judged to be at low risk of bias (C‐SURFER 2015Fernandez 1997Huraib 2001), and the remaining five studies were judged to have an unclear risk of bias (Alfurayh 2000Liu 2008aLuxon 2005TARGET C 2013Tuglular 2001).

Detection bias

Detection bias was judged as low in seven studies as the outcomes assessed were laboratory‐based (i.e. absence or presence of HCV RNA) (Campistol 1996Campistol 1999aFernandez 1997HELPS 2011Huraib 2001Liu 2008aRusso 2006). One study unmasked the placebo group after week 16 (C‐SURFER 2015) which might influence the assessment of outcomes such as treatment discontinuation and some adverse events and was judged to be at high risk of bias. The remaining five studies were judged to have an unclear risk of bias (Alfurayh 2000HELPER 2013Luxon 2005TARGET C 2013Tuglular 2001).

Incomplete outcome data

Two studies were judged to be at high risk of attrition bias (Alfurayh 2000Huraib 2001). Nine studies reported intention‐to‐treat analysis and were judged to be at low risk of attrition bias (Campistol 1996Campistol 1999aC‐SURFER 2015Fernandez 1997HELPER 2013HELPS 2011Liu 2008aRusso 2006TARGET C 2013). The remaining two studies were judged to have an unclear risk of attrition bias (Luxon 2005Tuglular 2001)

Selective reporting

Four studies were available only as conference abstracts (Alfurayh 2000Campistol 1996Luxon 2005Tuglular 2001) and were judged to be at high risk of reporting bias because the number of participants mentioned differed for each outcome (Alfurayh 2000); the follow‐up was only six months (Campistol 1996); there was no follow‐up (Tuglular 2001); or there was pooled reporting of results (Luxon 2005). The remaining nine studies were judged to be at low risk of bias (Campistol 1999aC‐SURFER 2015Fernandez 1997HELPER 2013HELPS 2011Huraib 2001Liu 2008aRusso 2006TARGET C 2013).

Other potential sources of bias

The potential for other biases was low in five studies (Campistol 1999aC‐SURFER 2015Fernandez 1997HELPER 2013Liu 2008a) and high in two (HELPS 2011 Russo 2006). HELPS 2011 and Russo 2006 were industry‐funded, and Russo 2006 was terminated early. The remaining six studies were judged to have an unclear risk of bias (Alfurayh 2000Campistol 1996Huraib 2001Luxon 2005TARGET C 2013Tuglular 2001).

Effects of interventions

See: Summary of findings 1 Standard interferon versus placebo or control for haemodialysis patients with hepatitis C virus infection; Summary of findings 2 Pegylated interferon alpha‐2a versus standard interferon for haemodialysis patients with hepatitis C virus infection; Summary of findings 3 High versus low dose pegylated interferon alpha‐2a or alpha‐2b for haemodialysis patients with hepatitis C virus infection; Summary of findings 4 Standard interferon plus ribavirin versus standard interferon alone for haemodialysis patients with hepatitis C virus infection; Summary of findings 5 Pegylated interferon plus ribavirin versus pegylated interferon alone for haemodialysis patients with hepatitis C infection; Summary of findings 6 Direct antivirals (grazoprevir and elbasvir) versus placebo for haemodialysis patients with hepatitis C infection; Summary of findings 7 Pegylated interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus pegylated interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) for haemodialysis patients with hepatitis C infection

Standard interferon versus placebo or control

See summary of findings Table 1

Five studies compared standard recombinant interferon with placebo or control (Alfurayh 2000Campistol 1996Campistol 1999aFernandez 1997Huraib 2001). Duration of treatment ranged from six months (Campistol 1999aFernandez 1997) to one year (Alfurayh 2000Huraib 2001), while Campistol 1996 did not report the duration of treatment. Follow‐up after treatment ranged from zero to 46 months. The dose of interferon used was 1.5 million units, 3 times/week (Fernandez 1997) and 3 million units, 3 times/week (Alfurayh 2000Campistol 1996Campistol 1999aHuraib 2001). Post‐kidney transplant follow‐up was reported in three studies (Alfurayh 2000Campistol 1999aHuraib 2001) with Huraib 2001 analysing only transplanted patients out of the total number randomised. Data on relapses was complete in Campistol 1999a.

Death

Standard interferon may make little or no difference to death compared to placebo or control (Analysis 1.1 (5 studies, 134 participants): RR 0.89, 95% CI 0.06 to 13.23; low certainty evidence). Only Campistol 1999a reported one death in each group over 6 to 52 months of follow‐up.

Relapse

Campistol 1999a reported six relapses in the 11 patients who initially responded to treatment (Analysis 1.2) up to 46 months after treatment. One patient in the control group 'responded' but relapsed by 46 months.  Two out of four responders (Fernandez 1997) and none out of four responders (Huraib 2001) in the standard interferon group relapsed. These studies could not be analysed due to the absence of response in the placebo or control groups. In one study there was no follow‐up after treatment (Campistol 1996), and data was not available in Alfurayh 2000.

End‐of‐treatment response

Standard interferon probably improves the end‐of‐treatment response compared to placebo or control (Analysis 1.3 (5 studies, 132 participants): RR 8.62, 95% CI 3.03 to 24.55; I² = 0%; moderate certainty evidence).

Sustained virological response

Standard interferon probably makes little or no difference to SVR compared to placebo or control (Analysis 1.4 (4 studies, 98 participants): RR 3.25, 95% CI 0.81 to 13.07; I² = 53%; moderate certainty evidence). There was no follow‐up data available in Campistol 1996.

Treatment discontinuation

Standard interferon probably makes little or no difference to the number of patients discontinuing treatment compared to placebo or control (Analysis 1.5 (4 studies, 116 participants): RR 4.59, 95% CI 0.49 to 42.69; I² = 63%; moderate certainty evidence).

Adverse events

Standard interferon probably makes little or no difference to the number of patients experiencing adverse events compared to placebo or control (Analysis 1.6 (5 studies, 143 participants): RR 3.56, 95% CI 0.98 to 13.01; I² = 25%; moderate certainty evidence). Adverse events are reported in Appendix 3.

Other outcomes

There were no data reported for time to recovery, QoL, cost‐effectiveness and outcomes such as myocardial infarction.

Pegylated interferon versus standard interferon

See summary of findings Table 2

Liu 2008a compared PEG interferon alpha‐2a and standard interferon alpha‐2a. The duration of treatment was 24 weeks with a follow‐up of 24 weeks after treatment. The dose of PEG interferon alpha‐2a was 135 µg once/week and for standard interferon 3 million units, 3 times/week with the doses reduced to 90 µg or 1.5 million units, respectively, or stopped in the event of adverse events. Dose modification was required in 3/25 in the PEG interferon group and in 5/25 in the standard interferon group. HCV genotype was tested but not stratified due to small numbers. Analysis was as per the intention‐to‐treat principle.

Death

Liu 2008a reported PEG interferon may make little or no difference to death compared to standard interferon (Analysis 2.1 (1 study, 50 participants): RR 0.33, 95% CI 0.01 to 7.81; low certainty evidence).

Relapse

Liu 2008a reported PEG interferon may make little or no difference to the number of relapses compared to standard interferon (Analysis 2.2 (1 study, 50 participants, 38 having relapse): RR 0.72, 95% CI 0.41 to 1.25; low certainty evidence).

End‐of‐treatment response

Liu 2008a reported PEG interferon may lead to more end‐of‐treatment response compared to standard interferon (Analysis 2.3 (1 study, 50 participants): RR 1.53, 95% CI 1.09 to 2.15; low certainty evidence).

Sustained virological response

Liu 2008a reported that PEG interferon may make little or no difference to the number of patients having SVR compared to standard interferon (Analysis 2.4 (1 study, 50 participants): RR 2.40, 95% CI 0.99 to 5.81; low certainty evidence).

Treatment discontinuation

Liu 2008a reported that PEG interferon may make little or no difference to the number of patients discontinuing treatment compared to standard interferon (Analysis 2.5 (1 study, 50 participants): RR 0.11, 95% CI 0.01 to 1.96; low certainty evidence).

Adverse events

Liu 2008a reported PEG interferon may make little or no difference to the number of patients having major adverse events requiring treatment withdrawal compared to standard interferon (Analysis 2.6 (1 study, 50 participants): RR 0.11, 95% CI 0.01 to 1.96; low certainty evidence). Refer to Appendix 3 for the description of adverse events.

Other outcomes

There were no data on time to recovery, QoL, cost‐effectiveness, and outcomes such as myocardial infarction.

Pegylated interferon: high versus low dose

See summary of findings Table 3

Two studies (HELPS 2011Russo 2006) compared two doses of PEG interferon. Subgroup analysis was done as two different PEG interferon preparations were used. The duration of treatment was 48 weeks with a follow‐up of 24 weeks after treatment. Doses were 135 µg/week and 90 µg/week of PEG interferon alpha‐2a in HELPS 2011 and 1 µg/kg/week and 0.5 µg/kg/week of PEG interferon alpha‐2b in Russo 2006. Doses were reduced or stopped in the event of adverse events. Stratification by country and HCV genotype were done in HELPS 2011. After randomisation, four patients in HELPS 2011 and five in Russo 2006 were not analysed as they did not receive any dose of the study medication. Russo 2006 was designed to enrol 50 participants but terminated after recruiting 16 due to adverse events and modifications in the study design. Both were industry‐funded.

Death

High‐dose PEG interferon probably makes little or no difference to death compared to low dose (Analysis 3.1 (2 studies, 97 participants): RR 4.30, 95% CI 0.76 to 24.33; I² = 0%; moderate certainty evidence).

Relapse

HELPS 2011 reported high‐dose PEG interferon may make little or no difference to the number of patients relapsing compared to the low‐dose group (Analysis 3.2 (1 study, 81 participants, 43 having relapse): RR 1.11, 95% CI 0.45 to 2.77; low certainty evidence).

Russo 2006 reported one relapse amongst three responders in the high‐dose group, but data could not be analysed as there were no responders in the low‐dose group.

End‐of‐treatment response

High‐dose PEG interferon probably makes little or no difference to end‐of‐treatment virological response compared to the low‐dose group (Analysis 3.3 (2 studies, 97 participants): RR 1.42, 95% CI 0.51 to 3.90; I² = 20%; moderate certainty evidence).

Sustained virological response

High‐dose PEG interferon probably makes little or no difference to SVR compared to the low‐dose group (Analysis 3.4 (2 studies, 97 participants): RR 1.19, 95% CI 0.68 to 2.07; I² = 0%; moderate certainty evidence).

Treatment discontinuation

High‐dose PEG interferon probably makes little or no difference to the number of patients discontinuing treatment compared to the low‐dose group (Analysis 3.5 (2 studies, 97 participants): RR 1.20, 95% CI 0.63 to 2.28; I² = 0%; moderate certainty evidence).

Adverse events

High‐dose PEG interferon probably makes little or no difference to the number of patients with adverse events compared to the low‐dose group (Analysis 3.6 (2 studies, 97 participants): RR 1.05, 95% CI 0.61 to 1.83; I² = 27%; moderate certainty evidence).

High‐dose PEG interferon probably makes little or no difference to the number of patients with serious adverse events compared to the low‐dose group (Analysis 3.7 (2 studies, 97 participants): RR 1.24, 95% CI 0.72 to 2.14; I² = 0%; moderate certainty evidence). Refer to Appendix 3 for details of adverse events.

Other outcomes

There were no data on time to recovery, QoL, cost‐effectiveness, and outcomes such as myocardial infarction.

Standard or pegylated interferon alone or in combination with ribavirin

See summary of findings Table 4summary of findings Table 5

Three studies compared interferons in combination with ribavirin against interferon alone. Tuglular 2001 compared standard interferon dose (3 million units, 3 times/week) combined with ribavirin (400 mg/day, reducing to 200 mg/day if side effects present) against standard interferon alone. Luxon 2005 compared PEG interferon alfa‐2b (1 µg/kg/week) combined with ribavirin (200 mg/week increased to two or three times/week if tolerated) against PEG interferon alone. Luxon 2005 reported results together for both groups in a pooled manner with 7/10 patients discontinuing treatment due to side effects and no virological response in three at the end of treatment. HELPER 2013 compared PEG interferon alfa‐2a (35 µg/week) combined with ribavirin (200 mg/day) for 24 to 48 weeks (genotype 1: 48 weeks; genotype 2: 24 weeks) against PEG interferon alone.

Tuglular 2001 reported a combination of standard interferon with ribavirin may lead to higher treatment discontinuation compared to standard interferon alone (Analysis 4.1 (1 study, 52 participants): RR 2.97, 95% CI 1.19 to 7.36; low certainty evidence). Data for other outcomes were not reported. Refer to Appendix 3 for details of adverse events.

In low certainty evidence, HELPER 2013 reported combination therapy may improve SVR (Analysis 5.1 (1 study, 377 participants): RR 1.80, 95% CI 1.46 to 2.21), may increase the number of patients with adverse events (Analysis 5.5 (1 study, 377 participants): RR 1.10, 95% CI 1.01 to 1.19), may make little or no difference to the end‐of‐treatment response (Analysis 5.2 (1 study, 377 participants): RR 1.01, 95% CI 0.94 to 1.09) and treatment discontinuation (Analysis 5.4 (1 study, 377 participants): RR 1.71, 95% CI 0.69 to 4.24), and may reduce the number of relapses (Analysis 5.3 (1 study, 377 participants): RR 0.33, 95% CI 0.23 to 0.48) compared to PEG interferon alone.

Data on death and other outcomes were not reported.

Direct‐acting antivirals

Grazoprevir and elbasvir versus placebo

See summary of findings Table 6

C‐SURFER 2015 compared a combination of grazoprevir (100 mg) and elbasvir (50 mg) once/day for 12 weeks with placebo. The end‐of‐treatment response was higher for grazoprevir plus elbasvir compared to placebo (Analysis 6.1 (1 study 235 participants): RR 174.99, 95% CI 11.03 to 2775.78; low certainty of evidence).

Other outcomes could not be assessed for participants on dialysis as the placebo group was crossed over to the intervention arm four weeks after the end of treatment and there were no responses in dialysis patients on placebo.

Direct‐acting antivirals in combination with pegylated interferon and ribavirin (different doses and duration)

See summary of findings Table 7

TARGET C 2013 compared a combination of telaprevir, PEG interferon and different initial doses of ribavirin for differing durations. It is uncertain whether a combination of telaprevir, a higher initial dose of ribavirin and PEG interferon for 24 weeks leads to an end‐of‐treatment response (Analysis 7.1 (1 study, 35 participants): RR 1.02, 95% CI 0.67 to 1.56; very low certainty evidence) or improved SVR (Analysis 7.2 (1 study, 35 participants): RR 1.02, 95% CI 0.67 to 1.56; very low certainty evidence) compared to telaprevir, a lower initial dose of ribavirin and PEG interferon for 48 weeks.

Data for other outcomes were not reported.

Discussion

Summary of main results

In this update, three new studies met our inclusion criteria (C‐SURFER 2015HELPER 2013TARGET C 2013), bringing the total number of included studies to 13 (997 randomised participants).

Five studies (152 participants) with low to moderate certainty of evidence and overall unclear to low risk of bias compared standard interferon with placebo or control. Standard interferon was relatively more effective than placebo or control in producing an end‐of‐treatment response and was well tolerated, but was not more effective in producing a SVR (summary of findings Table 1).

One study (50 participants) with low certainty of evidence and overall low risk of bias compared standard interferon and PEG interferon. PEG interferon was reported to be better in producing an end‐of‐treatment response but not a better SVR than standard interferon, and both were equally tolerated (summary of findings Table 2).

Two studies (97 participants) with low to moderate certainty of evidence and overall low risk of bias compared two doses of PEG interferon in two different preparations. Increasing doses of PEG interferon improved end‐of‐treatment response but not a better SVR. Higher doses were equally tolerated. The addition of ribavirin to standard interferon resulted in more treatment discontinuation in one small study (summary of findings Table 3summary of findings Table 4).

One study (377 participants) with low certainty of evidence and low risk of bias showed that the combination of PEG interferon and ribavirin had higher SVR and fewer relapses, but a higher number of adverse events (summary of findings Table 5).

Compared to placebo, the combination of direct‐acting antivirals (grazoprevir and elbasvir) produced a higher end‐of‐treatment response in one study (235 participants, 179 on dialysis, 173 analysed) with low certainty evidence and low risk of bias (summary of findings Table 6).

Compared to a combination of telaprevir for 12 weeks with PEG interferon and ribavirin for 24 weeks it is unclear whether a combination of telaprevir for 12 weeks, PEG interferon 48 weeks and initial low dose ribavirin for 12 weeks followed by 36 weeks of regular dose produced a SVR in one study (35 participants) with very low certainty evidence and unclear risk of bias (summary of findings Table 7).

Overall completeness and applicability of evidence

The studies included in this review investigated different interventions for HCV infection in CKD patients on dialysis. Direct‐acting antivirals have now replaced interferons in the treatment of HCV in view of better tolerability and near‐universal efficacy, which also may be the reason for their use without RCT evidence. The review highlights the small number of RCTs available and the small number of participants in most. The included studies addressed outcomes such as death, relapse of disease, end‐of‐treatment response, SVR, treatment discontinuation and adverse events. The primary outcome measure in the included studies was SVR. However, the utility of SVR as a valid surrogate for long‐term outcomes including death is not confirmed by RCT evidence. In this review, most included studies had a short follow‐up duration, while some did not report death data resulting in a lack of high‐certainty evidence in this area. Health‐related QoL was reported in C‐SURFER 2015 but not separately for those on dialysis.

This update identified one study HELPER 2013 using PEG interferon with or without ribavirin which had no data on death or cost‐effectiveness. Two studies tested direct‐acting antivirals against a placebo or in combination with interferons. One was available only as five conference abstracts (TARGET C 2013), and another placebo‐controlled RCT (C‐SURFER 2015) included CKD stages 4 and 5 reported data on SVR, relapse, treatment discontinuation and adverse events; analysis could only be done for the end‐of‐treatment response for participants on dialysis. No studies comparing different combinations of direct‐acting antivirals or direct‐acting antivirals compared to interferon‐based regimens were found. However, recent guidelines have recommended interferon‐free therapy for those with CKD on dialysis.

For standard interferon versus placebo or control, data were not available for relapses in two studies (Alfurayh 2000Campistol 1996), SVR in one study (Campistol 1996), and treatment discontinuation in one study (Alfurayh 2000). 

No data were available in any of the included studies for cost‐effectiveness, QoL and outcomes such as myocardial infarction. There were no studies comparing different durations of therapy or PEG interferon versus placebo or control. Most of the studies had considerable exclusion criteria in view of the known adverse events of the earlier used interventions namely interferons limiting their use to a select group amongst CKD patients. Hence, the evidence may only be valid for a group of patients who fit the inclusion and exclusion criteria of these studies. The previous practice of preferring PEG interferon over standard interferon may not be valid, and the addition of ribavirin along with standard interferon may result in more treatment discontinuation in this population.

Quality of the evidence

Figure 2 and Figure 3 summarise the quality of evidence. Studies comparing standard interferon with placebo or control were of low to moderate certainty evidence and had unclear to low risk of bias. Due to the small number of participants in the studies, data on relapses could only be analysed in Campistol 1999a. Follow‐up after treatment was not available in Campistol 1996 which prevented assessment of SVR. Only Liu 2008a compared PEG interferon with standard interferon, and this had moderate certainty evidence and a low risk of bias. Two studies (HELPS 2011Russo 2006) compared two doses of PEG interferon both with moderate certainty evidence and an overall low risk of bias. Two studies (Luxon 2005Tuglular 2001) with low certainty evidence comparing standard or PEG interferon alone or in combination with ribavirin did not have follow‐up data. Considering the small number of studies and the small number of participants, findings should be viewed with caution.

Studies comparing combination PEG interferon with or without ribavirin and direct‐acting antivirals with placebo had low to very low certainty evidence and a low risk of bias. C‐SURFER 2015 included CKD stages 4 and 5. TARGET C 2013 assessed the combination of PEG interferon, ribavirin and telaprevir and had very low certainty evidence and unclear risk of bias.

Potential biases in the review process

Strengths

This review was conducted as per protocol following pre‐specified inclusion criteria and included comprehensive literature searches to find all relevant studies. Three authors screened all titles, abstracts and full papers to avoid selection bias.

Limitations

Four studies were available only as abstracts (Alfurayh 2000Campistol 1996Luxon 2005Tuglular 2001), one of which reported outcomes in a pooled manner (Tuglular 2001). Older studies which considered HCV as non‐A non‐B hepatitis were excluded. This may lead to a loss of data and influence the results as the number of studies and participants is small. The review included only RCTs which may result in loss of data on rare events. Stratification according to known predictors of treatment response such as HCV genotype, HCV viral load, age, race, genetic polymorphisms, co‐infection, body mass index, and alcohol intake was not done due to lack of data or a small number of participants. The review limited itself to dialysis patients, and kidney transplant outcomes were not assessed.

Due to direct‐acting antivirals having efficacy in nearly all studies and treatment durations of three months, present outcome definitions do not consider the end‐of‐treatment response, and SVR is assessed at 12 weeks. Our review included both interferon and direct antiviral agent studies and definitions as per protocol were used. 

The update identified one study which was available as an abstract, one which included CKD 4 and 5, and which assessed SVR at 12 weeks instead of 24 weeks.

Agreements and disagreements with other studies or reviews

We found eight published reviews of interventions for HCV in dialysis patients five with interferon therapy and three with direct‐acting antivirals. All included both uncontrolled and controlled studies and presented results of pooled data.

  • Alavian 2010 assessed factors associated with SVR to standard interferon and PEG interferon in patients on HD with HCV infection. Twenty‐one studies using standard interferons (491 patients) found an SVR of 39.1% (95% CI 32.1 to 46.1) and 12 studies on PEG interferons (279 patients) found an SVR of 39.3% (95% CI 26.5 to 2.1) and treatment discontinuation in 22.6% (95% CI 10.4 to 34.8) and 29.7% (95% CI 21.7 to 37.7), respectively. Two RCTs were included in this meta‐analysis. In agreement with the present review, no additional benefit was found for PEG interferon.

  • Fabrizi 2003 considered monotherapy with interferon and included 14 clinical trials (269 participants) of which two were RCTs. The mean overall estimate for SVR and the drop‐out rate was 37% (95% CI 28% to 48%) and 17% (95% CI 10% to 28%), respectively, with heterogeneity with regard to both outcomes. They concluded that tolerance to interferon monotherapy was lower in dialysis and this may be due to no comparative analysis being provided with a placebo/control group.

  • Fabrizi 2008a included 13 studies with 539 unique patients, 10 of which concerned patients on maintenance dialysis, three being RCTs. SVR was significantly more in patients receiving antiviral therapy with a pooled odds ratio (OR) of failure to obtain an SVR being 0.08 (95% CI 0.03 to 0.23) including in the subgroup of studies with interferon monotherapy. The pooled OR of drop‐out rate was significantly increased in the study versus control patients (OR 0.39, 95% CI 0.16 to 0.96) but not significant in the subgroup of six studies considering interferon monotherapy. The studies were heterogeneous with regard to viral response and drop‐out rate. As compared to the present review response to treatment was better. This may reflect a publication bias as the review did not include RCTs published as abstracts and included uncontrolled studies.

  • Fabrizi 2008b included 28 studies (645 unique patients) of which three were RCTs including monotherapy with either standard or PEG interferon. For standard interferon, SVR was seen in 39% (95% CI 32% to 46%) and treatment discontinuation in 19% (95% CI 13% to 26%). For PEG interferon, SVR was seen in 31% (95% CI 7% to 55%) and treatment discontinuation in 27% (95% CI 1% to 52%). In agreement with the present review monotherapy with PEG interferon was not of additional benefit.

  • Russo 2003 included 11 studies (213 participants) two being RCTs for standard interferon monotherapy. Of the eight studies using 3 million units, 3 times/week dose, the pooled SVR was 33% (95 CI 21% to 51%) with a 29.6% treatment discontinuation rate. They concluded that response to standard interferon was more than in the normal population with more adverse events, but no comparative analysis was provided.

  • Li 2017 included 11 studies (264 participants) with one RCT. Sofosbuvir regimens were compared to other direct‐acting antivirals assessing SVR 12 weeks after treatment, adverse and serious adverse events in CKD stages 4 and 5. They found a pooled SVR12 of 93.2%, serious adverse events of 12.1% and treatment discontinuation of 2.2%.

  • Shehadeh 2020 included 20 studies (514 participants) with no RCTs and concluded that sofosbuvir regimens in HD patients with HCV produced an SVR in 95% (73 to 100%) with adverse events of fatigue, anaemia, nausea vomiting in 16%, 15% and 14%, respectively.

  • Majd Jabbari 2021 reviewed sofosbuvir regimens in advanced CKD and found 27 studies (1464 participants). The types of studies were not mentioned, and they found an SVR at 24 weeks after treatment of 95% (89% to 99%) and a serious adverse event incidence of 0.11.

PRISMA flow diagram including previous review and update

Figuras y tablas -
Figure 1

PRISMA flow diagram including previous review and update

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figuras y tablas -
Figure 2

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

Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Comparison 1: Standard interferon versus placebo or control, Outcome 1: Death

Figuras y tablas -
Analysis 1.1

Comparison 1: Standard interferon versus placebo or control, Outcome 1: Death

Comparison 1: Standard interferon versus placebo or control, Outcome 2: Relapse

Figuras y tablas -
Analysis 1.2

Comparison 1: Standard interferon versus placebo or control, Outcome 2: Relapse

Comparison 1: Standard interferon versus placebo or control, Outcome 3: End‐of‐treatment response

Figuras y tablas -
Analysis 1.3

Comparison 1: Standard interferon versus placebo or control, Outcome 3: End‐of‐treatment response

Comparison 1: Standard interferon versus placebo or control, Outcome 4: Sustained virological response

Figuras y tablas -
Analysis 1.4

Comparison 1: Standard interferon versus placebo or control, Outcome 4: Sustained virological response

Comparison 1: Standard interferon versus placebo or control, Outcome 5: Treatment discontinuation

Figuras y tablas -
Analysis 1.5

Comparison 1: Standard interferon versus placebo or control, Outcome 5: Treatment discontinuation

Comparison 1: Standard interferon versus placebo or control, Outcome 6: Adverse events

Figuras y tablas -
Analysis 1.6

Comparison 1: Standard interferon versus placebo or control, Outcome 6: Adverse events

Comparison 2: PEG interferon versus standard interferon, Outcome 1: Death

Figuras y tablas -
Analysis 2.1

Comparison 2: PEG interferon versus standard interferon, Outcome 1: Death

Comparison 2: PEG interferon versus standard interferon, Outcome 2: Relapse

Figuras y tablas -
Analysis 2.2

Comparison 2: PEG interferon versus standard interferon, Outcome 2: Relapse

Comparison 2: PEG interferon versus standard interferon, Outcome 3: End‐of‐treatment response

Figuras y tablas -
Analysis 2.3

Comparison 2: PEG interferon versus standard interferon, Outcome 3: End‐of‐treatment response

Comparison 2: PEG interferon versus standard interferon, Outcome 4: Sustained virological response

Figuras y tablas -
Analysis 2.4

Comparison 2: PEG interferon versus standard interferon, Outcome 4: Sustained virological response

Comparison 2: PEG interferon versus standard interferon, Outcome 5: Treatment discontinuation

Figuras y tablas -
Analysis 2.5

Comparison 2: PEG interferon versus standard interferon, Outcome 5: Treatment discontinuation

Comparison 2: PEG interferon versus standard interferon, Outcome 6: Serious adverse events

Figuras y tablas -
Analysis 2.6

Comparison 2: PEG interferon versus standard interferon, Outcome 6: Serious adverse events

Comparison 3: PEG interferon: high versus low dose, Outcome 1: Death

Figuras y tablas -
Analysis 3.1

Comparison 3: PEG interferon: high versus low dose, Outcome 1: Death

Comparison 3: PEG interferon: high versus low dose, Outcome 2: Relapse

Figuras y tablas -
Analysis 3.2

Comparison 3: PEG interferon: high versus low dose, Outcome 2: Relapse

Comparison 3: PEG interferon: high versus low dose, Outcome 3: End‐of‐treatment response

Figuras y tablas -
Analysis 3.3

Comparison 3: PEG interferon: high versus low dose, Outcome 3: End‐of‐treatment response

Comparison 3: PEG interferon: high versus low dose, Outcome 4: Sustained virological response

Figuras y tablas -
Analysis 3.4

Comparison 3: PEG interferon: high versus low dose, Outcome 4: Sustained virological response

Comparison 3: PEG interferon: high versus low dose, Outcome 5: Treatment discontinuation

Figuras y tablas -
Analysis 3.5

Comparison 3: PEG interferon: high versus low dose, Outcome 5: Treatment discontinuation

Comparison 3: PEG interferon: high versus low dose, Outcome 6: Adverse events

Figuras y tablas -
Analysis 3.6

Comparison 3: PEG interferon: high versus low dose, Outcome 6: Adverse events

Comparison 3: PEG interferon: high versus low dose, Outcome 7: Serious adverse events

Figuras y tablas -
Analysis 3.7

Comparison 3: PEG interferon: high versus low dose, Outcome 7: Serious adverse events

Comparison 4: Standard interferon + ribavirin versus standard interferon, Outcome 1: Treatment discontinuation

Figuras y tablas -
Analysis 4.1

Comparison 4: Standard interferon + ribavirin versus standard interferon, Outcome 1: Treatment discontinuation

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 1: Sustained virological response

Figuras y tablas -
Analysis 5.1

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 1: Sustained virological response

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 2: End‐of‐treatment response

Figuras y tablas -
Analysis 5.2

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 2: End‐of‐treatment response

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 3: Relapse

Figuras y tablas -
Analysis 5.3

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 3: Relapse

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 4: Treatment discontinuation

Figuras y tablas -
Analysis 5.4

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 4: Treatment discontinuation

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 5: Adverse events

Figuras y tablas -
Analysis 5.5

Comparison 5: PEG interferon + ribavirin versus PEG interferon, Outcome 5: Adverse events

Comparison 6: Direct‐acting antivirals (grazoprevir, elbasvir) versus placebo, Outcome 1: End‐of‐treatment response

Figuras y tablas -
Analysis 6.1

Comparison 6: Direct‐acting antivirals (grazoprevir, elbasvir) versus placebo, Outcome 1: End‐of‐treatment response

Comparison 7: PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) , Outcome 1: End‐of‐treatment response

Figuras y tablas -
Analysis 7.1

Comparison 7: PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) , Outcome 1: End‐of‐treatment response

Comparison 7: PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) , Outcome 2: Sustained virological response

Figuras y tablas -
Analysis 7.2

Comparison 7: PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) , Outcome 2: Sustained virological response

Summary of findings 1. Standard interferon versus placebo or control for haemodialysis patients with hepatitis C virus infection

Standard interferon versus placebo or control for HD patients with HCV infection

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention: standard interferon
Comparison: placebo or control

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of evidence
(GRADE)

Comments

Risk with placebo or control

Risk with standard interferon

Death
Follow‐up: 6 to 52 months

17 per 1000

15 per 1000
(1 to 224)

RR 0.89 
(0.06 to 13.23)

134 (5)

⊕⊕⊝⊝
Low1

Standard interferon may make little or no difference to death compared to a placebo or control 

Out of 5 studies only 1 reported death. This evidence should be read with caution due to the low certainty of the evidence

In 2 studies data was not available for 18 participants total. Hence, 134/152 were analysed

Relapse
(recurrence after stopping intervention)
Follow‐up: 46 months

1000 per 1000

720 per 1000
(280 to 1000)

RR 0.72 
(0.28 to 1.88)

12 (1)

⊕⊕⊝⊝
Low1,2

Standard interferon may make little or no difference to the number of relapses compared to placebo or control. This evidence should be read with caution due to the low certainty of the evidence

Out of 5 studies only 1 reported relapse. Data was not available in 1 study; 2 studies had no responses in the placebo/control group and could not be analysed, and 1 study did not report follow‐up data

End‐of‐treatment response
Follow‐up: 6 to 12 months

Study population3

RR 8.62 
(3.03 to 24.55)

132 (5)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably leads to more end‐of‐treatment response compared to the placebo or control

Two studies had events in the control group hence second highest and lowest control group risks also expressed to represent varying levels of risk

In 2 studies data was not available for 20 participants

34 per 1000

292 per 1000
(103 to 832)

Moderate3

59 per 1000

507 per 1000
(178 to 1000)

High3

62 per 1000

539 per 1000
(189 to 1000)

Sustained virological response 6 months after stopping treatment
Follow‐up: 6 to 12 months

Study population3

RR 3.25 
(0.81 to 13.07)

98 (4)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably makes little or no difference to sustained virological response compared to placebo or control

This outcome could not be assessed in 1 study as there was no follow‐up data and data was not available for 18 participants in 2 studies

Two studies had events in the control group hence absolute effects for the second highest and lowest control group risks also expressed to represent varying levels of risk

116 per 1000

378 per 1000
(94 to 1000)

Low3

59 per 1000

192 per 1000
(48 to 771)

Treatment discontinuation
Follow‐up: 6 to 12 months

Study population3

RR 4.59 
(0.49 to 42.69)

116 (4)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably makes 

little or no difference in the number of patients discontinuing treatment compared to placebo or control

The control group had events in 1 study hence absolute effects at 2 levels of risk were given to represent varying control group risks

Data was not available for 1 study and for 18 participants in 2 studies

38 per 1000

177 per 1000
(19 to 1000)

High3

222 per 1000

1000 per 1000
(109 to 1000)

Adverse events
Follow‐up: 24 to 52 months

Study population3

RR 3.56 
(0.98 to 13.01)

143 (5)

⊕⊕⊕⊝
Moderate1,4

Standard interferon probably makes little or no difference to the number of patients experiencing adverse events compared to placebo or control

The control group had events in 1 study hence absolute effects at 2 levels of risk were given to represent varying control group risks. Data was not available for 9 participants in 1 study

31 per 1000

110 per 1000
(30 to 400)

High3

222 per 1000

790 per 1000
(218 to 1000)

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1  Number of events is low
2  One study
3 Based on the second lowest and highest control group risks; events occurred in the control group in some studies for some outcomes hence absolute effects are presented for varying levels of risk

4 Risk of bias for random sequence generation was unclear, and allocation concealment was unclear to high

Figuras y tablas -
Summary of findings 1. Standard interferon versus placebo or control for haemodialysis patients with hepatitis C virus infection
Summary of findings 2. Pegylated interferon alpha‐2a versus standard interferon for haemodialysis patients with hepatitis C virus infection

PEG interferon alpha‐2a versus standard interferon for HD patients with HCV infection

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention: PEG interferon alpha‐2a 
Comparison: standard interferon alpha‐2a

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with standard interferon

Risk with PEG interferon

Death
Follow‐up: mean 24 weeks

40 per 1000

13 per 1000
(1 to 312)

RR 0.33 
(0.01 to 7.81)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to death compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Relapse
(recurrence after stopping)
Follow‐up: 72 weeks

667 per 1000

480 per 1000
(273 to 833)

RR 0.72 
(0.41 to 1.25)

38 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of relapses compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

End‐of‐treatment response
Follow‐up: 24 weeks

600 per 1000

918 per 1000
(654 to 1000)

RR 1.53 
(1.09 to 2.15)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may lead to more end‐of‐treatment response compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Sustained virological response 6 months after stopping treatment
Follow‐up: 48 weeks

200 per 1000

480 per 1000
(198 to 1000)

RR 2.4 
(0.99 to 5.81)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of patients having sustained virological response compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Treatment discontinuation
Follow‐up: 24 weeks

160 per 1000

18 per 1000
(2 to 314)

RR 0.11 
(0.01 to 1.96)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of patients discontinuing treatment compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

Adverse events 
Follow‐up: 24 months

160 per 1000

18 per 1000
(2 to 314)

RR 0.11 
(0.01 to 1.96)

50 (1)

⊕⊕⊝⊝
Low1,2

PEG interferon may make little or no difference to the number of patients having major adverse events requiring treatment withdrawal compared to standard interferon

This evidence should be read with caution due to the low certainty of the evidence

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; PEG: pegylated; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1 Number of events is low

2 One study 

Zero events in the PEG interferon group for death, treatment discontinuation, and number of participants having adverse events

Figuras y tablas -
Summary of findings 2. Pegylated interferon alpha‐2a versus standard interferon for haemodialysis patients with hepatitis C virus infection
Summary of findings 3. High versus low dose pegylated interferon alpha‐2a or alpha‐2b for haemodialysis patients with hepatitis C virus infection

High versus low dose PEG interferon for HD patients with HCV infection
(separate and combined results of two preparations: alpha‐2a and alpha‐2b)

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention 1: high dose PEG interferon alpha‐2a (135 µg/week)
Comparison 1: low dose PEG interferon alpha‐2a (90 µg/week)

Intervention 2: high dose PEG interferon alpha‐2b (1 µg/kg/week)

Comparison 2: low dose PEG interferon alpha‐2b (0.5 µg/kg/week)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with low dose PEG interferon 

Risk with high dose PEG interferon 

Death

PEG interferon alpha‐2a
Follow‐up: 24 week

23 per 10001

132 per 1000
(16 to 1000)

RR 5.66 
(0.69 to 46.31)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to death compared to a low dose of PEG interferon 

PEG interferon alpha‐2b

Follow‐up: 72 weeks

0 per 1000

0 per 1000

(0 to 0)

RR 2.40 (0.11 to 51.32)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

20 per 1000

86 per 1000
(15 to 487)

RR 4.30 (0.76 to 24.33)

97 (2)

⊕⊕⊕⊝
Moderate1,3

Relapse (recurrence after stopping treatment)

PEG interferon alpha‐2a

Follow‐up: 24 weeks

286 per 10001

320 per 1000
(114 to 631)

RR 1.12 
(0.4 to 2.21)

43 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon may make little or no difference to the number of patients having a disease relapse compared to a low dose of PEG interferon. In one study there were no events in the control group and could not be analysed

This should be viewed with caution due to the low certainty of the evidence

PEG interferon alpha‐2b 

Follow‐up: 72 weeks

No data

 ‐‐

 ‐‐

 ‐‐

 ‐‐

PEG interferon (combined)

Follow‐up; 24 to 72 weeks

286 per 1000

320 per 1000
(114 to 631)

RR 1.12 
(0.4 to 2.21)

43 (1)

⊕⊕⊝⊝
Low1,2,3

End‐of‐treatment response

PEG interferon alpha‐2a
Follow‐up: 24 weeks

488 per 10001

581 per 1000
(386 to 869)

RR 1.19 
(0.79 to 1.78)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to end‐of‐treatment virological response compared to a low dose of PEG interferon

PEG interferon (alpha‐2b)

Follow‐up: 72 weeks

0 per 1000

0 per 1000

RR 5.60
(0.34 to 93.35)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

20 per 1000

28 per 1000

(10 to 78)

RR 1.42 (0.51 to 3.90)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Sustained virological response after stopping treatment

PEG interferon alpha‐2a
Follow‐up: 72 weeks

349 per 10001

394 per 1000
(223 to 698)

RR 1.13 
(0.64 to 2)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to sustained virological response compared to a low dose of PEG interferon 

PEG interferon alpha‐2b

Follow‐up: 72 weeks

0 per 1000

0 per 1000

RR 4.00
(0.22 to 72.01)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

300 per 1000

357 per 1000

(204 to 621)

RR 1.19

(0.68 to 2.07)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Treatment discontinuation

PEG interferon alpha‐2a
Follow‐up: 24 weeks

256 per 10001

263 per 1000
(125 to 550)

RR 1.03 
(0.49 to 2.15)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to the number of patients discontinuing treatment compared to a low dose of PEG interferon

PEG interferon alpha‐2b

Follow‐up: 72 weeks

286 per 1000

554 per 1000
(151 to 1000)

RR 1.94
(0.53 to 7.2)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

260 per 1000

3112 per 1000

(164 to 593)

RR 1.20

(0.63 to 2.28)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Adverse events

PEG interferon alpha‐2a
Follow‐up: 24 weeks

860 per 10001

817 per 1000
(671 to 990)

RR 0.95 
(0.78 to 1.15)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to the number of patients with adverse events compared to a low dose of PEG interferon

PEG interferon alpha‐2b

Follow‐up: 72 weeks

286 per 1000

554 per 1000
(151 to 1000)

RR 1.94
(0.53 to 7.20)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up 24 to 72 weeks

780 per 1000

819 per 1000

(476 to 1000)

RR 1.05 (0.61 to 1.83)

97 (2)

⊕⊕⊕⊝
Moderate2,3

Serious adverse events

PEG interferon alpha‐2a
Follow‐up: 24 weeks

326 per 10001

368 per 1000
(202 to 671)

RR 1.13 
(0.62 to 2.06)

81 (1)

⊕⊕⊝⊝
Low1,2,3

A high dose of PEG interferon probably makes little or no difference to the number of patients with serious adverse events compared to a low dose of PEG interferon

PEG interferon alpha‐2b

Follow‐up: 72 weeks

286 per 1000

554 per 1000
(151 to 1000)

RR 1.94
(0.53 to 7.2)

16 (1)

⊕⊕⊝⊝
Low1,2,3

PEG interferon (combined)

Follow‐up: 24 to 72 weeks

320 per 1000

397 per 1000

(230 to 685)

RR 1.24

(0.72 to 2.14)

97 (2)

⊕⊕⊕⊝
Moderate2,3

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; PEG: pegylated; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1 One study

2 Number of events low

3 Risk of bias high for blinding of participants and personnel

Two studies compared different preparations of PEG interferon. Hence, each outcome is presented as three entries with results of each RCT and combined analysis result

Figuras y tablas -
Summary of findings 3. High versus low dose pegylated interferon alpha‐2a or alpha‐2b for haemodialysis patients with hepatitis C virus infection
Summary of findings 4. Standard interferon plus ribavirin versus standard interferon alone for haemodialysis patients with hepatitis C virus infection

Standard interferon plus ribavirin versus standard interferon alone for HD patients with HCV infection

Patient or population: patients on HD with HCV infection
Settings: outpatients
Intervention: standard interferon plus ribavirin
Comparison: standard interferon 

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Risk with standard interferon

Risk with standard interferon plus ribavirin

Death

No data

‐‐

‐‐

‐‐

‐‐

Relapse
(recurrence after stopping)

No data

‐‐

‐‐

‐‐

‐‐

End‐of‐treatment response

No data

‐‐

‐‐

‐‐

‐‐

Sustained virological response

No data

‐‐

‐‐

‐‐

‐‐

Treatment discontinuation
Follow‐up: 16 weeks

163 per 1000
(67 to 402)

484 per 1000

(194 to 1000)

RR 2.97 
(1.19 to 7.36)

52 (1)

⊕⊕⊝⊝
Low1,2

Adverse events

No data

‐‐

‐‐

‐‐

‐‐

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low certainty: We are very uncertain about the estimate

1 One study

2 Risk of bias unclear

Figuras y tablas -
Summary of findings 4. Standard interferon plus ribavirin versus standard interferon alone for haemodialysis patients with hepatitis C virus infection
Summary of findings 5. Pegylated interferon plus ribavirin versus pegylated interferon alone for haemodialysis patients with hepatitis C infection

PEG interferon plus ribavirin versus PEG interferon alone for HD patients with HCV infection

Patient or population: HD patients with HCV infection 
Setting: outpatients 
Intervention: PEG interferon alpha‐2a (135 μg/week) plus ribavirin (200 mg/day) for 48 weeks
Comparison: PEG interferon alpha‐2a (135 μg/week) for 48 weeks

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with PEG interferon

Risk with PEG interferon plus ribavirin

Death

No data

‐‐

‐‐

‐‐

‐‐

‐‐

Relapse
(recurrence after stopping)

Follow‐up: mean 18 months

463 per 1,000

153 per 1,000
(106 to 222)

RR 0.33
(0.23 to 0.48)

377 (1)

⊕⊕⊝⊝
Low1,2

The number of relapses of HCV infection was low in HD patients on PEG interferon with ribavirin therapy. This evidence was reported for HCV 1 and HCV 2 genotypes at 24 weeks and 48 weeks after intervention respectively. This effect should be read with caution because of the low certainty of the evidence

End‐of‐treatment response
Follow‐up: mean 18 months

867 per 1,000

876 per 1,000
(815 to 945)

RR 1.01
(0.94 to 1.09)

377 (1)

⊕⊕⊝⊝
Low1,2,3

The end‐of‐treatment response was more likely in patients treated with PEG interferon with ribavirin, with some limitations for the certainty of the evidence

Sustained virological response
Follow‐up: mean 18 months

383 per 1,000

689 per 1,000
(559 to 846)

RR 1.80
(1.46 to 2.21)

377 (1)

⊕⊕⊝⊝
Low2

Patients on PEG interferon with ribavirin were more likely to have sustained virologic response after treatment. The evidence reported is for both HCV genotype 1 and HCV genotype 2 with 24 weeks and 48 weeks of treatment, respectively

Treatment discontinuation
Follow‐up: mean 18 months

37 per 1,000

64 per 1,000
(26 to 158)

RR 1.71
(0.69 to 4.24)

377 (1)

⊕⊕⊝⊝
Low1,2,3,4

HD patients with HCV infection on PEG interferon with ribavirin were more likely to discontinue the treatment than patients on PEG interferon monotherapy. However, this evidence should be read with caution, due to the low certainty of the evidence

Adverse events
Follow‐up: mean 18 months

819 per 1,000

901 per 1,000
(827 to 975)

RR 1.10
(1.01 to 1.19)

377 (1)

⊕⊕⊝⊝
Low2

HD patients with HCV on PEG interferon with ribavirin therapy had a slightly higher risk of experiencing adverse events when compared to patients on PEG interferon alone. However, this evidence should be read with caution, due to the low certainty of the evidence

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; PEG: pegylated; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Less number of events

2 Only one study was available for analysis; Luxon 2005 reported pooled outcomes for both groups and could not be meta‐analysed

3 Risk estimate includes the null effect

4 High risk for blinding of participants 

Figuras y tablas -
Summary of findings 5. Pegylated interferon plus ribavirin versus pegylated interferon alone for haemodialysis patients with hepatitis C infection
Summary of findings 6. Direct antivirals (grazoprevir and elbasvir) versus placebo for haemodialysis patients with hepatitis C infection

Direct antivirals (grazoprevir and elbasvir) versus placebo for HD patients with HCV infection

Patient or population: HD patients with HCV infection 
Setting: outpatients, international, multicentre 
Intervention: Direct antivirals (grazoprevir 100 mg/day and elbasvir 50 mg/day) 
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with direct‐acting antivirals

Death

No data

‐‐

‐‐

‐‐

‐‐

Relapse

No data

‐‐

‐‐

‐‐

‐‐

End‐of‐treatment response

Follow‐up: mean 28 weeks

6 per 1,000

1000 per 1,000
(63 to 1000)

RR 174.99
(11.03 to 2775.78)

173 (1)

⊕⊕⊝⊝
Low 1,2

Patients on direct‐acting antivirals were more likely to report an end‐of‐treatment response when compared to patients on placebo Evidence should be considered with caution as the certainty of the evidence is low.

Out of 235 participants, those on dialysis (173) were analysed

Sustained virological response

No data

‐‐

‐‐

‐‐

‐‐

Treatment discontinuation

No data

‐‐

‐‐

‐‐

‐‐

Adverse events

No data

‐‐

‐‐

‐‐

‐‐

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Placebo group also received the treatment after 4 weeks of study. Difficult to determine the directness of evidence for end‐of‐treatment response

2 Number of events low; wide 95% CI

Figuras y tablas -
Summary of findings 6. Direct antivirals (grazoprevir and elbasvir) versus placebo for haemodialysis patients with hepatitis C infection
Summary of findings 7. Pegylated interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus pegylated interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) for haemodialysis patients with hepatitis C infection

PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) for HD patients with HCV infection

Patient or population: HD patients with HCV infection 
Setting: outpatients 
Intervention: PEG interferon + ribavirin (24 weeks) + initial telaprevir (12 weeks)
Comparison: PEG interferon (48 weeks) + initial telaprevir (12 weeks) + initial low dose ribavirin (12 + 36 weeks)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(RCTs)

Certainty of the evidence
(GRADE)

Comments

Risk with PEG interferon + teleprevir + initial low dose ribavirin (12 + 48 weeks)

Risk with PEG interferon + telaprevir + ribavirin (36 weeks)

Death

No data

‐‐

‐‐

‐‐

‐‐

Relapse

No data

‐‐

‐‐

‐‐

‐‐

Sustained virological response

706 per 1,000

720 per 1,000
(473 to 1,000)

RR 1.02
(0.67 to 1.56)

35 (1)

⊕⊝⊝⊝
Very low1,2,3

HD patients with HCV in the intervention group were more likely to have sustained virological response when compared to control.

Evidence should be read with caution due to the very low certainty of the evidence

End‐of‐treatment response

706 per 1,000

720 per 1,000
(473 to 1,000)

RR 1.02
(0.67 to 1.56)

35 (1)

⊕⊝⊝⊝
Very low1.2.3

HD patients with HCV in the intervention groups were more likely to report end‐of‐treatment response when compared to the control group. Evidence should be read with caution due to the very low certainty of the evidence

Treatment discontinuation

No data

‐‐

‐‐

‐‐

‐‐

Adverse events

No data

‐‐

‐‐

‐‐

‐‐

*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; PEG: pegylated; HCV: hepatitis C virus; HD: haemodialysis; RR: risk ratio; RCT: randomised controlled trial

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Unclear risk of bias for allocation random sequence generation, allocation concealment, blinding of participants and personnel

2 Evidence is reported from a single study for which only an abstract is available

3 Low number of events and low sample size. CI including no effect

Figuras y tablas -
Summary of findings 7. Pegylated interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus pegylated interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) for haemodialysis patients with hepatitis C infection
Comparison 1. Standard interferon versus placebo or control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Death Show forest plot

5

134

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.06, 13.23]

1.2 Relapse Show forest plot

1

12

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.28, 1.88]

1.3 End‐of‐treatment response Show forest plot

5

132

Risk Ratio (M‐H, Random, 95% CI)

8.62 [3.03, 24.55]

1.4 Sustained virological response Show forest plot

4

98

Risk Ratio (M‐H, Random, 95% CI)

3.25 [0.81, 13.07]

1.5 Treatment discontinuation Show forest plot

4

116

Risk Ratio (M‐H, Random, 95% CI)

4.59 [0.49, 42.69]

1.6 Adverse events Show forest plot

5

143

Risk Ratio (M‐H, Random, 95% CI)

3.56 [0.98, 13.01]

Figuras y tablas -
Comparison 1. Standard interferon versus placebo or control
Comparison 2. PEG interferon versus standard interferon

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Death Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.81]

2.2 Relapse Show forest plot

1

38

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.41, 1.25]

2.3 End‐of‐treatment response Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

1.53 [1.09, 2.15]

2.4 Sustained virological response Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

2.40 [0.99, 5.81]

2.5 Treatment discontinuation Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 1.96]

2.6 Serious adverse events Show forest plot

1

50

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 1.96]

Figuras y tablas -
Comparison 2. PEG interferon versus standard interferon
Comparison 3. PEG interferon: high versus low dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Death Show forest plot

2

97

Risk Ratio (M‐H, Random, 95% CI)

4.30 [0.76, 24.33]

3.1.1 1 µg/kg/week versus 0.5 µg/kg/week

1

16

Risk Ratio (M‐H, Random, 95% CI)

2.40 [0.11, 51.32]

3.1.2 135 µg/week versus 90 µg/week

1

81

Risk Ratio (M‐H, Random, 95% CI)

5.66 [0.69, 46.31]

3.2 Relapse Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.2.1 135 µg/week versus 90 µg/week

1

43

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.45, 2.77]

3.3 End‐of‐treatment response Show forest plot

2

97

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.51, 3.90]

3.3.1 1 µg/kg/week versus 0.5 µg/kg/week

1

16

Risk Ratio (M‐H, Random, 95% CI)

5.60 [0.34, 93.35]

3.3.2 135 µg/week versus 90 µg/week

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.79, 1.78]

3.4 Sustained virological response Show forest plot

2

97

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.68, 2.07]

3.4.1 1 µg/kg/week versus 0.5 µg/kg/week

1

16

Risk Ratio (M‐H, Random, 95% CI)

4.00 [0.22, 72.01]

3.4.2 135 µg/week versus 90 µg/week

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.64, 2.00]

3.5 Treatment discontinuation Show forest plot

2

97

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.63, 2.28]

3.5.1 1 µg/kg/week versus 0.5 µg/kg/week

1

16

Risk Ratio (M‐H, Random, 95% CI)

1.94 [0.53, 7.20]

3.5.2 135 µg/week versus 90 µg/week

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.49, 2.15]

3.6 Adverse events Show forest plot

2

97

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.61, 1.83]

3.6.1 1 µg/kg/week versus 0.5 µg/kg/week

1

16

Risk Ratio (M‐H, Random, 95% CI)

1.94 [0.53, 7.20]

3.6.2 135 µg/week versus 90 µg/week

1

81

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.78, 1.15]

3.7 Serious adverse events Show forest plot

2

97

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.72, 2.14]

3.7.1 1 µg/kg/week versus 0.5 µg/kg/week

1

16

Risk Ratio (M‐H, Random, 95% CI)

1.94 [0.53, 7.20]

3.7.2 135 µg/week versus 90 µg/week

1

81

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.62, 2.06]

Figuras y tablas -
Comparison 3. PEG interferon: high versus low dose
Comparison 4. Standard interferon + ribavirin versus standard interferon

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Treatment discontinuation Show forest plot

1

54

Risk Ratio (M‐H, Random, 95% CI)

2.97 [1.19, 7.36]

Figuras y tablas -
Comparison 4. Standard interferon + ribavirin versus standard interferon
Comparison 5. PEG interferon + ribavirin versus PEG interferon

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Sustained virological response Show forest plot

1

377

Risk Ratio (M‐H, Random, 95% CI)

1.80 [1.46, 2.21]

5.2 End‐of‐treatment response Show forest plot

1

377

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.94, 1.09]

5.3 Relapse Show forest plot

1

377

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.23, 0.48]

5.4 Treatment discontinuation Show forest plot

1

377

Risk Ratio (M‐H, Random, 95% CI)

1.71 [0.69, 4.24]

5.5 Adverse events Show forest plot

1

377

Risk Ratio (M‐H, Random, 95% CI)

1.10 [1.01, 1.19]

Figuras y tablas -
Comparison 5. PEG interferon + ribavirin versus PEG interferon
Comparison 6. Direct‐acting antivirals (grazoprevir, elbasvir) versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 End‐of‐treatment response Show forest plot

1

173

Risk Ratio (M‐H, Random, 95% CI)

174.99 [11.03, 2775.78]

Figuras y tablas -
Comparison 6. Direct‐acting antivirals (grazoprevir, elbasvir) versus placebo
Comparison 7. PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks) 

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 End‐of‐treatment response Show forest plot

1

35

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.67, 1.56]

7.2 Sustained virological response Show forest plot

1

35

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.67, 1.56]

Figuras y tablas -
Comparison 7. PEG interferon + ribavirin (24 weeks) + initial telepravir (12 weeks) versus PEG interferon (48 weeks) + initial telepravir (12 weeks) + initial low dose ribavirin (12 + 36 weeks)