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Dosis baja versus alta de estavudina para el tratamiento de pacientes con infección por VIH

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Antecedentes

La estavudina es un componente del tratamiento antirretroviral (TAR) de combinación en los países con recursos limitados debido al costo relativamente bajo, a pesar de las recomendaciones de la OMS de retirarla progresivamente como una estrategia para reducir los efectos tóxicos relacionados con la estavudina. Donde todavía se utiliza la estavudina, se recomienda una dosis inferior a la dosis estándar para reducir la toxicidad relacionada con la estavudina.

Objetivos

Comparar la seguridad y la eficacia virológica de una dosis baja versus una dosis alta de estavudina para tratar la infección por el VIH‐1.

Métodos de búsqueda

Se utilizó la estrategia exhaustiva de búsqueda desarrollada por el Grupo Cochrane de SIDA/VIH (Cochrane HIV/AIDS Review Group) para identificar ensayos controlados aleatorios que compararan la administración de una dosis baja versus una dosis alta de estavudina. La última búsqueda se realizó en febrero de 2014 y las búsquedas abarcaron el período de 1996 a 2014.

Criterios de selección

Ensayos controlados aleatorios que compararon la administración de una dosis baja y una dosis alta de estavudina como parte del TRA de combinación para tratar adultos.

Obtención y análisis de los datos

Dos revisores seleccionaron de forma independiente los ensayos elegibles, evaluaron la calidad metodológica de los estudios incluidos y completaron la extracción de datos y análisis.

Resultados principales

La búsqueda identificó 3952 resúmenes que se revisaron para determinar la relevancia. Tres ensayos cumplieron los criterios de inclusión (Milinkovic 2007; McComsey 2008; Sanchez‐Conde 2005). Los tres ensayos se realizaron en países desarrollados, los participantes recibían TRA y todos mantenían supresión virológica al inicio del ensayo. Se reclutó un total de 157 participantes en los ensayos. Los tamaños de la muestra variaron de 24 a 92 y más del 79% de los participantes fueron hombres. Los estudios tuvieron un alto riesgo de sesgos de selección, realización / detección e informe selectivo de resultados. Algunas características iniciales variaron entre los grupos, incluidos los niveles de triglicéridos en dos estudios y el índice de masa corporal en un estudio. Debido a la variación en el diseño y el seguimiento de los resultados de los estudios, no se realizó metanálisis y se presentan los resultados de estudios únicos. No hubo diferencias significativas en la supresión virológica en los estudios incluidos (Milinkovic 2007; McComsey 2008; Sanchez‐Conde 2005); cociente de riesgos (CR) 1,09 (IC del 95%: 0,93 a 1,28), 0,94 (IC del 95%: 0,59 a 1,50) y 1,03 (IC del 95%: 0,90 a 1,18), respectivamente. Se observó hiperlactatemia sintomática en el brazo de dosis alta del estudio Milinkovic 2007; CR 0,21; (IC del 95%: 0,01 a 4,66), en ningún participante del ensayo McComsey 2008 y no se informó en el ensayo Sanchez‐Conde 2005. McComsey 2008 y Milinkovic 2007 mostraron una reducción en la densidad mineral ósea (DMO), una reducción en la grasa de las extremidades y un aumento en los triglicéridos en el brazo de dosis alta. Los estudios no indican que alguno de los participantes interrumpiera el tratamiento debido a eventos adversos.

Conclusiones de los autores

Esta revisión sistemática identificó solamente tres ensayos pequeños que evaluaron la eficacia virológica y la seguridad de una dosis alta versus una dosis baja de estavudina. Los tres ensayos se realizaron en países desarrollados y ninguno informó sobre países en desarrollo; no obstante, la estavudina es un componente del TRA de combinación en muchos países en desarrollo. No fue posible realizar un metanálisis sobre estos ensayos. Los resultados individuales de los ensayos fueron poco precisos y no han identificado ventajas evidentes sobre la eficacia virológica o la seguridad entre la estavudina a dosis baja y alta. Además, los participantes reclutados recibían tratamiento y mantenían supresión virológica, por lo que los datos existentes no se pueden generalizar a contextos donde actualmente se administra estavudina a pacientes con cargas virales altas que no han recibido previamente TRA. Se justifica la realización de ensayos de reducción de la dosis de estavudina en pacientes que no han recibido TRA previamente en los países en desarrollo donde todavía se utiliza la estavudina, ya que es posible que el retiro progresivo recomendado por la OMS no sea posible de inmediato desde el punto de vista universal.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

Dosis baja versus alta de estavudina para el tratamiento de pacientes con infección por VIH

La estavudina ha sido el agente antirretroviral administrado más ampliamente como parte del tratamiento de combinación para tratar la infección por el VIH‐1 en los países de bajos ingresos. La administración de estavudina se ha asociado con complicaciones de la redistribución de la grasa en el cuerpo, anomalías en la insulina y los lípidos, acidosis láctica y problemas nerviosos. Algunas de estas complicaciones pueden ser potencialmente mortales. Las estrategias para evitar o reducir el riesgo de estas complicaciones han incluido utilizar fármacos alternativos donde estén disponibles o administrar dosis menores de estavudina.

Se utilizó la estrategia exhaustiva de búsqueda desarrollada por el Grupo Cochrane de SIDA/VIH para identificar los ensayos que compararon la seguridad y la eficacia para suprimir la carga viral de una dosis baja versus una dosis alta de estavudina en el contexto de tratar el VIH‐1 con tratamiento antirretroviral de combinación. Las búsquedas abarcaron el período de 1996 a 2014 e identificaron 3952 ensayos, solamente tres cumplieron los criterios de inclusión, todos los ensayos incluidos se realizaron en países desarrollados, el número de participantes varió de 24 a 92 y en su mayoría fueron hombres. Se encontró que la eficacia para suprimir la carga viral fue la misma en todos los ensayos, se utilizara una dosis alta o una dosis baja de estavudina. McComsey 2008 y Milinkovic 2007 demostraron una reducción en la densidad mineral ósea (DMO), una reducción en la grasa de las extremidades y un aumento en los triglicéridos en el brazo de dosis alta. Aunque no se demostró una diferencia en la eficacia para la supresión de la carga viral entre una dosis alta y una dosis baja de estavudina en los ensayos incluidos, los participantes incluidos en estos ensayos ya recibían tratamiento antirretroviral y tenían supresión de la carga viral. El hecho de que los participantes ya tenían supresión de la carga viral y los estudios fueron pequeños, condicionó que fuera difícil demostrar diferencias en la supresión de la carga viral entre los dos grupos. Los estudios no indican que alguno de los participantes interrumpiera el tratamiento debido a eventos adversos.

Esta revisión solamente identificó ensayos que probaran la seguridad y la eficacia para suprimir la carga viral de una dosis baja en comparación con una dosis alta de estavudina. Estos ensayos fueron pequeños, se realizaron en países desarrollados e incluyeron participantes con supresión de la carga viral que habían recibido tratamiento antirretroviral por mucho tiempo. Los resultados individuales de los ensayos no identificaron una ventaja evidente en la supresión de la carga viral o la seguridad entre una dosis baja o una dosis alta de estavudina. Es necesario realizar estudios que evalúen la seguridad y la eficacia para la supresión de la carga viral, en particular en países en desarrollo donde todavía se utiliza la estavudina y probablemente sea necesario mantener los programas de tratamiento, o donde las opciones son limitadas.

Authors' conclusions

Implications for practice

The use of stavudine has been linked to severe metabolic complications and fat redistribution or HIV‐associated lipodystrophy syndrome (HALS), hence the strategy to reduce the dose of stavudine in an attempt to lower adverse effects while maintaining virologic efficacy. While individual trial results have not identified clear advantages in virologic efficacy and lactic acidosis of either low dose or high dose arms, these trials were conducted in ART experienced patients with sustained viral load suppression. It is not known whether the use of low dose stavudine could contribute to treatment failure in patients who are treated with low dose stavudine as first line treatment in resource constrained countries where alternatives to stavudine may be unavailable or in short supply.

Implications for research

Only three trials that evaluated the efficacy and safety of high dose versus low dose stavudine in the setting of combination ART were identified. All three trials were conducted in developed countries, in predominantly males. All enrolled patients were ART experienced for many years and had sustained virologic suppression. The WHO Guidelines Development Group revised the initiation dose of stavudine in ART naive patients to the lower dose of 30 mg BD, regardless of body weight, based on available evidence (Hill 2007; Sanchez‐Conde 2005; Wolf 2004), and subsequently recommended the phasing out of stavudine. This review shows that evidence for virologic efficacy at low dose stavudine in ART naive patients in low‐income countries, where stavudine is still being used, and required to sustain treatment programs is lacking. Therefore dose reduction studies in ART naive patients may be warranted if stavudine continues to be used, as the phasing out of stavudine may not be universally feasible. The impact of stavudine dose reduction on treatment failure in ART naive patients is unknown. Randomized controlled trials investigating the efficacy and safety of low dose stavudine in ART naive patients are needed if stavudine continues to be used as it is presently. While the activism against investigation of stavudine is acknowledged, the reality is that stavudine continues to be used, including in ART naive patients, where there are no alternatives, at doses for which evidence is sparse. Given the criticism that has been attracted by the clinical trial that is currently ongoing, investigating low dose stavudine versus tenofovir, Venter 2013 it is unlikely that a clinical trial that compares low versus high dose stavudine in the future would be acceptable to some researchers and people affected by HIV. Therefore trials investigating the safety and efficacy of low dose stavudine will require much innovation including education of people affected by HIV.

Background

The HIV/AIDS epidemic is one of the worst catastrophes of our time. At the end of 2013 an estimated 35 million (33.2 ‐ 37.2 million) people were estimated to be living with HIV‐1 globally (UNAIDS 2014). Sub‐Saharan Africa is home to 10% of the world's population, yet more than 60% of all adults and children infected with HIV‐1 globally, live in this region. The introduction of antiretroviral therapy (ART) in 1996 revolutionalised the care of patients infected with HIV‐1 and drastically reduced the morbidity and mortality associated with HIV‐1 infection. When taken correctly, ART successfully decreases the HIV‐1 viral load, improves immunological function, delaying clinical events and death. WHO guidelines recommend initiation of combination ART in resource‐constrained countries with one non‐nucleoside reverse‐transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI) as first line therapy while protease inhibitors are an option for inclusion in first‐line regimens in high‐income countries (Gilks 2006).

Access to ART is currently being scaled up in low to middle income countries with NRTIs forming the cornerstone of ART. NRTIs inhibit HIV‐1 reverse transcriptase, thus preventing HIV‐1 DNA formation. NRTIs interact in the same way with human mitochondrial DNA polymerase gamma, the enzyme responsible for mitochondrial DNA replication. It has been proposed that NRTI toxicities are caused by cellular mitochondrial DNA depletion and subsequent mitochondrial dysfunction (Brinkman 1998; Lewis 1995; Kakuda 2000; Brinkman 1999). The severity of NRTI‐associated toxicity depends on the degree of mitochondrial DNA depletion. The rank order of NRTI according to their ability to cause mitochondrial dysfunction in vitro is greatest with zalcitabine, followed in declining order by didanosine, stavudine and zidovudine. The least toxic agents are abacavir, lamivudine and tenofovir, which are all considered equal (Birkus 2002).

Toxicities associated with NRTIs include hepatic steatosis, lactic acidosis, metabolic complications and fat redistribution or HIV‐associated lipodystrophy syndrome (HALS), which might lead to increased risk in morbidity especially cardiovascular disease. In particular, stavudine has been consistently the NRTI most associated with lactic acidosis, peripheral neuropathy and lipoatrophy (Birkus 2002). In a study that investigated the incidence of diabetes among HIV‐infected patients in the Adverse Events of Anti‐HIV Drugs (D:A:D) cohort, stavudine was significantly associated with new‐onset diabetes (De Wit 2008)

At the beginning of combination ART scale up in resource‐limited countries, the WHO recommended stavudine as one of the NRTI agents used for first‐line treatment, owing to its relatively low cost. Stavudine related toxicities necessitated consideration of alternative strategies. A meta‐analysis conducted in 2007 showed that there was no significant difference in virologic efficacy associated with the use of a low dose stavudine compared with the standard dose of 40 mg BD for patients weighing 60 kg or more and 30 mg BD for patients weighing less than 60 kg (Hill 2007). Furthermore, the safety profile was reportedly better at the lower dosage than the standard dosage. Findings of this meta‐analysis led to the modification of the WHO treatment guidelines for adults and stavudine use was recommended at lower than standard dosages (WHO 2007). The non‐thymidine analogue NRTI tenofovir (TDF) or zidovudine (AZT) was subsequently recommended as first‐line therapy replacing stavudine where resources permit as an additional strategy to reduce stavudine associated complications (WHO 2010).

Stavudine remains an option where TDF or AZT are contraindicated or unavailable. Furthermore, the AZT or TDF options are more expensive, require more laboratory monitoring and have higher initial discontinuation rates (Gallant 2004; Gallant 2006). It remains questionable whether stavudine should be completely phased out of the armamentarium for first‐line management of HIV‐1 infection, particularly in resource‐constrained settings where the cost of drugs and laboratory monitoring dictate sustainability of treatment programs. The WHO currently recommends stavudine at a dose of 30 mg BD regardless of weight as opposed to the previous standard dose of 40 mg BD or greater for patients with a body weight of 60 kg or more and 30 mg BD dosage for those with a body weight of less than 60 kg.

The aim of this systematic review was to apply the Cochrane Collaboration Methodology to evaluate the evidence supporting the effects of stavudine at dosages that are lower than standard dosage and the applicability of available data in resource‐limited settings where stavudine use plays a critical role. The protocol was published in the Cochrane Database of Systematic Reviews (Magula 2008).

Objectives

The objective was to compare the safety and virologic efficacy of low dose stavudine (30 mg BD or less for patients with a body weight of 60 kg or more and less than 30 mg BD for patients with a body weight of less than 60 kg) versus high dose stavudine (40 mg BD or greater for patients with a body weight of 60 kg or more and 30 mg BD dosage for patients with a body weight of less than 60 kg) for treating HIV‐1 infection in adults.

Methods

Criteria for considering studies for this review

Types of studies

Randomised, controlled blinded and non‐blinded clinical trials

Types of participants

HIV infected adults treated with combination ART

Types of interventions

Low dose stavudine versus high dose stavudine

Low dose stavudine is described as the stavudine dosage of 30 mg BD or less for patients with a body weight of 60 kg or more and less than 30 mg BD for patients with a body weight of less than 60 kg

High dose stavudine is described as the standard dosage of 40 mg BD or greater for patients with a body weight of 60 kg or more and 30 mg BD dosage for those with a body weight of less than 60 kg

Types of outcome measures

Primary Outcomes:

  • Viral load < 200 copies/ml

  • Major side‐effects leading to drug discontinuation such as lactic acidosis, pancreatitis or severe peripheral neuropathy

Secondary Outcomes:

  • Less severe side‐effects e.g. mild peripheral neuropathy, lipodystrophy, rash, etc.

Search methods for identification of studies

The HIV/AIDS Cochrane Review Group assisted with searching for studies that compared low dose stavudine versus high dose stavudine in the treatment of HIV‐1 infection. The search strategy was based on that of the HIV/AIDS Cochrane Review Group.

A search was undertaken using Medical Subject Headings (MeSH) and free text terms. All languages were included. The strategy was combined with the search strategy for RCTs as recommended by The Cochrane Collaboration. Studies conducted before and after Food and Drug Administration approval of stavudine were included. Each study was analysed in terms of the efficacy and safety outcomes.

Electronic searches

The following electronic databases were searched for randomised controlled trials: MEDLINE (Appendix 1); AIDSearch (Appendix 2); EMBASE and CINAHL (Appendix 3). The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Gateway and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were also searched (Appendix 4). Searches covering the time period 1996 to 2008 were conducted on 10 September 2008. The searches were repeated on 5 June 2009 for the period 2008 to 2009, on 23 November 2012 for the period 2009 to 2012 and on 5 February 2014 for the period 2012‐2014.

Searching other resources

The abstracts of relevant conferences, including the International AIDS Conference and the Conference on Retroviruses and Opportunistic Infections were also reviewed. The reference lists of all review articles and primary articles identified were also searched. The search strategy was iterative, in that references of included studies were searched for additional references. Contact was also made with investigators in the field for additional studies.

Data collection and analysis

Our methodology for data collection and analysis was based on the guidance of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008). Two authors independently selected potentially relevant studies by scanning the titles, abstracts, and descriptor terms of all downloaded material from the electronic searches. Irrelevant reports were discarded, and the full articles were obtained for all potentially relevant or uncertain reports.

Selection of studies

Two authors independently applied the inclusion criteria, using an eligibility form specific to this review. There were no disagreements between the two authors that required a third arbiter. Studies were reviewed for relevance, based on study design, types of participants, exposures and outcome measures. Authors were contacted to provide further clarification of data where necessary and possible.

Data extraction and management

Two authors independently extracted data using a standardized data extraction form. The following characteristics were extracted from each included study:

  • Administrative details: identification; author(s); published or unpublished; year of publication; number of studies included in paper; year in which study was conducted; details of other relevant papers cited.

  • Details of study: study design; type, duration and completeness of follow‐up; country and location of the study (developed versus developing country).

  • Characteristics of participants: prior exposure to antiretroviral therapy (type and duration); disease stage; baseline CD4 count; baseline HIV‐1 RNA level.

  • Details of intervention: types and doses of drugs used; duration of therapy; adverse events (method of surveillance for adverse events and type: minor or severe) and adherence measures (if reported).

  • Outcome data: death or occurrence of new event (death or AIDS defining event, lipodystrophy, lactic acidosis, peripheral neuropathy); subsequent and final CD4 counts and HIV‐1 RNA levels dichotomised as having reached, or as not having reached, a non‐detectable level, i.e. less than 200 copies/ml or in its continuous form.

Assessment of risk of bias in included studies

We used the Cochrane Collaboration tool (Higgins 2008) for assessing the risk of bias for each individual study, and present results in summary tables. For randomised trials, the Cochrane tool assesses risk of bias in individual studies across six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential biases.

Assessment of reporting biases

We minimised the potential for reporting bias by using comprehensive search strategies, which included searching scientific literature from a wide range of databases, published or unpublished, written in any language.

Data synthesis

For dichotomous data the overall measure of effect was calculated as a relative risk, with 95% confidence intervals, using the random effects model. We used an intention‐to‐treat analysis (ITT). Our definition of ITT includes analysing participants in their originally randomised groups, and also uses the initial number of randomised participants per group as the denominator. Continuous data was reported in medians and the duration of follow‐up and outcomes measured were different for each of the studies, the data is therefore reported separately for each of the studies.

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies.

The search conducted for period 1996 to 2012 identified 3952 abstracts which were then scanned for relevance Figure 1. Seven studies were selected for application of eligibility criteria. Three studies met the inclusion criteria (Milinkovic 2007; McComsey 2008; Sanchez‐Conde 2005). The Sanchez‐Conde 2005 trial was conducted in Madrid, Spain and it enrolled 92 participants. The Milinkovic 2007 trial was conducted in Barcelona, Spain. It had three arms that compared high dose versus low dose stavudine versus switching to tenofovir. Thirty‐one participants were enrolled in the stavudine dose comparison arms. The McComsey 2008 trial was also a small trial (N=24) conducted in the United States of America. All three trials included participants who were receiving antiretroviral therapy with suppressed HIV‐1 viral loads. The median baseline CD4 count in the Milinkovic 2007 trial was 569 cells/mm3 (IQR 417 to 811) and in the McComsey 2008 trial the median CD4 cell count was 558 cells/mm3 (IQR 207 to 1698). The mean CD4 count in the Sanchez‐Conde 2005 trial was more than 670 cells/mm3. Participants were predominantly male in all three trials; over 90% in the Milinkovic 2007, over 80% in the Sanchez‐Conde 2005 and 79% in the McComsey 2008 trials. The median duration on stavudine therapy was 4.5 years. The baseline characteristics differed between the two arms of the McComsey 2008 trial with a higher median triglyceride level in the low dose arm of 175mg/dL (IQR: 52 to 777) and a median triglyceride level of 113mg/dL (IQR: 63 to 181) in the high dose arm, p=0.02. The body mass index was also higher in the low dose arm at median 26.6(IQR: 22 to 35) and 23 (IQR: 20 to 27) in the high dose arm, p=0.003. Lean body mass was higher in the low dose arm at median 62,051g (IQR: 39,754 to 74,637) and 51,703 (IQR: 41,469 to 64,277) in the high dose arm, p=0.04. There was no difference in the baseline bone mineral density (BMD) or lipoatrophy score with a total median 1.18g/cm2 (0.99 to 1.36) and 5 (0 to 12) respectively.


Study flow prisma diagram.

Study flow prisma diagram.

Participants of the Milinkovic 2007 trial were on ART for a median duration of more than 6 years. The low dose and the high dose arms differed in their baseline triglyceride level with a median 207 mg/dL (IQR: 124 to 229) in the low dose arm and 141 mg/dL (IQR: 122 to 313) in the high dose arm. There was no difference in the baseline BMD between the two arms. The mean duration on stavudine in the Sanchez‐Conde 2005 trial was 12 months. The mean baseline triglyceride level in this trial was 158 mg/mL in the low dose arm and 161 mg/mL in the high‐dose arm.

In two of the trials that were excluded, Pollar 1997; Lange 1998, the participants were not treated with combination ART but with monotherapy or dual therapy (Lange 1998) or dual therapy only (Pollar 1997). One study, Makinson 2008, was a systematic review, Wolf 2004; Mashitisho 2013 were retrospective studies. Menezes 2012 compared the early effects of low dose and standard dose stavudine with tenofovir on adipocyte mitochondrial DNA number, gene expression and metabolic parameters in black South African HIV‐1 infected patients. This trial was excluded from the current review due to the short follow‐up of four weeks that would not have allowed for evaluation of the primary and secondary outcomes of this review. Pujades‐Rodriquez 2011 was a large study that compared the incidence and timing of toxicity associated with the use of a low dose stavudine (30 mg) compared with high dose stavudine (40 mg). The study was excluded from the review because it was an observational study. The study Fabian 2008 was identified through communication with authors for additional unidentified studies but was excluded because it was a retrospective study.

Risk of bias in included studies

See Figure 2; Figure 3


Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.


Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

GENERATION OF ALLOCATION SEQUENCE

The Milinkovic 2007 trial used a randomisation list that was computer generated. Participants were stratified according to current treatment (PI or non‐NRTI). The method used for generation of allocation sequence is thought to be adequate. In the McComsey 2008 trial the randomisation schedule was prepared by the data manager who was not linked to patient care. The randomisation is described as 3:2 but the method used to generate allocation sequence is not described in detail. The method used to generate allocation sequence in the Sanchez‐Conde 2005 is not described.

ALLOCATION CONCEALMENT

The Sanchez‐Conde 2005; Milinkovic 2007 and McComsey 2008 trials did not describe details of allocation concealment and since the trials were open‐labeled, there may not have been sufficient concealment of allocation.

BLINDING

There was no blinding in the Milinkovic 2007 and Sanchez‐Conde 2005 for both participants and providers as this was an open‐labeled trial. It is unclear if the outcome assessors were blinded. The McComsey 2008 was also open‐labeled with no blinding for participants and providers, however, the outcome assessors were blinded. The DEXA scans were read centrally by a reader who was blinded to the timing of the DEXA scan and participants' characteristics. The laboratory personnel was also blinded to sample characteristics.

INCOMPLETE OUTCOME DATA

The Sanchez‐Conde 2005 randomised 45 participants to continue with 40 mg twice a day stavudine and 47 participants to reduce to 30 mg twice a day. Forty‐one (45%) did not complete the 12‐month follow‐up period. Six participants were lost to follow‐up, eight withdrew voluntarily, twelve changed antiretroviral therapy for reasons other than virologic failure and six were discontinued because they were started on treatment for hepatitis C infection. Nine participants were discontinued because they developed virologic failure. The specific time points for the development of virologic failure is not reported.

The Milinkovic 2007 randomised 22 participants to continue high dose stavudine and 19 to reduce to low dose. One participant in the high dose arm was excluded due to symptomatic hyperlactataemia at baseline. Altogether three participants were lost to follow‐up, two in the low dose arm and one in the high dose arm. Analysis was by intention to treat using the policy of last‐date‐carried‐forward analysis adopted for patients with missing data for the remaining follow‐up period.

Of the 24 participants enrolled in the McComsey 2008 trial, 21 (88%) completed the trial. Two participants in the low dose arm and one in the high dose arm did not complete the trial. One participant in the low dose arm withdrew at week four because of scheduling conflict and the second participant in the low dose arm died of an overdose of illegal drugs and respiratory failure that was unrelated to study participation at week 37. The withdrawal of the one participant in the high dose arm was because of incarceration. It is unclear if intention‐to‐treat analysis was used.

Effects of interventions

The three trials that were eligible for inclusion differed in the primary outcomes they measured and duration of follow‐up. The cut‐off for viral load suppression is reported at different levels in each of the studies with the McComsey 2008 trial using a cut‐off of 50 copies/mL, the Sanchez‐Conde 2005 also at 50 copies/mL and Milinkovic 2007 using a cut‐off of 200 copies/mL. The proportion of participants achieving viral load suppression below 200 copies/mL is shown in Analysis 1.1Figure 4. The proportion of participants developing symptomatic hyperlactatemia are shown in Analysis 2.1Figure 5. The rest of the outcomes reported in the two trials McComsey 2008; Milinkovic 2007 on lipids, limb fat mass, fat mitochondrial DNA, glucose, lactate and bone mineral density are all reported in median (IQR) in both studies and are shown in Table 1.


Forest plot of comparison: 2 Low dose vs high dose stavudine, outcome: 2.1 Proportion of participants with HIV‐1 RNA < 200 copies/ml.

Forest plot of comparison: 2 Low dose vs high dose stavudine, outcome: 2.1 Proportion of participants with HIV‐1 RNA < 200 copies/ml.


Forest plot of comparison: 3 Low dose versus high dose stavudine, outcome: 3.1 Proportion of participants developing symptomatic hyperlactatemia.

Forest plot of comparison: 3 Low dose versus high dose stavudine, outcome: 3.1 Proportion of participants developing symptomatic hyperlactatemia.

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Table 1. Secondary Outcomes

McComsey 2008

Milinkovic 2007

Sanchez‐Conde 2005

Outcome

Measure

Low dose

High‐dose

P value

Low‐dose

High dose

p‐value

Low dose

High dose

P value

Limb fat,

g

189 (‐2256 to 3173)

‐194(‐1160 to 5098)

0.45

527 (‐343 to 694)

‐182 (‐469 to‐50)

0.12

ND

ND

Limb fat %

6.9 (‐23.8 to 34.4)

‐5.0 (‐39.8 to 92.4)

0.23

ND

ND

ND

ND

Trunk fat,

g

804 (‐4356 to 2898)

‐50 (‐1560 to 7233)

0.80

937.5 (‐336 to 1316)

‐145 (‐461 to 161)

ND

ND

Total lean body mass,g

‐155(‐4917 to 6261)

‐187(‐3176 to 3911)

0.45

394 (‐577 to 1032)

816 (‐683 to 1220)

ND

ND

Triglyceride,

mg/dL

‐38 (‐606 to 82)

5 (‐74 to 64)

0.16

‐16.5 (‐62 to 18.5)

11 (‐21 to 51)

ND

ND

Total

cholesterol,mg/dL

‐1 (‐59 to 24)

‐11.5 (‐44 to 11)

0.56

1.5 (‐7 to 22)

‐3 (‐7 to 22)

ND

ND

HDL

Cholesterol,mg/dL

6 (‐11 to 15)

0 (‐35 to 16)

0.15

1 (‐5 to 6)

‐2 (‐7 to 3)

ND

ND

Fat MtDNA

Copes/Cell

40 (‐49 to 261)

39 (‐97 to 115)

0.36

ND

ND

ND

ND

PMBC mtDNA Copies/Cell

1.5 (9 to 121)

‐2.5 (‐46 to 8)

0.22

ND

ND

ND

ND

Total Lean Mass Change,g

394 (‐577 to 1.032)

816 (‐683 to 1220)

0.99

ND

ND

Glucose

‐4 (‐2.3 to 51 )

3 (‐51 to 18)

0.91

‐1.5 (‐11 to 4)

2.1 ( ‐7 to 9)

ND

ND

Lactate

0 (‐3 to 4)

3 (‐1 to 6)

ND

ND

BMD

g/cm2

0.0 (‐1.2 to 4)

‐1.7 (‐6.3 to 0.8)

0.003

0.007(0.003 to 0.012)

‐0.001(‐0.007 to 0.0100)

ND

ND

ND= Not Done

Milinkovic 2007

This trial compared stavudine at the standard dose of 40 mg twice a day with a reduced dose of 30 mg twice a day. Participants that were enrolled were receiving a stable ART regimen that included stavudine at 40 mg twice a day. Participants were randomised to either continue the standard dose or change to the reduced dose of 30 mg twice a day. At entry, all participants had a viral load of <200copies/ml for at least six months. Participants were followed up for 24 weeks.

PRIMARY OUTCOMES

Viral load suppression:

Two of 22 participants in the high dose arm and none of the 19 in the low dose arm experienced viral load rebound after a 24 week follow‐up. The Risk Ratio (RR) for suppressing viral load was 1.09 (95% CI: 0.93 to 1.28) (Table 1). The lower limit cut‐off for the HIV‐1 RNA was 200 copies/ml.

There were no cases of lactic acidosis and other major side‐effects leading to drug discontinuation such as pancreatitis or severe peripheral neuropathy were not reported.

SECONDARY OUTCOMES (Table 1)

Symptomatic hyperlactatemia

The RR for developing symptomatic hyperlactatemia was 0.23 (95% CI 0.01 to 4.51) with two of the 22 participants in the high dose arm developing symptomatic hyperlactatemia at lactate levels >22 mg/dL.

Body composition

There was an increase in the median limb fat from baseline to 24 weeks of follow‐up in the low dose arm of 527g (95% CI: ‐343 to 694) and a reduction in the high dose arm of ‐182g (95% CI: ‐469 to ‐50). The difference in limb fat change from baseline to 24 weeks follow‐up between the low dose and the high dose arm was not statistically significant, p=0.12. There was an increase in the median trunk fat from baseline to 24 weeks follow‐up in the low dose arm of 937.5g (95% CI: ‐336 to 1316) and a reduction in the high dose arm of ‐145g (95% CI: ‐461 to 161). There was an increase in the median total lean body mass in both the low dose arm 394g (95% CI: ‐577 to 1032) from baseline to 24 weeks follow‐up and in the high dose arm 816g (95% CI: ‐683 to 1220).

Metabolic changes

There was a reduction in triglycerides in the low dose arm at 24 weeks with a median change of ‐16.5mg/dL (IQR: ‐62 to 18.5) and an increase of 11 mg/dL (IQR: ‐21 to 51) in the high dose arm. The change in total cholesterol was median 1.5 mg/dL (IQR: ‐7 to 22) in the low dose arm and ‐3 mg/dL (IQR: ‐7 to 22) in the high dose arm. There was a modest increase in the median HDL cholesterol of 1 mg/dL (IQR: ‐5 to 6) in the low dose arm and a reduction of ‐2 mg/dL (IQR: ‐7 to 3) in the high dose arm. The median change in BMD in the low dose arm was 0.007g/cm2 (IQR: 0.003 to 0.012) and ‐0.001g/cm2 (‐0.007 to 0.010) in the high dose arm.

McComsey 2008

This trial randomised participants in a ratio of 3:2 to either continue the standard dose of stavudine at 40 mg twice a day for weight ≥ 60 kg and 30 mg twice a day for weight < 60 kg or reduced stavudine to 20 mg twice a day for weight ≥ 60 kg or 15 mg for weight < 60 kg. Participants enrolled in the study were on stable ART containing stavudine for 24 weeks or more. All had viral load suppression of <50 copies/ml or branched DNA < 75 copies/ml. Participants were followed up for 48 weeks.

PRIMARY OUTCOME

Viral load suppression

Eleven of 15 participants in the low dose arm and seven of nine participants in the high dose arm had viral load suppression. The RR for developing viral load suppression was 0.94 (95% CI: 0.59 to 1.50) (Analysis 1.1). The lower limit cut‐off for HIV‐1 RNA was 50 copies/ml.

There were no major side‐effects that led to discontinuation of therapy.

SECONDARY OUTCOMES (Table 1)

Symptomatic hyperlactataemia

No participants had symptomatic hyperlactatemia in both the low dose and high dose arms.

Limb fat changes:

There was an increase in limb fat in the low dose arm with median change at 48 weeks of 189g( IQR: ‐2256 to 3173) and reduction in limb fat in the high dose arm was ‐194 (IQR: ‐160 to 5098); p= 0.45. The limb fat percentage gain in the low dose arm was 6.0% (IQR: ‐23.8 to 34.4) with a loss in the high dose arm of ‐5.0% (IQR: ‐39.8 to 92.4). Consistent with the limb fat changes, there was a trunk fat gain at 48 weeks in the low dose arm of 804g (IQR: ‐4356 to 2898) and a reduction in the high dose arm of ‐50g(IQR: ‐1560 to 7233); p=0.80. A loss in total lean body mass was seen in both arms with a median change of ‐155g (IQR: ‐4917 to 6261) in the low dose arm and ‐187g (‐3176 to 3911) in the high dose arm, p=0.45.

Metabolic changes:

There was a reduction in triglycerides in the low dose arm at 48 weeks with a median change of ‐38 mg/dL (IQR: ‐606 to 82) and an increase in the high dose arm of 5 mg/dL (IQR: ‐74 to 64); p=0.16. There was a reduction in total cholesterol in both arms but more in the high dose arm with median change in the high dose arm of ‐11.5 mg/dL (IQR: ‐44 to 11) and the low dose arm of ‐1 mg/dL (IQR: ‐59 to 24); p=0.56. There was no change in BMD from baseline in the low dose arm but a median reduction in BMD in the high dose arm of ‐1.7g/cm2 (‐6.3 to 0.8), p=0.003.

Sanchez‐Conde 2005

This trial randomised half of the participants to standard dose stavudine, 40 mg twice a day and the other half to reduce dosage from 40 mg twice a day to 30 mg twice a day. All participants were on a stavudine containing regimen and had a suppressed viral load with plasma HIV‐1 RNA < 50 copies/mL over at least the previous three months. The mean time on stavudine prior to enrolment was 12 months. Participants were followed up for 12 months.

PRIMARY OUTCOME

Viral load suppression

Forty‐three of 47 participants in the low dose arm and 40 of 45 participants in the high dose arm had viral load suppression. The RR for developing viral load suppression was 1.03 (95% CI: 0.90‐1.18) Analysis 1.1. Fourty‐one participants did not complete the 12 month follow‐up.

Since the drop out rate in this trial was very high, a number of case scenarios were considered as possible outcomes. The first scenario considered was a best case scenario for the low dose arm where in all the participants that dropped out had virologic suppression. The RR for this scenario was 1.96 (95% CI: 1.42‐2.71) Analysis 1.2Figure 6. In the low dose worst case scenario, where all those that dropped out did not have virologic suppression, the RR was 0.72 (95% CI: 0.57‐0.91) Analysis 1.3.


Forest plot of comparison: 1 Low dose versus high dose stavudine, outcome: 1.2 Low dose best case‐scenario.

Forest plot of comparison: 1 Low dose versus high dose stavudine, outcome: 1.2 Low dose best case‐scenario.

SECONDARY OUTCOMES

No data is reported on symptomatic hyperlactatemia, limb fat and metabolic changes.

Discussion

Summary of main results

This review evaluated the safety and virologic efficacy of the use of low dose compared with high dose stavudine as part of ART. The review identified only three randomised controlled trials that tested the safety and virologic efficacy of low dose compared with high dose stavudine. The most significant finding of this review is that in all three trials that met criteria for inclusion (Sanchez‐Conde 2005; Milinkovic 2007; McComsey 2008), participants were all ART experienced and had sustained virologic suppression at the time of enrolment. Since these studies were small and participants already virologically suppressed, this meant finding an outcome of virologic efficacy was highly unlikely, as it would be for any primary outcome. The duration of follow‐up was different in each of the trials, however, there was no significant difference in virologic suppression between the low dose and high dose arms at the end of follow‐up for each of the trials. None of the three trials reported the CD4 cell count outcomes at the end of follow‐up.

There were no differences in lactic acidosis between the low dose and high dose stavudine arms and no reported major side‐effects that led to discontinuation of treatment in all three trials. There was no associated significant changes in body fat composition. Both McComsey 2008 and Milinkovic 2007 trials showed a reduction in BMD in the high dose arms. Total lean body mass increased in both arms of Milinkovic 2007 and decreased in both arms of McComsey 2008. In the Milinkovic 2007 and McComsey 2008 there was an increase in limb fat in both the low dose arms and a reduction in both high dose arms, however the changes were not statistically significant. There was also an increase in triglycerides for the high dose arms of both trials. In theses trials, high dose stavudine was associated with a reduction in BMD, reduction in limb fat and an increase in triglycerides.

There was a high drop out rate in the Sanchez‐Conde 2005 trial but no significant difference in viral load suppression and outcomes of metabolic changes were not reported on.

Overall completeness and applicability of evidence

Metabolic toxicities associated with the use of stavudine have led to investigations to reduce these toxicities including reducing the dose of stavudine or switching to less toxic non‐thymidine analogues such as tenofovir as in the trials included in this review (Sanchez‐Conde 2005; Milinkovic 2007; McComsey 2008). The use of stavudine remains a cornerstone of ART in many resource‐constrained countries. Stavudine is an alternative agent in the first line therapy in many patients with contra‐indications for use of tenofovir or AZT, where monitoring for tenofovir or AZT is not available or where stocks of these preferred agents are in short supply. Although the WHO now recommends the phasing out of stavudine as the main strategy of reducing stavudine related toxicities, this strategy may not be feasible for the majority of countries with limited resources due to high costs. Phasing out completely of stavudine, an agent that is relatively inexpensive, may impact negatively on sustainability of antiretroviral programs.

This review found that the clinical trials that have been conducted on stavudine dose reduction were performed in developed countries, the majority of participants were male and all were ART experienced with suppressed viral load. Evidence is most needed in resource‐constrained countries as stavudine is no longer used at large scale in resource‐rich countries. However, the fact that these studies were conducted in patients who were ART experienced with suppressed viral load, makes the data not to be applicable to countries where stavudine is used in ART naive patients who do not have virologic suppression. Furthermore, sub‐Saharan Africa now accounts for 67% of all people living with HIV‐1 infection, with 60% of those living with the infection being women UNAIDS 2010, the majority of the included participants are men and do not reflect background demographics in resource constrained countries.

A multi‐site randomized controlled trial that is aimed at demonstrating the non‐inferiority of low dose stavudine compared with tenofovir when each is combined with lamivudine and efavirenz Venter 2013 has drawn much debate between researchers on the one hand who believe this investigation is warranted and researchers, HIV activists and people living with HIV on the other hand who believe that stavudine should not be investigated.Andrieux‐Meyer 2012; Venter 2012 At the heart of the debate is the stavudine related toxicity that has led the WHO to recommend phasing out of stavudine use altogether. The investigators of the study argue for dose optimization to reduce stavudine related toxicity so that stavudine can be kept as an alternative agent for cost‐effective purposes or where options are limited. The opposition argues that such an investigation should not be carried out as stavudine is more toxic than the currently recommended standard of care with tenofovir. The study is being conducted in India, South Africa and Uganda and recruitment is anticipated to be concluded at the end of 2013 with results at the beginning of 2016. The stavudine dose of 20 mg BD chosen for this investigation is lower than the dose recommended in the WHO and South African National antiretroviral treatment guidelines.WHO 2010; DOH 2013 The study is funded by the Bill and Melinda Gates Foundation.

Quality of evidence and potential biases in the review

The trials that have been conducted comparing the effectiveness and safety of low dose and high dose stavudine have been small trials, approximately 80% of participants were male. The methods of sequence generation were well described for Milinkovic 2007 trial, not described in detail for the McComsey 2008 trial and not described at all for the Sanchez‐Conde 2005 trial. Since the included participants were already on ART, the randomisation was based on reducing or maintaining the standard dose. Providers and participants were not blinded and it is likely that there was no allocation concealment. Using the GRADE criteria it is felt the overall quality of evidence in the three studies included in this review is low, due to limitations in the trials as described above and in the characteristics of studies table.

Agreements and disagreements with other reviews and studies

Findings of this review are in agreement with those of a previous one (Hill 2007) where virologic suppression was found not to be significantly different whether low dose or high dose stavudine was used, however the two reviews differ significantly on included studies. The current review has included three randomised controlled trials whereas Hill 2007 included fifteen studies. Hill 2007 included nine clinical trials (Browne 1993; Petersen 1995; Pollard 1999; Anderson 1995; Ruxrungtham 2000; Slangphoe 2004; Ribera 2005; Milinkovic 2007; Sanchez‐Conde 2005), and six observational cohort studies (Koegl 2003; Urbina A 2005; Hanvanich 2003; Delpierre 2005; Armitage 1994; Cross 2002). Observational cohort studies and clinical trials not conducted in the context of ART were excluded from this review.

A significant reduction in BMD was found in the high dose arm of the McComsey 2008 but this was not shown in the Milinkovic 2007. There were no differences in lactic acidosis and other major side‐effects such as pancreatitis and peripheral neuropathy were not reported on in the Milinkovic 2007; Sanchez‐Conde 2005 trials. McComsey 2008 reported that there were no major side‐effects that led to discontinuation of therapy. While complications such as neuropathy and lactic acidosis were not seen, there was reduction in BMD, reduction in limb fat and an increase in triglycerides in the high dose arms. These findings are different from reports in Africa where low rates of lipid abnormalities (Buchacz 2008), high rates of lactic acidosis (Geddes 2006), and neuropathy (Maritz 2010) have been reported. It may be that Africans metabolize drugs differently as shown by Wang 2006, where they found significantly higher steady state levels of efavirenz in association with CYP2B6*16 among Africans compared to Swedes and Turks.

The WHO Guidelines Development Group made an addendum (WHO 2007) to the 2006 WHO guidelines on antiretroviral therapy for HIV‐1 infection in adults and adolescents following evaluation of evidence from a systematic review of nine randomised trials, six observational cohort studies (Hill 2007) and other complementary studies (Wolf 2004; Sanchez‐Conde 2005). The new recommendation suggests initiation of stavudine at a lower dose of 30 mg twice a day regardless of body weight in ART naive patients. The WHO has further recommended the phasing out of stavudine as a strategy to reduce stavudine related toxicitiesWHO 2010, however this recommendation is not universally feasible due to the higher cost of alternative agents and the pressing need to expand ART programs.

Study flow prisma diagram.
Figures and Tables -
Figure 1

Study flow prisma diagram.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figures and Tables -
Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Forest plot of comparison: 2 Low dose vs high dose stavudine, outcome: 2.1 Proportion of participants with HIV‐1 RNA < 200 copies/ml.
Figures and Tables -
Figure 4

Forest plot of comparison: 2 Low dose vs high dose stavudine, outcome: 2.1 Proportion of participants with HIV‐1 RNA < 200 copies/ml.

Forest plot of comparison: 3 Low dose versus high dose stavudine, outcome: 3.1 Proportion of participants developing symptomatic hyperlactatemia.
Figures and Tables -
Figure 5

Forest plot of comparison: 3 Low dose versus high dose stavudine, outcome: 3.1 Proportion of participants developing symptomatic hyperlactatemia.

Forest plot of comparison: 1 Low dose versus high dose stavudine, outcome: 1.2 Low dose best case‐scenario.
Figures and Tables -
Figure 6

Forest plot of comparison: 1 Low dose versus high dose stavudine, outcome: 1.2 Low dose best case‐scenario.

Comparison 1 Low dose versus high dose stavudine, Outcome 1 Proportion of participants with HIV RNA < 200 copies/ml.
Figures and Tables -
Analysis 1.1

Comparison 1 Low dose versus high dose stavudine, Outcome 1 Proportion of participants with HIV RNA < 200 copies/ml.

Comparison 1 Low dose versus high dose stavudine, Outcome 2 Proportion of participants with suppressed viral load:Low dose best case‐scenario.
Figures and Tables -
Analysis 1.2

Comparison 1 Low dose versus high dose stavudine, Outcome 2 Proportion of participants with suppressed viral load:Low dose best case‐scenario.

Comparison 1 Low dose versus high dose stavudine, Outcome 3 Proportion of participants with suppressed viral load: Low dose worst case‐scenario.
Figures and Tables -
Analysis 1.3

Comparison 1 Low dose versus high dose stavudine, Outcome 3 Proportion of participants with suppressed viral load: Low dose worst case‐scenario.

Comparison 2 Low dose versus high dose stavudine, Outcome 1 Proportion of participants developing symptomatic hyperlactatemia.
Figures and Tables -
Analysis 2.1

Comparison 2 Low dose versus high dose stavudine, Outcome 1 Proportion of participants developing symptomatic hyperlactatemia.

Table 1. Secondary Outcomes

McComsey 2008

Milinkovic 2007

Sanchez‐Conde 2005

Outcome

Measure

Low dose

High‐dose

P value

Low‐dose

High dose

p‐value

Low dose

High dose

P value

Limb fat,

g

189 (‐2256 to 3173)

‐194(‐1160 to 5098)

0.45

527 (‐343 to 694)

‐182 (‐469 to‐50)

0.12

ND

ND

Limb fat %

6.9 (‐23.8 to 34.4)

‐5.0 (‐39.8 to 92.4)

0.23

ND

ND

ND

ND

Trunk fat,

g

804 (‐4356 to 2898)

‐50 (‐1560 to 7233)

0.80

937.5 (‐336 to 1316)

‐145 (‐461 to 161)

ND

ND

Total lean body mass,g

‐155(‐4917 to 6261)

‐187(‐3176 to 3911)

0.45

394 (‐577 to 1032)

816 (‐683 to 1220)

ND

ND

Triglyceride,

mg/dL

‐38 (‐606 to 82)

5 (‐74 to 64)

0.16

‐16.5 (‐62 to 18.5)

11 (‐21 to 51)

ND

ND

Total

cholesterol,mg/dL

‐1 (‐59 to 24)

‐11.5 (‐44 to 11)

0.56

1.5 (‐7 to 22)

‐3 (‐7 to 22)

ND

ND

HDL

Cholesterol,mg/dL

6 (‐11 to 15)

0 (‐35 to 16)

0.15

1 (‐5 to 6)

‐2 (‐7 to 3)

ND

ND

Fat MtDNA

Copes/Cell

40 (‐49 to 261)

39 (‐97 to 115)

0.36

ND

ND

ND

ND

PMBC mtDNA Copies/Cell

1.5 (9 to 121)

‐2.5 (‐46 to 8)

0.22

ND

ND

ND

ND

Total Lean Mass Change,g

394 (‐577 to 1.032)

816 (‐683 to 1220)

0.99

ND

ND

Glucose

‐4 (‐2.3 to 51 )

3 (‐51 to 18)

0.91

‐1.5 (‐11 to 4)

2.1 ( ‐7 to 9)

ND

ND

Lactate

0 (‐3 to 4)

3 (‐1 to 6)

ND

ND

BMD

g/cm2

0.0 (‐1.2 to 4)

‐1.7 (‐6.3 to 0.8)

0.003

0.007(0.003 to 0.012)

‐0.001(‐0.007 to 0.0100)

ND

ND

ND= Not Done

Figures and Tables -
Table 1. Secondary Outcomes
Comparison 1. Low dose versus high dose stavudine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Proportion of participants with HIV RNA < 200 copies/ml Show forest plot

3

157

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.95, 1.16]

2 Proportion of participants with suppressed viral load:Low dose best case‐scenario Show forest plot

3

157

Risk Ratio (M‐H, Random, 95% CI)

1.40 [0.94, 2.10]

3 Proportion of participants with suppressed viral load: Low dose worst case‐scenario Show forest plot

3

157

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.60, 1.20]

Figures and Tables -
Comparison 1. Low dose versus high dose stavudine
Comparison 2. Low dose versus high dose stavudine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Proportion of participants developing symptomatic hyperlactatemia Show forest plot

2

65

Risk Ratio (M‐H, Fixed, 95% CI)

0.23 [0.01, 4.51]

Figures and Tables -
Comparison 2. Low dose versus high dose stavudine