Abstract: The search identified 3952 abstracts which were scanned for relevance. Three trials met the inclusion criteria (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005). All three trials were conducted in developed countries, participants were ART experienced and all had sustained virologic suppression at baseline. A total of 157 participants were recruited to the trials. Sample sizes ranged from 24 to 92 and more than 79% of participants were male.The studies were at a high risk of selection, performance/detection and selective outcome reporting biases. Some baseline characteristics differed among the groups, including triglyceride levels in two studies and body mass index in one study. In light of variation in the design and follow-up of the study results, no meta-analysis was performed and the results of single studies are presented. There was no significant difference in virologic suppression in the included studies (Milinkovic 2007; McComsey 2008; Sanchez-Conde 2005); Risk Ratio (RR) 1.09 (95% CI: 0.93 to 1.28), 0.94 (95% CI:0.59 to 1.50) and 1.03 (95% CI: 0.90 to 1.18) respectively. Symptomatic hyperlactatemia was seen in the high dose arm of the Milinkovic 2007 study; RR 0.21 (95% CI: 0.01 to 4.66), in no participants in the McComsey 2008 trial and not reported on in the Sanchez-Conde 2005 trial. McComsey 2008 and Milinkovic 2007 demonstrated a reduction in bone mineral density (BMD), reduction in limb fat and an increase in triglycerides in the high dose arms. The studies did not indicate that any participants discontinued treatment due to adverse events. This systematic review identified only three small trials that evaluated virologic efficacy and safety of high dose versus low dose stavudine. All three trials were conducted in developed countries and none reported from developing countries yet stavudine remains a component of ART combination therapy in many developing countries. It was not possible to perform a meta-analysis on these trails. Individual results from the trials were imprecise and have not identified a clear advantage in virologic efficacy or safety between low and high dose stavudine. Furthermore, enrolled participants were treatment experienced with sustained virologic suppression and so existing data cannot be generalized to settings where stavudine is currently used in ART naive patients with high viral loads. Stavudine dose reduction trials in ART naive patients, in developing countries where stavudine is still being used are warranted as the phasing out of stavudine that is recommended by WHO may not be immediately universally feasible.

Plain-language summary: The comprehensive search strategy developed by the Cochrane HIV/AIDS Review Group was used to identify trials that compared the safety and efficacy in suppressing the viral load of low dose versus high dose stavudine in the context of treating HIV-1 with combination antiretroviral therapy. The searches covered the period 1996 to 2014.The search identified 3952 trials and only three met the inclusion criteria, all the included trials were conducted in developed countries, the number of participants ranged from 24 to 92 and the majority were male. The efficacy of suppressing the viral load was found to be the same in all the trials whether high dose or low dose of stavudine was used. McComsey 2008 and Milinkovic 2007 demonstrated a reduction in bone mineral density (BMD), reduction in limb fat and an increase in triglycerides in the high dose arms. While there was no demonstration of a difference in efficacy of viral load suppression between high dose and low dose stavudine in the included trials, participants included in these trials were already treated with antiretroviral therapy and had suppressed viral load. The fact that participants already had suppression of the viral load and the studies were small, meant it would be difficult to demonstrate the differences in viral load suppression between the two groups. The studies did not indicate that any participants discontinued treatment due to adverse events. This review identified only trials that tested the safety and efficacy in suppressing the viral load of low dose compared to high dose stavudine. These trials were small, conducted in developed countries and included participants with suppressed viral loads that had been on antiretroviral treatment for a long time. Individual results from the trials have not identified a clear advantage in viral load suppression or safety between low and high dose stavudine.Studies that evaluate the safety and efficacy in viral load suppression need to be conducted particularly in developing countries where stavudine is still being used and probably needed to either sustain treatment programs or where alternatives are limited.