A systematic review and meta-analysis assessing antiretroviral therapy for treatment-experienced HIV adult patients using an optimized background therapy approach: is there evidence enough for a standardized third-line strategy?

Background: The World Health Organization (WHO) has identified the need for evidence on third-line antiretroviral therapy (ART) for adults living with HIV/AIDS, given that some controversy remains as to the best combinations of ART for experienced HIV-1-infected patients. Therefore, we conducted a systematic review and meta-analysis to (i) assess the efficacy of third-line therapy for adults with HIV/AIDS based on randomized controlled trials (RCT) that adopted the "new antiretroviral (ARV) + optimized background therapy (OBT)" approach and (ii) address the key issues identified in WHO's guidelines on the use of third-line therapy. Methods: MEDLINE, EMBASE, LILACS, ISI Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials were searched for RCTs assessing third-line ARV therapy that used an OBT approach between 1966 and 2015. Data was extracted using an Excel-structured datasheet based on the Consolidated Standards of Reporting Trials (CONSORT) recommendations. The primary outcome of this meta-analysis was the proportion of patients reaching undetectable HIV RNA levels (<50 copies/mL) at 48 weeks of follow-up. Included studies were evaluated using the Cochrane's Risk of Bias assessment tool. Summarized evidence was rated according to the GRADE approach. Results: Eighteen trials assessing 9 new ARV+ OBT combinations defined as third-line HIV therapy provided the efficacy data: 7 phase Ilb trials and 11 phase III trials. Four of the 18 trials provided extension data, thus resulting in 14 trials providing 48-week efficacy data. In the meta-analysis, considering the outcome regarding the proportion of patients with a viral load below 50 copies/ml at 48 weeks, 9 out of 14 trials demonstrated the superiority of the new combination being studied (risk difference = 0.18, 95% CI 0.13-0.23). The same analysis stratified by the number of fully active ARVs demonstrated a risk difference of 0.29 (95% CI 0.12-0.46), 0.28 (95% CI 0.17-0.38) and 0.17 (95% CI 0.10-0.24) respectively from zero, one, and two or more active drugs strata. Nine of the 18 trials were considered to have a high risk of bias. Conclusions: Efficacy results demonstrated that the groups of HIV-experienced patients receiving the new ARV+ OBT were more likely to achieve viral suppression when compared to the control groups. However, most of these trials may be at a high risk of bias. Thus, there is still not enough evidence to stipulate which combinations are the most effective for therapeutic regimens that are to be used sequentially due to documented multi-resistance.