initial treatment of HIV infection in antiretroviral-naïve individuals

Stavudine or zidovudine in three-drug combination therapy for initial treatment of HIV infection in antiretroviral-naïve individuals.

Spaulding A, Rutherford GW, Siegfried N. Cochrane Database Syst Rev. 2010;8:CD008651

The introduction of highly active antiretroviral therapy as treatment for HIV infection has greatly improved mortality and morbidity for adults and children living with HIV around the world. Two common medications given in first-line antiretroviral therapy are the nucleoside reverse transcriptase inhibitors (NRTI) stavudine (d4T) or zidovudine (AZT). The objective of the study was to assess the efficacy of d4T compared to AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI), two additional NNRTIs, or one NRTI and one protease inhibitor (PI), as part of first-line antiretroviral therapy for HIV-infected people in low-resource settings. Standard Cochrane methods were used to search electronic databases and conference proceedings with relevant search terms without limits to language. Randomised controlled trials of HIV-infected patients 5 years of age and older were included. Primary outcomes of interest included mortality, severe adverse events, virologic response to antiretroviral therapy, adherence, tolerance, and retention. Secondary outcomes included immunologic response to antiretroviral therapy, development of antiretroviral therapy drug resistance, and prevention of sexual transmission of HIV. Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form. Nine randomised controlled trials were identified as meeting the inclusion criteria. The nine trials enrolled 2,159 participants but looked at a multiplicity of drug combinations. Despite this, a reasonably robust literature suggests no statistically significant difference between the two drug combinations, including severe adverse events and adherence/tolerance/retention. The quality of the literature was found overall to be low to very low for all key outcomes. Only one study reported on drug resistance, and no studies reported on sexual transmission of HIV. The length of follow-up time and study settings varied greatly. While ideally future research would focus on direct comparison of standard therapeutic combinations of d4T+3TC+an NNRTI and AZT+3TC+an NNRTI to compare these regimens more directly, it is unlikely that additional trials will be mounted. Observational studies should focus on understanding outcomes, including toxicity and tolerability, in low- and middle-income countries.

This Cochrane Review focused on 9 randomised controlled trials comparing the NRTI (nucleoside reverse transcriptase inhibitor) backbone drugs d4T and AZT used in first-line regimens. Essentially, although the key regimens d4T/3TC/ NNRTI and AZT/3TC/NNRTI were not directly compared, there did not appear to be a difference in efficacy between them. WHO has recommended that countries move progressively away from d4T in favour of AZT-based or tenofovir-based (TDF) first-line regimens because of significant toxicity and tolerability concerns. Cumulative exposure to d4T may cause disfiguring lipodystrophy, painful peripheral neuropathy, and life threatening lactic acidosis. People who remain on d4T should be closely monitored. One option being considered by some countries to provide effective HIV treatment without wasting drugs unnecessarily is to initiate treatment with d4T combinations and then switch to an AZT or TDF-based regimens by 12 months. This pragmatic approach, combined with close clinical monitoring for safety, could allow more people to start antiretroviral therapy in settings with limited financial and human resources.