A significant proportion
of the 6.6 million persons receiving combination antiretroviral therapy (cART) in low and middle income countries of the world reside in sub-Saharan Africa.1
Large numbers of national initiatives offering public nonnucleoside reverse transcriptase inhibitor (NNRTI)-based cART have commenced in the region with preliminary data documenting impressive efficacy outcomes among the vast majority of cART-treated adults.2–6
In resource-rich settings, based on available data from numerous clinical trials,7–13
efavirenz (EFV) is the NNRTI of choice, and is “preferred
” for first-line cART, along with the NRTIs tenofovir (TDF) and emtricitabine (FTC).7
This recommendation is based on efficacy and more favorable tolerability data.7–13
In resource-limited limited settings, however, the majority of cART-treated adults are female2–6,14–18
and have been prescribed nevirapine (NVP)-based cART regimens due to the potential teratogenic effects of EFV. Family planning considerations in sub-Saharan Africa also strongly influence the choice of NNRTI, especially as pregnancy rates among cART-treated women are high and EFV is limited to women committing to using at least two reliable contraceptive methods.
The 2NN trial,19
a large adult randomized trial, compared 1216 adults receiving stavudine (d4T) plus lamuvidine (3TC) with either NVP or EFV in North and South America, Australia, Europe, South Africa, and Thailand. They found non-inferiority (NVP vs. EFV) in their primary outcome of virologic failure. Additional 2NN analyses,19
however, showed an association between NVP and higher rates of serious toxicity. The CPCRA 058 and INSIGHT study20
team, reporting randomized clinical trial data from NNRTI-treated adults in the United States and Western Europe, however, did show inferiority in primary endpoint, namely higher rates of virologic failure with and without resistance among NVP-treated vs. EFV-treated patients. Wester et al.14
performed an analysis of the Adult Antiretroviral Treatment and Drug Resistance (“Tshepo
”) study in Botswana using Cox proportional hazards analysis and concluded that there was no significant difference by assigned NNRTI in time to death or virologic failure. Women receiving NVP-based cART, however, trended toward higher virological failure rates when compared to EFV-treated women, Holm-corrected log-rank p
There were no differences among men.14
Furthermore, they concluded that individuals treated with NVP had significantly shorter times to treatment modifying toxicity when compared to those receiving EFV-based cART.14
Current methods used to evaluate effect modification (often referred to as statistical interaction) in time to event data, such as the Cox proportional hazards model, posit highly restrictive parametric models and attempt to estimate parameters that are specific to the model proposed.21
These methods tend to be biased and force providers to estimate parameters out of convenience rather that what they are actually interested in. The targeted maximum likelihood estimation (TMLE) methodology, originally proposed by van der Laan and Rubin,21,22
and applied to time to event outcomes by Moore and van der Laan23
improves on the currently implemented methods in both robustness (its ability to provide unbiased estimates) and flexibility (allowing providers to estimate parameters of direct interest to them).
Evaluating data from the recently completed Tshepo study, a clinical trial comparing the efficacy and tolerability of various first-line cART regimens in Botswana, we compared TMLE results to results obtained from conventional Cox proportional hazards analyses. In doing so, we aimed to definitively evaluate the causal effect of NNRTI treatment and effect modification by sex and baseline CD4+ cell count on the time to virologic failure or death [intent-to-treat (ITT)] and the time to minimum of virologic failure, death, or treatment modifying toxicity [time to loss of virological response (TLOVR)], the preferred FDA outcome in this unique sub-Saharan African clinical trial population.