Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: A systematic review of clinical trials

Background. Resistance to antiretroviral combination therapy is associated with increased mortality. Understanding the relative risks of emerging resistance to first-line therapy is of importance for both resource-rich and resource-poor settings. Methods. We undertook an overview of clinical trials of adults receiving first-line highly active antiretroviral therapy (HAART), which consisted of dual nucleoside reverse-transcriptase inhibitors (NRTIs) combined with a third agent (either a nonnucleoside reverse-transcriptase inhibitor [NNRTI] or a ritonavir-boosted protease inhibitor [bPI]). The primary outcome measures were incidences of mutations conferring resistance to key drugs (NRTIs, NNRTIs, or bPIs) per trial at week 48. For meta-analysis, inverse-variance weighting was used to create estimates of overall incidences per group, with exact 95% confidence intervals (95% CIs). Results. The study included 20 clinical trials that comprised 30 treatment arms and 7970 patients. Virologic failure at 48 weeks occurred in 4.9% (95% CI, 3.9%-6.1%) of NNRTI recipients, compared with 5.3% (95% CI, 4.4%-6.4%; P = .50 ) of bPI recipients. Of failures that were successfully genotyped, the M184V mutation in the HIV reverse transcriptase (lamivudine resistance) occurred in 35.3% (95% CI, 29.3%-41.6%) of patients who started NNRTI-based HAART, compared with 21.0% (95% CI, 14.4%-28.8%; P < .01) for those who received a bPI. For the K65R mutation in the HIV reverse transcriptase (multinucleoside resistance), incidences were 5.3% (95% CI, 2.4%-9.9%) and 0.0% (95% CI, 0.0%-3.6%;), respectively, in patients treated with non-zidovudine-containing regimens. Resistance to the third agent (an NNRTI or PI) occurred in 53% (95% CI, 46%-60%) and 0.9% (95% CI, 0.0%-6.2%; P < .001) of such patients, respectively. Conclusions. Initial therapy with bPI-based regimens resulted in less resistance within and across drug classes. This finding is of particular significance for the developing world, where rates of resistance to NRTIs and NNRTIs at 48 weeks are much higher than has been seen in both cohorts and clinical trials in well-resourced countries.