Residual activity of two HIV antiretroviral regimens prescribed without virological monitoring

Abstract

Virological residual activity (VRA) denotes the degree of HIV RNA suppression achieved by antiretroviral therapy in the presence of resistant virus. This concept is particularly important in resource-limited settings, where rapid switching after detection of virological failure may not be feasible. Using data from the NORA trial, we estimated VRA for two regimens-zidovudine-lamivudine-abacavir (ZDV-3TC-ABC) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP)-and related this to the phenotypic drug sensitivity of the component drugs in the two regimens. Plasma samples at weeks 0, 48, and 96 were retrospectively assayed for HIV-1 RNA, and genotypic/phenotypic resistance testing was performed if HIV-1 RNA exceeded 1,000 copies/ml. Virological residual activity (VRA) was defined as the difference between log(10)(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC(50)) relative to wild-type virus for ZDV and ABC (fold change [FC]). Twenty-seven samples in the ZDV-3TC-NVP group and 56 in the ZDV-3TC-ABC group contributed to the analysis. Mean VRA was significantly higher in the ZDV-3TC-ABC group than in the ZDV-3TC-NVP at week 48 (1.62 versus 0.90) and week 96 (1.29 versus 0.78). There was a weak and nonsignificant relationship between VRA and ZDV FC, with VRA decreasing by 0.1 log(10) copies/ml per 2-fold increase in ZDV. The association with ABC FC was much stronger, with a marked reduction in VRA occurring at ABC FC values greater than approximately 2. This information should be considered in future treatment guidelines relevant to resource-poor settings.

Fig. 1.

(a) Virological residual activity (VRA) related to zidovudine fold change (FC) in ZDV-3TC-NVP group: individual data and predicted values. Predicted values for baseline HIV RNA of 5.6 log₁₀ copies/ml. (b) VRA related to abacavir FC in ZDV-3TC-ABC group: individual data and predicted values. Predicted values for baseline HIV RNA of 5.6 log₁₀ copies/ml and ZDV FC of 1 (black line), ZDV FC of 5 (dark-gray line), and ZDV FC of 20 (light-gray line). (c) VRA related to zidovudine FC in ZDV-3TC-ABC group: individual data and predicted values. Predicted values for baseline HIV RNA of 5.6 log₁₀ copies/ml and ABC FC of 1 (black line), ABC FC of 2 (dark-gray line), and ABC FC of 5 (light-gray line).

Fig. 2.

Correlation between abacavir fold change (FC) and zidovudine FC. Circles, week 48; squares, week 96.