Antiretroviral medication adherence and the development of class-specific antiretroviral resistance

Abstract

Objective: To assess the association between antiretroviral adherence and the development of class-specific antiretroviral medication resistance.

Design and methods: Literature and conference abstract review of studies assessing the association between adherence to antiretroviral therapy and the development of antiretroviral medication resistance.

Results: Factors that determine class-specific adherence-resistance relationships include antiretroviral regimen potency, viral fitness or, more specifically, the interplay between the fold-change in resistance and fold-change in fitness caused by drug resistance mutations, and the genetic barrier to antiretroviral resistance. During multidrug therapy, differential drug exposure increases the likelihood of developing resistance. In addition, antiretroviral medications with higher potency and higher genetic barriers to resistance decrease the incidence of resistance for companion antiretroviral medications at all adherence levels.

Conclusion: Knowledge of class-specific adherence-resistance relationships may help clinicians and patients tailor therapy to match individual patterns of adherence in order to minimize the development of resistance at failure. In addition, this information may guide the selection of optimal drug combinations and regimen sequences to improve the durability of antiretroviral therapy.

Fig. 1

The average ratio of luciferase activity of viruses obtained from individuals with phenotypically defined drug-resistant HIV (resistance) relative to luciferase activity of drug-susceptible virus (reference) is shown at various drug concentrations. gr1 The dotted line corresponds to a luciferase ratio of 1; luciferase ratios above this level imply that the resistant virus is more fit than the wild-type virus. The range of adherence levels (1–100%) corresponding to protein-adjusted C_min is shown in each figure; (a) nevirapine and (b) nelfinavir [23].

Fig. 2

Prevalence of complete viral suppression (HIV-RNA <50 copies/ml, light gray) and virological failure with (black) and without (dark gray) drug resistance by adherence quartile and drug regimen: (a) patients treated with nonnucleoside reverse transcriptase inhibitor (NNRTI); (b) patients treated with protease inhibitor [23]. gr2

Fig. 3

Theoretical example of effect of different half-lives on drug exposure during a period of poor adherence (≈, every 96h) with multidrug antiretroviral therapy. gr3 For simplification, peak drug concentrations and the zones of potential replication were standardized, despite differences by medication in vivo. Half-lives are as follows: dashed line=22h (approximate intracellular half-life of lamivudine triphosphate), dotted line=7h (approximate intracellular half-life for zidovudine triphosphate), solid line figure (a)=47.5h (approximate half-life of efavirenz), solid line figure (b)=5.5h (approximate half-life of lopinavir with ritonavir).

Fig. 4

Predicted and observed probability of maintaining viral control (HIV RNA < 400 copies/ml) according to the longest interval of treatment discontinuation in individuals with viral suppression on nonnucleoside reverse transcriptase inhibitor (NNRTI)-based combination antiretroviral therapy. gr4 Based on this logistic model, a treatment interruption of 15 days was associated with a 50% probability [95% confidence interval (CI) 15%, 86%] of virological rebound [42].