Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch

Abstract

Background: High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification.

Methods: Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression.

Results: One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77-263) and 4.3 log10 copies/mL (IQR, 3.8-4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥ 1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL.

Conclusions: Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.

Keywords: adherence; resistance; second-line antiretroviral therapy; virological failure.

Figure 1.

Study flow diagram. Selection of patients for analysis, from a cohort of patients initiating first-line, nonnucleoside reverse transcriptase inhibitor–based antiretroviral therapy between 1 January 2003 and 31 December 2008. Abbreviations: ART, antiretroviral therapy; PI, protease inhibitor; VL, viral load. ¹Patients with clustering on phylogenetic analysis were also excluded from having drug concentrations measured. One patient had insufficient sample to perform genotyping; however, after genotyping was performed, an additional 44 patients had insufficient samples available for measurement of drug concentrations.

Figure 2.

First-line antiretroviral therapy (ART) drug concentrations in stored plasma samples taken prior to switching to second-line ART. Included in this figure are patients with a drug concentration above the limit of quantification of the assay (n = 30/47 patients on efavirenz, n = 23/33 on nevirapine, and n = 44/79 on lamivudine). Excludes outside values: efavirenz, n = 4 (10.9 mg/L, 11.4 mg/L, 14.9 mg/L, 27.6 mg/L); nevirapine, n = 3 (10.6 mg/L, 11.4 mg/L, 17.6 mg/L); lamivudine, n = 0. For each box plot, the median value is denoted by the solid horizontal line; the inter-quartile range by the box; the upper and lower adjacent values by the whiskers; and C_trough by the dashed line.