Virologic Failure of Protease Inhibitor-Based Second-Line Antiretroviral Therapy without Resistance in a Large HIV Treatment Program in South Africa

Julie H Levison,Kenneth A Freedberg,Robin Wood,Catherine Orrell,Sébastien Gallien,Elena Losina,Daniel R Kuritzkes,Naishin Fu

doi:10.1371/journal.pone.0032144

Abstract

BackgroundWe investigated the prevalence of wild-type virus (no major drug resistance) and drug resistance mutations at second-line antiretroviral treatment (ART) failure in a large HIV treatment program in South Africa.Methodology/ Principal FindingsHIV-infected patients ≥15 years of age who had failed protease inhibitor (PI)-based second-line ART (2 consecutive HIV RNA tests >1000 copies/ml on lopinavir/ritonavir, didanosine, and zidovudine) were identified retrospectively. Patients with virologic failure were continued on second-line ART. Genotypic testing for drug resistance was performed on frozen plasma samples obtained closest to and after the date of laboratory confirmed second-line ART failure. Of 322 HIV-infected patients on second-line ART, 43 were adults with confirmed virologic failure, and 33 had available plasma for viral sequencing. HIV-1 RNA subtype C predominated (n = 32, 97%). Mean duration on ART (SD) prior to initiation of second-line ART was 23 (17) months, and time from second-line ART initiation to failure was 10 (9) months. Plasma samples were obtained 7(9) months from confirmed failure. At second-line failure, 22 patients (67%) had wild-type virus. There was no major resistance to PIs found. Eleven of 33 patients had a second plasma sample taken 8 (5.5) months after the first. Median HIV-1 RNA and the genotypic resistance profile were unchanged.Conclusions/ SignificanceMost patients who failed second-line ART had wild-type virus. We did not observe evolution of resistance despite continuation of PI-based ART after failure. Interventions that successfully improve adherence could allow patients to continue to benefit from second-line ART therapy even after initial failure.

Highlights

South Africa has the largest government-sponsored antiretroviral treatment (ART) program in the world [1]
Thirty-one percent of individuals failing treatment with HIV RNA.10,000 copies/ml had drug-resistant virus, compared with 43% of individuals with HIV RNA#10,000 copies/ml (p = 0.66). In this large ART roll-out program in South Africa we identified patients with confirmed virologic failure on second-line ART
Despite the absence of major protease inhibitor (PI) resistance at first-line ART failure, most individuals failed second-line ART quickly and two-thirds failed with wild-type virus

Summary

Introduction

South Africa has the largest government-sponsored antiretroviral treatment (ART) program in the world [1]. Up to 40% of HIV-1 infected adults in South Africa develop confirmed virologic failure on second-line ART [6,7,8,9]. In resource-limited settings such as South Africa, many unanswered questions remain about the contribution of drug resistance to second-line ART failure. They include uncertainties about the susceptibility of HIV-1 subtype C, which accounts for nearly half of global infections and the majority in South Africa [4,10,11]; effectiveness of ART delivery in public health clinics; and medication non-adherence. We investigated the prevalence of wild-type virus (no major drug resistance) and drug resistance mutations at second-line antiretroviral treatment (ART) failure in a large HIV treatment program in South Africa

Methods

Results

Conclusion