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

Background: 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. Methodology/ Principal Findings HIV-infected patients $\geq$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/ Significance: Most 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

Study flow diagram.

<p>Study flow diagram.</p

Distribution of genotypic drug resistance mutations for patients with virologic failure on second-line ART in a large ART roll-out program in South Africa.

<p>ART: antiretroviral treatment. PI: protease inhibitor. NRTI: nucleoside reverse transcriptase inhibitor. NNRTI: non-nucleoside reverse transcriptase inhibitor.</p>*<p>Thymidine analog mutation.</p>†<p>Mutations at codons L100I, V108I, Y188C, were not detected.</p>§<p>Mutations reducing etravirine susceptibility. Others found in the cohort include V90I, K101E/P, V106I, and V179D. The A98G, L100I, Y181I/V, and M230L mutations were not detected.</p