Accumulation of Protease Mutations among Patients Failing Second-Line Antiretroviral Therapy and Response to Salvage Therapy in Nigeria

Abstract

BackgroundTo date, antiretroviral therapy (ART) guidelines and programs in resource-limited settings (RLS) have focused on 1st- and 2nd-line (2 L) therapy. As programs approach a decade of implementation, policy regarding access to 3rd-line (3 L) ART is needed. We aimed to examine the impact of maintaining patients on failing 2 L ART on the accumulation of protease (PR) mutations.Methods and FindingsFrom 2004–2011, the Harvard/APIN PEPFAR Program provided ART to >100,000 people in Nigeria. Genotypic resistance testing was performed on a subset of patients experiencing 2 L failure, defined as 2 consecutive viral loads (VL)>1000 copies/mL after ≥6 months on 2 L. Of 6714 patients who received protease inhibitor (PI)-based ART, 673 (10.0%) met virologic failure criteria. Genotypes were performed on 61 samples. Patients on non-suppressive 2 L therapy for <12 months prior to genotyping had a median of 2 (IQR: 0–5) International AIDS Society (IAS) PR mutations compared with 5 (IQR: 0–6) among patients failing for >24 months. Patients developed a median of 0.6 (IQR: 0–1.4) IAS PR mutations per 6 months on failing 2 L therapy. In 38% of failing patients no PR mutations were present. For patients failing >24 months, high- or intermediate-level resistance to lopinavir and atazanavir was present in 63%, with 5% to darunavir.ConclusionsThis is the first report assessing the impact of duration of non-suppressive 2 L therapy on the accumulation of PR resistance in a RLS. This information provides insight into the resistance cost of failing to switch non-suppressive 2 L regimens and highlights the issue of 3 L access.

Polymorphisms and drug resistance analysis of HIV-1 isolates from patients on first line antiretroviral therapy (ART) in South-eastern Nigeria

“…All the patients had preserved susceptibility to DRV/r since it is the only PI drug analysed that was not selected by any resistance mutation. Similar observations had been reported in a more widespread study in Nigeria which examined the impact of maintaining patients on failing second line ART on the accumulation of PR mutations [30]. Isolates in this study also showed high level of susceptibility (96.4%) to SQV/r.…”

HIV‐1 drug resistance testing at second‐line regimen failure in Arua, Uganda: avoiding unnecessary switch to an empiric third‐line

“…This time is a period of potential accumulation of resistance mutation and transmission of resistant HIV strains. The time between first detectable VL (suspicion of failure) and DRT sample reception in the laboratory was not associated with the presence of major PI mutation in our study, but it has been shown that a long duration of non‐suppressive second‐line may increase this risk . The high work load at the clinic led to difficulties to follow the recommended procedure which was to use SAMBA POC VL results to collect blood samples for DRT on the same day as the second detectable VL.…”

In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix

“…In future work it would be interesting and important to know whether Gag mutations are capable of facilitating emergence of major protease mutations in prolonged culture conditions under suboptimal drug pressure. This could potentially explain why prevalence of major protease mutations increases over time during PI exposure in clinical studies (43). Next one could perform population dynamics simulations to incorporate RC and susceptibility data in order to model the proportion of resistant and susceptible viruses over time, and possibly therefore predict emergence of major mutations in protease.…”