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

Background: To 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 Findings: From 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 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. Conclusions: This 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

Patient Characteristics by Duration of Second-Line Treatment Failure.

a<p>Time from 2 L initiation, or last suppressed VL on 2 L, to genotype sample.</p>b<p>Numbers represent: Median (IQR) unless otherwise indicated.</p>c<p>Time from 2 L initiation to genotype sample.</p

Prevalence of reverse transcriptase mutations.

<p>(A) NRTI resistance mutations; thymidine analog mutations (TAMs) are in light grey. (B) NNRTI resistance mutations; minor mutations indicated by light grey.</p

Characteristics for Patients who Initiated Third-Line ART.

c<p>Results represent median (IQR) except where indicated.</p>d<p>Time from 2 L initiation, or last suppressed VL on 2 L, to genotype sample.</p

Accumulation of Protease Mutations According to Duration of Second-Line Treatment Failure.

<p>Accumulation of Protease Mutations According to Duration of Second-Line Treatment Failure.</p