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

Patterns and Predictors of First-Line Antiretroviral Therapy Modification in HIV-1-Infected Adults in a Large Urban Outpatient Cohort in Nigeria

Objective: We described the magnitude, type, and factors associated with first-line antiretroviral therapy (ART) modification in HIV-1-infected adults on ART in Jos, Nigeria. Method: Data on 6309 patients initiated on first-line ART between January 2004 and December 2006 were analyzed retrospectively. Factors predictive of modification to initial ART were assessed by chi-square and multivariable logistic regression analysis. Results: Overall, 5212 (83%) included patients incurred a modification (73.3% drug substitution and 9.7% drug switch) to their initial first-line ARV regimen during a median (interquartile range) follow-up period of 7 (3-8) years. Drug substitutions of zidovudine (ZDV) were less likely than of tenofovir (TDF; adjusted odd ratio [AOR] 0.6; 95% confidence interval [CI]: 0.51-0.71), and Drug substitutions of efavirenz (EFV) were more likely than of nevirapine (NVP)-containing (AOR 1.82; 95% CI: 1.42-2.33) regimens. Predictors of switch to second-line regimen include older age (AOR 2.05; 95% CI: 1.68-2.51), CD4 count ≤100 cells/mm 3 (AOR 1.89; 95% CI: 1.49-2.37), EFV compared to NVP (AOR 1.38; 95% CI: 1.02-1.88), and drug toxicity (AOR 1.90; 95% CI: 1.48-2.43). Conclusion: Modification to initial ART was common in this study. Further evaluation of the contribution of guideline changes on regimen modification and treatment outcomes is recommended

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

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

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

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