HIV-1 second-line failure and drug resistance at high-level and low-level viremia in Western Kenya

Abstract

Objective: Characterize failure and resistance above and below guidelines-recommended 1000 copies/ml virologic threshold, upon second-line failure.

Design: Cross-sectional study.

Methods: Kenyan adults on lopinavir/ritonavir-based second-line were enrolled at AMPATH (Academic Model Providing Access to Healthcare). Charts were reviewed for demographic/clinical characteristics and CD4/viral load were obtained. Participants with detectable viral load had a second visit and pol genotyping was attempted in both visits. Accumulated resistance was defined as mutations in the second, not the first visit. Low-level viremia (LLV) was detectable viral load less than 1000 copies/ml. Failure and resistance associations were evaluated using logistic and Poisson regression, Fisher Exact and t-tests.

Results: Of 394 participants (median age 42, 60% women, median 1.9 years on second-line) 48% had detectable viral load; 21% had viral load more than 1000 copies/ml, associated with younger age, tuberculosis treatment, shorter time on second-line, lower CD4count/percentage, longer first-line treatment interruption and pregnancy. In 105 sequences from the first visit (35 with LLV), 79% had resistance (57% dual-class, 7% triple-class; 46% with intermediate-to-high-level resistance to ≥1 future drug option). LLV was associated with more overall and NRTI-associated mutations and with predicted resistance to more next-regimen drugs. In 48 second-visit sequences (after median 55 days; IQR 28-33), 40% accumulated resistance and LLV was associated with more mutation accumulation.

Conclusion: High resistance upon second-line failure exists at levels above and below guideline-recommended virologic-failure threshold, impacting future treatment options. Optimization of care should include increased viral load monitoring, resistance testing and third-line ART access, and consideration of lowering the virologic failure threshold, though this demands further investigation.

Figure 1:. Prevalence of drug resistance by drug-class, viral load category, and HIV-1 subtype

The figure demonstrates the proportion of patients with sequences (Y axis) that contained resistance mutations associated with different combinations of drug resistance categories (X axis). For each category left bars represent VL≤1,000 copies/mL (represented by ‘≤10³’) and right bars represent VL>1,000 copies/mL (represented by ‘>10³’). Major subtypes are also shown (A-black, C-dark gray, D-light gray, Other-white; per the legend). Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

Figure 2:. Predicted susceptibility to future drug options upon 2^nd-line failure.

The figure demonstrates the proportion of patients (Y axis) that had one of five levels of predicted susceptibility (legend) to antiretroviral medications that might be considered for future treatment options (X axis). Results are provided for (i) 105 patients with genotypes at the first visit (All; left bars for each drug); (ii) Timepoint 1 (T1=first visit; center bars for each drug; for 48/105 participants with genotypes at both visits); and (iii) Timepoint 2 (T2=second visit; for 48/105 participants with genotypes at both visit right bars). Data are provided for all participants (top graph); those with low level viremia (middle graph); and those with viral load >1,000 copies/mL (lower graph).