Low-abundance HIV species and their impact on mutational profiles in patients with virological failure on once-daily abacavir/lamivudine/zidovudine and tenofovir

Abstract

BackgroundHIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir.MethodsHIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA ≥ 400 copies/mL at 24–48 weeks).ResultsFourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log10 copies/mL, and 4.0 log10 copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) ± M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample.ConclusionsThe majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.

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

“…M184V mutation and TAMs became undetectable supporting the hypothesis that lack of drug exposure due to ART non-adherence was the most likely cause of ART failure. In addition, consideration of archived resistance mutations is important in selection of second-line ART [33] .…”

Emergence of Minor Drug-Resistant HIV-1 Variants after Triple Antiretroviral Prophylaxis for Prevention of Vertical HIV-1 Transmission

“…There is evidence that minor drug-resistant variants can re-emerge in subsequent regimens leading to failure of salvage therapy [21]. While Metzner et al [53] reported of successful treatment despite pre-existing minor K65R, K103N and M184V-variants in German Truvada cohort, several other studies have shown that the presence of drug-resistant minor variants increased the risk for subsequent treatment failure for NNRTI- [18]–[24], protease inhibitor- [17], [54], [55] and AZT-containing treatment [56]. While a single NNRTI-resistance mutation confers high-level resistance to some NNRTIs (an association with virologic failure in efavirenz-containing regimen was found for K103N variants at frequencies of > = 0.5% by Halvas et al [57]), resistance to PI and AZT requires an accumulation of several mutations [58].…”

Zidovudine and Lamivudine for HIV Infection

“…101 Taken together, these observations provide a rationale to further study the use of ZDV as a resistance modulator in combination with other antiretroviral drugs. 102 …”