Low-Frequency Nevirapine (NVP)–Resistant HIV-1 Variants Are Not Associated With Failure of Antiretroviral Therapy in Women Without Prior Exposure to Single-Dose NVP

Boltz, Valerie F.; Bao, Yajing; Lockman, Shahin; Kearney, Mary F.; McIntyre, James; Schooley, Robert T.; Hughes, Michael D.; Coffin, John M.; Mellors, John W.; Team, Actg A Study; Zwickl, Beth; Mutuluuza, C. Kityo; Kaseba, Christine; Maponga, Charles C.; Watts, Heather; Kuritzkes, Daniel R.; Campbell, Thomas; Kidd-Freeman, Lynn; Carten, Monica; Hitti, Jane; Marovich, Mary; Mugyenyi, Peter; Rwambuya, Sandra; Sanne, Ian; Putnam, Beverly; Marcus, Cheryl; Wester, Carolyn; DiFrancesco, Robin; Halvas, Elias K.; Beddison, Annie; Lehrman, Sandra Nusinoff; Aweeka, Francesca; Dong, Betty J.; Ziba, Peter Ndhleni; Saag, Michael S.; Holmes, William C.; Hammer, Scott M.

doi:10.1093/infdis/jit635

Cited by 29 publications

(33 citation statements)

References 32 publications

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“…Preexisting dominant NVP mutations were a major risk factor for failure. Subsequent studies also showed that a high risk of treatment failure was also observed in women who had received single-dose NVP and had NVP-resistant HIV-1 variants at low frequency (49,71).…”

Section: Discussionmentioning

confidence: 98%

“…However, physicians typically switch to a salvage treatment regimen if treatment failure continues and HIV drug resistance was not detected by the Sanger-based test on the previous visit sample. Based on (i) the strong correlations between the detection of low-frequency HIV drug resistance mutations and continued treatment failure (here) and (ii) previous studies in Ugandan women showing that lowfrequency NVP mutations led to failure of NNRTI-containing cART (49,71), our ethics committee decided against a study in which the same cART was continued when low-frequency HIV drug resistance mutations were detected at Ͼ5%. More importantly, we have also adopted DeepGen as the preferred HIV drug resistance genotyping test in the JCRC.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies suggest that preexisting minority drugresistant variants in treatment-naive patients have minimal to no effect on the treatment outcome even if the treatment involves drugs associated with the drug resistance pattern (e.g., treatment with NVP when a patient has 3% NVP-resistant variants) (32,49). However, the impact of these drug-resistant minority variants in treatment-naive patients is also highly dependent on the level of resistance conferred by the specific mutation, cross-resistance to other drugs in the regimen, and the replicative fitness of the HIV-1-resistant strain.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, there have been few research studies examining the impact of low-frequency drug-resistant HIV-1 variants in treatment-experienced patients due to the current success of cART in HICs; very low failure rates; and, so far, limited availability of clinical tests aimed at quantifying low-frequency HIV-1 variants (24,73). The OCTANE/A5208 study by the AIDS Clinical Trial Group provides our best indication that low-frequency mutations can impact treatment outcomes (49,71,74,75). Women who had previously received a single-dose of NVP to prevent mother-to-child transmission had a 30% rate of treatment failure if randomized to receive an NVP-containing regimen versus a Ͻ10% failure rate with a ritonavir-boosted lopinavir (LPV/r)-containing regimen of FTC plus TDF.…”

Section: Discussionmentioning

confidence: 99%

“…However, minority NNRTI-resistant variants appeared to feature prominently in treatment failures for women in Africa who had received an NVP-based treatment regimen following single-dose NVP treatment to prevent mother-tochild transmission (47,48). Interestingly, NVP selective pressure, rather than the natural occurrence of K103N and Y181C at low frequencies (Ͼ1%) in the intrapatient HIV-1 population, was related to failure of NNRTI-based treatment regimens (49).…”

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confidence: 99%

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Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Kyeyune

Gibson

Nankya

et al. 2016

Antimicrob Agents Chemother

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Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified lowfrequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drugresistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Kyeyune

Gibson

Nankya

et al. 2016

Antimicrob Agents Chemother

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HIV-1 genotypic drug resistance testing: digging deep, reaching wide?

Laethem

Theys

Vandamme

2015

Current Opinion in Virology

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For many years, population-based Sanger sequencing has been the golden standard for drug resistance testing within the routine follow-up of HIV-1 infected patients in resource-rich settings. Often, the data generated within this framework were subsequently used for research and surveillance purposes: to understand therapy response and to gain insights into epidemiological processes. Sanger sequencing was however ill suited for diagnostic and prognostic use in resource-limited settings (RLS) and therefore not broadly implemented. Next-generation sequencing (NGS) technologies provide high-throughput approaches by the rapid acquisition of thousands to millions of short nucleotide sequences. Depending on the experimental design, the roll-out of NGS drug resistance testing at a larger scale is feasible, providing better characterization and understanding of the evolving population of viral variants within a patient and potentially improving the prognostic value of drug resistance testing. Whether the same will become true for RLS will largely depend on affordability and sample logistics, and this may affect other mutation-specific approaches.

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Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya

Beck¹,

Levine²,

McGrath

et al. 2020

eClinicalMedicine

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Background: Pre-treatment HIV-drug-resistance (PDR) to WHO-recommended 1st-line non-nucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral treatment (ART) is increasing in low-resource communities. We evaluated the risk of PDR on treatment failure if detected at single or multiple codons, at minority (2À9%) or higher (10%) frequencies during efavirenz-vs. nevirapine-ART. Methods: We conducted a pooled analysis across three cohorts of Kenyans initiating 1st-line NNRTI-ART between 2006 and 2014. Mutations K103N, Y181C, G190A, M184V and K65R were detected by an oligonucleotide ligation assay (OLA) and confirmed by Sanger and next-generation sequencing (NGS). PDR was defined as detection of any mutation by OLA when confirmed by NGS. Treatment failure, defined as plasma HIV RNA 400 copies/mL at month-12 of ART, was compared by PDR genotypes. Findings: PDR was detected in 59/1231 (4¢8%) participants. Compared to wild-type genotypes, PDR in participants prescribed nevirapine-ART was associated with increased treatment failure [PDR 69¢2% (27/39) vs. wild-type 10¢4% (70/674); p = 0¢0001], whether detected as minority [66¢7% (4/6)] or higher [69¢7% (23/33)] frequencies in an individual's HIV quasispecies (p = 0¢002 and p < 0¢0001, respectively), or mutations at single [50¢0% (12/24)] or multiple [100¢0% (15/15)] codons (p < 0¢0001). During efavirenz-ART, PDR was also associated with increased virologic failure [PDR 25¢0% (5/20) vs. wild-type 5¢0% (25/498); p = 0¢005], but only if detected at multiple drugresistant codons [50¢0% (3/6); p = 0¢003] or high frequencies PDR [33¢3% (5/15); p = 0¢001]. Interpretation: The risk that PDR confers for treatment failure varies by number of mutant codons and their frequency in the quasispecies, with a lower risk for efavirenz-compared to nevirapine-based regimens. PDR detection and management could extend the effective use of efavirenz-ART in low-resource settings.

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Low-Frequency Nevirapine (NVP)–Resistant HIV-1 Variants Are Not Associated With Failure of Antiretroviral Therapy in Women Without Prior Exposure to Single-Dose NVP

Abstract: NCT00089505.

Cited by 29 publications

References 32 publications

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

HIV-1 genotypic drug resistance testing: digging deep, reaching wide?

Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya

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