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Observational Study
. 2022 Nov 15;36(14):1949-1958.
doi: 10.1097/QAD.0000000000003361. Epub 2022 Aug 18.

Low-frequency pre-treatment HIV drug resistance: effects on 2-year outcome of first-line efavirenz-based antiretroviral therapy

Ross S Milne  1 , Ingrid A Beck  1 , Molly Levine  1 , Isaac So  1 , Nina Andersen  1 , Wenjie Deng  2 , Nuttada Panpradist  2 , James Kingoo  2   3 , Catherine Kiptinness  2 , Nelly Yatich  2 , James N Kiarie  4 , Samah R Sakr  3 , Michael H Chung  2 , Lisa M Frenkel  1   2
Affiliations
Observational Study

Low-frequency pre-treatment HIV drug resistance: effects on 2-year outcome of first-line efavirenz-based antiretroviral therapy

Ross S Milne et al. AIDS. .

Abstract

Objectives: Assess the impact of pre-treatment high-frequency and low-frequency drug-resistant HIV variants on long-term outcomes of first-line efavirenz-based antiretroviral therapy (ART).

Design: Prospective observational study.

Methods: Participants' pre-treatment plasma RNA had two sections of HIV pol encoding reverse transcriptase sequenced (Illumina, MiSeq) using unique molecular identifiers to detect wild-type (pre-treatment drug-resistant variants less than 1% of viral quasispecies), low-frequency (1-9%) or high-frequency drug-resistant variants (10-100%). Associations between pre-treatment drug resistance and virologic outcomes over 24 months of efavirenz-based ART were assessed for the number and frequency of mutations by drug class and other resistance parameters.

Results: Virologic failure was detected in 30 of 352 (9%) and pre-treatment drug-resistant variants were detected in the viral quasispecies of 31 of 352 (9%) participants prescribed efavirenz-based ART. Survival analyses revealed statistically significant associations between pre-treatment drug resistance at low (P < 0.0001) and high (P < 0.001) frequencies, at oligonucleotide ligation assay (OLA) (P < 0.00001) and non-OLA (P < 0.01) codons, to a single-antiretroviral class (P < 0.00001), and a shorter time to virologic failure of efavirenz-based ART. Regression analyses detected independent effects across resistance categories, including both low-frequency (P < 0.01) and high-frequency (P < 0.001) drug-resistant variants.

Conclusion: We observed that pre-treatment HIV drug resistance detected at low frequencies increased the risk of virologic failure over 24 months of efavirenz-based ART, but that most failures, regardless of drug-resistant variants' frequencies, were detected within a year of ART initiation. These observations suggest that when efavirenz-based ART is prescribed, screening for pre-treatment drug resistance by an assay capable of detecting low-frequency variants, including OLA, may guide clinicians to prescribe more effective ART.

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Conflict of interest statement

Conflicts of Interest:

No author declared a conflict of interest.

Figures

Figure 1.
Figure 1.. Schema of participant enrollment, drug-resistance genotyping, and virologic outcomes.
Figure 2.
Figure 2.. Kaplan Meier Survival Analysis of participants with and without pretreatment drug-resistant variants detected by next-generation sequencing.
Panel A: Shorter time to virologic failure was observed among study participants with low-frequency variants alone (P<0.001) or any high-frequency variants (P<0.001), compared to those with wild-type virus. Panel B: Participants with variants at OLA (P<0.001) or non-OLA codons alone (P=0.003) experienced shorter time to virologic failure. Panel C: Shorter time to virologic failure was observed among participants with variants encoding resistance to both a single class (NRTI or NNRTI) alone or dual-drug classes (at least one variant resistant to NRTIs and at least one variant resistant to NNRTIs), although sample size limited testing for statistical significance. Panel D: Shorter time to virologic failure was observed among participants with drug-resistant variants encoding Stanford resistance penalty scores of both less-than-or-equal-to 60 or greater-than 60, but sample size prohibited testing for statistical significance. * = P<0.01; ** = P<0.001
See this image and copyright information in PMC

References

    1. Silverman RA, Beck IA, Kiptinness C, et al. Prevalence of Pre-antiretroviral-Treatment Drug Resistance by Gender, Age, and Other Factors in HIV-Infected Individuals Initiating Therapy in Kenya, 2013–2014. J Infect Dis. 2017;216(12):1569–1578. doi:10.1093/infdis/jix544 - DOI - PMC - PubMed
    1. Gupta RK, Gregson J, Parkin N, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis. 2018;18(3):346–355. doi:10.1016/S1473-3099(17)30702-8 - DOI - PMC - PubMed
    1. Update of Recommendations on First- and Second-Line Antiretroviral Regimens. World Health Organization; 2019.
    1. Kouamou V, Mavetera J, Manasa J, et al. Pretreatment HIV Drug Resistance Among Adults Initiating or Re-Initiating First-Line Antiretroviral Therapy in Zimbabwe: Fast-Tracking the Transition to Dolutegravir-Based First-Line Regimens? AIDS Res Hum Retroviruses. 2021. Feb 5. doi: 10.1089/AID.2020.0242. Epub ahead of print. - DOI - PubMed
    1. Kantor R, Smeaton L, Vardhanabhuti S, et al. Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 2015;60(10):1541–1549. doi:10.1093/cid/civ102 - DOI - PMC - PubMed

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