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Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya.
EClinicalMedicine. 2020 Jan; 18:100239.E

Abstract

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 (2-9%) 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 drug-resistant 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.

Funding

NIH, PEPFAR.

Authors+Show Affiliations

Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States.Department of Global Health, University of Washington, Seattle, WA, United States.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States.Department of Global Health, University of Washington, Seattle, WA, United States. Coptic Hope Center for Infectious Diseases, Coptic Hospital, Nairobi, Kenya.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States. Department of Global Health, University of Washington, Seattle, WA, United States.Department of Medicine, University of Washington, Seattle, WA, United States. Department of Laboratory Medicine, University of Washington, Seattle, WA, United States.Department of Obstetrics and Gynecology, University of Nairobi, Nairobi, Kenya.Department of Global Health, University of Washington, Seattle, WA, United States. Kenya Medical Research Institute, Nairobi, Kenya.Coptic Hope Center for Infectious Diseases, Coptic Hospital, Nairobi, Kenya.Department of Global Health, University of Washington, Seattle, WA, United States. Department of Medicine, Aga Khan University, Nairobi, Kenya.Center for Infectious Diseases Research, Seattle Children's Research Institute, Seattle, WA, United States. Department of Global Health, University of Washington, Seattle, WA, United States. Department of Medicine, University of Washington, Seattle, WA, United States. Department of Laboratory Medicine, University of Washington, Seattle, WA, United States. Department of Pediatrics, University of Washington, Seattle, WA, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31956856

Citation

Beck, Ingrid A., et al. "Pre-treatment HIV-drug Resistance Associated With Virologic Outcome of First-line NNRTI-antiretroviral Therapy: a Cohort Study in Kenya." EClinicalMedicine, vol. 18, 2020, p. 100239.
Beck IA, Levine M, McGrath CJ, et al. Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya. EClinicalMedicine. 2020;18:100239.
Beck, I. A., Levine, M., McGrath, C. J., Bii, S., Milne, R. S., Kingoo, J. M., So, I., Andersen, N., Dross, S., Coombs, R. W., Kiarie, J., Chohan, B., Sakr, S. R., Chung, M. H., & Frenkel, L. M. (2020). Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya. EClinicalMedicine, 18, 100239. https://doi.org/10.1016/j.eclinm.2019.100239
Beck IA, et al. Pre-treatment HIV-drug Resistance Associated With Virologic Outcome of First-line NNRTI-antiretroviral Therapy: a Cohort Study in Kenya. EClinicalMedicine. 2020;18:100239. PubMed PMID: 31956856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: A cohort study in Kenya. AU - Beck,Ingrid A, AU - Levine,Molly, AU - McGrath,Christine J, AU - Bii,Steve, AU - Milne,Ross S, AU - Kingoo,James M, AU - So,Isaac, AU - Andersen,Nina, AU - Dross,Sandra, AU - Coombs,Robert W, AU - Kiarie,James, AU - Chohan,Bhavna, AU - Sakr,Samah R, AU - Chung,Michael H, AU - Frenkel,Lisa M, Y1 - 2020/01/14/ PY - 2019/09/04/received PY - 2019/12/05/revised PY - 2019/12/09/accepted PY - 2020/1/21/entrez PY - 2020/1/21/pubmed PY - 2020/1/21/medline KW - Efavirenz KW - First-line ART KW - Minority drug resistant variants KW - NNRTI drug resistance KW - Pre-treatment HIV drug resistance KW - Virologic failure SP - 100239 EP - 100239 JF - EClinicalMedicine JO - EClinicalMedicine VL - 18 N2 - 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 (2-9%) 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 drug-resistant 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. Funding: NIH, PEPFAR. SN - 2589-5370 UR - https://www.unboundmedicine.com/medline/citation/31956856/Pre_treatment_HIV_drug_resistance_associated_with_virologic_outcome_of_first_line_NNRTI_antiretroviral_therapy:_A_cohort_study_in_Kenya_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2589-5370(19)30244-5 DB - PRIME DP - Unbound Medicine ER -
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