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Oligonucleotide ligation assay detects HIV drug resistance associated with virologic failure among antiretroviral-naive adults in Kenya.
J Acquir Immune Defic Syndr. 2014 Nov 01; 67(3):246-53.JA

Abstract

BACKGROUND

Transmitted drug resistance (TDR) is increasing in some areas of Africa. Detection of TDR may predict virologic failure of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). We evaluated the utility of a relatively inexpensive oligonucleotide ligation assay (OLA) to detect clinically relevant TDR at the time of ART initiation.

METHODS

Pre-ART plasmas from ART-naive Kenyans initiating an NNRTI-based fixed-dose combination ART in a randomized adherence trial conducted in 2006 were retrospectively analyzed by OLA for mutations conferring resistance to NNRTI (K103N, Y181C, and G190A) and lamivudine (M184V). Post-ART plasmas were analyzed for virologic failure (≥1000 copies/mL) at 6-month intervals over 18-month follow-up. Pre-ART plasmas of those with virologic failure were evaluated for drug resistance by consensus and 454-pyrosequencing.

RESULTS

Among 386 participants, TDR was detected by OLA in 3.89% (95% confidence interval: 2.19 to 6.33) and was associated with a 10-fold higher rate of virologic failure (hazard ratio: 10.39; 95% confidence interval: 3.23 to 32.41; P < 0.001) compared with those without TDR. OLA detected 24 TDR mutations (K103N: n = 13; Y181C: n = 5; G190A: n = 3; M184V: n = 3) in 15 subjects (NNRTI: n = 15; 3TC: n = 3). Among 51 participants who developed virologic failure, consensus sequencing did not detect additional TDR mutations conferring high-level resistance, and pyrosequencing only detected additional mutations at frequencies <2%. Mutant frequencies <2% at ART initiation were significantly less likely to be found at the time of virologic failure compared with frequencies ≥2% (22% vs. 63%; P < 0.001).

CONCLUSIONS

Detection of TDR by a point mutation assay may prevent the use of suboptimal ART.

Authors+Show Affiliations

Departments of *Global Health; †Medicine; ‡Epidemiology, University of Washington, Seattle, WA; §Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA; ‖Department of Obstetrics and Gynaecology, University of Nairobi, Nairobi, Kenya; ¶Department of Biostatistics, University of Washington, Seattle, WA; #Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; **Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA; ††Coptic Hospital, Nairobi, Kenya; Departments of ‡‡Pediatrics; and §§Laboratory Medicine, University of Washington, Seattle, WA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

25140907

Citation

Chung, Michael H., et al. "Oligonucleotide Ligation Assay Detects HIV Drug Resistance Associated With Virologic Failure Among Antiretroviral-naive Adults in Kenya." Journal of Acquired Immune Deficiency Syndromes (1999), vol. 67, no. 3, 2014, pp. 246-53.
Chung MH, Beck IA, Dross S, et al. Oligonucleotide ligation assay detects HIV drug resistance associated with virologic failure among antiretroviral-naive adults in Kenya. J Acquir Immune Defic Syndr. 2014;67(3):246-53.
Chung, M. H., Beck, I. A., Dross, S., Tapia, K., Kiarie, J. N., Richardson, B. A., Overbaugh, J., Sakr, S. R., John-Stewart, G. C., & Frenkel, L. M. (2014). Oligonucleotide ligation assay detects HIV drug resistance associated with virologic failure among antiretroviral-naive adults in Kenya. Journal of Acquired Immune Deficiency Syndromes (1999), 67(3), 246-53. https://doi.org/10.1097/QAI.0000000000000312
Chung MH, et al. Oligonucleotide Ligation Assay Detects HIV Drug Resistance Associated With Virologic Failure Among Antiretroviral-naive Adults in Kenya. J Acquir Immune Defic Syndr. 2014 Nov 1;67(3):246-53. PubMed PMID: 25140907.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oligonucleotide ligation assay detects HIV drug resistance associated with virologic failure among antiretroviral-naive adults in Kenya. AU - Chung,Michael H, AU - Beck,Ingrid A, AU - Dross,Sandra, AU - Tapia,Kenneth, AU - Kiarie,James N, AU - Richardson,Barbra A, AU - Overbaugh,Julie, AU - Sakr,Samah R, AU - John-Stewart,Grace C, AU - Frenkel,Lisa M, PY - 2014/8/21/entrez PY - 2014/8/21/pubmed PY - 2014/12/17/medline SP - 246 EP - 53 JF - Journal of acquired immune deficiency syndromes (1999) JO - J. Acquir. Immune Defic. Syndr. VL - 67 IS - 3 N2 - BACKGROUND: Transmitted drug resistance (TDR) is increasing in some areas of Africa. Detection of TDR may predict virologic failure of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). We evaluated the utility of a relatively inexpensive oligonucleotide ligation assay (OLA) to detect clinically relevant TDR at the time of ART initiation. METHODS: Pre-ART plasmas from ART-naive Kenyans initiating an NNRTI-based fixed-dose combination ART in a randomized adherence trial conducted in 2006 were retrospectively analyzed by OLA for mutations conferring resistance to NNRTI (K103N, Y181C, and G190A) and lamivudine (M184V). Post-ART plasmas were analyzed for virologic failure (≥1000 copies/mL) at 6-month intervals over 18-month follow-up. Pre-ART plasmas of those with virologic failure were evaluated for drug resistance by consensus and 454-pyrosequencing. RESULTS: Among 386 participants, TDR was detected by OLA in 3.89% (95% confidence interval: 2.19 to 6.33) and was associated with a 10-fold higher rate of virologic failure (hazard ratio: 10.39; 95% confidence interval: 3.23 to 32.41; P < 0.001) compared with those without TDR. OLA detected 24 TDR mutations (K103N: n = 13; Y181C: n = 5; G190A: n = 3; M184V: n = 3) in 15 subjects (NNRTI: n = 15; 3TC: n = 3). Among 51 participants who developed virologic failure, consensus sequencing did not detect additional TDR mutations conferring high-level resistance, and pyrosequencing only detected additional mutations at frequencies <2%. Mutant frequencies <2% at ART initiation were significantly less likely to be found at the time of virologic failure compared with frequencies ≥2% (22% vs. 63%; P < 0.001). CONCLUSIONS: Detection of TDR by a point mutation assay may prevent the use of suboptimal ART. SN - 1944-7884 UR - https://www.unboundmedicine.com/medline/citation/25140907/Oligonucleotide_ligation_assay_detects_HIV_drug_resistance_associated_with_virologic_failure_among_antiretroviral_naive_adults_in_Kenya_ L2 - http://dx.doi.org/10.1097/QAI.0000000000000312 DB - PRIME DP - Unbound Medicine ER -