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.
Departments of *Global Health;
‡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.
Correspondence to: Michael H. Chung, MD, MPH, Departments of Global Health and Medicine, University of Washington, 325 Ninth Ave, Box 359909, Seattle, WA 98104 (e-mail:email@example.com).
Supported by grants and by an American Recovery and Reinvestment Act supplement from the National Institutes of Health (R01-AI058723 to L.M.F. and K23-AI065222 to M.H.C.). The study was also supported by the University of Washington Center for AIDS Research [P30AI027757]. The Coptic Hope Center for Infectious Diseases is supported by the President's Emergency Plan for AIDS Relief through a cooperative agreement [U62/CCU024512] from the Centers for Disease Control and Prevention.
Presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011), February 27–March 2, 2011, Boston, MA (Oral Abstract No. 41).
The authors have no conflicts of interest to disclose.
M.H.C. designed and implemented the study, supervised the on-site data management, interpreted the data, and wrote the article. L.M.F. led the laboratory analysis, designed the study, interpreted the data, and wrote the article. I.A.B conducted the laboratory analysis, interpreted the data, and helped to write the article. S.D. conducted the laboratory analysis, interpreted the data, and helped to write the article. K.T. analyzed the data and helped to interpret the results. J.N.K. helped to implement the study, oversee data collection, and helped to write the article. B.A.R. analyzed the data and interpreted the results. J.O. helped to conduct and analyze the laboratory data and to write the article. S.R.S. helped to implement and design the study. G.C.J.-S. helped to interpret the data and to write the article.
Received March 02, 2014
Accepted July 15, 2014