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Drug Resistance and Viral Tropism in HIV-1 Subtype C-Infected Patients in KwaZulu-Natal, South Africa: Implications for Future Treatment Options

Singh, Ashika PhD*; Sunpath, Henry MBBS, MFamMed, MPH; Green, Taryn N. MMedSc*; Padayachi, Nagavelli MMedSc*; Hiramen, Keshni BMedSc*; Lie, Yolanda BA; Anton, Elizabeth D. BA; Murphy, Richard MD, MPH§; Reeves, Jacqueline D. PhD; Kuritzkes, Daniel R. MD‖,¶; Ndung'u, Thumbi BVM, PhD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1st, 2011 - Volume 58 - Issue 3 - p 233–240
doi: 10.1097/QAI.0b013e318228667f
Basic and Translational Science

Background Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.

Methods We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.

Results Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.

Conclusions The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.

*HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

McCord Hospital, Durban, KwaZulu-Natal, South Africa

Monogram Biosciences Inc, South San Francisco, CA

§Operational Support Unit, Doctors Without Borders, New York, NY

the Section of Retroviral Therapeutics, Brigham and Women's Hospital, Boston, MA

Harvard Medical School, Boston, MA.

This study was funded by the US National Institutes of Health (grant AI060354-05) through a Harvard University Center for AIDS Research (CFAR) feasibility grant and grant 5R44AT057068 to Monogram Biosciences. Additional funding was provided by the South African Department of Science and Technology/National Research Foundation Research Chair Initiative to T.N. A.S. was supported by the Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, National Institutes of Health (grant D43TW00231) and by a training grant from the East Coast Biotechnology Research Innovation Centre (LIFElab), funded by the South African Department of Science and Technology.

The authors have no conflicts of interest to disclose.

Correspondence to: Thumbi Ndung'u, PhD, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Private Bag X7, Congella, Durban 4001, South Africa (e-mail: ndungu@ukzn.ac.za).

Received April 5, 2011

Accepted June 8, 2011

© 2011 Lippincott Williams & Wilkins, Inc.