title: HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.
abstract: The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA, United States of America.
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.affiliation: Tufts University School of Medicine, Boston, MA, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jordan
authors.affiliation: Division of Global HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, GA, United States of America.
authors.forename: Elliot
authors.initials: E
authors.lastname: Raizes
authors.affiliation: Medecins Sans Frontieres, Access Campaign, Geneva, Switzerland.|Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Arlene
authors.initials: A
authors.lastname: Chua
authors.affiliation: Data First Consulting, Belmont, CA, United States of America.
authors.forename: Neil
authors.initials: N
authors.lastname: Parkin
authors.affiliation: Alpert Medical School, Brown University, Providence, RI, United States of America.
authors.forename: Rami
authors.initials: R
authors.lastname: Kantor
authors.affiliation: National Health Laboratory Service, Tygerberg, Coastal Branch, South Africa.|Division of Medical Virology, Stellenbosch University, Parow, South Africa.
authors.forename: Gert U
authors.initials: GU
authors.lastname: Van Zyl
authors.affiliation: National AIDS and Sexually Transmitted Infection (STI) Control Programme, Ministry of Health, Nairobi, Kenya.
authors.forename: Irene
authors.initials: I
authors.lastname: Mukui
authors.affiliation: UNC Project, Lilongwe, Malawi.
authors.forename: Mina C
authors.initials: MC
authors.lastname: Hosseinipour
authors.affiliation: University of Washington and Seattle Children's Research Institute, Seattle, WA, United States of America.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Frenkel
authors.affiliation: Institute of Human Virology, Abuja, Nigeria.
authors.forename: Nicaise
authors.initials: N
authors.lastname: Ndembi
authors.affiliation: Amsterdam Institute for Global Health and Development (AIGHD), Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Raph L
authors.initials: RL
authors.lastname: Hamers
authors.affiliation: Amsterdam Institute for Global Health and Development (AIGHD), Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Tobias F
authors.initials: TF
authors.lastname: Rinke de Wit
authors.affiliation: Lancet Laboratories and BARC-SA, Johannesburg, South Africa.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.affiliation: Department of Infection, University College London, London, United Kingdom.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
authors.affiliation: Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management, Yaoundé, Cameroon.|Faculty of Medicine and Biomedical Sciences (FMBS) of the University of Yaounde 1, Yaounde, Cameroon.
authors.forename: Joseph
authors.initials: J
authors.lastname: Fokam
authors.affiliation: Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors.forename: Clement
authors.initials: C
authors.lastname: Zeh
authors.affiliation: National Hemophilia Center, Tel Hashomer, Israel.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa.|National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Sergio
authors.initials: S
authors.lastname: Carmona
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Tang
authors.affiliation: Virology Laboratory CREMER-IMPM, Yaoundé, Cameroon.
authors.forename: Avelin F
authors.initials: AF
authors.lastname: Aghokeng
authors.affiliation: Africa Centre for Health and Population Studies, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Tulio
authors.initials: T
authors.lastname: De Oliveira
authors.affiliation: Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
authors.affiliation: Southwest CARE Center, Santa Fe, NM, United States of America.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Gallant
authors.affiliation: McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, United States of America.|Veterans Affairs San Diego Healthcare System, San Diego, CA, United States of America.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.affiliation: Drug Development and Clinical Sciences Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Fitzgibbon
authors.affiliation: HJF-DAIDS, A Division of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Schito
authors.affiliation: HIV Department WHO, Geneva, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bertagnolio
authors.affiliation: Division of Global HIV/AIDS, Centers for Disease Control and Prevention, Atlanta, GA, United States of America.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Shafer
mesh_terms: D000069446:Atazanavir Sulfate / Q000494:pharmacology / Q000627:therapeutic use; D000069454:Darunavir / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D060005:Genotyping Techniques / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics*; D019095:Point-of-Care Systems; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019438:Ritonavir / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D011480:Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D000069454:Darunavir