Herbert A Mbunkah1,2,3, Silvia Bertagnolio4, Raph L Hamers5,6,7, Gillian Hunt8, Seth Inzaule5, Tobias F Rinke De Wit5, Roger Paredes9, Neil T Parkin10, Michael R Jordan11, Karin J Metzner1,2. 1. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zürich, Switzerland. 2. Institute of Medical Virology, University of Zurich, Zürich, Switzerland. 3. Paul-Ehrlich-Institut, Langen, Germany. 4. HIV Department, World Health Organization, Geneva, Switzerland. 5. Amsterdam Institute for Global Health and Development, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 6. Eijkman-Oxford Clinical Research Unit, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. 7. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. 8. National Institute for Communicable Diseases, Johannesburg, South Africa. 9. Infectious Diseases Service and IrsiCaixa AIDS Research Institute for AIDS Research, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain. 10. Data First Consulting, Sebastopol, California, USA. 11. Division of Geographic Medicine and Infectious Disease, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA.
Abstract
BACKGROUND: The presence of high-abundance drug-resistant HIV-1 jeopardizes success of antiretroviral therapy (ART). Despite numerous investigations, the clinical impact of low-abundance drug-resistant HIV-1 variants (LA-DRVs) at levels <15%-25% of the virus population in antiretroviral (ARV) drug-naive individuals remains controversial. METHODS: We systematically reviewed 103 studies assessing prevalence, detection methods, technical and clinical detection cutoffs, and clinical significance of LA-DRVs in antiretroviral drug-naive adults. RESULTS: In total, 14 919 ARV drug-naive individuals were included. Prevalence of LA-DRVs (ie, proportion of individuals harboring LA-DRVs) was 0%-100%. Technical detection cutoffs showed a 4 log range (0.001%-10%); 42/103 (40.8%) studies investigating the impact of LA-DRVs on ART; 25 studies included only individuals on first-line nonnucleoside reverse transcriptase inhibitor-based ART regimens. Eleven of those 25 studies (44.0%) reported a significantly association between preexisting LA-DRVs and risk of virological failure whereas 14/25 (56.0%) did not. CONCLUSIONS: Comparability of the 103 studies is hampered by high heterogeneity of the studies' designs and use of different methods to detect LA-DRVs. Thus, evaluating clinical impact of LA-DRVs on first-line ART remains challenging. We, the WHO HIVResNet working group, defined central areas of future investigations to guide further efforts to implement ultrasensitive resistance testing in routine settings.
BACKGROUND: The presence of high-abundance drug-resistant HIV-1 jeopardizes success of antiretroviral therapy (ART). Despite numerous investigations, the clinical impact of low-abundance drug-resistant HIV-1 variants (LA-DRVs) at levels <15%-25% of the virus population in antiretroviral (ARV) drug-naive individuals remains controversial. METHODS: We systematically reviewed 103 studies assessing prevalence, detection methods, technical and clinical detection cutoffs, and clinical significance of LA-DRVs in antiretroviral drug-naive adults. RESULTS: In total, 14 919 ARV drug-naive individuals were included. Prevalence of LA-DRVs (ie, proportion of individuals harboring LA-DRVs) was 0%-100%. Technical detection cutoffs showed a 4 log range (0.001%-10%); 42/103 (40.8%) studies investigating the impact of LA-DRVs on ART; 25 studies included only individuals on first-line nonnucleoside reverse transcriptase inhibitor-based ART regimens. Eleven of those 25 studies (44.0%) reported a significantly association between preexisting LA-DRVs and risk of virological failure whereas 14/25 (56.0%) did not. CONCLUSIONS: Comparability of the 103 studies is hampered by high heterogeneity of the studies' designs and use of different methods to detect LA-DRVs. Thus, evaluating clinical impact of LA-DRVs on first-line ART remains challenging. We, the WHO HIVResNet working group, defined central areas of future investigations to guide further efforts to implement ultrasensitive resistance testing in routine settings.
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