Browsing by Author "Saravanan, Shanmugam"

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    Diverse Human Immunodeficiency Virus-1 Drug Resistance Profiles at Screening for ACTG A5288: A Study of People Experiencing Virologic Failure on Second-line Antiretroviral Therapy in Resource-limited Settings
    (Oxford University Press, 2020-10) Wallis, Carole L.; Hughes, Michael D.; Ritz, Justin; Viana, Raquel; de Jesus, Carlos Silva; Saravanan, Shanmugam; van Schalkwyk, Marije; Mngqibisa, Rosie; Salata, Robert; Mugyenyi, Peter; Hogg, Evelyn; Hovind, Laura; Wieclaw, Linda; Gross, Robert; Godfrey, Catherine; Collier, Ann C.; Grinsztejn, Beatriz; Mellors, John W.
    Background: Human immunodeficiency virus (HIV) drug resistance profiles are needed to optimize individual patient management and to develop treatment guidelines. Resistance profiles are not well defined among individuals on failing second-line antiretroviral therapy (ART) in low- and middle-income countries (LMIC). Methods: Resistance genotypes were performed during screening for enrollment into a trial of third-line ART (AIDS Clinical Trials Group protocol 5288). Prior exposure to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs and confirmed virologic failure on a protease inhibitor-containing regimen were required. Associations of drug resistance with sex, age, treatment history, plasma HIV RNA, nadir CD4+T-cell count, HIV subtype, and country were investigated. Results: Plasma HIV genotypes were analyzed for 653 screened candidates; most had resistance (508 of 653; 78%) to 1 or more drugs. Genotypes from 133 (20%) showed resistance to at least 1 drug in a drug class, from 206 (32%) showed resistance to at least 1 drug in 2 drug classes, and from 169 (26%) showed resistance to at least 1 drug in all 3 commonly available drug classes. Susceptibility to at least 1 second-line regimen was preserved in 59%, as were susceptibility to etravirine (78%) and darunavir/ritonavir (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+ T-cell counts, and those who had received lopinavir/ritonavir, but was lower among prior nevirapine recipients. Conclusions: Highly divergent HIV drug resistance profiles were observed among candidates screened for third-line ART in LMIC, ranging from no resistance to resistance to 3 drug classes. These findings underscore the need for access to resistance testing and newer antiretrovirals for the optimal management of third-line ART in LMIC.
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    Mutational correlates of virological failure in individuals receiving a WHO-recommended tenofovir-containing first-line regimen : an international collaboration
    (Elsevier, 2017) Rhee, Soo-Yon; Varghese, Vici; Holmes, Susan P.; Van Zyl, Gert U.; Steegen, Kim; Boyd, Mark A.; Cooper, David A.; Nsanzimana, Sabin; Saravanan, Shanmugam; Charpentier, Charlotte; De Oliveira, Tulio; Etiebet, Mary-Ann A.; Garcia, Federico; Goedhals, Dominique; Gomes, Perpetua; Gunthard, Huldrych F.; Hamers, Raph L.; Hoffmann, Christopher J.; Hunt, Gillian; Jiamsakul, Awachana; Kaleebu, Pontiano; Kanki, Phyllis; Kantor, Rami; Kerschberger, Bernhard; Marconi, Vincent C.; Ndahimana, Jean D'amour; Ndembi, Nicaise; Ngo-Giang-Huong, Nicole; Rokx, Casper; Santoro, Maria M.; Schapiro, Jonathan M.; Schmidt, Daniel; Seu, Lillian; Sigaloff, Kim C. E.; Sirivichayakul, Sunee; Skhosana, Lindiwe; Sunpath, Henry; Tang, Michele; Yang, Chunfu; Carmona, Sergio; Gupta, Ravindra K.; Shafer, Robert W.
    Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.