Browsing by Author "Gupta, Ravindra K."

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    Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation
    (Public Library of Science, 2017-07-28) Paredes, Roger; Tzou, Philip L.; Van Zyl, Gert; Barrow, Geoff; Camacho, Ricardo; Carmona, Sergio; Grant, Philip M.; Gupta, Ravindra K.; Hamers, Raph L.; Harrigan, P. Richard; Jordan, Michael R.; Kantor, Rami; Katzenstein, David A.; Kuritzkes, Daniel R.; Maldarelli, Frank; Otelea, Dan; Wallis, Carole L.; Schapiro, Jonathan M.; Shafer, Robert W.
    Introduction: HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. Methods: An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs). Results: There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with “/r” indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required. Conclusions: The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.
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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.