Browsing by Author "Hughes, Michael D."

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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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    Feasibility of identifying household contacts of rifampin-and multidrug-resistant tuberculosis cases at high risk of progression to tuberculosis disease
    (Oxford University Press, 2020-01) Gupta, Amita; Swindells, Susan; Kim, Soyeon; Hughes, Michael D.; Naini, Linda; Wu, Xingye; Dawson, Rodney; Mave, Vidya; Sanchez, Jorge; Mendoza, Alberto; Gonzales, Pedro; Kumarasamy, Nagalingeswaran; Comins, Kyla; Conradie, Francesca; Shenje, Justin; Fontain, Sandy Nerette; Garcia-Prats, Anthony; Asmelash, Aida; Nedsuwan, Supalert; Mohapi, Lerato; Lalloo, Umesh G.; Ferreira, Ana Cristina Garcia; Mugah, Christopher; Harrington, Mark; Jones, Lynne; Cox, Samyra R.; Smith, Betsy; Shah, N Sarita; Hesseling, Anneke C.; Churchyard, Gavin
    Background: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. Methods: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. Results: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. Conclusions: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.
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    Inclusion of key populations in clinical trials of new antituberculosis treatments : current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons
    (Public Library of Science, 2019) Gupta, Amita; Hughes, Michael D.; Garcia-Prats, Anthony J.; McIntire, Katherine; Hesseling, Anneke C.
    ENGLISH ABSTRACT: Pregnant women, children < 15 years old and, HIV-infected persons contribute approximately 20% of the global tuberculosis (TB) burden, with an estimated 216,000, 1,000,000, and 1,040,000 cases each year, respectively, yet these populations are currently largely excluded from TB clinical trials, leading to suboptimal treatment and poor access to new therapeutics. • Special considerations in these populations include specific TB disease spectrum and severity, lower sensitivity of commonly used TB diagnostic tests, potential differential drug dosing and treatment responses, drug–drug interactions, and challenges in acquiring high-quality data through clinical trials. • To counter the automatic exclusion of pregnant and lactating women that currently pervades the TB trial landscape, early discussions among trialists, pharmaceutical companies, maternal–child clinical experts, ethicists, and regulatory bodies are needed to address risks, benefits, and compelling rationale for inclusion. Reconsenting women when pregnancy occurs on a trial to allow continuation of study drug by informed choice is a practical and valuable approach to expand the currently limited evidence base. • Children tend to have less severe, often paucibacillary TB disease and may respond better to treatment than adults. Consequently, trials of shorter, less intense TB treatment regimens in children are needed; pharmacokinetic and safety studies should be initiated earlier and involve age groups in parallel rather than in an age-de-escalation approach. More rapid development of child-friendly drug formulations is needed. • All HIV-infected populations, including those with advanced disease, who are likely to be the intended population of the TB therapy, should be involved in Phase IIb and/or Phase III trials, as appropriate, to maximize knowledge of treatment, toxicities, drug– drug interactions, and outcomes.
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    Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children
    (Massachusetts Medical Society, 2012) Violari, Avy; Paed, F. C.; Lindsey, Jane C.; Hughes, Michael D.; Mujuru, Hilda A.; Barlow-Mosha, Linda; Kamthunzi, Portia; Chi, Benjamin H.; Cotton, Mark F.; Moultrie, Harry; Khadse, Sandhya; Schimana, Werner; Bobat, Raziya; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne M.; Jean-Philippe, Patrick; Palumbo, Paul
    BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log 10 copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P = 0.04), as was the time to death (P = 0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.