Browsing by Author "Cotton, Mark F."

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    Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure
    (New England Journal of Medicine, 2010) Palumbo, Paul; Lindsey, Jane C.; Hughes, Michael D.; Cotton, Mark F.; Bobat, Raziya; Meyers, Tammy; Dangarembizi, Mutsawashe Bwakura; Chi, Benjamin H.; Musoke, Philippa; Kamthunzi, Portia; Schimana, Werner; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne M.; Philippe, Patrick Jean; Violari, Avy
    Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown.We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events.Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151. opens in new tab.)
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    The Evidence For Using Conjugate Vaccines To Protect HIV-Infected Children Against Pneumococcal Disease
    (The Lancet infectious diseases, 2008) Bliss, Sandra J.; O’Brien, Katherine L.; Janoff, Edward N.; Cotton, Mark F.; Musoke, Philippa; Coovadia, Hoosen; Levine, Orin S.
    Pneumococcal conjugate vaccines (PCVs) are a potentially useful complement to existing treatment strategies in HIV-infected children, for whom pneumococcal infections are common and serious. This Review summarises available data on the burden of pneumococcal disease and the safety and efficacy of PCVs in HIV-infected children. The data demonstrate that children with HIV have significantly increased risk of pneumococcal disease compared with uninfected children; the serotypes included in currently licensed or near-licensure conjugate vaccines include most serotypes that cause invasive pneumococcal disease (IPD) in HIV-infected children and adults; PCVs provide substantial protection against IPD and clinical pneumonia when given to HIV-infected infants; and HIV-infected adults gain an indirect benefit when children in the community are vaccinated. PCV should be considered as an important intervention for improving the lives of HIV-infected children.
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    Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial
    (The Lancet Child & Adolescent Health, 2021) Gaur, Aditya H.; Cotton, Mark F.; Rodriguez, Carina A.; McGrath, Eric J.; Helström, Elizabeth; Liberty, Afaaf; Natukunda, Eva; Kosalaraksa, Pope; Chokephaibulkit, Kulkanya; Maxwell, Heather; Wong, Pamela; Porter, Danielle; Majeed, Sophia; Sang Yue, Mun; Graham, Hiba; Martin, Hal; Brainard, Diana M.; Pikora, Cheryl
    Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. Methods In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per μL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m² by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. Findings Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0–93·0] for AUCtau and 65·4% [58·3–73·3] for Ctau in adolescents; GLSM 125% [90% CI 117–134] for AUCtau and 88·9% [80·6–98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. Interpretation In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide singletablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population.