Browsing by Author "Chakhtoura N"

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Association of Maternal Viral Load and CD4 Count With Perinatal HIV-1 Transmission Risk During Breastfeeding in the PROMISE Postpartum Component.
(2021-Oct-01) Flynn PM; Taha TE; Cababasay M; Butler K; Fowler MG; Mofenson LM; Owor M; Fiscus S; Stranix-Chibanda L; Coutsoudis A; Gnanashanmugam D; Chakhtoura N; McCarthy K; Frenkel L; Beck I; Mukuzunga C; Makanani B; Moodley D; Nematadzira T; Kusakara B; Patil S; Vhembo T; Bobat R; Mmbaga BT; Masenya M; Nyati M; Theron G; Mulenga H; Shapiro DE; University of North Carolina Project-Malawi, Kamuzu Central Hospital, Lilongwe, Malawi.; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA.; Wits Reproductive Health and HIV Institute, Johannesburg, South Africa.; Division of AIDS, National Institute of Allergy and Immunology, National Institutes of Health, Bethesda, MD.; Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC.; Maternal and Pediatric Infectious Disease Branch, Division of Extramural Research, Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD.; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN.; Department of Pediatrics and Child Health, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.; Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda.; Department of Obstetrics and Gynaecology, Centre for the AIDS Programme of Research in South Africa and School of Clinical Medicine, College of Health Sciences, University of KwaZulu Natal, Durban, South Africa.; University of Zimbabwe Clinical Trials Research Centre, Harare, Zimbabwe.; Department of Obstetrics and Gynecology, College of Medicine, University of Malawi, Blantyre, Malawi.; Perinatal HIV Research Unit, Chris Baragwanath Hospital, Johannesburg, South Africa.; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe.; Department of Obstetrics and Gynecology, Byramjee Jeejeebhoy Government Medical College and Johns Hopkins Clinical Trials Unit, Pune, India.; Department of Pediatrics and Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.; Department of Pediatrics, Kilimanjaro Christian Medical Centre and Kilimanjaro Christian Medical University College, Moshi, Tanzania.; Center for Biostatistics in AIDS Research, Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA.; Department of Pediatrics and Child Health, University of KwaZulu-Natal, Durban, South Africa.; Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; and.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.; FHI 360, Durham, NC.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Breastfeeding mothers with HIV infection not qualifying for antiretroviral therapy (ART) based on country-specific guidelines at the time of the Promoting Maternal-Infant Survival Everywhere trial and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) postpartum. HIV transmission proportions were similar (<1%) in the 2 arms. We assessed whether maternal viral load (MVL) and CD4 cell counts were associated with breastfeeding HIV transmission. METHODS: MVL was collected at entry (7-14 days postpartum) and at weeks 6, 14, 26, and 50 postpartum. CD4 cell counts were collected at entry and weeks 14, 26, 38, and 50 postpartum. Infant HIV-1 nucleic acid test was performed at weeks 1 and 6, every 4 weeks until week 26, and then every 12 weeks. The associations of baseline and time-varying MVL and CD4 cell counts with transmission risk were assessed using time-to-event analyses by randomized treatment arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled in the study. Baseline MVL (P = 0.11) and CD4 cell counts (P = 0.51) were not significantly associated with infant HIV-1 infection. Time-varying MVL was significantly associated with infant HIV-1 infection {hazard ratio [95% confidence interval (CI)]: 13.96 (3.12 to 62.45)} in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 1.04 (0.20 to 5.39)]. Time-varying CD4 cell counts were also significantly associated with infant HIV-1 infection [hazard ratio (95% CI): 0.18 (0.03 to 0.93)] in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 0.38 (0.08 to 1.77)]. CONCLUSIONS: In women receiving mART, increased MVL and decreased CD4 cell counts during breastfeeding were associated with increased risk of infant HIV-1 infection.
Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years.
(2019-Aug-01) Bwakura Dangarembizi M; Samson P; Capparelli EV; Moore CB; Jean-Philippe P; Spector SA; Chakhtoura N; Benns A; Zimmer B; Purdue L; Jackson C; Wallis C; Libous JL; Chadwick EG; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.; Rady Children's Hospital, San Diego, CA.; IMPAACT Operations Center, FHI360, Durham, NC.; BARC-SA and Lancet Laboratories, Johannesburg, South Africa.; National Institutes of Allergy and Infectious Diseases, Bethesda, MD.; Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA.; Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA.; Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD.; Department of Pediatrics, Texas Children's Hospital Baylor College of Medicine, Houston, TX.; Northwestern University's Feinberg School of Medicine, Chicago, IL.; Frontier Science and Technology Research Foundation, Amherst, NY.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; University of Alabama at Birmingham, Birmingham, AL.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection. METHODS: Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 μg × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks. RESULTS: Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) μg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) μg × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC. CONCLUSIONS: Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.
Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age.
(2022-Mar-15) Nikanjam M; Tran L; Chadwick EG; Bwakura-Dangarembizi M; Bolton Moore C; Samson P; Spector SA; Chakhtoura N; Jean-Philippe P; Frenkel L; Zimmer B; Benns A; Libous J; Capparelli EV; Maternal and Pediatric Infectious Disease Branch (MPIDB), Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health.; Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.; Frontier Science and Technology Research Foundation, Amherst, New York.; Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.; Department of Pediatrics, University of Washington, Seattle, Washington.; Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.; Statistical and Data Management Center (SDMC) Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research/Frontier Science Foundation, Boston, Massachusetts.; Division of AIDS, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland, USA.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; Centre for Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama.; IMPAACT Operations Center, FHI360, Durham, North Carolina, USA.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
OBJECTIVE: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. DESIGN: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. METHODS: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. RESULTS: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). CONCLUSION: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women With High CD4 Cell Count (IMPAACT PROMISE): A Randomized, Open-Label, Clinical Trial.
(2018-Apr-01) Flynn PM; Taha TE; Cababasay M; Fowler MG; Mofenson LM; Owor M; Fiscus S; Stranix-Chibanda L; Coutsoudis A; Gnanashanmugam D; Chakhtoura N; McCarthy K; Mukuzunga C; Makanani B; Moodley D; Nematadzira T; Kusakara B; Patil S; Vhembo T; Bobat R; Mmbaga BT; Masenya M; Nyati M; Theron G; Mulenga H; Butler K; Shapiro DE; Wits Reproductive Health and HIV Institute, Johannesburg, South Africa.; Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.; Division of AIDS, National Institute of Allergy and Immunology, National Institutes of Health, Bethesda, MD.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC.; Department of Pediatrics, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN.; Department of Pediatrics and Child Health, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.; Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda.; Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD.; Elisabeth Glaser Pediatric AIDS Foundation, Washington, DC.; Department of Obstetrics and Gynecology, College of Medicine, University of Malawi, Blantyre, Malawi.; Perinatal HIV Research Unit, Chris Baragwanath Hospital, Johannesburg, South Africa.; University of Zimbabwe-University of California, San Francisco, Harare, Zimbabwe.; Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, MA.; Department of Obstetrics and Gynecology, Byramjee Jeejeebhoy Government Medical College and Johns Hopkins Clinical Trials Unit, Pune, India.; Department of Obstetrics and Gynecology, Centre for the AIDS Programme of Research in South Africa and School of Clinical Medicine, College of Health Sciences, University of KwaZulu Natal, Durban, South Africa.; University of North Carolina-Lilongwe, Lilongwe, Malawi.; Department of Paediatrics and Child Health, College of Health Sciences, University of Zimbabwe, Harare, Zimbabwe.; Department of Pediatrics and Child Health, University of KwaZulu-Natal, Durban, South Africa.; George Clinic, Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia.; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.; FHI 360, Durham, NC.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period. SETTING: Fourteen sites in Sub-Saharan Africa and India. METHODS: A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts ≥350 cells/mm (or ≥country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry. RESULTS: Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life-threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively). CONCLUSIONS: Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.
Slow Acceptance of Universal Antiretroviral Therapy (ART) Among Mothers Enrolled in IMPAACT PROMISE Studies Across the Globe.
(2019-Sep) Stranix-Chibanda L; Brummel S; Pilotto J; Mutambanengwe M; Chanaiwa V; Mhembere T; Kamateeka M; Aizire J; Masheto G; Chamanga R; Maluwa M; Hanley S; Joao E; Theron G; Nevrekar N; Nyati M; Santos B; Aurpibul L; Mubiana-Mbewe M; Oliveira R; Anekthananon T; Mlay P; Angelidou K; Tierney C; Ziemba L; Coletti A; McCarthy K; Basar M; Chakhtoura N; Browning R; Currier J; Fowler MG; Flynn P; Instituto of Pediatrics Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.; Kilimanjaro Christian Medical Centre, Moshi, Tanzania.; Harvard T.H. Chan School of Public Health, Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.; Centre Aids Prevention Research South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.; Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, USA.; University of Zimbabwe College of Health Sciences, Paediatrics and Child Health, Harare, Zimbabwe. lstranix@uzchs-ctrc.org.; College of Medicine - Johns Hopkins Research Project, Blantyre, Malawi.; University of North Carolina Project, Lilongwe, Malawi.; University of Zimbabwe College of Health Sciences - Clinical Trials Research Centre, 15 Phillips Avenue, Belgravia, Harare, Zimbabwe.; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.; Perinatal HIV Research Unit, Johannesburg, South Africa.; Division of Infectious Diseases, University of California Los Angeles, Los Angeles, USA.; Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research in the Department of Biostatistics, Boston, USA.; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, USA.; Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.; Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town, South Africa.; FHI 360, IMPAACT Operations Center, Durham, NC, USA.; University of Zimbabwe College of Health Sciences - Clinical Trials Research Centre, 15 Phillips Avenue, Belgravia, Harare, Zimbabwe. lstranix@uzchs-ctrc.org.; Frontier Science and Technology Research Foundation, Amherst, USA.; Department of Infectious Diseases, Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA.; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, China.; Hospital Nossa Senhora da Conceicao, Porto Alegre, Brazil.; Laboratorio de AIDS e Imunologia Molecular - Fiocruz, Hospital Geral de Nova Iguacu, Rio de Janeiro, Brazil.; Makerere University - Johns Hopkins University Research Collaboration, Kampala, Uganda.; Department of Obstetrics and Gynaecology, BJ Government Medical College, Pune, India.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
The PROMISE trial enrolled asymptomatic HIV-infected pregnant and postpartum women not eligible for antiretroviral treatment (ART) per local guidelines and randomly assigned proven antiretroviral strategies to assess relative efficacy for perinatal prevention plus maternal/infant safety and maternal health. The START study subsequently demonstrated clear benefit in initiating ART regardless of CD4 count. Active PROMISE participants were informed of results and women not receiving ART were strongly recommended to immediately initiate treatment to optimize their own health. We recorded their decision and the primary reason given for accepting or rejecting the universal ART offer after receiving the START information. One-third of participants did not initiate ART after the initial session, wanting more time to consider. Six sessions were required to attain 95% uptake. The slow uptake of universal ART highlights the need to prepare individuals and sensitize communities regarding the personal and population benefits of the "Treat All" strategy.