Browsing by Author "Violari A"

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Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.
(2016-Nov-03) Fowler MG; Qin M; Fiscus SA; Currier JS; Flynn PM; Chipato T; McIntyre J; Gnanashanmugam D; Siberry GK; Coletti AS; Taha TE; Klingman KL; Martinson FE; Owor M; Violari A; Moodley D; Theron GB; Bhosale R; Bobat R; Chi BH; Strehlau R; Mlay P; Loftis AJ; Browning R; Fenton T; Purdue L; Basar M; Shapiro DE; Mofenson LM; From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).
Effect on growth of exposure to maternal antiretroviral therapy in breastmilk versus extended infant nevirapine prophylaxis among HIV-exposed perinatally uninfected infants in the PROMISE randomized trial.
(2021) Stranix-Chibanda L; Tierney C; Pinilla M; George K; Aizire J; Chipoka G; Mallewa M; Naidoo M; Nematadzira T; Kusakara B; Violari A; Mbengeranwa T; Njau B; Fairlie L; Theron G; Mubiana-Mbewe M; Khadse S; Browning R; Fowler MG; Siberry GK; FHI 360, Durham, NC, United States of America.; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.; University of North Carolina Project, Lilongwe, Malawi.; Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.; University of Zimbabwe Clinical Trials Research Centre, Harare, Zimbabwe.; Office of HIV/AIDS, United States Agency for International Development, Washington, DC, United States of America.; Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research in the Department of Biostatistics, Boston, MA, United States of America.; Department of Obstetrics and Gynaecology, Stellenbosch University, Cape Town, South Africa.; Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa.; Perinatal HIV Research Unit, Johannesburg, South Africa.; Makerere University-Johns Hopkins University Research Programme, Kampala, Uganda.; University of KwaZulu-Natal, Centre Aids Prevention Research South Africa (CAPRISA), Durban, South Africa.; College of Medicine-Johns Hopkins University Project, Blantyre, Malawi.; University of Zimbabwe Faculty of Medicine and Health Sciences, Child and Adolescent Health Unit, Harare, Zimbabwe.; Department of Obstetrics and Gynaecology, BJ Government Medical College, Pune, India.; Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States of America.; Kilimanjaro Christian Medical Center, Moshi, United Republic of Tanzania.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. METHODS AND FINDINGS: We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)). CONCLUSIONS: In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01061151.
Effects of preterm birth, maternal ART and breastfeeding on 24-month infant HIV-free survival in a randomized trial.
(2024-Jul-15) Dadabhai S; Chou VB; Pinilla M; Chinula L; Owor M; Violari A; Moodley D; Stranix-Chibanda L; Matubu TA; Chareka GT; Theron G; Kinikar AA; Mubiana-Mbewe M; Fairlie L; Bobat R; Mmbaga BT; Flynn PM; Taha TE; McCarthy KS; Browning R; Mofenson LM; Brummel SS; Fowler MG; Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Soweto.; Department of Paediatrics and Child Health, University of KwaZulu-Natal, Durban, South Africa.; National Institute of Allergy and Infectious Diseases/NIH, Rockville, MD.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.; Division of Global Women's Health, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; St. Jude Children's Research Hospital, Memphis, TN.; B.J. Government Medical College, Department of Paediatrics, Pune, India.; Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.; Elizabeth Glaser Pediatric AIDS Foundation, Washington DC, USA.; MU-JHU Research Collaboration; Upper Mulago Hill Road, Kampala, Uganda.; Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA.; Wits RHI, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg.; University of North Carolina Project Malawi, Tidziwe Centre, Lilongwe, Malawi.; Centre for Infectious Disease Research in Zambia, George CRS, Lusaka, Zambia.; Centre for the AIDS Programme of Research in South Africa and School of Clinical Medicine, University of KwaZulu Natal, Congella, South Africa.; Kamuzu University of Health Sciences-Johns Hopkins Research Project, Blantyre, Malawi.; Child, Adolescent and Women's Health Department, Faculty of Medicine and Health Sciences, University of Zimbabwe, Avondale.; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health.; Kilimanjaro Christian Medical Centre, Kilimanjaro Clinical Research Institute and Kilimanjaro Christian Medical University College/Kilimanjaro CRS, Moshi, Tanzania.; University of Zimbabwe Clinical Trials Research Centre, Belgravia, Harare, Zimbabwe.; FHI 360, Durham, NC.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: IMPAACT 1077BF/FF (PROMISE) compared the safety/efficacy of two HIV antiretroviral therapy (ART) regimens to zidovudine (ZDV) alone during pregnancy for HIV prevention. PROMISE found an increased risk of preterm delivery (<37 weeks) with antepartum triple ART (TDF/FTC/LPV+r or ZDV/3TC/LPV+r) compared with ZDV alone. We assessed the impact of preterm birth, breastfeeding, and antepartum ART regimen on 24-month infant survival. METHODS: We compared HIV-free and overall survival at 24 months for liveborn infants by gestational age, time-varying breastfeeding status, and antepartum ART arm at 14 sites in Africa and India. Kaplan-Meier survival probabilities and Cox proportional hazards ratios were estimated. RESULTS: Three thousand four hundred and eighty-two live-born infants [568 (16.3%) preterm and 2914 (83.7%) term] were included. Preterm birth was significantly associated with lower HIV-free survival [0.85; 95% confidence interval (CI) 0.82-0.88] and lower overall survival (0.89; 95% CI 0.86-0.91) versus term birth (0.96; 95% CI 0.95-0.96). Very preterm birth (<34 weeks) was associated with low HIV-free survival (0.65; 95% CI 0.54-0.73) and low overall survival (0.66; 95% CI 0.56-0.74). Risk of HIV infection or death at 24 months was higher with TDF-ART than ZDV-ART (adjusted hazard ratio 2.37; 95% CI 1.21-4.64). Breastfeeding initiated near birth decreased risk of infection or death at 24 months (adjusted hazard ratio 0.05; 95% CI 0.03-0.08) compared with not breastfeeding. CONCLUSION: Preterm birth and antepartum TDF-ART were associated with lower 24-month HIV-free survival compared with term birth and ZDV-ART. Any breastfeeding strongly promoted HIV-free survival, especially if initiated close to birth. Reducing preterm birth and promoting infant feeding with breastmilk among HIV/antiretroviral drug-exposed infants remain global health priorities.
Safety of combined long-acting injectable cabotegravir and long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA): a phase 1/2, multicentre, open-label, non-comparative, dose-finding study.
(2025-Mar) Moore CB; Baltrusaitis K; Best BM; Moye JH; Townley E; Violari A; Heckman B; Buisson S; Van Solingen-Ristea RM; Capparelli EV; Marzinke MA; Lowenthal ED; Ward S; Krotje C; Milligan R; Agwu AL; Huang J; Cheung SYA; McCoig C; Yin DE; Roberts G; Crauwels H; Van Eygen V; Zabih S; Masheto G; Ounchanum P; Aurpibul L; Korutaro V; Gaur AH; Center for Biostatistics in AIDS Research, Harvard T H Chan School of Public Health, Boston, MA, USA.; University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Janssen Research and Development, Beerse, Belgium.; St Jude Children's Research Hospital, Memphis, TN, USA.; SMG Pharma Safety GlaxoSmithKline, Middlesex, UK.; FHI 360, Durham, NC, USA.; Centre for Infectious Disease Research in Zambia, Lusaka, Zambia; University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: carolyn.bolton@cidrz.org.; ViiV Healthcare, Madrid, Spain.; Certara, Radnor, PA, USA; GlaxoSmithKline, Collegeville, PA, USA.; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.; Frontier Science Foundation, Amherst, NY, USA.; Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand.; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.; Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Botswana Harvard Health Partnership, Gaborone, Botswana.; Baylor College of Medicine Children's Foundation Uganda, Kampala, Uganda.; Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa.; University of California San Diego, La Jolla, CA, USA.; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.; University of California Los Angeles, Los Angeles, CA, USA.; GlaxoSmithKline, Mississauga, ON, Canada.; Frontier Science Foundation, Brookline, MA, USA.; CIDRZ; Centre for Infectious Disease Research in Zambia (CIDRZ)
BACKGROUND: Long-acting cabotegravir and long-acting rilpivirine constitute a completely intramuscular antiretroviral therapy (ART) regimen for adults with HIV. We aimed to assess the safety, antiviral activity, and pharmacokinetics of oral cabotegravir and rilpivirine followed by a combination of long-acting cabotegravir and long-acting rilpivirine in virologically suppressed adolescents with HIV. METHODS: The IMPAACT 2017/MOCHA study is a phase 1/2, multicentre, open-label, non-comparative, dose-finding trial being conducted at 18 sites across Botswana, South Africa, Thailand, Uganda, and the USA. In cohort 2 of this study, adolescents (aged 12-18 years; weight ≥35 kg) with HIV and no serious comorbidities who were receiving stable combination ART with confirmed virological suppression and had either previously enrolled in the first cohort or had not previously participated in the study were eligible for inclusion. Participants stopped their background combination ART and received oral cabotegravir 30 mg once daily and oral rilpivirine 25 mg once daily orally for 4-6 weeks, followed by long-acting injectable cabotegravir 600 mg (3 mL) and long-acting injectable rilpivirine 900 mg (3 mL) intramuscularly at weeks 4 and 8, and every 8 weeks thereafter. The primary outcome was safety, including all adverse events, at week 24. Primary safety outcome measures were summarised as frequencies, percentages, and exact Clopper-Pearson 95% CIs in the evaluable analysis population, which included participants who were treated exclusively with the regimen and either completed all scheduled treatments or experienced severe adverse events, permanently discontinued the treatment, or died, whichever occurred first; and in the all-treated analysis population, which included all participants who received at least one dose of any study product. This study is registered with ClinicalTrials.gov (NCT3497676) and is ongoing. FINDINGS: Between July 26, 2021, and Aug 27, 2022, 44 (80·0%) of 55 adolescents who participated in cohort 1 and 100 (87·0%) of 115 screened study-naive adolescents were enrolled in cohort 2. 74 (51·4%) participants were female and 70 (48·6%) were male. Overall, 15 (10·8% [95% CI 6·2-17·2]) of all 139 participants in the evaluable analysis population had at least one adverse event of grade 3 or above by week 24. Among 142 participants who received at least one injection, 43 (30%) experienced at least one injection site reaction (ISR). All 106 ISRs were either grade 1 (98 [92·5%]) or grade 2 (eight [7·5%]), and 97 (91·5%) resolved within 7 days. No participant experienced a drug-related serious adverse event or prematurely discontinued treatment due to a drug-related adverse event. INTERPRETATION: Long-acting injectable cabotegravir and long-acting injectable rilpivirine, administered to adolescents at recommended adult dosages every 8 weeks, showed no unanticipated safety concerns in the 24 weeks following administration. FUNDING: National Institutes of Health, ViiV Healthcare, and Johnson & Johnson.