Browsing by Author "Owor, Maxensia"
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Item Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial(The Lancet, 2003) Jackson, J. Brooks; Musoke, Philippa; Fleming, Thomas; Guay, Laura A.; Bagenda, Danstan; Allen, Melissa; Nakabiito, Clemensia; Sherman, Joseph; Bakaki, Paul; Owor, Maxensia; Ducar, Constance; Deseyve, Martina; Mwatha, Anthony; Emel, Lynda; Duefield, Corey; Mirochnick, Mark; Glenn Fowler, Mary; Mofenson, Lynne; Miotti, Paolo; Gigliotti, Maria; Bray, Dorothy; Mmiro, FrancisIn 1999, we reported safety and efficacy data for short-course nevirapine from a Ugandan perinatal HIV-1 prevention trial when 496 babies were followed up to age 14–16 weeks. Safety and efficacy data are now presented for all babies followed up to 18 months of age. Methods From November, 1997, to April, 1999, HIV-1 infected pregnant women in Kampala, Uganda, were randomly assigned nevirapine (200 mg at labour onset and 2 mg/kg for babies within 72 h of birth; regimen A) or zidovudine (600 mg orally at labour onset and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily for babies for 7 days, regimen B). Infant HIV-1 testing was done at birth, age 6–8 and 14–16 weeks, and age 12 months by HIV-1 RNA PCR, and by HIV-1 antibody at 18 months. HIV-1 transmission and HIV-1-free survival were assessed using Kaplan-Meier analysis. We recorded adverse experiences through 6–8 weeks postpartum for mothers, and 18 months for babies. Efficacy analyses were by intention to treat. Findings We enrolled 645 mothers to the study: 313 were assigned regimen A, 313 regimen B, and 19 placebo. Eight mothers were lost to follow-up before delivery. 99% of babies were breastfed (median duration 9 months). Estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were 10·3% and 8·1% at birth (p=0·35); 20·0% and 11·8% by age 6–8 weeks (p=0·0063); 22·1% and 13·5% by age 14–16 weeks (p=0·0064); and 25·8% and 15·7% by age 18 months (p=0·0023). Nevirapine was associated with a 41% (95% CI 16–59) reduction in relative risk of transmission through to age 18 months. Both regimens were well-tolerated with few serious side-effects. Interpretation Intrapartum/neonatal nevirapine significantly lowered HIV-1 transmission risk in a breastfeeding population in Uganda compared with a short intrapartum/neonatal zidovudine regimen. The absolute 8·2% reduction in transmission at 6–8 weeks was sustained at age 18 months (10·1% [95% CI 3·5–16·6]). This simple, inexpensive, welltolerated regimen has the potential to significantly decrease HIV-1 perinatal transmission in less-developed countries.Item Long Term Follow-up of Children in the HIVNET 012 Perinatal HIV Prevention Trial: Five-Year Growth and Survival(Journal of acquired immune deficiency syndromes, 2013) Owor, Maxensia; Mwatha, Anthony; Donnell, Deborah; Musoke, Philippa; Mmiro, Francis; Allen, Melissa; Jackson, J. Brooks; Fowler, Mary Glenn; Laura A; Guay, Laura A.To describe five year growth, survival and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012.All study children who were alive at eighteen months of age were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every six months from 24 to 60 months. At each visit, history, physical exam and growth measures were taken. From these measurements Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis.528 study children were alive at age 18 months, and 491 (426 HIV uninfected; 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable to WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the two study arms were similar.Both infected and uninfected children in the five-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource limited settings. Likewise, the low five year survival among HIV infected children support the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.Item Maternal Human Immunodeficiency Virus (HIV) Drug Resistance Is Associated With Vertical Transmission and Is Prevalent in Infected Infants(Clinical Infectious Diseases, 2021) Boyce, Ceejay L.; Sils, Tatiana; Ko, Daisy; Wong-on-Wing, Annie; Beck, Ingrid A.; Styrchak, Sheila M.; DeMarrais, Patricia; Tierney, Camlin; Stranix-Chibanda, Lynda; Flynn, Patricia M.; Taha, Taha E.; Owor, Maxensia; Glenn Fowler, Mary; Frenkel, Lisa M.We aimed to assess if maternal human immunodeficiency virus (HIV) drug resistance is associated with an increased risk of HIV vertical transmission and to describe the dynamics of drug resistance in HIV-infected infants. Methods. This was a case-control study of PROMISE study participants. “Cases” were mother-infant pairs with HIV vertical transmission during pregnancy or breastfeeding and “controls” were mother-infant pairs without transmission matched 1:3 by delivery date and clinical site. Genotypic HIV drug resistance analyses were performed on mothers’ and their infants’ plasma at or near the time of infant HIV diagnosis. Longitudinal analysis of genotypic resistance was assessed in available specimens from infants, from diagnosis and beyond, including antiretroviral therapy (ART) initiation and last study visits. Results. Our analyses included 85 cases and 255 matched controls. Maternal HIV drug resistance, adjusted for plasma HIV RNA load at infant HIV diagnosis, enrollment CD4 count, and antepartum regimens, was not associated with in utero/peripartum HIV transmission. In contrast, both maternal plasma HIV RNA load and HIV drug resistance were independent risk factors associated with vertical transmission during breastfeeding. Furthermore, HIV drug resistance was selected across infected infants during infancy. Conclusions. Maternal HIV drug resistance and maternal viral load were independent risk factors for vertical transmission during breastfeeding, suggesting that nevirapine alone may be insufficient infant prophylaxis against drug-resistant variants in maternal breast milk. These findings support efforts to achieve suppression of HIV replication during pregnancy and suggest that breastfeeding infants may benefit from prophylaxis with a greater barrier to drug resistance than nevirapine alone.Item Maternal Humoral Immune Responses Do Not Predict Postnatal HIV-1 Transmission Risk in Antiretroviral-Treated Mothers from the IMPAACT PROMISE Study(Msphere, 2019) Hompe, Eliza D.; Jacobson, Denise L.; Eudailey, Joshua A.; Butler, Kevin; Edwards, Whitney; Pollara, Justin; Brummel, Sean S.; Fouda, Genevieve G.; Chinula, Lameck; Kamanga, Melvin; Kinikar, Aarti; Moodley, Dhayendre; Owor, Maxensia; Fowler, Mary Glenn; Permar, Sallie R.To design immune interventions that can synergize with antiretroviral therapy (ART) to reduce the rate of HIV mother-to-child transmission (MTCT), it is essential to characterize maternal immune responses in the setting of ART during pregnancy and breastfeeding and define their effect on MTCT. Prior studies reported an association between breast milk envelope (Env)-specific antibodies and antibodydependent cell cytotoxicity (ADCC) activity with reduced postnatal transmission. In this study, we investigated whether these immune correlates were similarly associated with protection in a matched case-control study of mother-infant pairs receiving maternal ART or infant nevirapine prophylaxis during breastfeeding in the International Maternal-Pediatric-Adolescent AIDS Clinical Trials Network Promoting Maternal-Infant Survival Everywhere (PROMISE) trial, assessing postnatal transmission risk in 19 transmitting and 57 nontransmitting mothers using conditional logistic regression models adjusted for maternal plasma viral load. The odds ratios of postnatal MTCT for a 1-unit increase in an immune correlate were 3.61 (95% confidence interval [CI], 0.56, 23.14) for breast milk Env-specific secretory IgA (sIgA), 2.32 (95% CI, 0.43, 12.56) for breast milk and 2.16 (95% CI, 0.51, 9.14) for plasma Env-specific IgA, and 4.57 (95% CI, 0.68, 30.48) for breast milk and 0.96 (95% CI, 0.25, 3.67) for plasma ADCC activity, with all CIs spanning 1.0. Interestingly, although mucosal IgA responses are poor in untreated HIV-infected women, there was a strong correlation between the magnitudes of breast milk and plasma Env-specific IgA in this cohort. In this analysis of the small number of postnatal virus transmissions in the landmark PROMISE study, no single antibody response was associated with breast milk transmission risk.Item Perinatal HIV and Its Prevention: Progress Toward an HIV-free Generation(Clinics in perinatology, 2010) Fowler, Mary Glenn; Gable, Alicia R.; Lampe, Margaret A.; Etima, Monica; Owor, MaxensiaSince the first cases of infant HIV infection were described in the early 1980s, significant progress has been made in our understanding of risk factors for mother-to-child transmission (MTCT) of HIV as well as effective interventions to prevent transmission. MTCT of the human immunodeficiency virus type-1 (HIV-1) can occur during pregnancy particularly in the third trimester, during the intrapartum period, and for infants exposed to HIV, who are breastfed, throughout the period of lactation.1 Before the availability of antiretroviral and obstetric interventions, about 1 in 4 infants born to women infected with HIV became infected. Among these infected infants, 50% to 60% of transmission occurred around the time of labor or delivery based on newborn infants exposed to HIV having negative cord blood or newborn polymerase chain reaction (PCR) tests that subsequently became positive within the first weeks of life.2 Among HIV-infected breastfeeding populations, about 20% to 25% of infections occurred in utero based on positive PCRs at birth; 35% to 50% intrapartum; and another 25% to 35% of infants negative at birth and in the first 6 weeks became infected later, presumably as a result of transmission through breast milk.Item Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092(The Pediatric Infectious Disease Journal, 2021) Owor, Maxensia; Tierney, Camlin; Ziemba, Lauren; Browning, Renee; Moye, John; Graham, Bobbie; Reding, Christina; Costello, Diane; Norman, Jennifer; Wiesner, Lubbe; Hughes, Emma; Whalen, Meghan E.; Purdue, Lynette; Mmbaga, Blandina Theophil; Kamthunzi, Portia; Kawalazira, Rachel; Nathoo, Kusum; Bradford, Sarah; Coletti, Anne; Aweeka, Francesca; Musoke, PhilippaSevere acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. Materials and methods: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0–12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. Results: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) −3.4 (IQR −4.0, −3.0) and 27 non-SAM had median WHZ −1.0 (IQR −1.8, −0.1). No significant differences in mean AUC0–12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0–12h (GMR, 0.60; 95% CI, 0.4–1.0; P = 0.047) at week 12, higher ZDV AUC0–12h (GMR, 1.52; 1.2–2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). Conclusion: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.Item Pregnancy outcomes of women conceiving on antiretroviral therapy (ART) compared to those commenced on ART during pregnancy.(Clinical Infectious Diseases, 2021) Theron, Gerhard; Brummel, Sean; Fairlie, Lee; Pinilla, Mauricio; McCarthy, Katie; Owor, Maxensia; Chinula, Lameck; Makanani, Bonus; Violari, Avy; Moodley, Dhayendre; Chakhtoura, Nahida; Browning, Renee; Hoffman, Risa; Glenn Fowler, MaryGlobally, the number of HIV-infected women of child-bearing age conceiving on ART is increasing. Evidence of ART safety at conception and during pregnancy and adverse pregnancy outcomes remains conflicting. The PROMISE 1077 breastfeeding (BF) and formula feeding (FF) international multisite trials provide an opportunity to examine the impact of ART at conception on pregnancy outcomes with subsequent pregnancies. Methods The PROMISE 1077BF/1077FF trials were designed to address key questions in the management of HIV-infected women who did not meet clinical guidelines for ART treatment during the time of the trials. After the period of risk of mother-to-child transmission was over, women were randomized to either continue or discontinue ART. We compared subsequent pregnancy outcomes of non-breastfeeding women randomized to continue ART following delivery, or breastfeeding women randomized to continue ART following breastfeeding cessation who conceived while on ART to women randomized to discontinue ART, who re-started ART after pregnancy was diagnosed. Results Pregnancy outcomes of 939 subsequent pregnancies of 826 mothers were recorded. The intention-to-treat analyses showed increased incidence of low birth weight (<2500gm) for women who conceived while on ART {relative risk 2.65 (95% CI 1.20, 5.81)}, and also a higher risk of spontaneous abortion, stillbirth, or neonatal death {hazard ratio 1.40 (0.99, 1.98)} compared to women who re-started ART after they were found to be pregnant during trial follow up. Downloaded from https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciaa805/5860458 by guest on 22 June 2020 Accepted Manuscript Conclusions We found an increased risk for adverse pregnancy outcomes in women conceiving on ART emphasising the need for improved obstetric and neonatal care for this group.Item 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(Journal of acquired immune deficiency syndromes, 2018) Flynn, Patricia M.; Taha, Taha E.; Cababasay, Mae; Glenn Fowler, Mary; Mofenson, Lynne M.; Owor, Maxensia; Fiscus, Susan; Stranix-Chibanda, Lynda; Coutsoudis, Anna; Gnanashanmugam, Devasena; Chakhtoura, Nahida; McCarthy, Katie; Mukuzunga, Cornelius; Makanani, Bonus; Moodley, Dhayendre; Nematadzira, Teacler; Kusakara, Bangini; Patil, Sandesh; Vhembo, Tichaona; Bobat, Raziya; Mmbaga, Blandina T.; Masenya, Maysseb; Nyati, Mandisa; Theron, Gerhard; Mulenga, Helen; Butler, Kevin; Shapiro, David E.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/mm3 (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 prophylaxis (iNVP) continued until 18 months post-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-October 2014, 2431 mother-infant pairs were enrolled; 97% of women were WHO Clinical Stage I, median screening CD4 count 686 cells/mm3. Median infant gestational age/birthweight were 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and seven of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio [HR] 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). Conclusion—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.Item Risk Factors for Adverse Birth Outcomes in the PROMISE 1077BF/1077FF Trial(Journal of acquired immune deficiency syndromes, 2019) Sebikari, Dorothy; Farhad, Mona; Fenton, Terry; Owor, Maxensia; Stringer, Jeffrey S. A.; Qin, Min; Chakhtoura, Nahida; Chi, Benjamin H.; Saidi, Friday; Nevrekar, Neetal; Violari, Avy; Chipato, Tsungai; McIntyre, James A.; Moodley, Dhayendre; Taha, Taha E.; Theron, Gerhard; Glenn Fowler, MaryIn the multi-country PROMISE 1077BF trial, the risk of low birth weight (LBW; <2500g) and preterm delivery (PTD; <37 weeks) was higher among women initiating a protease inhibitor (PI)-based antiretroviral treatment (ART) regimen than in those receiving ZDV alone. Among those assigned to a PI regimen, tenofovir/emtricitibine was associated with the more severe outcomes of very LBW (VLBW; <1500g) and very PTD (VPTD; <34 weeks) compared to zidovudine/lamivudine. Methods: We used multivariate logistic regression to further explore treatment findings, taking into account demographic baseline clinical and post-entry obstetrical factors. We evaluated individual adverse outcomes and composites that included stillbirth and early loss/spontaneous abortion. Results: Among 3333 women delivering at least one live infant, median maternal age at enrollment was 26 years; 661 (20%) were primiparous, and 110 (3.3%) reported at least one prior PTD. Seventeen percent of newborns were LBW, 1% were VLBW, 17% had PTD, and 3% VPTD. Treatment allocation remained strongly associated with multiple adverse outcomes after controlling for other risk factors with both ART regimens exhibiting increased risk relative to ZDV alone. Other risk factors remaining significant in at least one of the multivariate models included: country, gestational age at entry, maternal age, maternal BMI, prior PTD, history of alcohol use, baseline HIV viral titer, multiple gestation and several obstetric risk factors. Conclusion: ART effects on adverse pregnancy outcomes reported in the randomized PROMISE trial remained strongly significant even after controlling for demographic, baseline clinical and obstetrical risk factors, which were also associated with these outcomes.Item Tenofovir concentrations in hair strongly predict virologic suppression in breastfeeding women(AIDS (London, England), 2019) Murnane, Pamela M.; Bacchetti, Peter; Currier, Judith S.; Brummel, Sean; Okochi, Hideaki; Phung, Nhi; Louie, Alexander; Kuncze, Karen; Hoffman, Risa M.; Nematadzira, Teacler; Soko, Dean K.; Owor, Maxensia; Saidi, Friday; Flynn, Patricia M.; Glenn Fowler, Mary; Gandhi, MonicaAntiretroviral treatment (ART) adherence is often suboptimal in the perinatal period. We measured hair tenofovir (TFV) concentrations as a metric of adherence in postpartum women to understand patterns and predictors of adherence throughout this critical period. Additionally, we examined the association between hair TFV concentrations and virologic outcomes. Methods: Between 12/2012–09/2016, hair samples were collected longitudinally from delivery through breastfeeding from women on ART in the PROMISE study (NCT01061151) in sub-Saharan Africa. Hair TFV levels were measured using validated methods. Using generalized estimating equations, we estimated the association between hair TFV levels and virologic suppression (<400 copies/mL) over time and assessed predictors of hair TFV levels. Results: Hair TFV levels were measured at 370 visits in 71 women from delivery through a median of 14 months (IQR 12–15) of breastfeeding. Levels ranged from below detection (0.002) to 1.067 nanograms/milligram (geometric mean: 0.047). After ≥90 days on ART, 69 women had at least one viral load measured (median 5 measures, range 1–9); 18 (26%) experienced viremia at least once. Each doubling of TFV level more than doubled odds of concurrent virologic suppression (OR 2.35, 95%CI: 1.44–3.84, p=0.0006) and was associated with 1.43 times the odds of future suppression (95%CI: 0.75–2.73, p=0.28). Relative to the first 3 months after delivery, hair levels were highest in months 6–12 (1.42 fold higher, 95%CI: 1.09–1.85, p=0.01). Conclusion: Hair TFV levels strongly predicted concurrent virologic suppression among breastfeeding women. Objective adherence metrics can supplement virologic monitoring to optimize treatment outcomes in this important transition period.