Browsing by Author "Chipato, Tsungai"
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Item The Association Between the Ratio of Monocytes: Lymphocytes and Risk of Tuberculosis Among HIV-Infected Postpartum Women(BMC medicine, 2014) Naranbhai, Vivek; Moodley, Dhayendre; Chipato, Tsungai; Chibanda, Lynda Stranix; Nakabaiito, Clemensia; Kamateeka, Moreen; Musoke, Philippa; Manji, Karim; George, Kathleen; Emel, Lynda M.; Richardson, Paul; Andrew, Philip; Fowler, MaryGlenn; Fletcher, Helen; McShane, Helen; Coovadia, Hoosen M.; Hill, Adrian V. S.; for the HPTN 046 Protocol TeamRecent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV.We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious.Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%).Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.Item Efficacy And Safety Of An Extended Nevirapine Regimen In Infant Children Of Breastfeeding Mothers With HIV-1 Infection For Prevention Of Postnatal HIV-1 Transmission (HPTN 046): A Randomised, Double-Blind, Placebo-Controlled Trial(The Lancet, 2012) Coovadia, Hoosen M.; Brown, Elizabeth R.; Fowler, Mary Glenn; Chipato, Tsungai; Moodley, Dhayendre; Manji, Karim; Musoke, Philippa; Chibanda, Lynda StranixNevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months.In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412.Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1·1% (95% CI 0·3–1·8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2·4% (1·3–3·6) of controls (difference 1·3%, 95% CI 0–2·6), equating to a 54% reduction in transmission (p=0·049). However, mortality (1·2% for nevirapine vs 1·1% for placebo; p=0·81) and combined HIV infection and mortality rates (2·3% vs 3·2%; p=0·27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age.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.