Browsing by Author "Bobat, Raziya"

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    Low vitamin-D levels combined with PKP3-SIGIRR-TMEM16J host variants is associated with tuberculosis and death in HIV-infected and -exposed infants
    (Public Library of Science, 2016) Gupta, Amita; Montepiedra, Grace; Gupte, Akshay; Zeldow, Bret; Jubulis, Jennifer; Detrick, Barbara; Violari, Avy; Madhi, Shabir; Bobat, Raziya; Cotton, Mark; Mitchell, Charles; Spector, Stephen; IMPAACT NWCS113 and P1041 Study Team
    Background: This study examined the associations of 25-hydroxyvitamin D and specific host genetic variants that affect vitamin D levels or its effects on immune function, with the risk of TB or mortality in children. Methods: A case-cohort sample of 466 South African infants enrolled in P1041 trial (NCT00080119) underwent 25-hydroxyvitamin D testing by chemiluminescent immunoassay. Single nucleotide polymorphisms (SNPs) that alter the effect of vitamin D [e.g. vitamin D receptor (VDR)], vitamin D levels [e.g. vitamin D binding protein (VDBP)], or toll like receptor (TLR) expression (SIGIRR including adjacent genes PKP3 and TMEM16J) were identified by real-time PCR. Outcomes were time to TB, and to the composite of TB or death by 192 weeks of follow-up. Effect modification between vitamin D status and SNPs for outcomes was assessed. Findings: Median age at 25-hydroxyvitamin D determination was 8 months; 11% were breastfed, 51% were HIV-infected and 26% had low 25-hydroxyvitamin D (<32ng/mL). By 192 weeks, 138 incident TB cases (43 definite/probable, and 95 possible) and 26 deaths occurred. Adjusting for HIV status and potential confounders, low 25-hydroxyvitamin D was associated with any TB (adjusted hazard ratio [aHR] 1.76, 95% CI 1.01–3.05; p = 0.046) and any TB or death (aHR 1.76, 95% CI 1.03–3.00; p = 0.038). Children with low 25-hydroxyvitamin D and TMEM 16J rs7111432-AA or PKP3 rs10902158-GG were at increased risk for probable/definite TB or death (aHR 8.12 and 4.83, p<0.05) and any TB or death (aHR 4.78 and 3.26, p<0.005) respectively; SNPs in VDBP, VDR, and vitamin D precursor or hydroxylation genes were not. There was significant interaction between low 25-hydroxyvitamin D and, TMEM 16J rs7111432-AA (p = 0.04) and PKP3 rs10902158-GG (p = 0.02) SNPs. Conclusions: Two novel SNPs, thought to be associated with innate immunity, in combination with low vitamin D levels were identified as increasing a young child’s risk of developing TB disease or death. Identifying high-risk children and providing targeted interventions such as vitamin D supplementation may be beneficial.
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    Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children
    (Massachusetts Medical Society, 2012) Violari, Avy; Paed, F. C.; Lindsey, Jane C.; Hughes, Michael D.; Mujuru, Hilda A.; Barlow-Mosha, Linda; Kamthunzi, Portia; Chi, Benjamin H.; Cotton, Mark F.; Moultrie, Harry; Khadse, Sandhya; Schimana, Werner; Bobat, Raziya; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne M.; Jean-Philippe, Patrick; Palumbo, Paul
    BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log 10 copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P = 0.04), as was the time to death (P = 0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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    A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries
    (PLoS, 2019-07-01) Cotton, Mark F.; Rabie, Helena; Nemes, Elisa; Mujuru, Hilda; Bobat, Raziya; Njau, Boniface; Violari, Avy; Mave, Vidya; Mitchell, Charles; Oleske, James; Zimmer, Bonnie; Varghese, George; Pahwa, Savita
    Background: The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India. Methods and findings: We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). Conclusions: IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.
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    Viral hepatitis B and C in HIV-exposed South African infants
    (BMC (part of Springer Nature), 2020) Tchuem, Cynthia Tamandjou; Cotton, Mark Fredric; Nel, Etienne; Tedder, Richard; Preiser, Wolfgang; Violari, Avy; Bobat, Raziya; Hovind, Laura; Aaron, Lisa; Montepiedra, Grace; Mitchell, Charles; Andersson, Monique Ingrid
    Background: Whilst much attention is given to eliminating HIV mother-to-child transmission (MTCT), little has been done to ensure the same for hepatitis B virus (HBV) transmission. The introduction of HBV immunization at six weeks of age has reduced HBV horizontal transmission in South Africa. However, in order to eliminate HBV MTCT, further interventions are needed. The risk of hepatitis C virus (HCV) MTCT in HIV-infected (HIV+) African women is not yet well described. This study aimed to determine the rate of HBV and HCV vertical transmission in HIV-exposed infants in South Africa. Methods: Serum samples from infants enrolled in an isoniazid prevention study (P1041) were screened for HBV and HCV serology markers; screening was performed on samples collected at approximately 60 weeks of age of the infants. HBV DNA was quantified in HBsAg positive samples and HBV strains characterized through gene sequencing. All HCV antibody samples with inconclusive results underwent molecular testing. Results: Three of 821 infants were positive for both HBsAg and HBV DNA. All HBV strains belonged to HBV subgenotype A1. The rtM204I mutation associated with lamivudine resistance was identified in one infant, a second infant harboured the double A1762T/G1764A BCP mutation. Phylogenetic analysis showed clustering between mother and infant viral genomic sequences. Twenty-one of 821 HIV-exposed infants tested had inconclusive HCV antibody results, none were HCV PCR positive. Conclusions: This study suggests that HBV vertical transmission is likely to be occurring in HIV-exposed infants in South Africa.. A more robust strategy of HBV prevention, including birth dose vaccination, is required to eradicate HBV MTCT. HCV infection was not detected.