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- ItemBwakura-Dangarembizi, M., Szubert, A.J., Mumbiro, V., Kityo, C.M., Lugemwa, A., Doerholt, K., Chabala, C., Nyathi, M., Nduna, B., Burger, D. and Shakeshaft, C.(medRxiv, 2024-04-15) Bwakura-Dangarembizi, M.; Szubert, A.J.; Mumbiro, V.; Kityo, C.M.; Lugemwa, A.; Doerholt, K.; Chabala, C.; Nyathi, M.; Nduna, B; Burger, D.; Shakeshaft, C.Background Children living with HIV requiring second-line antiretroviral therapy (ART) have limited options, an unmet need considering children require life-long ART. Methods Children from Uganda, Zambia, Zimbabwe were randomised to one of four second-line anchor drugs: dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r), or lopinavir(LPV/r) in the factorial CHAPAS-4 trial (second randomisation to tenofovir alafenamide fumarate(TAF) or standard-of-care(SOC) backbone, reported elsewhere). Dosing followed WHO weight-bands. The primary endpoint was viral load(VL) <400copies/mL at week-96, analysed using logistic regression, hypothesising that DTG and DRV/r would be superior (threshold p=0.03) to LPV/r and ATV/r arms combined and ATV/r would be non-inferior to LPV/r(12% margin). Secondary endpoints included immunology and safety. Analyses were intention-to-treat. Results 919 children, median(IQR) age 10(8-13) years, 54% male, baseline VL 17,573(5549,55700) copies/mL, CD4 669(413, 971) cells/mm, weight-for-age Z-score -1.6(-2.4,-0.9), had spent median(IQR) 5.6(3.3,7.8) years on first-line ART. At week-96, DTG was superior (by 9.7%(95% CI 4.8%, 14.5%); p<0.0001) and DRV/r showed a trend to superiority(by 5.6%(0.3%, 11.0%); p=0.04) compared to LPV/r and ATV/r arms combined. ATV/r was non-inferior to LPV/r(+3.4%(-3.4%,+10.2%); p=0.33). CD4 counts increased with no differences between arms. Toxicity was lowest with DTG. All arms except LPV/r showed age-appropriate weight/height gains at week-96. DTG was not associated with excess absolute weight-gain(<1kg) vs. DRV/r or ATZ/r, irrespective of backbone randomisation. Conclusions DTG-based regimens are safe and cost-effective for second-line ART. DRV/r and ATV/r are also good options. Fixed-dose combinations of DTG, DRV/r or ATV/r with nucleoside/nucleotide-reverse-transcriptase-inhibitors(NRTIs) would increase access to robust, essential second-line options for children.(ISRCTN22964075)
- ItemSecond-line tenofovir alafenamide for children with HIV in Africa(medRxiv, 2024-04-21) Musiime, V.; Musiime, V., Szubert, A.J.; Mujuru, H.A.; Kityo, C.; Doerholt, K.; Makumbi, S.; Mulenga, V.; Ndebele, W.; Mwamabazi, M.; McIlleron, H.; Bwakura-Dangarembizi, M.Background Children living with HIV have few second-line antiretroviral therapy(ART) options, especially fixed-dose-combinations(FDC). Methods Children from Uganda, Zambia, Zimbabwe were randomised to second-line tenofovir alafenamide(TAF)/emtricitabine(FTC) or standard-of-care(SOC) backbone (abacavir(ABC) or zidovudine(ZDV) with lamivudine(3TC)) in the factorial CHAPAS-4 trial. The second randomisation (reported elsewhere) was to dolutegravir(DTG), ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) as anchor drug. All drugs were dosed using WHO weight-bands and children <25kg received a new paediatric TAF/FTC(15/120mg) FDC tablet. The primary endpoint was viral load(VL)<400copies/ml at week-96, analysed using logistic regression, hypothesising that TAF/FTC would be non-inferior to SOC (10% margin). Secondary endpoints included safety and immunological outcomes. Analyses were intention-to-treat. Results 919 children 3–15years, 497(54%) male, median[IQR] baseline viral load(VL) 17,573copies/ml [5549-55,700] and CD4 count 669cells/mm3[413-971], spent 99% of time on allocated NRTI backbone. At week-96, 406/454(89.4%) receiving TAF/FTC vs. 378/454(83.3%) receiving SOC had VL<400copies/mL (adjusted difference[95%CI]: 6.3%[2.0%,10.6%], p=0.004), with no evidence that this varied by ABC/3TC or ZDV/3TC SOC. CD4 count improved similarly in both arms. Growth was better with TAF/FTC vs. SOC, without evidence of excess weight-gain with any backbone/anchor drug combination (including DTG±TAF/FTC, interaction p=0.51). Bone health parameters were similar between arms, irrespective of anchor drug. One child died (treatment-unrelated); 29(3%) had serious adverse events without differences between arms. Conclusions TAF/FTC was virologically superior to SOC ZDV/3TC or ABC/3TC with a favourable safety profile, irrespective of anchor drug. Development of child-friendly TAF/FTC FDCs (±anchor drug) would increase cost-effective ART options for children and reduce drug access gaps between children and adults.(ISRCTN22964075)
- ItemRepeated benzodiazepines ingestions affected behavioral and neurochemical profiles, with mild effect on histological integrities: modulatory efficacy of Nigella sativa oil(The Journal of Neurobehavioral Sciences, 2024-08-30) Imam, A.; Lambe-oladeji, K.F.; Lawal, A.T.; Ajibola, O.E.; Chengetanai, S.; Ajibola, M.I.; Ibrahim, A.; Ajao, M.S.Background Benzodiazepines (BZDs) are a class of depressant drugs that have enjoyed widespread use in conventional clinical management of anxiety-related conditions such as panic disorders that require therapeutic central relaxation and sedation. Meanwhile, prolonged administration of benzodiazepines even at low doses has however been linked to variety of undesirable effects such as discontinuation relapse with the associated risk of abuse and dependency. Aim This study investigated the behavioral, histological and biochemical outcomes of long-term low dose diazepam use and explored the potential role of nigella sativa oil (NSO) in the amelioration of the associated side effects. Methods Adult Wistar rats (n=32) were randomized into four groups that received normal saline; diazepam; diazepam + NSO; or NSO only, respectively for 14 days. At the end of the period of the various exposures, the rats were taken through behavioral paradigms after which they were sacrificed for chemical and histological profiling. Results diazepam-exposed rats exhibited stress-related manifestations with relatively poor performance in memory-related tasks. Repeated diazepam ingestion reduced brain antioxidant biomarkers while causing elevation of brain oxidative stress markers. On histological observation, mild degenerative changes were evident in the various brain regions of the diazepam-exposed rats. Conclusion Interventional nigella sativa oil administration showed therapeutic potentials by mitigating and reversing the observed effects of diazepam, largely due to its antioxidant and anti-inflammatory effects as observed in the present study.
- ItemDetermining the burden of fungal infections in Zimbabwe(Springer Nature, 2021-06-24) Pfavayi, L.T.; Denning, D.W.; Baker, S.; Sibanda, E.N.; Mutapi, F.Zimbabwe currently faces several healthcare challenges, most notably HIV and associated infections including tuberculosis (TB), malaria and recently outbreaks of cholera, typhoid fever and COVID-19. Fungal infections, which are also a major public health threat, receive considerably less attention. Consequently, there is dearth of data regarding the burden of fungal diseases in the country. We estimated the burden of fungal diseases in Zimbabwe based on published literature and ‘at-risk’ populations (HIV/AIDS patients, survivors of pulmonary TB, cancer, chronic obstructive pulmonary disease, asthma and patients receiving critical care) using previously described methods. Where there was no data for Zimbabwe, regional, or international data was used. Our study revealed that approximately 14.9% of Zimbabweans suffer from fungal infections annually, with 80% having tinea capitis. The annual incidence of cryptococcal meningitis and Pneumocystis jirovecii pneumonia in HIV/AIDS were estimated at 41/100,000 and 63/100,000, respectively. The estimated prevalence of recurrent vulvovaginal candidiasis (RVVC) was 2,739/100,000. The estimated burden of fungal diseases in Zimbabwe is high in comparison to other African countries, highlighting the urgent need for increased awareness and surveillance to improve diagnosis and management.
- ItemIdentification of factors associated with stillbirth in Zimbabwe – a cross sectional study(BMC pregnancy and childbirth, 2021-09-29) Dube, K.; Lavender, T.; Blaikie, K.; Sutton, C.J.; Heazell, A.E.; Smyth, R.M.Introduction 98% of the 2.6 million stillbirths per annum occur in low and middle income countries. However, understanding of risk factors for stillbirth in these settings is incomplete, hampering efforts to develop effective strategies to prevent deaths. Methods A cross-sectional study of eligible women on the postnatal ward at Mpilo Hospital, Zimbabwe was undertaken between 01/08/2018 and 31/03/2019 (n = 1779). Data were collected from birth records for maternal characteristics, obstetric and past medical history, antenatal care and pregnancy outcome. A directed acyclic graph was constructed with multivariable logistic regression performed to fit the corresponding model specification to data comprising singleton pregnancies, excluding neonatal deaths (n = 1734), using multiple imputation for missing data. Where possible, findings were validated against all women with births recorded in the hospital birth register (n = 1847). Results Risk factors for stillbirth included: previous stillbirth (29/1691 (2%) of livebirths and 39/43 (91%) of stillbirths, adjusted Odds Ratio (aOR) 2628.9, 95% CI 342.8 to 20,163.0), antenatal care (aOR 44.49 no antenatal care vs. > 4 antenatal care visits, 95% CI 6.80 to 291.19), maternal medical complications (aOR 7.33, 95% CI 1.99 to 26.92) and season of birth (Cold season vs. Mild aOR 14.29, 95% CI 3.09 to 66.08; Hot season vs. Mild aOR 3.39, 95% CI 0.86 to 13.27). Women who had recurrent stillbirth had a lower educational and health status (18.2% had no education vs. 10.0%) and were less likely to receive antenatal care (20.5% had no antenatal care vs. 6.6%) than women without recurrent stillbirth. Conclusion The increased risk in women who have a history of stillbirth is a novel finding in Low and Middle Income Countries (LMICs) and is in agreement with findings from High Income Countries (HICs), although the estimated effect size is much greater (OR in HICs ~ 5). Developing antenatal care for this group of women offers an important opportunity for stillbirth prevention.