Systematic review and meta-analysis of the pharmacokinetics of benznidazole in the treatment of Chagas disease

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), the time to Cmax, the elimination rate constant (kel), the absorption rate constant (Ka), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and Cmax were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. Ka and kel were 1.16 h-1 (95% CrI, 0.59, 1.76 h-1) and 0.052 h-1 (95% CrI, 0.045, 0.059 h-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.Fil: Wiens, Matthew O.. University of British Columbia; CanadáFil: Kanters, Steve. Precision Global Health;Fil: Mills, Edward. Mc Master University; CanadáFil: Peregrina Lucano, Alejandro A.. Universidad de Guadalajara; MéxicoFil: Gold, Silvia. Fundación Mundo Sano; ArgentinaFil: Ayers, Dieter. Precision Global Health;Fil: Ferrero, Luis. Fundación Mundo Sano; ArgentinaFil: Krolewiecki, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentin

Mortality along the continuum of HIV care in Rwanda: a model-based analysis

HIV is the leading cause of death among adults in sub-Saharan Africa. However, mortality along the HIV care continuum is poorly described. We combine demographic, epidemiologic, and health services data to estimate where are people with HIV dying along Rwanda's care continuum.; We calibrated an age-structured HIV disease and transmission stochastic simulation model to the epidemic in Rwanda. We estimate mortality among HIV-infected individuals in the following states: untested, tested without establishing care in an antiretroviral therapy (ART) program (unlinked), in care before initiating ART (pre-ART), lost to follow-up (LTFU) following ART initiation, and retained in active ART care. We estimated mortality among people living with HIV in Rwanda through 2025 under current conditions, and with improvements to the HIV care continuum.; In 2014, the greatest portion of deaths occurred among those untested (35.4%), followed by those on ART (34.1%), reflecting the large increase in the population on ART. Deaths among those LTFU made up 11.8% of all deaths among HIV-infected individuals in 2014, and in the base case this portion increased to 18.8% in 2025, while the contribution to mortality declined among those untested, unlinked, and in pre-ART. In our model only combined improvements to multiple aspects of the HIV care continuum were projected to reduce the total number of deaths among those with HIV, estimated at 8177 in 2014, rising to 10,659 in the base case, and declining to 5,691 with combined improvements in 2025.; Mortality among those untested for HIV contributes a declining portion of deaths among HIV-infected individuals in Rwanda, but the portion of deaths among those LTFU is expected to increase the most over the next decade. Combined improvements to the HIV care continuum might be needed to reduce the number of deaths among those with HIV

Impact of implementing performance-based financing on childhood malnutrition in Rwanda

Background: Malnutrition remains a serious concern in Rwanda, particularly among children under-5 years. Performance-based financing (PBF), an innovative health systems financing strategy, has been implemented at the national level since 2008. This study aimed to assess the impact of PBF and other factors associated with the prevalence of three classifications of malnutrition (stunting, wasting and underweight) in children under-5 years in Rwanda. Methods: The study is a cross-sectional study comprising of 713 children under five years old from 557 households, whose anthropometric measurements (height, weight and age) had been obtained as part of the 2008 Rwanda General Health and HIV household survey. Z-scores for height-for-age, weight-for-age, weight-for-height, and body mass index-for-age were analyzed according to the World Health Organization 2006 Child Growth Standards. Random intercept logistic regression models were used to regress each anthropometric measure (WAZ, HAZ and WHZ) against child, maternal and household characteristics. Results: Child participants ranged in age from 0 to 60 months, 20.2% of children were under 12 months and 5.1% were HIV positive. The prevalence of wasting was 8.8%; of stunting was 58.4%; and of underweight status was 20.7%. Maternal emotional and social wellbeing was protective of wasting in children under-5 years of age. Living in districts implementing PBF was protective of wasting (Adjusted Odds Ratio: 0.43; 95% confidence interval: 0.19-0.97). Living in a district with PBF was not found to be associated with either stunting or underweight status among children under-5. Conclusions: PBF may have a protective association with particular forms of malnutrition among children under-5 years in Rwanda. These findings warrant further investigation in relation to the impact of implementing innovative financing schemes on health outcomes

Clinical outcomes in patients relapsed/refractory after ≥2 prior lines of therapy for follicular lymphoma: A systematic literature review and meta-analysis

BACKGROUND: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review. METHODS: Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis. RESULTS: The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval [CI]: 51.13-65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02-24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8-68.78) and median PFS was 9.78 months (95% CI: 9.01-10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%). CONCLUSIONS: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe

Life expectancy among HIV-positive patients in Rwanda: a retrospective observational cohort study

Background Rwanda has achieved substantial progress in scaling up of antiretroviral therapy. We aimed to assess the eff ect of increased access to antiretroviral therapy on life expectancy among HIV-positive patients in two distinct periods of lower and higher antiretroviral therapy coverage (1997–2007 and 2008–11). Methods In a retrospective observational cohort study, we collected clinical and demographic data for all HIV-positive patients enrolled in care at 110 health facilities across all fi ve provinces of Rwanda. We included patients aged 15 years or older with a known enrolment date between 1997 and 2014. We constructed abridged life tables from age-specifi c mortality rates and life expectancy stratifi ed by sex, CD4 cell count, and WHO disease stage at enrolment in care and initiation of antiretroviral therapy. Findings We included 72 061 patients in this study, contributing 213 983 person-years of follow-up. The crude mortality rate was 33·4 deaths per 1000 person-years (95% CI 32·7–34·2). Life expectancy for the overall cohort was 25·6 additional years (95% CI 25·1–26·1) at 20 years of age and 23·3 additional years (95% CI 22·9–23·7) at 35 years of age. Life expectancy at 20 years of age in the period of 1997–2007 was 20·4 additional years (95% CI 19·5–21·3); for the period of 2008–11, life expectancy had increased to 25·6 additional years (95% CI 24·8–26·4). Individuals enrolling in care with CD4 cell counts of 500 cells per μL or more, and with WHO disease stage I, had the highest life expectancies. Interpretation This study adds to the growing body of evidence showing the benefi t to HIV-positive patients of early enrolment in care and initiation of antiretroviral therapy

Incidence and Predictors of Pregnancy among a Cohort of HIV-Positive Women Initiating Antiretroviral Therapy in Mbarara, Uganda

Objective: Many people living with HIV in sub-Saharan Africa desire biological children. Implementation of HIV preventionstrategies that support the reproductive goals of people living with HIV while minimizing HIV transmission risk to sexualpartners and future children requires a comprehensive understanding of pregnancy in this population. We analyzedprospective cohort data to determine pregnancy incidence and predictors among HIV-positive women initiatingantiretroviral therapy (ART) in a setting with high HIV prevalence and fertility.Methods:Participants were enrolled in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort of HIV-positiveindividuals initiating ART in Mbarara. Bloodwork (including CD4 cells/mm3, HIV viral load) and questionnaires (includingsocio-demographics, health status, sexual behavior, partner dynamics, HIV history, and self-reported pregnancy) werecompleted at baseline and quarterly. Our analysis includes 351 HIV-positive women (18–49 years) who enrolled between2005–2011. We measured pregnancy incidence by proximal and distal time relative to ART initiation and used multivariableCox proportional hazards regression analysis (with repeated events) to identify baseline and time-dependent predictors ofpregnancy post-ART initiation.Results:At baseline (pre-ART initiation), median age was 33 years [IQR: 27–37] and median prior livebirths was four [IQR: 2–6]. 38% were married with 61% reporting HIV-positive spouses. 73% of women had disclosed HIV status to a primary sexualpartner. Median baseline CD4 was 137 cells/mm3[IQR: 81–207]. At enrolment, 9.1% (31/342) reported current pregnancy.After ART initiation, 84 women experienced 105 pregnancies over 3.8 median years of follow-up, yielding a pregnancyincidence of 9.40 per 100 WYs. Three years post-ART initiation, cumulative probability of at least one pregnancy was 28%and independently associated with younger age (Adjusted Hazard Ratio (AHR): 0.89/year increase; 95%CI: 0.86–0.92) and HIVserostatus disclosure to primary sexual partner (AHR: 2.45; 95%CI: 1.29–4.63).Conclusions:Nearly one-third of women became pregnant within three years of initiating ART, highlighting the need forintegrated services to prevent unintended pregnancies and reduce periconception-related risks for HIV-infected womenchoosing to conceive. Association with younger age and disclosure suggests a role for early and couples-based safer conception counselling

Timing of antiretroviral therapy and adverse pregnancy outcomes : a systematic review and meta-analysis

BACKGROUND: Although life-long combination antiretroviral therapy (ART) is recommended for all HIV-infected individuals, there are limited data on pregnancy outcome with ART initiation pre-conception. We assessed the safety of ART initiated pre-conception versus post-conception on adverse pregnancy outcome. METHODS: We conducted a systematic review of studies from low-, middle-, and high-income countries. We searched Cochrane Central Register of Controlled Trials, EMBASE, LILACS, MEDLINE for randomized trials, quasi-randomized trials and prospective cohort studies conducted between 01 January 1980 to 01 June 2016). Risk ratios were pooled using a random-effects model. FINDINGS: Eleven studies were included (N=19,189 mother-infant pairs). Women initiating ART pre-conception compared to post-conception were significantly more likely to deliver preterm (pooled risk ratio[RR]=1·20, 95% confidence interval[CI] 1·01-1·14, 10 studies), very preterm (RR=1·53, 95%CI 1·22-1·92, two studies), or have low birth weight (LBW) infants (RR=1·30, 95%CI 1·04-1·62, two studies). Data on neonatal mortality was limited. We found no increase in very LBW (RR=0.18, 95% CI 0.02-1.51, one study), small for gestational age (SGA) (RR = 1·13, 95% CI 0·94-1·35, two studies), severe SGA (RR=1·09, 95%CI 0·82-1·45, one study), stillbirth (RR= RR=1·30, 95% CI 0·99-1·69, two studies) or congenital anomalies (RR= RR=1·24, 95% CI 0·61-2·49, one study). INTERPRETATION: The benefits of ART for maternal health and prevention of perinatal transmission outweigh risks, but there remain limited, poor quality data on the extent/severity of these risks. We found elevated preterm delivery and low birth weight rates associated with pre-conception ART. As pre-conception ART rapidly increases globally, it will be critical to monitor for potential adverse pregnancy outcomes

Conspiracy Beliefs and Knowledge About HIV Origins Among Adolescents in Soweto, South Africa

We examined adolescents\u27 knowledge regarding the origin of HIV/AIDS and correlates of beliefs surrounding conspiracy theories in Soweto, South Africa. Now, a decade post-AIDS denialism, South Africa has the largest antiretroviral therapy roll-out worldwide. However, conspiracy theories stemming from past AIDS denialism may impact HIV prevention and treatment efforts

The financial cost of doctors emigrating from sub-Saharan Africa: human capital analysis

Objective To estimate the lost investment of domestically educated doctors migrating from sub-Saharan African countries to Australia, Canada, the United Kingdom, and the United States