Dignitas International

Timely care for open tibia fractures remains difficult in low-resource settings. We evaluated a task-sharing model in Malawi in which trained orthopedic clinical officers (OCOs) delivered external fixation supported by a remote quality assessment tool. We conducted a prospective implementation evaluation across one central and four district hospitals (May 2023-July 2024). The intervention bundled OR refurbishment assured external fixator supply, refresher training, mentoring (on-site and remote), national guideline reinforcement, and a novel Fracture Fixation Assessment Tool for External Fixation (FFATEF). OCOs submitted postoperative radiographs and construct photographs for scoring across four domains (reduction, stability, implantation, and surgical impression; total 0-12 and satisfactory ≥8). Nonparametric tests compared performance by the hospital type; temporal trends were assessed with Spearman correlation. Forty-seven patients (89% male and mean age 32.3years) were treated (central: n=28 and district: n=19). The central hospital managed more severe injuries (Gustilo IIIA/B 69.6% vs. 15.8%). Median FFATEF scores were higher at the central hospital (10.0 [IQR 9-11]) than district hospitals (6.0 [5, 6, 7, 8], p<0.001). Satisfactory scores (≥8) occurred in 93% of central versus 32% of district cases. Central scores improved over time (ρ=0.52; p=0.005) whereas district scores were unchanged (ρ=0.15; p=0.540). Preoperative antibiotic compliance was 100% at the central versus 47% at district hospitals. When embedded within integrated surgical teams and adequate infrastructure, task sharing for open fracture external fixation yielded satisfactory technical performance but lagged district-level implementation despite training. Comprehensive institutional support-mentoring intensity, equipment, supply chains, and referral adherence-is likely required for safe scale-up. Validation of FFATEF against clinical outcomes and economic evaluation of delivery models are priorities.

IntroductionIn Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years.Methods and analysisWe will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study’s primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints.Ethics and disseminationThe University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN42862937.

Cryptococcus neoformans (C. neoformans var. grubii) is an environmentally acquired pathogen causing 181,000 HIV-associated deaths each year. We sequenced 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. The phylogeny of C. neoformans reveals a recent exponential population expansion, consistent with the increase in the number of susceptible hosts. In our study population, this expansion has been driven by three sub-clades of the C. neoformans VNIa lineage; VNIa-4, VNIa-5 and VNIa-93. These three sub-clades account for 91% of clinical isolates sequenced in our study. Combining the genome data with clinical information, we find that the VNIa-93 sub-clade, the most common sub-clade in Uganda and Malawi, was associated with better outcomes than VNIa-4 and VNIa-5, which predominate in Southeast Asia. This study lays the foundation for further work investigating the dominance of VNIa-4, VNIa-5 and VNIa-93 and the association between lineage and clinical phenotype.

BackgroundMortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain.MethodsThe effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER.ResultsThe mean costs per patient were US $847 (95% confidence interval [CI] $776–927) for FLU+5FC, and US $628 (95% CI $557–709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9–41.7%) with FLU+5FC and 53.8% (95% CI 43.1–64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28–208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved.ConclusionsThe addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus–infected persons in Africa.

IntroductionSince June 2016, the national HIV programme in Malawi has adopted Universal Test and Treat (UTT) guidelines requiring that all persons who test HIV positive will be referred to start antiretroviral therapy (ART). Although there is strong evidence from clinical trials that early initiation of ART leads to reduced morbidity and mortality, the impact of UTT on retention on ART in real‐life programmatic settings in Africa is not yet known.MethodsWe conducted a retrospective cohort study in Zomba district, Malawi to compare ART outcomes of patients who initiated ART under 2016 UTT guidelines and those who started ART prior to rollout of UTT (pre‐UTT). We analysed data from 32 rural and urban health facilities of various sizes. Cox proportional hazards modelling was used to determine the independent risk factors of attrition from ART at 12 months. All analyses were adjusted for clustering by health facility using a robust standard errors approach.ResultsAmong 1492 patients (mean age 34.4 years, 933 (63%) female) who initiated ART during the study period, 501 were enrolled in the pre‐UTT cohort and 911 during UTT. At 12 months, retention on ART in the UTT cohort was higher than in the pre‐UTT cohort 83.0% (95% confidence interval (CI): 81.0% to 85.0%) versus 76.2% (95% CI 73.9% to 78.5%). Adolescents, aged 10 to 19 years (adjusted hazard ratio (aHR) 1.53; 95% CI 1.01 to 2.32), and women who were pregnant or breastfeeding at ART initiation (aHR 1.87; 95% CI 1.30 to 2.38) were at higher risk of attrition in the combined pre‐UTT and UTT cohort.ConclusionsRetention on ART was nearly 6% higher after UTT introduction. Young adults and women who were pregnant or breastfeeding at the start of ART were at increased risk of attrition, emphasizing the need for targeted interventions for these groups to achieve the 90‐90‐90 UNAIDS targets in the UTT era.

Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)-containing regimens is unclear. We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models. Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48-88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40-48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5-2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05). Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development. NCT00988039.

Abstract C. neoformansvar.grubii(C. neoformans) is an environmentally acquired pathogen causing 181 000 HIV-associated deaths each year. We used whole genome sequencing (WGS) to characterise 699 isolates, primarilyC. neoformansfrom HIV-infected patients, from 5 countries in Asia and Africa. We found that 91% of our clinical isolates belonged to one of three highly clonal sub-clades of VNIa, which we have termed VNIa-4, VNIa-5 and VNIa-93. Parsimony analysis revealed frequent, long distance transmissions ofC. neoformans; international transmissions took place on 13% of VNIa-4 branches, and intercontinental transmissions on 7% of VNIa-93 branches. The median length of within sub-clade internal branches was 3-6 SNPs, while terminal branches were 44.5-77.5 SNPs. The short median internal branches were partly driven by the large number (12-15% of internal branches) of polytomies in the within-sub-clade trees. To simultaneously explain our observation of no apparent molecular clock, short internal branches and frequent polytomies we hypothesise thatC. neoformansVNIa spends much of its time in the environment in a quiescent state, while, when it is sampled, it has almost always undergone an extended period of growth. Infections with VNIa-93 were associated with a significantly reduced risk of death by 10 weeks compared with infections with VNIa-4 (Hazard Ratio = 0.45, p = 0.003). We detected a recombination in the mitochondrial sequence of VNIa-5, suggesting that mitochondria could be involved in the propensity of this sub-clade to infect HIV-uninfected patients. These data highlight the insight into the biology and epidemiology of pathogenic fungi which can be gained from WGS data.

Noncommunicable diseases and injuries (NCDIs) account for nearly 70% of deaths worldwide, with an estimated 75% of these deaths occurring in low- and middle-income countries. Globally, the burden of disease from noncommunicable diseases (NCDs) is most often caused by the "big 4," namely: diabetes, cardiovascular diseases, cancer, and chronic lung diseases. However, in Malawi, these 4 conditions account for only 29% of the NCDI disease burden. The Malawi National NCDI Poverty Commission was launched in November 2016 and will describe and evaluate the current NCDI situation in Malawi, with a focus on the poorest populations. The National Commission will investigate which NCDIs cause the biggest burden, which are more present in the young, and which interventions are available to avert death and disability from NCDIs in Malawi, particularly among the poorest segments of the population. The evidence gained through the work of this Commission will help inform research, policy, and programme interventions, all through an advocacy lens, as we strive to address the impact of NCDIs among all populations in Malawi.

BackgroundIn Ethiopia there is no complete registration system to measure disease burden and risk factors accurately. In this study, the 2015 global burden of diseases, injuries and risk factors (GBD) data were used to analyse the incidence, prevalence and mortality rates of malaria in Ethiopia over the last 25 years.MethodsGBD 2015 used verbal autopsy surveys, reports, and published scientific articles to estimate the burden of malaria in Ethiopia. Age and gender-specific causes of death for malaria were estimated using cause of death ensemble modelling.ResultsThe number of new cases of malaria declined from 2.8 million [95% uncertainty interval (UI) 1.4–4.5 million] in 1990 to 621,345 (95% UI 462,230–797,442) in 2015. Malaria caused an estimated 30,323 deaths (95% UI 11,533.3–61,215.3) in 1990 and 1561 deaths (95% UI 752.8–2660.5) in 2015, a 94.8% reduction over the 25 years. Age-standardized mortality rate of malaria has declined by 96.5% between 1990 and 2015 with an annual rate of change of 13.4%. Age-standardized malaria incidence rate among all ages and gender declined by 88.7% between 1990 and 2015. The number of disability-adjusted life years lost (DALY) due to malaria decreased from 2.2 million (95% UI 0.76–4.7 million) in 1990 to 0.18 million (95% UI 0.12–0.26 million) in 2015, with a total reduction 91.7%. Similarly, age-standardized DALY rate declined by 94.8% during the same period.ConclusionsEthiopia has achieved a 50% reduction target of malaria of the millennium development goals. The country should strengthen its malaria control and treatment strategies to achieve the sustainable development goals.