Week 48 outcomes from the BRAAVE 2020 study: a randomised switch to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in African American adults with HIV

Background: Black Americans are disproportionately impacted by HIV. The BRAAVE 2020 study, evaluated the safety and efficacy of switching to the guidelines- recommended single- tablet regimen bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) in Black adults through week (W) 48. Method: Adults with HIV self- identifying as Black or African American and virologically suppressed on 2 NRTIs plus a 3rd agent were randomised (2:1) to switch to open- label B/F/TAF once daily or stay on their baseline regimen (SBR). Prior virologic failure was allowed except failure on an INSTI. Prior resistance to NNRTIs, PIs and/or NRTIs was permitted except K65R/E/N, ≥3 thymidine analog mutations or T69- insertions. Primary INSTI- resistance was excluded. SBR participants switched to B/F/TAF at W24. Efficacy was assessed at W24 (Primary endpoint, noninferiority margin 6%) and at W48 as the proportion with HIV- 1 RNA ≥50 c/mL by FDA Snapshot and by changes in CD4 count. Safety was assessed by adverse events (AE) and lab results. Results: 495 were randomised and treated (B/F/TAF n = 330, SBR n = 165): 32% cis women, 2% transgender women, median age 49 years (range 18– 79) and 10% had pre- existing M184V/I mutation. At W24, 1% (2/328) on B/F/TAF vs 2% (3/165) on SBR had HIV- 1 RNA ≥50 c/mL (difference - 1.2%; 95% CI - 4.8% to 0.9%) demonstrating non-inferiority of B/F/TAF; 2 with pre- existing primary INSTI resistance were excluded from analysis. 163 assigned to SBR completed W24 and switched to B/F/TAF (SBR to B/F/TAF). At W48 1% (3/328) originally randomised to B/F/TAF and 0 SBR to B/F/TAF had HIV- 1 RNA ≥50 c/mL. Baseline NRTI resistance did not affect the efficacy of B/F/TAF. No treatment emergent resistance was detected. Median (IQR) weight increased 0.9 kg (- 1.5, 4.1) and 0.6 kg (- 1.0, 3.1) for B/F/TAF and SBR to B/F/TAF groups, respectively. Study drug- related AEs occurred in 10% of participants while on B/F/TAF; most were grade 1. Conclusion: Switching to B/F/TAF was highly effective for Black adults regardless of baseline regimen or pre- existing NRTI resistance and was associated with few treatment re-lated AEs or discontinuations

Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial

Background: Current treatment for HIV-infected individuals with renal failure on haemodialysis frequently requires complex regimens with multiple pills. A daily single-tablet regimen of coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is approved in Europe, the USA, and in other regions for use in HIV-1-infected individuals with mild-to-moderate chronic kidney disease (creatinine clearance 30–69 mL/min). We aimed to assess the safety, efficacy, and pharmacokinetics of this regimen in HIV-infected adults with end-stage renal disease on chronic haemodialysis. Methods: We did an open-label, single-arm, multicentre, phase 3b trial at 26 outpatient clinics in Austria, France, Germany, and the USA. Participants were HIV-1-infected adults with end-stage renal disease (creatinine clearance <15 mL/min), on chronic haemodialysis for at least 6 months before screening. Virological suppression (ie, plasma HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen was required for at least 6 months before screening with a CD4 count of at least 200 cells per μL. We switched all participants to coformulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once daily, taken after haemodialysis for up to 96 weeks. We did assessments at study visits at weeks 2, 4, 8, 12, 24, 36, and 48, and every 12 weeks thereafter up to 96 weeks. The primary endpoint was the incidence of treatment-emergent adverse events of grade 3 or higher up to week 48. All participants who received at least one dose of study drug were included in the primary analysis. This study is registered with ClinicalTrials.gov (NCT02600819) and is closed to new participants. Findings: Between Feb 1, and Nov 3, 2016, 55 participants were enrolled and received at least one dose of study drug. Through week 48, 18 of 55 participants (33%, 95% CI 20–45) had an adverse event of grade 3 or higher on study treatment. Treatment-emergent grade 3 or higher adverse events that occurred in more than one participant included anaemia, osteomyelitis, prolonged electrocardiogram QT, fluid overload, hyperkalaemia, hypertension, and hypotension (all n=2). No adverse event of grade 3 or higher was considered by the site investigators to be treatment related. Three participants (5%, 95% CI 0–11) discontinued treatment because of adverse events; one of these (grade 1 allergic pruritus) was considered treatment related. Treatment-related adverse events were reported for six individuals (11%, 95% CI 3–19), the most common of which was nausea (in four individuals [7%]); all treatment-related adverse events were grade 1 or 2 in severity. Interpretation: At 48 weeks, switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was well tolerated. This regimen might provide a tolerable and convenient option for ongoing treatment of HIV-1 infection in adults with end-stage renal disease on chronic haemodialysis. Funding: Gilead Sciences

Sleeping sickness and its relationship with development and biodiversity conservation in the Luangwa valley, Zambia

The Luangwa Valley has a long historical association with Human African trypanosomiasis (HAT) and is a recognised geographical focus of this disease. It is also internationally acclaimed for its high biodiversity and contains many valuable habitats. Local inhabitants of the valley have developed sustainable land use systems in co-existence with wildlife over centuries, based on non-livestock keeping practices largely due to the threat from African Animal Trypanosomiasis. Historical epidemics of human sleeping sickness have influenced how and where communities have settled and have had a profound impact on development in the Valley. Historical attempts to control trypanosomiasis have also had a negative impact on conservation of biodiversity. Centralised control over wildlife utilisation has marginalised local communities from managing the wildlife resource. To some extent this has been reversed by the implementation of community based natural resource management programmes in the latter half of the 20th century and the Luangwa Valley provides some of the earliest examples of such programmes. More recently, there has been significant uncontrolled migration of people into the mid-Luangwa Valley driven by pressure on resources in the eastern plateau region, encouragement from local chiefs and economic development in the tourist centre of Mfuwe. This has brought changing land-use patterns, most notably agricultural development through livestock keeping and cotton production. These changes threaten to alter the endemically stable patterns of HAT transmission and could have significant impacts on ecosystem health and ecosystem services. In this paper we review the history of HAT in the context of conservation and development and consider the impacts current changes may have on this complex social-ecological system. We conclude that improved understanding is required to identify specific circumstances where win-win trade-offs can be achieved between the conservation of biodiversity and the reduction of disease in the human population.Ecosystem Services for Poverty Alleviation (ESPA

Stainable hepatic iron in 341 African American adults at coroner/medical examiner autopsy

BACKGROUND: Results of previous autopsy studies indicate that increased hepatic iron stores or hepatic iron overload is common in African Americans dying in hospitals, but there are no reports of hepatic iron content in other cohorts of African Americans. METHODS: We investigated the prevalence of heavy liver iron deposition in African American adults. Using established histochemical criteria, we graded Perls' acid ferrocyanide-reactive iron in the hepatocytes and Kupffer cells of 341 consecutive African American adults who were autopsied in the coroner/medical examiner office. Heavy staining was defined as grade 3 or 4 hepatocyte iron or grade 3 Kupffer cell iron. RESULTS: There were 254 men and 85 women (mean age ± 1 SD: 44 ± 13 y vs. 48 ± 14 y, respectively; p = 0.0255); gender was unstated or unknown in two subjects. Approximately one-third of subjects died of natural causes. Heavy staining was observed in 10.2% of men and 4.7% of women. 23 subjects had heavy hepatocyte staining only, six had heavy Kupffer cell staining only, and one had a mixed pattern of heavy staining. 15 subjects had histories of chronic alcoholism; three had heavy staining confined to hepatocytes. We analyzed the relationships of three continuous variables (age at death in years, hepatocyte iron grade, Kupffer cell iron grade) and two categorical variables (sex, cause of death (natural and non-natural causes)) in all 341 subjects using a correlation matrix with Bonferroni correction. This revealed two positive correlations: hepatocyte with Kupffer cell iron grades (p < 0.01), and male sex with hepatocyte iron grade (p < 0.05). We also analyzed the relationship of steatosis, inflammation, and fibrosis/cirrhosis in 30 subjects with heavy iron staining using a correlation matrix with Bonferroni correction. There were significant positive correlations of steatosis with inflammation (r = 0.5641; p < 0.01), and of inflammation with fibrosis/cirrhosis (r = 0.6124; p < 0.01). CONCLUSIONS: The present results confirm and extend previous observations that heavy liver iron staining is relatively common in African Americans. The pertinence of these observations to genetic and acquired causes of iron overload in African Americans is discussed

THE PREVALENCE OF TUBERCULOSIS IN CATTLE AND THEIR HANDLERS IN NORTH TONGU, VOLTA REGION, GHANA

Background: The need to understand the contribution of bovine tuberculosis (BTB) to the general tuberculosis burden in a poor resource setting is paramount. The aim of this study is to determine the burden of BTB among herdsmen and cattle in the North Tongu district of Volta Region in Ghana. Materials and Methods: A cross- sectional study was conducted in the North Tongu District of the Volta Region between the period of October 2011- March 2012. A well-structured questionnaire was used to collect socio-demographic information and possible risk factor information on cattle from participants. Sputum samples from 68 herdsmen and blood samples from 200 cattle belonging to these herdsmen were also collected. Sputum samples were analyzed using Ziehl- Neelsen staining while Anigen Rapid BTB Test was used for Cattle blood samples. Results: Ninety percent (61/68) of respondents were also found to consume fresh milk while 84% (57/68) do not use protective clothing. Of a total of 1580 cattle owned by the herdsmen, 200 cattle consisting of 14 bulls and 186 cows were screened where the prevalence of bovine TB was 19% (38/200) and those affected were all females. All (100%) human sample tested negative for Acid- Fast Bacilli (AFB). However, the seropositivity of cattle and kraal density were statistically associated (p= 0.001). Conclusion: Bovine TB is prevalent in cattle in North Tongu district. Although herdsmen indulge in risky lifestyles that expose them to BTB, a zero prevalence of BTB was observed, further study is envisaged using a larger sample size

Accuracy of clinical pallor in the diagnosis of anaemia in children: a meta-analysis

BACKGROUND: Anaemia is highly prevalent in children of developing countries. It is associated with impaired physical growth and mental development. Palmar pallor is recommended at primary level for diagnosing it, on the basis of few studies. The objective of the study was to systematically assess the accuracy of clinical signs in the diagnosis of anaemia in children. METHODS: A systematic review on the accuracy of clinical signs of anaemia in children. We performed an Internet search in various databases and an additional reference tracking. Studies had to be on performance of clinical signs in the diagnosis of anaemia, using haemoglobin as the gold standard. We calculated pooled diagnostic likelihood ratios (LR's) and odds ratios (DOR's) for each clinical sign at different haemoglobin thresholds. RESULTS: Eleven articles met the inclusion criteria. Most studies were performed in Africa, in children underfive. Chi-square test for proportions and Cochran Q for DOR's and for LR's showed heterogeneity. Type of observer and haemoglobin technique influenced the results. Pooling was done using the random effects model. Pooled DOR at haemoglobin <11 g/dL was 4.3 (95% CI 2.6–7.2) for palmar pallor, 3.7 (2.3–5.9) for conjunctival pallor, and 3.4 (1.8–6.3) for nailbed pallor. DOR's and LR's were slightly better for nailbed pallor at all other haemoglobin thresholds. The accuracy did not vary substantially after excluding outliers. CONCLUSION: This meta-analysis did not document a highly accurate clinical sign of anaemia. In view of poor performance of clinical signs, universal iron supplementation may be an adequate control strategy in high prevalence areas. Further well-designed studies are needed in settings other than Africa. They should assess inter-observer variation, performance of combined clinical signs, phenotypic differences, and different degrees of anaemia