Shabbar Jaffar

Cryptococcal meningitis: A neglected NTD?

Citation for published version (APA): Molloy, S. F., Chiller, T., Greene, G. S., Burry, J., Govender , N. P., Kanyama, C., Mfinanga, S., Lesikari, S., Mapoure, Y. N., Kouanfack, C., Sini, V., Temfack, E., Boulware, D. R., Dromer, F., Denning, D. W., Day, J. N., Stone, N. R. H., Bicanic, T., Jarvis, J. N., ... Loyse, A. (2017). Cryptococcal meningitis: A neglected NTD? PL o S Neglected Tropical Diseases, 11(6), [e0005575]. https://doi.org/10.1371/journal.pntd.0005575

Prevalence of obesity, hypertension, and diabetes, and cascade of care in sub-Saharan Africa: a cross-sectional, population-based study in rural and urban Malawi

Summary Background Sub-Saharan Africa is in rapid demographic transition, and non-communicable diseases are increasingly important causes of morbidity and mortality. We investigated the burden of diabetes, overweight and obesity, hypertension, and multimorbidity, their treatment, and their associations with lifestyle and other factors in Malawi, a very poor country with a predominantly rural—but rapidly growing urban—population, to identify high-risk populations and inform appropriate interventions. Methods In this cross-sectional, population-based study, we enrolled all adults (≥18 years) residing in two defined geographical areas within Karonga District and Lilongwe city. All adults self-defining as usually resident in the study areas were eligible, and recruited at household level. Participants were interviewed, had anthropometry and blood pressure measured, and had fasting blood samples collected. The study outcomes were prevalence estimates and risk ratios for diabetes (defined as fasting blood glucose of at least 7·0 mmol/L or self-report of a previous diagnosis of diabetes), hypertension (systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or self-report of current antihypertensive medication), overweight (BMI of 25·0–29·9 kg/m2) and obesity (BMI of 30·0 kg/m2 or more), and multimorbidity (two or more of the above conditions) by location-specific (urban vs rural), age-specific, and sex-specific groups, calculated using negative binomial regression. We used χ2 likelihood ratio tests to assess heterogeneity by age, location, and sex. Findings Between May 16, 2013, and Feb 8, 2016, we enrolled 15 013 (62%) of 24 367 eligible urban adults in Lilongwe and 13 878 (88%) of 15 806 eligible rural adults in Karonga District. Overweight and obesity, hypertension, and diabetes were highly prevalent, more so in urban residents, the less poor, and better educated than in rural, the poorest, and least educated participants. 18% of urban men (961 of 5211 participants) and 44% (4115 of 9282) of urban women, and 9% (521 of 5834) of rural men and 27% (2038 of 7497) of rural women were overweight or obese; 16% (859 of 5212), 14% (1349 of 9793), 13% (787 of 5847), and 14% (1101 of 8025) had hypertension; and 3% (133 of 3928), 3% (225 of 7867), 2% (84 of 5004), and 2% (124 of 7116) had diabetes, respectively. Of 566 participants with diabetes, 233 (41%) were undiagnosed, and of 4096 participants with hypertension, 2388 (58%) were undiagnosed. Fewer than half the participants on medication for diabetes or hypertension had well controlled diabetes (84 [41%] of 207 participants) or blood pressure (440 [37%] of 1183 participants). Multimorbidity was highest in urban women (n=519, 7%). Interpretation Overweight and obesity, hypertension, and diabetes are highly prevalent in urban and rural Malawi, yet many patients are undiagnosed and management is limited. Local-evidence-informed multisectoral, innovative, and targeted interventions are needed urgently to manage the already high burden. Funding Wellcome Trust.

Diabetes and other non-communicable diseases in Africa: a potential disaster in the waiting

www.thelancet.com/diabetes-endocrinology Vol 4 November 2016 875 Despite the study’s limitations, van Beers and colleagues’ conclusion that appropriate CGM use can reduce the risk of hypoglycaemia while maintaining, and even improving, time in normoglycaemia, despite the presence of hypoglycaemia unawareness, adds further evidence in support of CGM use in patients with type 1 diabetes. Until these data became available, whether appropriate CGM use (with either continuous subcutaneous insulin infusion or multiple daily insulin injections) truly aff ects hypoglycaemia was unclear. Although perhaps not providing a fi nal verdict, van Beers and colleagues’ fi ndings strengthen the evidence in favour of obtaining approval from regulatory agencies for CGM use in this setting, certainly in patients who have clearly defi ned impaired awareness of hypoglycaemia. Furthermore, CGM use in other technological advancements, such as in sensor-augmented pump therapy, sensor-driven hypoglycaemia minimisers, and fully closed-loop insulin delivery, continues to push the boundaries for reducing hypoglycaemic events, especially during the overnight period, in people with type 1 diabetes. Still, many questions remain. Improvement in hypoglycaemia unawareness with use of CGM is not clearly proven. Can CGM use completely eliminate hypoglycaemia? Could CGM or other technological advancements also assist in the return of hypoglycaemia awareness with more long-term use, beyond that which is obtained with proper education about hypoglycaemia prevention? Certainly more information needs to be gathered to provide answers to these questions, but dedicated randomised controlled trials, such as IN CONTROL, will continue to fi ll the gaps in the evidence. Joseph El Youssef Harold Schnitzer Diabetes Health Center, Department of Internal Medicine, Oregon Health and Science University, Portland, OR 97239, USA elyoussj@ohsu.edu

Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus–associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial

Background We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration ISRCTN 10248064.Cryptococcal meningitis (CM) causes 10-20% of HIV-related deaths in Africa. We performed a phase-II non-inferiority trial examining the Early Fungicidal Activity (EFA) of three short-course, high-dose liposomal amphotericin B (L-AmB) regimens for CM in Tanzania and Botswana. HIV-infected adults with CM were randomized to: (i) L-AmB 10mg/kg day 1 (single dose); (ii) L-AmB 10mg/kg day 1, 5mg/kg day 3 (two doses); (iii) L-AmB 10mg/kg day 1, 5 mg/kg days 3 and 7 (three doses); (iv) standard 14-day L-AmB 3mg/kg/day (control); all given with fluconazole 1200mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid (CSF) cryptococal infection (EFA). Non-inferiority was defined as an upper limit of the two-sided 95% confidence interval (CI) of difference in EFA between intervention and control less than 0.2 log10CFU/ml/day. 80 participants were enrolled. EFA for daily L-AmB was -0.41 (standard deviation 0.11, n=17) log10CFU/mL/day. Difference in mean EFA from control was -0.11 (95%CI -0.29,0.07) log10CFU/mL/day faster with single dose (n=16); -0.05 (95%CI -0.20,0.10) log10CFU/mL/day faster with two doses (n=18); and -0.13 (95%CI -0.35,0.09) log10CFU/mL/day faster with three doses (n=18). EFA in all short-course arms was non-inferior to control at the predefined non-inferiority margin. Overall 10-week mortality was 29% (n=23) with no statistical difference between arms. All arms were well tolerated. Single dose 10mg/kg L-AmB was well tolerated and led to non-inferior EFA compared to 14 days of 3mg/kg/d L-AmB in HIV-associated CM. Induction based on single 10mg/kg L-AmB dose is being taken forward to a phase-III clinical endpoint trial.

The crisis of diabetes in sub-Saharan Africa

In The Lancet Diabetes & Endocrinology, Rifat Atun and colleagues1 report findings of a Commission on diabetes in sub-Saharan Africa, bringing together and critically analysing evidence to paint a sobering picture of the disease in the region. The prevalence of diabetes in sub-Saharan Africa has increased rapidly in the past 10 years or so,2 affecting people in all sectors of society but, in particular, and disproportionally compared with high-income settings, affecting younger people, with substantial economic effects.

Integrated care for human immunodeficiency virus, diabetes and hypertension in Africa

The rising burden from non-communicable diseases (NCDs) poses a huge challenge for health care delivery in Africa, where health systems are already struggling with the long-term care requirements for the millions of people now on antiretroviral therapy requiring regular visits to health facilities for monitoring, adherence support and drugs. The HIV chronic disease management programme is comparatively well-funded, well-organised and well-informed and offers many insights and opportunities for the expansion of NCD prevention and treatment services. Some degree of human immunodeficiency virus (HIV) and NCD service integration is essential, but how to do this without risking the HIV treatment gains is unclear. Both HIV and NCD services must expand within a resource-constrained environment and policymakers are in urgent need of evidence to guide cost-effective and acceptable changes in these health services.

Dietary sodium intake in urban and rural Malawi, and directions for future interventions

ABSTRACT Background High dietary sodium intake is a major risk factor for hypertension. Data on population sodium intake are scanty in sub-Saharan Africa, despite a high hypertension prevalence in most countries. Objective We aimed to determine daily sodium intake in urban and rural communities in Malawi. Design In an observational cross-sectional survey, data were collected on estimated household-level per capita sodium intake, based on how long participants reported that a defined quantity of plain salt lasts in a household. In a subset of 2078 participants, 24-h urinary sodium was estimated from a morning spot urine sample. Results Of 29,074 participants, 52.8% of rural and 50.1% of urban individuals lived in households with an estimated per capita plain salt consumption >5 g/d. Of participants with urinary sodium data, 90.8% of rural and 95.9% of urban participants had estimated 24-h urinary sodium >2 g/d; there was no correlation between household per capita salt intake and estimated 24-h urinary sodium excretion. Younger adults were more likely to have high urinary sodium and to eat food prepared outside the home than were those over the age of 60 y. Households with a member with previously diagnosed hypertension had reduced odds (OR: 0.59; 95% CI: 0.51, 0.68) of per capita household plain salt intake >5 g/d, compared with those where hypertension was undiagnosed. Conclusions Sodium consumption exceeds the recommended amounts for most of the population in rural and urban Malawi. Population-level interventions for sodium intake reduction with a wide focus are needed, targeting both sources outside the home as well as home cooking. This trial was registered at clinicaltrials.gov as NCT03422185.

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHOs preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

Association of Antenatal Micronutrient Supplementation With Adolescent Intellectual Development in Rural Western China: 14-Year Follow-up From a Randomized Clinical Trial

Importance The association of micronutrient supplementation during pregnancy with the intellectual development of adolescent offspring is unknown. Objective To assess the long-term association of antenatal micronutrient supplementation with adolescent intellectual development. Design, Setting, and Participants This 14-year follow-up study of a randomized clinical trial of micronutrient supplementation in pregnancy was conducted in 2 counties in rural western China in 2118 adolescent offspring (aged 10 to 14 years) of mothers who were randomized to take a daily capsule of either folic acid, folic acid plus iron, or multiple micronutrients from August 1, 2002, through February 28, 2006. Follow-up was conducted from June 1, 2016, through December 31, 2016. Data analyses took place from April 1, 2017, to June 20, 2017. Main Outcomes and Measures Adolescent full-scale intelligence quotient and aspects of verbal comprehension, working memory, perceptual reasoning, and processing speed indexes were assessed by the Wechsler Intelligence Scale for Children. Results Of 2118 adolescent offspring, 1252 (59.1%) were boys and 866 (40.9%) were girls, with a mean (SD) age of 11.7 (0.87) years, representing 47.2% of the 4488 single live births that were eligible to participate. Compared with folic acid supplementation, multiple micronutrient supplementation was associated with a 1.13-point higher full-scale intelligence quotient (95% CI, 0.15-2.10) and a 2.03-point higher verbal comprehension index (95% CI, 0.61-3.45); similar results were found in comparison with folic acid plus iron. When mothers initiated supplementation early (<12 weeks of gestation) and had an adequate dose (≥180 capsules), multiple micronutrient capsules were associated with a 2.16-point higher full-scale intelligence quotient (95% CI, 0.41-3.90) and 4.29-point higher verbal comprehension index (95% CI, 1.33-7.24) compared with folic acid capsules. The mean test scores were lower in the substratum of supplementation initiated late (≥12 weeks of gestation) and with an inadequate dose (<180 capsules). The multiple micronutrient group had higher scores than the other 2 treatment groups, and significant differences were observed for full-scale intelligence quotient (adjusted mean difference, 2.46; 95% CI, 0.98-3.94) when compared with the folic acid plus iron group. Conclusions and Relevance Compared with folic acid plus iron or folic acid capsules supplementation, antenatal multiple micronutrient supplementation appeared to be associated with increased adolescent intellectual development; initiating supplementation in the first trimester and then continuing for at least 180 days were associated with the greatest rewards. Trial Registration isrctn.org Identifier: ISRCTN08850194

Glycated haemoglobin A1c (HbA1c) for detection of diabetes mellitus and impaired fasting glucose in Malawi: a diagnostic accuracy study

Objectives To examine the accuracy of glycated haemoglobin A1c (HbA1c) in detecting type 2 diabetes and impaired fasting glucose among adults living in Malawi. Design A diagnostic validation study of HbA1c. Fasting plasma glucose (FPG) ≥7.0 mmol/L was the reference standard for type 2 diabetes, and FPG between 6.1 and 6.9 mmol/L as impaired fasting glucose. Participants 3645 adults (of whom 63% were women) recruited from two demographic surveillance study sites in urban and rural Malawi. This analysis excluded those who had a previous diagnosis of diabetes or had history of taking diabetes medication. Results HbA1c demonstrated excellent validity to detect FPG-defined diabetes, with an area under the receiver operating characteristic (AUROC) curve of 0.92 (95% CI 0.90 to 0.94). At HbA1c ≥6.5% (140 mg/dL), sensitivity was 78.7% and specificity was 94.0%. Subgroup AUROCs ranged from 0.86 for participants with anaemia to 0.94 for participants in urban Malawi. There were clinical and metabolic differences between participants with true diabetes versus false positives when HbA1c was ≥6.5% (140 mg/dL). Conclusions The findings from this study provide justification to use HbA1c to detect type 2 diabetes. As HbA1c testing is substantially less burdensome to patients than either FPG testing or oral glucose tolerance testing, it represents a useful option for expanding access to diabetes care in sub-Saharan Africa.