Study protocol: the effects of air pollution exposure and chronic respiratory disease on pneumonia risk in urban Malawian adults - the Acute Infection of the Respiratory Tract Study (The AIR Study)

Background Pneumonia is the 2nd leading cause of years of life lost worldwide and is a common cause of adult admissions to hospital in sub-Saharan Africa. Risk factors for adult pneumonia are well characterised in developed countries, but are less well described in sub-Saharan Africa where HIV is a major contributing factor. Exposure to indoor and outdoor air pollution is high, and tobacco smoking prevalence is increasing in sub-Saharan Africa, yet the contribution of these factors to the burden of chronic respiratory diseases in sub-Saharan Africa remains poorly understood. Furthermore, the extent to which the presence of chronic respiratory diseases and exposure to air pollution contribute to the burden of pneumonia is not known. Design The Acute Infection of the Respiratory Tract Study (The AIR Study) is a case–control study to identify preventable risk factors for adult pneumonia in the city of Blantyre, Malawi. Cases will be adults admitted with pneumonia, recruited from Queen Elizabeth Central Hospital, the largest teaching hospital in Malawi. Controls will be adults without pneumonia, recruited from the community. The AIR Study will recruit subjects and analyse data within strata defined by positive and negative HIV infection status. All participants will undergo thorough assessment for a range of potential preventable risk factors, with an emphasis on exposure to air pollution and the presence of chronic respiratory diseases. This will include collection of questionnaire data, clinical samples (blood, urine, sputum and breath samples), lung function data and air pollution monitoring in their home. Multivariate analysis will be used to identify the important risk factors contributing to the pneumonia burden in this setting. Identification of preventable risk factors will justify research into the effectiveness of targeted interventions to address this burden in the future. Discussion The AIR Study is the first study of radiologically confirmed pneumonia in which air pollution exposure measurements have been undertaken in this setting, and will contribute important new information about exposure to air pollution in urban SSA. Through identification of preventable risk factors, the AIR Study aims to facilitate future research and implementation of targeted interventions to reduce the high burden of pneumonia in SSA

Pharmacokinetics and safety profile of artesunate-amodiaquine co-administered with antiretroviral therapy in malaria uninfected HIV-positive Malawian adults.

There are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared area under the concentration time curve from 0 to 28 days (AUC0-28 days) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria uninfected adults (n=6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n=25/arm) received the full regimen. In step 1, there were no safety signals and significant differences in desethylamodiaquine AUC0-28 days among participants in the ritonavir-boosted lopinavir, nevirapine and antiretroviral therapy-naive arms. In step 2, compared with the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0-28 days, (geometric mean [95% CI]; 23,822 [17,458-32506] vs 48,617 [40,787-57,950] ng.hr/mL, p < 0.001). No significant differences in AUC0-28 days were observed between nevirapine and antiretroviral therapy-naïve arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy naïve (0.0% [0/25]) arm (risk difference 20% [95% CI:4.3-35.7] p=0.018). Ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure which may compromise artesunate-amodiaquine’s efficacy. Co-administration of nevirapine and artesunate amodiaquine may be associated with hepatoxicity

Challenges with targeted viral load testing for medical inpatients at Queen Elizabeth Central Hospital in Blantyre, Malawi

BackgroundApproximately 75% of medical inpatients at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi are HIV seropositive, and a third of these patients are on antiretroviral therapy (ART). Malawi guidelines recommend targeted viral load (VL) testing for patients on ART for at least one year who report excellent adherence and present with a WHO clinical stage 3 or 4 HIV disease. A switch to secondlineART is only indicated if a VL result &gt;5000 copies/mL confirms treatment failure.MethodsDuring an audit of targeted VL testing at QECH, all adult medical admissions were screened to identify those in need of VL testing. Daily review of inpatient notes ascertained whether VL testing was ordered and carried out. At 8 weeks  post-discharge the laboratory database was checked for results and was  triangulated with the HIV outpatient database to ascertain whether patients had attended clinic, received results, and if these results had been acted upon.ResultsOut of 81 patients recruited, 63 (77%) had a VL requested. At 8 weeks  post-discharge, nine patients (14%) had VL results available. The median (IQR) waiting time for those with results was 29 days (20-47). Five patients had a VL &gt;5000 copies/mL. Of these patients, three attended clinic and one was switched to second-line ART. Of the remaining 55 patients awaiting results, the median (IQR) waiting time at the 8-week follow-up point was 72 days (67-80). At 8 weeks post-discharge, 8 patients (33%) had died.ConclusionsOur findings demonstrate challenges with targeted VL testing at QECH. Only two-thirds of patients with clinical ART failure were identified as eligible for targeted VL testing, and of these less than one-sixth had VL results available after 8 weeks. Interventions such as point-of-care targeted VL testing could result in faster turnaround times. In the interim, we suggest further evaluation of the possibilityof switching patients with clinical ART failure and a low CD4 count to second-line ART while awaiting VL results

Household air pollution, chronic respiratory disease and pneumonia in Malawian adults: A case-control study

Background: Four million people die each year from diseases caused by exposure to household air pollution. There is an association between exposure to household air pollution and pneumonia in children (half a million attributable deaths a year); however, whether this is true in adults is unknown. We conducted a case-control study in urban Malawi to examine the association between exposure to household air pollution and pneumonia in adults. Methods: Hospitalized patients with radiologically confirmed pneumonia (cases) and healthy community controls underwent 48 hours of ambulatory and household particulate matter (µg/m3) and carbon monoxide (ppm) exposure monitoring. Multivariate logistic regression, stratified by HIV status, explored associations between these and other potential risk factors with pneumonia. Results: 145 (117 HIV-positive; 28 HIV-negative) cases and 253 (169 HIV-positive; 84 HIV-negative) controls completed follow up. We found no evidence of association between household air pollution exposure and pneumonia in HIV-positive (e.g. ambulatory particulate matter adjusted odds ratio [aOR] 1.00 [95% CI 1.00–1.01, p=0.141]) or HIV-negative (e.g. ambulatory particulate matter aOR 1.00 [95% CI 0.99–1.01, p=0.872]) participants. Chronic respiratory disease was associated with pneumonia in both HIV-positive (aOR 28.07 [95% CI 9.29–84.83, p<0.001]) and HIV-negative (aOR 104.27 [95% CI 12.86–852.35, p<0.001]) participants. Conclusions: We found no evidence that exposure to household air pollution is associated with pneumonia in Malawian adults. In contrast, chronic respiratory disease was strongly associated with pneumonia

Stavudine toxicity in adult longer-term ART patients in Blantyre, Malawi

BACKGROUND: Stavudine is an effective and inexpensive antiretroviral drug, but no longer recommended by WHO for first-line antiretroviral regimens in resource-limited settings due to toxicity concerns. Because of the high cost of alternative drugs, it has not been feasible to replace stavudine in most adults in the Malawi ART programme. We aimed to provide policy makers with a detailed picture of stavudine toxicities in Malawians on longer-term ART, in order to facilitate prioritization of stavudine replacement among other measures to improve the quality of ART programmes. METHODS: Prospective cohort of Malawian adults who had just completed one year of stavudine containing ART in an urban clinic, studying peripheral neuropathy, lipodystrophy, diabetes mellitus, high lactate syndromes, pancreatitis and dyslipidemia during 12 months follow up. Stavudine dosage was 30 mg irrespective of weight. Cox regression was used to determine associations with incident toxicities. RESULTS: 253 patients were enrolled, median age 36 years, 62.5% females. Prevalence rates (95%-confidence interval) of toxicities after one year on stavudine were: peripheral neuropathy 21.3% (16.5-26.9), lipodystrophy 14.7% (2.4-8.1), high lactate syndromes 0.0% (0-1.4), diabetes mellitus 0.8% (0-2.8), pancreatitis 0.0% (0-1.5). Incidence rates per 100 person-years (95%-confidence interval) during the second year on stavudine were: peripheral neuropathy 19.8 (14.3-26.6), lipodystrophy 11.4 (7.5-16.3), high lactate syndromes 2.1 (0.7-4.9), diabetes mellitus 0.4 (0.0-1.4), pancreatitis 0.0 (0.0-0.2). Prevalence of hypercholesterolemia and hypertriglyceridemia increased from 12.1% to 21.1% and from 29.5% to 37.6% respectively between 12 and 24 months. 5.5% stopped stavudine, 1.3% died and 4.0% defaulted during follow up. Higher age was an independent risk factor for incident peripheral neuropathy and lipodystrophy. CONCLUSION: Stavudine associated toxicities continued to accumulate during the second year of ART, especially peripheral neuropathy and lipodystrophy and more so at increasing age. Our findings support investments for replacing stavudine in first-line regimens in sub-Saharan Africa

Immediate Versus Triggered Transfusion for Children with Uncomplicated Severe Anaemia

Background: The World Health Organization recommends a haemoglobin transfusion threshold of 0.2) nor evidence of differences between groups in re-admissions (p=0.36), serious adverse events (p=0.36) nor in haemoglobin recovery at 180-days (p=0.08). Length-of-stay was mean 0.9 days longer in the triggered group. Conclusions: There was no evidence of differences in clinical outcomes over 6 months with triggered vs immediate transfusion. Triggered transfusion reduced blood-volume requirements by 60% but increased length-of-stay by 20% and required repeated haemoglobin monitoring and surveillance

Mathematical Modeling to Assess the Drivers of the Recent Emergence of Typhoid Fever in Blantyre, Malawi

Background. Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains. Methods. To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R(0)) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype. Results. Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data. Conclusions. Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa

Circulating microparticles are increased amongst people presenting with HIV and advanced immune suppression in Malawi and correlate closely with arterial stiffness: a nested case control study [version 2; peer review: 2 approved, 1 approved with reservations]

BACKGROUND: We aim to investigate whether circulating microparticle (CMPs) subsets were raised amongst people presenting with a new diagnosis of HIV and advanced immune suppression in Malawi, and whether they associated with arterial stiffness. Methods: Microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) were carried out in a cohort of adults with a new HIV diagnosis and CD4 <100 cells/µL at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic BP and diastolic BP in a 1:1 ratio. Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. METHODS: Microparticle characterisation and carotid femoral Pulse Wave Velocity (cfPWV) were carried out in a cohort of adults with a new HIV diagnosis and CD4 <100 cells/µL at 2 weeks post ART initiation. HIV uninfected controls were matched on age, systolic BP and diastolic BP in a 1:1 ratio. Circulating microparticles were identified from platelet poor plasma and stained for endothelial, leucocyte, monocyte and platelet markers. RESULTS: The median (IQ) total CMP count for 71 participants was 1 log higher in HIV compared to those without (p<0.0001) and was associated with arterial stiffness (spearman rho 0.47, p<0.001). In adjusted analysis, every log increase in circulating particles showed a 20% increase in cfPWV (95% CI 4 – 40%, p=0.02). In terms of subsets, endothelial and platelet derived microparticles were most strongly associated with HIV. Endothelial derived E-selectin+ CMPs were 1.3log-fold higher and platelet derived CD42a+ CMPs were 1.4log-fold higher (both p<0.0001). Endothelial and platelet derived CMPs also correlated most closely with arterial stiffness [spearman rho: E-selectin+ 0.57 and CD42a 0.56, both p<0.0001). CONCLUSIONS: Circulating microparticles associate strongly with arterial stiffness among PLWH in Malawi. Endothelial and platelet microparticles are the predominant cell origin types, indicating that platelet driven endothelial dysfunction pathways warrant further investigation in HIV associated arterial stiffness

The cost-effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa

Introduction: Many HIV-positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced-prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4<100 cells/mm3. We investigated the cost-effectiveness of this enhanced-prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4<200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision-analytic model was developed to estimate the cost-effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard-prophylaxis, enhanced-prophylaxis, standard-prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced-prophylaxis (CrAg-positive) or standard-prophylaxis (CrAg-negative), the second to enhanced-prophylaxis (CrAg-positive) or enhanced-prophylaxis without fluconazole (CrAg-negative) and the third to standard-prophylaxis with fluconazole (CrAg-positive) or without fluconazole (CrAg-negative). The model estimated costs, life-years and quality-adjusted life-years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results: Enhanced-prophylaxis was cost-effective at cost-effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost-effectiveness ratio (ICER) of US$157 per QALY in the CD4<200 cells/mm3 population providing enhanced-prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4<100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced-prophylaxis components. Enhanced-prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced-prophylaxis still conveyed health gains in CrAg-negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost-effective unless the price of CrAg testing fell below US$2.30. Conclusions: The REALITY enhanced-prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost-effective. Efforts should continue to ensure that components are accessed at lowest available prices. Funding REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development (DFID), the Wellcome Trust and Medical Research Council (MRC)