TST positivity in household contacts of tuberculosis patients : a case-contact study in Malawi

This work was supported by a Wellcome Trust Fellowship awarded to DJ Sloan (086757/Z/08/A) a Malawi Liverpool Wellcome Trust (MLW) Core grant awarded by the Wellcome Trust and by a grant from the European Union Action for Diseases of Poverty Program (Sante–2006–105-061).Background:  Screening household contacts of active tuberculosis (TB) patients is recommended for TB control. Due to resource constraints this rarely occurs in lower income countries. Demographic and clinical features of index cases may influence the likelihood of onwards TB transmission. It has also been proposed that accumulation of intracellular lipid bodies within M. tuberculosis cells may also enhance bacterial transmissibility. This study explored whether clinical and bacteriological observations recorded at baseline in TB cases in Malawi could help identify those with the highest risk of onwards transmission, to prioritise contact tracing. Methods:  In this case-contact study, data on clinical presentation, sputum bacterial load and the percentage of lipid body positive acid-fast bacilli (%LB + AFB) on sputum smears were recorded in adults with sputum smear and culture positive pulmonary TB before initiation of therapy. The Tuberculin Skin Test (TST) was used to detect infection with M. tuberculosis amongst household contacts under the age of 15 years. TST positivity of the child contacts was related to characteristics of the index case. Results:  Thirty four index cases brought 56 contacts (median: 1, range: 1–4 contacts each). 37 (66%) of contacts had a positive TST. Cavities or a high percentage of lung affected on index patient CXRs were associated with TST positivity. Multivariate analysis of non-radiological factors showed that male sex, HIV-negative status and raised peripheral blood white blood count (WBC) in index patients were also independent risk factors of TST positivity. Lower %LB + AFB counts were associated with TST positivity on univariate analysis only. Conclusion:  TST positivity is common amongst household contacts of sputum smear positive adult TB patients in Malawi. Contact tracing in this high risk population could be guided by prioritising index cases with CXR cavities and extensive radiological disease or, in the absence of CXRs, those who are HIV-negative with a raised WBC.Publisher PDFPeer reviewe

Genetic determinants of the pharmacokinetic variability of rifampin in Malawian adults with pulmonary tuberculosis

D.J.S. was supported by a Wellcome Trust Clinical PhD Fellowship (086757/Z/08/A to D.J.S.). A.D.M. was supported by a National Institute for Health Research Integrated Clinical Academic Training Fellowship and a Wellcome Trust Clinical PhD Fellowship (105/392/B/14/Z). The Malawi Liverpool Wellcome Trust Clinical Research Programme is supported by a strategic award from the Wellcome Trust.Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.Publisher PDFPeer reviewe

Effectiveness of milk whey protein‐based ready‐to‐use therapeutic food in treatment of severe acute malnutrition in M

The cost of ready-to-use therapeutic food (RUTF) used in community-based management of acute malnutrition has been a major obstacle to the scale up of this important child survival strategy. The current standard recipe for RUTF [peanut-based RUTF (P-RUTF)] is made from peanut paste, milk powder, oil, sugar, and minerals and vitamins. Milk powder forms about 30% of the ingredients and may represent over half the cost of the final product. The quality of whey protein concentrates 34% (WPC34) is similar to that of dried skimmed milk (DSM) used in the standard recipe and can be 25-33% cheaper. This blinded, parallel group, randomised, controlled non-inferiority clinical trial tested the effectiveness in treating severe acute malnutrition (SAM) of a new RUTF formulation WPC-RUTF in which WPC34 was used to replace DSM. Average weight gain (non-inferiority margin Δ=-1.2gkg-1day-1) and recovery rate (Δ=-10%) were the primary outcomes, and length of stay (LOS) was the secondary outcome (Δ=+14days). Both per-protocol (PP) and intention-to-treat (ITT) analyses showed that WPC-RUTF was not inferior to P-RUTF for recovery rate [difference and its 95% confidence interval (CI) of 0.5% (95% CI -2.7, 3.7) in PP analysis and 0.6% (95% CI -5.2, 6.3) in ITT analysis] for average weight gain [0.2 (-0.5; 0.9) for both analyses] and LOS [-1.6days (95% CI, -4.6, 1.4days) in PP analysis and -1.9days (95% CI, -4.6, 0.8days) for ITT analysis]. In conclusion, whey protein-based RUTF is an effective cheaper alternative to the standard milk-based RUTF for the treatment of SAM. © 2014 John Wiley & Sons Ltd.SCOPUS: ar.jFLWOAinfo:eu-repo/semantics/publishe

Longitudinal PKPD biomarkers correlate with treatment outcome in drug sensitive pulmonary tuberculosis; a population pharmacokinetic-pharmacodynamic analysis

Funding: Wellcome Trust Clinical PhD Fellowship awarded to D.S. (086757/Z/08/A). Funding for the minimum inhibitory concentration assays was provided by a grant from the British Society for Antimicrobial Chemotherapy (GA2015_036P). F.K. has conducted the research as part of his Medical Research Council fellowship (MR/P014534/1).Background . This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions. Methods . Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing. Results . Higher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid CMAX (P < .05), isoniazid CMAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05). Conclusions . Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as CMAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.Publisher PDFPeer reviewe

SARS-CoV-2 Prevalence in Malawi Based on Data from Survey of Communities and Health Workers in 5 High-Burden Districts, October 2020.

To determine early COVID-19 burden in Malawi, we conducted a multistage cluster survey in 5 districts. During October-December 2020, we recruited 5,010 community members (median age 32 years, interquartile range 21-43 years) and 1,021 health facility staff (HFS) (median age 35 years, interquartile range 28-43 years). Real-time PCR-confirmed SARS-CoV-2 infection prevalence was 0.3% (95% CI 0.2%-0.5%) among community and 0.5% (95% CI 0.1%-1.2%) among HFS participants; seroprevalence was 7.8% (95% CI 6.3%-9.6%) among community and 9.7% (95% CI 6.4%-14.5%) among HFS participants. Most seropositive community (84.7%) and HFS (76.0%) participants were asymptomatic. Seroprevalence was higher among urban community (12.6% vs. 3.1%) and HFS (14.5% vs. 7.4%) than among rural community participants. Cumulative infection findings 113-fold higher from this survey than national statistics (486,771 vs. 4,319) and predominantly asymptomatic infections highlight a need to identify alternative surveillance approaches and predictors of severe disease to inform national response