Attenuated tuberculin skin test responses associated with Mycobacterium intracellulare sputum colonization in an adolescent TB prevalence survey in Western Kenya.

INTRODUCTION: Exposure to Non-tuberculous Mycobacteria (NTM) varies regionally and may partly explain the disparate outcomes of BCG vaccination and tuberculosis (TB) susceptibility. METHODS: We examined NTM sputum colonization, associations with clinical characteristics, and tuberculin skin test (TST) responses in an adolescent TB prevalence survey. RESULTS: Among 5004 adolescents screened, 2281 (45.5 %) were evaluated further. TB and NTM prevalence rates were 0.3 % and 8.0 %, respectively. Among 418 NTM isolates, 103 were unidentifiable, and 315 (75 %) comprised 15 species, the most frequent being M. intracellulare (MAC) (108, 26 %), M. scrofulaceum (96, 23 %) and M. fortuitum (51, 12 %). "NTM colonized" adolescents had less frequent chronic cough and night sweats (adjusted odds ratio [aOR] 0.62, 95 % confidence interval [CI] 0.44-0.87and aOR 0.61, CI 0.42-0.89 respectively), and lower TST induration (median 11 mm (interquartile range [IQR] 0-16) vs 13 mm (IQR 6-17; p = 0.006)) when compared to "NTM not colonized" participants. MAC, but not M. scrofulaceum or M. fortuitum, was associated with decreased TST induration (median 7.5 mm (IQR 0-15) vs 13 mm (IQR 6-17) among "MAC colonized" vs "not colonized", p = 0.001). CONCLUSION: We observed high NTM prevalence rates with species-specific associations with TST induration, consistent with a model of species-dependent heterologous immunity among mycobacteria.

TBscreen: A passive cough classifier for tuberculosis screening with a controlled dataset.

Recent respiratory disease screening studies suggest promising performance of cough classifiers, but potential biases in model training and dataset quality preclude robust conclusions. To examine tuberculosis (TB) cough diagnostic features, we enrolled subjects with pulmonary TB (N = 149) and controls with other respiratory illnesses (N = 46) in Nairobi. We collected a dataset with 33,000 passive coughs and 1600 forced coughs in a controlled setting with similar demographics. We trained a ResNet18-based cough classifier using images of passive cough scalogram as input and obtained a fivefold cross-validation sensitivity of 0.70 (±0.11 SD). The smartphone-based model had better performance in subjects with higher bacterial load {receiver operating characteristic-area under the curve (ROC-AUC): 0.87 [95% confidence interval (CI): 0.87 to 0.88], P < 0.001} or lung cavities [ROC-AUC: 0.89 (95% CI: 0.88 to 0.89), P < 0.001]. Overall, our data suggest that passive cough features distinguish TB from non-TB subjects and are associated with bacterial burden and disease severity.

Towards pharmacogenomics-guided tuberculosis (TB) therapy: N-acetyltransferase-2 genotypes among TB-infected Kenyans of mixed ethnicity.

BACKGROUND: Though persons of African descent have one of the widest genetic variability, genetic polymorphisms of drug-metabolising enzymes such as N-Acetyltransferase-2 (NAT2) are understudied. This study aimed to identify prevalent NAT2 single nucleotide polymorphisms (SNPs) and infer their potential effects on enzyme function among Kenyan volunteers with tuberculosis (TB) infection. Genotypic distribution at each SNP and non-random association of alleles were evaluated by testing for Hardy-Weinberg Equilibrium (HWE) and Linkage Disequilibrium (LD). METHODS: We isolated genomic DNA from cryopreserved Peripheral Blood Mononuclear Cells of 79 volunteers. We amplified the protein-coding region of the NAT2 gene by polymerase chain reaction (PCR) and sequenced PCR products using the Sanger sequencing method. Sequencing reads were mapped and aligned to the NAT2 reference using the Geneious software (Auckland, New Zealand). Statistical analyses were performed using RStudio version 4.3.2 (2023.09.1 + 494). RESULTS: The most frequent haplotype was the wild type NAT2*4 (37%). Five genetic variants: 282C > T (NAT2*13), 341 T > C (NAT2*5), 803A > G (NAT2*12), 590G > A (NAT2*6) and 481C > T (NAT2*11) were observed with allele frequencies of 29%, 18%, 6%, 6%, and 4% respectively. According to the bimodal distribution of acetylation activity, the predicted phenotype was 76% rapid (mainly consisting of the wildtype NAT2*4 and the NAT2*13A variant). A higher proportion of rapid acetylators were female, 72% vs 28% male (p = 0.022, odds ratio [OR] 3.48, 95% confidence interval [CI] 1.21 to 10.48). All variants were in HWE. NAT2 341 T > C was in strong complete LD with the 590G > A variant (D' = 1.0, r2 = - 0.39) but not complete LD with the 282C > T variant (D' = 0.94, r2 = - 0.54). CONCLUSION: The rapid acetylation haplotypes predominated. Despite the LD observed, none of the SNPs could be termed tag SNP. This study adds to the genetic characterisation data of African populations at NAT2, which may be useful for developing relevant pharmacogenomic tools for TB therapy. To support optimised, pharmacogenomics-guided TB therapy, we recommend genotype-phenotype studies, including studies designed to explore gender-associated differences.

Biomarker-confirmed suboptimal adherence to isoniazid preventive therapy among children with HIV in western Kenya.

OBJECTIVES: The aim of this study was to assess the level and correlates of biomarker-confirmed adherence to isoniazid (INH) preventive therapy (IPT) among children with HIV (CLHIV). DESIGN: This prospective cohort study assessed adherence among CLHIV on IPT in public sector HIV clinics from 2019 through 2020. METHODS: Adherence was assessed by pill counts or caregiver or self-reports, and urine biomarkers (in-house dipstick and Isoscreen). Both urine biomarker tests detect INH metabolites within 48 h of ingestion. Consistent adherence was defined as having positive results on either biomarker at all visits. Correlates of biomarker-confirmed nonadherence at each visit were evaluated using generalized estimating equations. The in-house dipstick was validated using Isoscreen as the reference. RESULTS: Among 97 CLHIV on IPT with adherence assessments, median age was 10 years (IQR 7-13). All were on ART at IPT initiation (median duration 46 months [IQR 4-89]); 81% were virally suppressed (<1000 copies/ml). At all visits, 59% ( n  = 57) of CLHIV reported taking at least 80% of their doses, while 39% ( n  = 38) had biomarker-confirmed adherence. Viral nonsuppression (adjusted risk ratio [aRR] = 1.65; 95% confidence interval [95% CI] 1.09-2.49) and the sixth month of IPT use (aRR = 2.49; 95% CI 1.34-4.65) were independent correlates of biomarker-confirmed nonadherence at each visit. Sensitivity and specificity of the in-house dipstick were 98.1% ( 94.7 - 99.6%) and 94.7% ( 88.1 - 98.3%) , respectively, versus Isoscreen. CONCLUSION: Biomarker-confirmed adherence to IPT was sub-optimal and was associated with viral nonsuppression and duration of IPT. Urine dipstick testing may be useful in assessing adherence to IPT in clinical care.

Trends, treatment outcomes, and determinants for attrition among adult patients in care at a large tertiary HIV clinic in Nairobi, Kenya: a 2004-2015 retrospective cohort study.

BACKGROUND: Understanding trends in patient profiles and identifying predictors for adverse outcomes are key to improving the effectiveness of HIV care and treatment programs. Previous work in Kenya has documented findings from a rural setting. This paper describes trends in demographic and clinical characteristics of antiretroviral therapy (ART) treatment cohorts at a large urban, referral HIV clinic and explores treatment outcomes and factors associated with attrition during 12 years of follow-up. METHODS: This was a retrospective cohort analysis of HIV-infected adults who started ART between January 1, 2004, and September 30, 2015. ART-experienced patients and those with missing data were excluded. The Cochran-Armitage test was used to determine trends in baseline characteristics over time. Cox proportional hazards models were used to determine the effect of baseline characteristics on attrition. RESULTS: ART uptake among older adolescents (15-19 years), youth, and young adults increased over time (p=0.0001). Independent predictors for attrition included (adjusted hazard ratio [95% CI]) male sex: 1.30 (1.16-1.45), p=0.0001; age: 15-19 years: 1.83 (1.26-2.66), p=0.0014; 20-24 years: 1.93 (1.52-2.44), p=0.0001; and 25-29 years: 1.31 (1.11-1.54), p=0.0012; marital status - single: 1.27 (1.11-1.44), p=0.0005; and divorced/separated: 1.56 (1.30-1.87), p=0.0001; urban residence: 1.40 (1.20-1.64), p=0.0001; entry into HIV care following hospitalization: 1.31 (1.10-1.57), p=0.0026, or transfer from another facility: 1.60 (1.26-2.04), p=0.0001; initiation of ART more than 12 months after the date of HIV diagnosis: 1.36 (1.19-1.55), p=0.0001, and history of a current or past opportunistic infection (OI): 1.15 (1.02-1.30), p=0.0284. CONCLUSION: Although ART uptake among adolescents and young people increased over time, this group was at increased risk for attrition. Single marital status, urban residence, history of hospitalization or OI, and delayed initiation of ART also predicted attrition. This calls for focused evidence-informed strategies to address attrition and improve outcomes.

Trends in clinical characteristics and outcomes of Pre-ART care at a large HIV clinic in Nairobi, Kenya: a retrospective cohort study.

BACKGROUND: The success of antiretroviral therapy in resource-scarce settings is an illustration that complex healthcare interventions can be successfully delivered even in fragile health systems. Documenting the success factors in the scale-up of HIV care and treatment in resource constrained settings will enable health systems to prepare for changing population health needs. This study describes changing demographic and clinical characteristics of adult pre-ART cohorts, and identifies predictors of pre-ART attrition at a large urban HIV clinic in Nairobi, Kenya. METHODS: We conducted a retrospective cohort analysis of data on HIV infected adults (≥15 years) enrolling in pre-ART care between January 2004 and September 2015. Attrition (loss to program) was defined as those who died or were lost to follow-up (having no contact with the facility for at least 6 months). We used Kaplan-Meier survival analysis to determine time to event for the different modes of transition, and Cox proportional hazards models to determine predictors of pre-ART attrition. RESULTS: Over the 12 years of observation, there were increases in the proportions of young people (age 15 to 24 years); and patients presenting with early disease (by WHO clinical stage and higher median CD4 cell counts), p = 0.0001 for trend. Independent predictors of attrition included: aHR (95% CI): male gender 1.98 (1.69-2.33), p = 0.0001; age 20-24 years 1.80 (1.37-2.37), p = 0.0001), or 25-34 years 1.22 (1.01-1.47), p = 0.0364; marital status single 1.55 (1.29-1.86), p = 0.0001) or divorced 1.41(1.02-1.95), p = 0.0370; urban residency 1.83 (1.40-2.38), p = 0.0001; CD4 count of 0-100 cells/µl 1.63 (1.003-2.658), p = 0.0486 or CD4 count >500 cells/µl 2.14(1.46-3.14), p = 0.0001. CONCLUSIONS: In order to optimize the impact of HIV prevention, care and treatment in resource scarce settings, there is an urgent need to implement prevention and treatment interventions targeting young people and patients entering care with severe immunosuppression (CD4 cell counts <100 cells/µl). Additionally, care and treatment programmes should strengthen inter-facility referrals and linkages to improve care coordination and prevent leakages in the HIV care continuum.