Pediatric tuberculosis outcomes and factors associated with unfavorable treatment outcomes in Botswana, 2008-2019: a retrospective analysis.

INTRODUCTION: Globally, the amount of research on the outcomes of pediatric tuberculosis (TB) is disproportionately less than that of adult TB. The diagnosis of paediatric TB is also problematic in developing countries. The aim of this study was to describe the outcomes of pediatric TB in Botswana and to identify the factors associated with unfavorable outcomes. METHODS: This was a retrospective analysis of pediatric TB outcomes in Botswana, over a 12-year period from January 2008 to December 2019. Treatment success (treatment completion or cured) was considered a favorable outcome, while death, loss to follow-up and treatment failure were considered unfavorable outcomes. Program data from drug-sensitive TB (DS-TB) cases under the age of 15 years were included. Sampling was exhaustive. Binary logistic regression was used to determine the factors associated with unfavorable outcomes during TB treatment. A p value of < 0.05 was considered a statistically significant association between the predictor variables and unfavorable outcomes. RESULTS: The data of 6,004 paediatric TB cases were extracted from the Botswana National TB Program (BNTP) electronic registry and analyzed. Of these data, 2,948 (49.4%) were of female patients. Of the extracted data, 1,366 (22.8%) were of HIV positive patients and 2,966 (49.4%) were of HIV negative patients. The rest of the data were of patients with unknown HIV status. Pulmonary TB accounted for 4,701 (78.3%) of the cases. Overall, 5,591 (93.1%) of the paediatric TB patient data showed treatment success, 179 (3.0%) were lost to follow-up, 203 (3.4%) records were of patients who died, and 31 (0.5%) were of patients who experienced treatment failure. The factors associated with unfavorable outcomes were positive HIV status (AOR 2.71, 95% CI: 2.09-3.52), unknown HIV status (AOR 2.07, 95% CI: 1.60-2.69) and retreatment category (AOR 1.92, 95% CI: 1.30-2.85). Compared with the 0-4 years age category, the 5-9 years (AOR 0.62, 95% CI: 0.47-0.82) and 10-14 years (AOR 0.76, 95% CI: 0.60-0.98) age categories were less likely to experience the unfavorable outcomes. CONCLUSION: This study shows a high treatment success rate among paediatric TB cases in Botswana. The government under the National TB Program should maintain and consolidate the gains from this program. Public health interventions should particularly target children with a positive or unknown HIV status, those under 5 years, and those who have been previously treated for TB.

Outcomes and predictors of tuberculosis mortality in Kweneng West District, Botswana: a retrospective cohort study.

Introduction: Botswana is among the countries with the highest tuberculosis (TB) notification rates in the world. However, there is paucity of data on the outcomes and predictors of TB mortality at district level in Botswana. This study was aimed at describing the TB outcomes and identifying the predictors of mortality in Kweneng West district, Botswana. Methods: this was a retrospective cohort study of TB outcomes in Kweneng West, from January 2008 to December 2016. All documented drug-sensitive TB (DS-TB) patients aged 16 years and above were included. The World Health Organization (WHO) definitions of treatment outcomes for DS-TB were used. Binary logistic regression was used to identify predictors of mortality. Results: there were 1475 TB notifications in the study period. The median age was 36 years and 41.5% were female. A total of 728 (49.4%) were HIV positive. Pulmonary TB (PTB) accounted for 87.3% of all cases. The overall treatment success rate (TSR) was 81.9% and the mortality rate was 9.4%. Compared to the 16-25 years age group, patients aged more than 65 years had the highest risk of mortality (AOR=9.63). Other significant predictors of mortality were male sex (AOR=1.63), no sputum microscopy (AOR=1.77), positive HIV (AOR=2.13) and unknown HIV status (AOR=4.47). Positive sputum microscopy (AOR=0.50) and extra-pulmonary TB (EPTB) (AOR=0.56) were associated with less mortality. Conclusion: while Botswana has relatively good TB treatment success rates, the mortality rates are high. Public health interventions should target the identified risk factors of mortality.

Acceptance rate and risk perception towards the COVID-19 vaccine in Botswana.

BACKGROUND: The COVID-19 disease burden continues to be high worldwide and vaccines continue to be developed to help combat the pandemic. Acceptance and risk perception for COVID-19 vaccines is unknown in Botswana despite the government's decision to roll out the vaccine nationally. OBJECTIVES: This study aims to assess the acceptance rate and risk perception of COVID-19 vaccines amongst the general population in Botswana. METHODS: We interviewed 5300 adults in Botswana from 1-28 February 2021 using self-administered questionnaires. The main outcomes of the study were vaccine acceptance and hesitancy rates. Demographic, experiential and socio-cultural factors were explored for their association with outcome variables. RESULTS: Two-thirds of the participants were females (3199), with those aged 24-54 making the highest proportion (61%). The acceptance rate of COVID-19 vaccine was 73.4% (95% CI: 72.2%-74.6%) with vaccine hesitancy at 31.3% (95% CI: 30.0%-32.6%). When the dependent variable was vaccine acceptance, males had higher odds of accepting the vaccine compared to females (OR = 1.2, 95% CI: 1.0, 1.4). Individuals aged 55-64 had high odds of accepting the vaccine compared to those aged 65 and above (OR = 1.2, 95% CI: 0.6, 2.5). The odds of accepting the vaccine for someone with primary school education were about 2.5 times that of an individual with post graduate level of education. Finally, individuals with comorbidities had higher odds (OR = 1.2, 95% CI: 1.0, 1.5) of accepting the vaccine compared to those without any underlying conditions. CONCLUSION: This study demonstrated a high acceptance rate for the COVID-19 vaccine and a low risk perception in Botswana. In order to achieve a high vaccine coverage and ensure a successful vaccination process, there is need to target populations with high vaccine hesitancy rates. A qualitative study to assess the factors associated with vaccine acceptance and hesitancy is recommended to provide an in-depth analysis of the findings.

Derivation and external validation of a risk score for predicting HIV-associated tuberculosis to support case finding and preventive therapy scale-up: A cohort study.

BACKGROUND: Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV-TB care. METHODS AND FINDINGS: We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/µL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/µL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) <18.5kg/m2 (2 points), and severe anemia (hemoglobin <8g/dL) (3 points). Sensitivity using WHO 4-symptom TB screen was 73%, 80%, 94%, and 94% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, but increased to 88%, 87%, 97%, and 97%, when a clinical score of ≥2 was used. Negative predictive value (NPV) also increased 1%, 0.3%, 1.6%, and 1.7% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, when the clinical score of ≥2 replaced WHO 4-symptom TB screen. Categorizing risk scores into low (<2), moderate (2 to 10), and high-risk categories (>10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. CONCLUSIONS: The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV-TB care to maximize impact of available resources.

Risk scores for predicting early antiretroviral therapy mortality in sub-Saharan Africa to inform who needs intensification of care: a derivation and external validation cohort study.

BACKGROUND: Clinical scores to determine early (6-month) antiretroviral therapy (ART) mortality risk have not been developed for sub-Saharan Africa (SSA), home to 70% of people living with HIV. In the absence of validated scores, WHO eligibility criteria (EC) for ART care intensification are CD4 < 200/µL or WHO stage III/IV. METHODS: We used Botswana XPRES trial data for adult ART enrollees to develop CD4-independent and CD4-dependent multivariable prognostic models for 6-month mortality. Scores were derived by rescaling coefficients. Scores were developed using the first 50% of XPRES ART enrollees, and their accuracy validated internally and externally using South African TB Fast Track (TBFT) trial data. Predictive accuracy was compared between scores and WHO EC. RESULTS: Among 5553 XPRES enrollees, 2838 were included in the derivation dataset; 68% were female and 83 (3%) died by 6 months. Among 1077 TBFT ART enrollees, 55% were female and 6% died by 6 months. Factors predictive of 6-month mortality in the derivation dataset at p < 0.01 and selected for the CD4-independent score included male gender (2 points), ≥ 1 WHO tuberculosis symptom (2 points), WHO stage III/IV (2 points), severe anemia (hemoglobin < 8 g/dL) (3 points), and temperature > 37.5 °C (2 points). The same variables plus CD4 < 200/µL (1 point) were included in the CD4-dependent score. Among XPRES enrollees, a CD4-independent score of ≥ 4 would provide 86% sensitivity and 66% specificity, whereas WHO EC would provide 83% sensitivity and 58% specificity. If WHO stage alone was used, sensitivity was 48% and specificity 89%. Among TBFT enrollees, the CD4-independent score of ≥ 4 would provide 95% sensitivity and 27% specificity, whereas WHO EC would provide 100% sensitivity but 0% specificity. Accuracy was similar between CD4-independent and CD4-dependent scores. Categorizing CD4-independent scores into low (< 4), moderate (4-6), and high risk (≥ 7) gave 6-month mortality of 1%, 4%, and 17% for XPRES and 1%, 5%, and 30% for TBFT enrollees. CONCLUSIONS: Sensitivity of the CD4-independent score was nearly twice that of WHO stage in predicting 6-month mortality and could be used in settings lacking CD4 testing to inform ART care intensification. The CD4-dependent score improved specificity versus WHO EC. Both scores should be considered for scale-up in SSA.

Outcomes of HIV-positive patients with non-tuberculous mycobacteria positive culture who received anti-tuberculous treatment in Botswana: Implications of using diagnostic algorithms without non-tuberculous mycobacteria.

BACKGROUND: Patients with non-tuberculous mycobacteria (NTM) or Mycobacterium tuberculosis (MTB) pulmonary disease may have similar clinical presentation. The potential for misdiagnosis and inappropriate treatment exists in settings with limited testing capacity for Xpert® MTB/RIF (Xpert), phenotypic culture and NTM speciation. We describe treatment outcomes among people living with HIV (PLHIV) who received anti-tuberculosis treatment and were found to have NTM or MTB positive sputum cultures. METHODS: PLHIV attending one of the 22 participating HIV clinics, who screened positive for ≥1 tuberculosis (TB) symptoms (cough, fever, night sweats, or weight loss) were asked to submit sputa for culture and speciation from August 2012 to November 2014. The national intensified TB case finding algorithms were followed: initially symptomatic patients were evaluated by testing sputum samples using a smear (smear-based TB diagnostic algorithm) and, after GeneXpert instruments were installed, by testing with Xpert (Xpert-based TB diagnostic algorithm). Within the study period, TB diagnostic algorithms used for MTB did not include screening, diagnosis, and management of NTM. Despite MTB negative culture, some symptomatic patients, including those with NTM positive culture, received empirical anti-TB treatment at the discretion of treating clinicians. Per the World Health Organization treatment outcomes classification: died, treatment failure or loss-to-follow-up were classified as unfavorable (unsuccessful) outcome; cured and treatment completed were classified as favorable (successful) outcome. Empiric treatment was defined as initiating treatment without or before receiving a test result indicating MTB. We compare treatment outcomes and characteristics among patients with NTM or MTB positive culture who received anti-TB treatment. RESULTS: Among 314 PLHIV, who were found co-infected with TB, 146 cases had microbiological evidence; and for 131/146 MTB positive cultures were reported. One-hundred fifty-two of the 314 were clinically diagnosed with TB and treated empirically. Among those empirically treated for TB, 36/152 had culture results positive for NTM, and another 43/152 had culture results positive for MTB, reported after patients received empirical anti-TB treatment. Overall, MTB positive culture results were reported for 174 (131 plus 43) patients. Treatment outcomes were available for 32/36 NTM and 139/174 MTB; unfavorable outcomes were 12.5% and 8.7% for NTM and MTB, respectively, p = 0.514, respectively. For 34/36 tested NTM patients, all Xpert results indicated 'no MTB'. Among patients who initially received empiric anti-TB treatment and ultimately were found to have MTB positive culture, the unfavorable outcome was 11.8% (4/34), compared to 12.5% (4/32) of patients with NTM positive culture, Fisher's exact test p = 1.00. CONCLUSIONS: While the higher unfavorable outcome was non statistically significant, the impact of inappropriate treatment among NTM patients should not be overlooked. Our findings suggest that Xpert has the potential to rapidly rule-out NTM and avoid sub-optimal treatment; further research is needed to evaluate such potential.

Overweight and Obesity among Recipients of Antiretroviral Therapy at HIV Clinics in Gaborone, Botswana: Factors Associated with Change in Body Mass Index.

BACKGROUND: Factors associated with overweight/obesity among antiretroviral therapy (ART) recipients have not been sufficiently studied in Botswana. OBJECTIVES: To: (i) estimate the prevalence and trends in overweight/obesity by duration of exposure to ART among recipients, (ii) assess changes in BMI categories among ART recipients between their first clinic visit (BMI-1) and their last clinic visit (BMI-2), (iii) identify ART regimen that predicts overweight/obesity better than the others and factors associated with BMI changes among ART recipients. METHODS: A 12-year retrospective record-based review was conducted. Potential predictors of BMI change among patients after at least three years of ART exposure were examined using a multiple logistic regression model. Adjusted odds ratios (AOR) and their 95% confidence intervals (CIs) were computed. ART regimens, duration of exposure to ART, and recipients' demographic and biomedical characteristics including the presence or absence of diabetes mellitus-related comorbidities (DRC), defined as any morbidity associated with type 2 diabetes as described in the international statistical classification of diseases and related health problems (ICD-10-CM) codebook index, were investigated as potential predictors of overweight/obesity. RESULTS: Twenty-nine percent of recipients were overweight, 16.6% had obesity of whom 2.4% were morbidly-obese at the last clinic visit. Overweight/obese recipients were more likely to be female, to have DRC and less likely to have CD4 count between 201 and 249 cells/mm3. Neither the first-line nor the second-, third-line ART regimens predicted overweight/obesity better than the other and neither did the duration of exposure to ART. No significant linear trends were observed in the prevalence of overweight/obesity by the duration of exposure to ART. CONCLUSION: These results suggest that the ART regimens studied have a comparable effect on overweight/obesity and that the duration of exposure does not affect the outcome. This study calls for further research to elucidate the relative contribution of various factors to BMI change among recipients, including ART regimens.

Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial.

BACKGROUND: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. METHODS: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. RESULTS: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/µL in SOC, 246/µL in EC, and 241/µL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. CONCLUSIONS: Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. TRIAL REGISTRATION: Retrospectively registered: ClinicalTrials.gov (NCT02538952).

Detection of Second Line Drug Resistance among Drug Resistant Mycobacterium Tuberculosis Isolates in Botswana.

The emergence and transmission of multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (M.tb) strains is a threat to global tuberculosis (TB) control. The early detection of drug resistance is critical for patient management. The aim of this study was to determine the proportion of isolates with additional second-line resistance among rifampicin and isoniazid resistant and MDR-TB isolates. A total of 66 M.tb isolates received at the National Tuberculosis Reference Laboratory between March 2012 and October 2013 with resistance to isoniazid, rifampicin or both were analyzed in this study. The genotypes of the M.tb isolates were determined by spoligotyping and second-line drug susceptibility testing was done using the Hain Genotype MTBDRsl line probe assay version 2.0. The treatment outcomes were defined according to the Botswana national and World Health Organization (WHO) guidelines. Of the 57 isolates analyzed, 33 (58%) were MDR-TB, 4 (7%) were additionally resistant to flouroquinolones and 3 (5%) were resistant to both fluoroquinolones and second-line injectable drugs. The most common fluoroquinolone resistance-conferring mutation detected was gyrA A90V. All XDR-TB cases remained smear or culture positive throughout the treatment. Our study findings indicate the importance of monitoring drug resistant TB cases to ensure rapid detection of second-line drug resistance.

Clinical and Virological Outcomes of TB/HIV Coinfected Patients Treated With Dolutegravir-Based HIV Antiretroviral Regimens: Programmatic Experience From Botswana.

BACKGROUND: Dolutegravir (DTG) has recently been recommended as a preferred first-line regimen for the treatment of new and treatment-experienced HIV-infected patients. However, potential drug interactions between DTG and rifampicin remain a clinical and public health concern. METHODS: We analyzed HIV and Tuberculosis (TB) treatment outcomes of HIV-infected patients concomitantly receiving rifampicin- and DTG-based regimens under programmatic conditions in Botswana. The outcomes of interest were successful TB treatment and viral load suppression. We used multivariable logistic models to determine predictors for each outcome of interest. RESULTS: A total of 1225 patients were included in the analysis to evaluate predictors of successful TB outcome. Among patients on DTG and non-DTG regimens, 90.9% and 88.3% achieved favorable TB treatment outcomes, respectively. Of those who received DTG-based regimen; 44% received once-daily dosing and 53% twice-daily dosing. We found that DTG was associated with favorable TB treatment outcome (adjusted odds ratio = 1.56; 95% confidence interval = 1.06 to 2.31), after adjusting for age, gender, and CD4 cell counts. High rates of viral load suppression were found across all antiretroviral therapy (ART) regimen categories (>92% for all). We did not find an independent association between DTG and viral suppression after adjustment of other covariates. CONCLUSIONS: The use of DTG-based ART regimens in patients coinfected with TB and HIV lead to favorable TB and HIV treatment outcomes, comparable to those achieved with alternative ART regimens. Our results provide reassurance to TB and HIV programs about the overall programmatic concomitant use of these first-line treatment regimens for the management of HIV and TB coinfected patients.

Relationship between combination antiretroviral therapy regimens and diabetes mellitus-related comorbidities among HIV patients in Gaborone Botswana.

BACKGROUND: Combination antiretroviral therapy (cARTs) regiments are known to prolong the recipients' life even though they are risk factors for diabetes mellitus-related comorbidities (DRCs). We sought to: (i) examine cART relationship with DRCs among patients attending HIV clinics in Gaborone, Botswana (which cART regimens are associated with shorter/longer time to the event), (ii) characterize patients' underlying biomedical and demographic risk factors of DRC and identify the most important, (iii) investigate survival of patients on different cART regimens in the presence of these risk factors. METHODS: Data from two major HIV clinics in Botswana were reviewed. Relationships between different cART regimens and DRCs were investigated among 531 recipients. Recipients' DRC risk factors were identified. Cox regression model was run. Unadjusted and adjusted hazard ratios were computed, and hazard and survival functions for different cART regimens were plotted. RESULTS: Major findings were: patients on second- and third-line cART were less likely to develop DRCs earlier than those on first-line cART. Patients with CD4 count ≤ 200 cells/mm3 at cART initiation were more likely to develop DRCs earlier than those who had CD4 count > 200 cells/mm3. Overweight patients at cART initiation had a higher risk of developing DRCs earlier than those who had normal body mass index. Males had a lower risk of developing DRCs earlier than females. CONCLUSION: The risk of new onset of DRC among cART recipients is a function of the type of cART regimen, duration of exposure and patients' underlying biomedical and demographic DRC risk factors. The study has provided a survival model highlighting DRCs' significant prognostic factors to guide clinical care, policy and management of recipients of cARTs. Further studies in the same direction will likely improve the survival to the development of DRC of every cART recipient in this community.

Incidence of diabetes mellitus-related comorbidities among patients attending two major HIV clinics in Botswana: a 12-year retrospective cohort study.

OBJECTIVES: Exposure to combination antiretroviral therapy (cART) is associated with the development of diabetes mellitus related comorbidities (DRCs). This study aims to: (i) estimate the incidence of DRCs among cART recipients, (ii) assess the time-to-event (development of DRC) and, (iii) compare survival function between recipients on first-line regimen and those on second-, third-line cART regimen. RESULTS: The incidence of DRCs was 26.8/1000 person-years, with total time of exposure of 3316 person-years. The average time to event for all the three regimens was 11.72 ± 0.20 years. The first-line cART regimen had a shorter mean ± SE of 10.59 ± 0.26 years to the event compared to 12.69 ± 0.24 years for the second-, third-line cART regimen. Recipients on the first-line had a shorter survival than recipients on second-, third-line cART (Log-rank X2 = 8.98, p < 0.003). Data from this study showed that the risk of developing DRCs per year of exposure was significantly greater for patients on first-line compared to those who were on second-, third-line regimen; which, suggests that monitoring of cART long-term side effects and regular reviewing of cART regimens is important. Meticulous selection of drug combinations is a key to improving recipients' survival.