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ObjectiveTo compare daily exposure to tuberculosis (TB) patients between HIV-infected and non-HIV-infected health care workers (HCWs), and examine the uptake of antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) among HIV-infected HCWs in Botswana.DesignWe conducted a cross-sectional study among HCWs in 30 hospitals and clinics. We determined self-reported exposure frequency to TB patients and HIV status through in-person interviews. HCWs with unknown or negative HIV status were offered rapid HIV testing. Multivariable Poisson regression modeling with robust variance was used to estimate the association between HIV status and daily exposure to TB patients.ResultsOf 1877 participants enrolled, 1388 (73.9%) with complete data were included in this study. Among 277 (20.0%) HIV-infected participants, 14.3% were newly diagnosed, 57.8% were on ART, and 34.3% reported previously receiving IPT. Daily exposure to TB patients was reported by respectively 48.4% and 52.9% of HIV-infected and non-infected participants. After adjusting for sex, age, occupation, and department, the rates of daily TB exposure remained similar between HIV-infected and non-HIV-infected participants (prevalence ratio 0.96, 95%CI 0.85-1.08).ConclusionsWe found similar rates of exposure to TB patients between HIV-infected and non-HIV-infected HCWs. Improved efforts are needed to reduce nosocomial exposure to TB among HIV-infected HCWs.

OBJECTIVES: Screening for human immunodeficiency virus (HIV) infection in the emergency department (ED) has been proposed as an effective approach to increase early HIV diagnosis. To evaluate the potential for the implementation of routine screening, we determined the prevalence of unknown HIV infection among patients being seen in an urban public hospital ED. METHODS: We conducted a cross-sectional study among patients presenting to the San Francisco General Hospital's ED during March 2007. We reviewed patients' medical records to determine HIV infection status. In patients with unknown or negative HIV-infection status, we tested de-identified remnant blood specimens by HIV-antibody and nucleic-acid assays. We used a sensitive/less sensitive testing algorithm to determine the duration of HIV infection. RESULTS: During the study period, 1,820 patients had blood collected for clinical evaluation. Of those patients, 146 (8.0%) were known to be HIV-infected. Among the remaining 1,674 patients with unknown HIV-infection status, HIV-infection prevalence was 0.9% (15 of 1,674, 95% confidence interval [CI] 0.55, 1.47). In addition, one case of acute HIV infection (HIV-antibody negative, HIV RNA detected) was identified. Patients with unknown HIV infection vs. those who were uninfected were more likely to be homeless (odds ratio [OR] = 3.89, 95% CI 1.32, 11.45, p<0.05) and 18 to 30 years of age (OR=3.15, 95% CI 1.03, 9.61, p<0.05). CONCLUSIONS: In a sample of patients visiting a county ED, the relative prevalence of unknown HIV infection (10%) was modest and less than national estimates (25%). Acutely HIV-infected patients might account for a significant proportion of those with unknown HIV infection in an ED setting. [ABSTRACT FROM AUTHOR]

Combining genomic and geospatial data can be useful for understanding Mycobacterium tuberculosis transmission in high-burden tuberculosis (TB) settings. We performed whole-genome sequencing on M. tuberculosis DNA extracted from sputum cultures from a population-based TB study conducted in Gaborone, Botswana, during 2012-2016. We determined spatial distribution of cases on the basis of shared genotypes among isolates. We considered clusters of isolates with ≤5 single-nucleotide polymorphisms identified by whole-genome sequencing to indicate recent transmission and clusters of ≥10 persons to be outbreaks. We obtained both molecular and geospatial data for 946/1,449 (65%) participants with culture-confirmed TB; 62 persons belonged to 5 outbreaks of 10-19 persons each. We detected geospatial clustering in just 2 of those 5 outbreaks, suggesting heterogeneous spatial patterns. Our findings indicate that targeted interventions applied in smaller geographic areas of high-burden TB identified using integrated genomic and geospatial data might help interrupt TB transmission during outbreaks.

Smoking adversely affects tuberculosis (TB) outcomes and may be associated with depression and anxiety among people diagnosed with TB in Botswana. We conducted a cross-sectional study among patients newly diagnosed with TB in Gaborone, Botswana, evaluating factors associated with self-reported cigarette smoking. We performed Poisson regression analyses with robust variance to examine whether depressive and anxiety symptoms were associated with smoking. Among 180 participants with TB enrolled from primary health clinics, depressive symptoms were reported in 47 (26.1%) participants and anxiety symptoms were reported in 85 (47.2%) participants. Overall, 45 (25.0%) participants reported current smoking. Depressive symptoms were associated with a higher prevalence of smoking (adjusted prevalence ratio [aPR]: 2.04; 95% confidence interval [CI]: 1.29-3.25) in the adjusted analysis. The association between anxiety symptoms and smoking did not reach statistical significance (aPR: 1.26; 95% CI: 0.77-2.05). Future studies should further investigate these associations when addressing TB care.

Identifying host factors that influence infectious disease transmission is an important step toward developing interventions to reduce disease incidence. Recent advances in methods for reconstructing infectious disease transmission events using pathogen genomic and epidemiological data open the door for investigation of host factors that affect onward transmission. While most transmission reconstruction methods are designed to work with densely sampled outbreaks, these methods are making their way into surveillance studies, where the fraction of sampled cases with sequenced pathogens could be relatively low. Surveillance studies that use transmission event reconstruction then use the reconstructed events as response variables (i.e., infection source status of each sampled case) and use host characteristics as predictors (e.g., presence of HIV infection) in regression models. We use simulations to study estimation of the effect of a host factor on probability of being an infection source via this multi-step inferential procedure. Using TransPhylo-a widely-used method for Bayesian estimation of infectious disease transmission events-and logistic regression, we find that low sensitivity of identifying infection sources leads to dilution of the signal, biasing logistic regression coefficients toward zero. We show that increasing the proportion of sampled cases improves sensitivity and some, but not all properties of the logistic regression inference. Application of these approaches to real world data from a population-based TB study in Botswana fails to detect an association between HIV infection and probability of being a TB infection source. We conclude that application of a pipeline, where one first uses TransPhylo and sparsely sampled surveillance data to infer transmission events and then estimates effects of host characteristics on probabilities of these events, should be accompanied by a realistic simulation study to better understand biases stemming from imprecise transmission event inference., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SSS declares receiving consulting fees from Beckman Coulter and Hycor Biomedical on unrelated studies. All other authors have declared that no competing interests exist., (Copyright: © 2022 Goldstein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Healthcare facilities are a well-known high-risk environment for transmission of M. tuberculosis , the etiologic agent of tuberculosis (TB) disease. However, the link between M. tuberculosis transmission in healthcare facilities and its role in the general TB epidemic is unknown. We estimated the proportion of overall TB transmission in the general population attributable to healthcare facilities., Methods: We combined data from a prospective, population-based molecular epidemiologic study with a universal electronic medical record (EMR) covering all healthcare facilities in Botswana to identify biologically plausible transmission events occurring at the healthcare facility. Patients with M. tuberculosis isolates of the same genotype visiting the same facility concurrently were considered an overlapping event. We then used TB diagnosis and treatment data to categorize overlapping events into biologically plausible definitions. We calculated the proportion of overall TB cases in the cohort that could be attributable to healthcare facilities., Results: In total, 1,881 participants had TB genotypic and EMR data suitable for analysis, resulting in 46,853 clinical encounters at 338 healthcare facilities. We identified 326 unique overlapping events involving 370 individual patients; 91 (5%) had biologic plausibility for transmission occurring at a healthcare facility. A sensitivity analysis estimated that 3%-8% of transmission may be attributable to healthcare facilities., Conclusions: Although effective interventions are critical in reducing individual risk for healthcare workers and patients at healthcare facilities, our findings suggest that development of targeted interventions aimed at community transmission may have a larger impact in reducing TB.

Background: Human papillomavirus (HPV) is a sexually transmitted infection and a causative agent of cervical cancer. It is common in adolescent girls and young women, and the majority of infections are transient and asymptomatic. In Botswana, there are currently no data on the HPV prevalence against which the impact of prophylactic HPV vaccines can be measured., Objectives: To establish a baseline HPV prevalence in an unvaccinated cohort of young women., Methods: Women aged ≥18 years were recruited from the University of Botswana between September 2016 and May 2020. Demographic and behavioural characteristics of participants were collected. Subsequently, cervicovaginal swabs were obtained and tested for HPV using polymerase chain reaction-restriction fragment length polymorphism. We determined the prevalent HPV types, and evaluated the risk factors associated with HPV positivity., Results: A total of 978 young women were recruited. Overall, there were 589 (60.2%) participants with HPV infection and 12 (1.2%) with HIV. The median (interquartile range) age of the study participants was 19 (18 - 20) years. Multivariate logistic regression analysis showed that significant factors associated with HPV positivity were sexual activity (adjusted odds ratio (aOR) 2.06; 95% confidence interval (CI) 1.49 - 2.63; p&lt;0.001), number of sex partners ≥3 (aOR 2.10; 95% CI 1.39 - 3.18; p&lt;0.001), and smoking (aOR 2.00; 95% CI 1.26 - 3.20; p=0.004)., Conclusion: Our results demonstrate for the first time the prevalence of HPV in unvaccinated young women in Botswana. We found a high prevalence of HPV infection, with statistical differences with different risk factors. This finding supports the need for HPV vaccination strategies for females prior to sexual debut to reduce the future burden of cervical cancer in Botswana.

Mycobacterium tuberculosis transmission dynamics in high-burden settings are poorly understood. Growing evidence suggests transmission may be characterized by extensive individual heterogeneity in secondary cases (i.e., superspreading), yet the degree and influence of such heterogeneity is largely unknown and unmeasured in high burden-settings. We conducted a prospective, population-based molecular epidemiology study of TB transmission in both an urban and rural setting of Botswana, one of the highest TB burden countries in the world. We used these empirical data to fit two mathematical models (urban and rural) that jointly quantified both the effective reproductive number, [Formula: see text], and the propensity for superspreading in each population. We found both urban and rural populations were characterized by a high degree of individual heterogeneity, however such heterogeneity disproportionately impacted the rural population: 99% of secondary transmission was attributed to only 19% of infectious cases in the rural population compared to 60% in the urban population and the median number of incident cases until the first outbreak of 30 cases was only 32 for the rural model compared to 791 in the urban model. These findings suggest individual heterogeneity plays a critical role shaping local TB epidemiology within subpopulations., (© 2022. The Author(s).)

Objective: To determine the association between food insecurity and HIV infection with depression and anxiety among new tuberculosis (TB) patients., Design: Our cross-sectional study assessed depression, anxiety and food insecurity with Patient Health Questionnaire (PHQ-9), Zung Anxiety Self-Assessment Scale (ZUNG) and Household Food Insecurity Access Scale, respectively. Poisson regression models with robust variance were used to examine correlates of depression (PHQ-9 ≥ 10) and anxiety (ZUNG ≥ 36)., Setting: Gaborone, Botswana., Participants: Patients who were newly diagnosed with TB., Results: Between January and December 2019, we enrolled 180 TB patients from primary health clinics in Botswana. Overall, 99 (55·0 %) were HIV positive, 47 (26·1 %), 85 (47·2 %) and 69 (38·5 %) indicated depression, anxiety and moderate to severe food insecurity, respectively. After adjusting for potential confounders, food insecurity was associated with a higher prevalence of depression (adjusted prevalence ratio (aPR) = 2·30; 95 % CI 1·40, 3·78) and anxiety (aPR = 1·41; 95 % CI 1·05, 1·91). Prevalence of depression and anxiety was similar between HIV-infected and HIV-uninfected participants. Estimates remained comparable when restricted to HIV-infected participants., Conclusions: Mental disorders may be affected by food insecurity among new TB patients, regardless of HIV status.

Objectives: Vulvar cancer is a rare gynecological malignancy. However, the incidence of human papillomavirus (HPV)-associated vulvar disease is increasing, particularly in low- and middle-income countries. HIV infection is associated with an increased risk of HPV-associated vulvar cancer. We evaluated treatment patterns and survival outcomes in a cohort of vulvar cancer patients in Botswana. The primary objective of this study was to determine overall survival and the impact of treatment modality, stage, and HIV status on overall survival., Methods: Women with vulvar cancer who presented to oncology care in Botswana from January 2015 through August 2019 were prospectively enrolled in this observational cohort study. Demographics, clinical characteristics, treatment, and survival data were collected. Factors associated with survival including age, HIV status, stage, and treatment were evaluated., Results: Our cohort included 120 women with vulvar cancer. Median age was 42 (IQR 38-47) years. The majority of patients were living with HIV (89%, n=107) that was well-controlled on antiretroviral treatment. Among women with HIV, 54.2% (n=58) were early stage (FIGO stage I/II). In those without HIV, 46.2% (n=6) were early stage (stage I/II). Of the 95 (79%) patients who received treatment, 20.8% (n=25) received surgery, 67.5% (n=81) received radiation therapy, and 24.2% (n=29) received chemotherapy, either alone or in combination. Median follow-up time of all patients was 24.7 (IQR 14.2-39.1) months and 2- year overall survival for all patients was 74%. Multivariate analysis demonstrated improved survival for those who received surgery (HR 0.26; 95% CI 0.08 to 0.86) and poor survival was associated with advanced stage (HR 2.56; 95% CI 1.30 to 5.02). Survival was not associated with HIV status., Conclusions: The majority of women with vulvar cancer in Botswana are young and living with HIV infection. Just under half of patients present with advanced stage, which was associated with worse survival. Improved survival was seen for those who received surgery., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cervical cancer remains the most common cancer among women in sub-Saharan Africa and is also a leading cause of cancer related deaths among these women. The benefit of chemoradiation in comparison with radiation alone for patients with stage IIIB disease has not been evaluated prospectively in women living with human immunodeficiency virus (HIV). We assessed the survival of chemoradiation versus radiation alone among stage IIIB cervical cancer patients based on HIV status., Methods: Between February 2013 and June 2018, patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIIB cervical cancer with or without HIV and treated with chemoradiation or radiation alone, were prospectively enrolled in an observational cohort study. Overall survival was evaluated using the Kaplan-Meier method. Cox proportional hazards modeling was used to analyze associations with survival., Results: Among 187 patients, 63% (n=118) of women had co-infection with HIV, and 48% (n=69) received chemoradiation. Regardless of HIV status, patients who received chemoradiation had improved 2 year overall survival compared with those receiving radiation alone (59% vs 41%, p<0.01), even among women living with HIV (60% vs 38%, p=0.02). On multivariable Cox regression analysis, including all patients regardless of HIV status, 2 year overall survival was associated with receipt of chemoradiation (hazard ratio (HR) 0.63, p=0.04) and total radiation dose ≥80 Gy (HR 0.57, p=0.02). Among patients who received an adequate radiation dose of ≥80 Gy, adjusted overall survival rates were similar between chemoradiation versus radiation alone groups (HR 1.07; p=0.90). However, patients who received an inadequate radiation dose of <80 Gy, adjusted survival was significantly higher in chemoradiation versus radiation alone group (HR 0.45, p=0.01)., Conclusions: Addition of chemotherapy to standard radiation improved overall survival, regardless of HIV status, and is even more essential in women who cannot receive full doses of radiation., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To compare updated prospective 5-year survival outcomes of cervical cancer patients living with and without human immunodeficiency virus (HIV) infection who initiated curative chemoradiation therapy (CRT) in a resource-limited setting., Methods & Materials: Women in Botswana with locally advanced cervical cancer were enrolled in a prospective, observational, cohort study from July 2013 through January 2015. Survival outcomes were analyzed after 5 years of follow-up., Results: This cohort included 143 women initiating curative CRT. Sixty-seven percent (n = 96) of cohort were women living with HIV (WLWH), all of whom were receiving antiretroviral therapy (ART) at the time of treatment initiation and boasted a median CD4 count of 481 cells/μL (IQR, 351-579 μL). The 5-year overall survival (OS) rates were 56.8% (95% CI, 40.0-70.5%) for patients without HIV infection and 55.1% (95% CI, 44.2-64.7%) for WLWH (p = 0.732). Factors associated with superior 5-year OS on multivariate analyses included baseline hemoglobin > 10 g/dL (hazard ratio (HR) 0.90, 95% CI, 0.83-0.98, p = 0.015), lower stage at diagnosis (stage I and II vs. III and IV) (HR 1.39, 95% CI 1.09-1.76, p = 0.007), and higher EQD2 (HR 0.98, 95% CI 0.97-0.99, p = 0.001)., Conclusions: Five-year OS was not impacted by HIV status in this population of WLWH with well-managed infection who initiated curative treatment for cervical cancer in Botswana. Regardless of HIV status, hemoglobin levels and stage at diagnosis were associated with survival. These findings suggest that treatment for cervical cancer in WLWH with well-controlled infection need not be altered solely due to HIV status., (© 2021. The Author(s).)

Objectives/hypothesis: Head and neck cancer (HNC) is the fifth most common malignancy in sub-Saharan Africa, a region with hyperendemic human immunodeficiency virus (HIV)-infection. HIV patients have higher rates of HNC, yet the effect of HIV-infection on oncologic outcomes and treatment toxicity is poorly characterized., Study Design: Prospective observational cohort study., Methods: HNC patients attending a government-funded oncology clinic in Botswana were prospectively enrolled in an observational cohort registry from 2015 to 2019. Clinical characteristics were analyzed via Cox proportional hazards and logistic regression followed by secondary analysis by HIV-status. Overall survival (OS) was evaluated via Kaplan-Meier., Results: The study enrolled 149 patients with a median follow-up of 23 months. Patients presented with advanced disease (60% with T4-primaries), received limited treatment (19% chemotherapy, 8% surgery, 29% definitive radiation [RT]), and had delayed care (median time from diagnosis to RT of 2.5 months). Median OS was 36.2 months. Anemia was associated with worse survival (HR 2.74, P = .001). Grade ≥ 3 toxicity rate with RT was 30% and associated with mucosal subsite (OR 4.04, P = .03) and BMI < 20 kg/m 2 (OR 6.04, P = .012). Forty percent of patients (n = 59) were HIV-infected; most (85%) were on antiretroviral therapy, had suppressed viral loads (90% with ≤400 copies/mL), and had immunocompetent CD4 counts (median 400 cells/mm 3 ). HIV-status was not associated with decreased receipt or delays of definitive RT, worse survival, or increased toxicity., Conclusions: Despite access to government-funded care, HNC patients in Botswana present late and have delays in care, which likely contributes to suboptimal survival outcomes. While a disproportionate number has comorbid HIV infection, HIV-status does not adversely affect outcomes., Level of Evidence: 2c Laryngoscope, 131:E1558-E1566, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Tuberculosis (TB) elimination requires interrupting transmission of Mycobacterium tuberculosis. We used a multidisciplinary approach to describe TB transmission in 2 sociodemographically distinct districts in Botswana (Kopanyo Study). During August 2012-March 2016, all patients who had TB were enrolled, their sputum samples were cultured, and M. tuberculosis isolates were genotyped by using 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats. Of 5,515 TB patients, 4,331 (79%) were enrolled. Annualized TB incidence varied by geography (range 66-1,140 TB patients/100,000 persons). A total of 1,796 patient isolates had valid genotyping results and residential geocoordinates; 780 (41%) patients were involved in a localized TB transmission event. Residence in areas with a high burden of TB, age <24 years, being a current smoker, and unemployment were factors associated with localized transmission events. Patients with known HIV-positive status had lower odds of being involved in localized transmission.

Purpose: Cervical cancer is one of the leading causes of cancer death among women worldwide, and women living with human immunodeficiency virus (HIV) carry the highest burden of disease. Chemoradiation (CRT) is the current standard treatment for locally advanced cervical cancer, without specific treatment modifications based on HIV status. This systematic review evaluates existing literature reporting differences in outcomes between HIV+ and HIV- women with invasive cervical cancer treated with CRT., Methods and Materials: Searches were conducted through Pubmed, Ovid MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library. Two researchers independently conducted article selection; articles were selected by title, then abstract, and then by full text content. Data were extracted using a structured form., Results: Thirteen articles were included in the analysis, all of which were either retrospective or prospective cohort studies published between 2012 and 2018, and most of which were conducted in Sub-Saharan Africa. Treatment outcomes included treatment response, survival, toxicities, and quality of life. The majority of studies (8 of 13) reported no differences in treatment outcomes by HIV status. Out of 8 studies that assessed survival, 6 reported no significant difference based on HIV status. All 4 studies assessing treatment response found no significant differences based on HIV status. Among 6 studies primarily assessing treatment toxicity, 3 showed no differences based on HIV status. Factors affecting treatment outcomes, such as treatment selection bias, pretreatment hemoglobin levels, and antiretroviral therapy administration, were not systematically accounted for., Conclusions: The majority of studies analyzed showed no differences in treatment outcomes, including overall toxicity, treatment response, or mortality, on the basis of HIV infection status. These results suggest CRT should continue to be the treatment of choice for locally invasive cervical cancer regardless of HIV status. Further study is required to more precisely account for other variables that influence treatment outcome., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: In Botswana, nearly two-thirds of cervical cancer patients are HIV-positive. This study examined the relationship between CD4 count and chemoradiation therapy outcomes among cervical cancer patients with HIV., Setting: A prospective cohort study of 231 HIV-positive women with locally invasive cervical cancer was conducted in Gaborone, Botswana from January 2015 to February 2018., Methods: Primary outcome was survival, defined as time from scheduled end of chemoradiation therapy to death or last contact with patient. Nadir CD4 count was defined as lowest CD4 available before cancer diagnosis. Delta CD4 count was defined as improvement from nadir CD4 to CD4 at cancer diagnosis. Hazard ratio (HR) analyses were adjusted for presenting variables (age, baseline hemoglobin, cancer stage, and performance status) and treatment variables (chemotherapy cycles and radiation dose)., Results: Two hundred thirty-one patients were included in nadir CD4 analysis; 139 were included in delta CD4 analysis. Higher delta CD4 was significantly associated with reduced mortality after adjusting for presenting and treatment variables (CD4 100-249: HR 0.45, 95% CI: 0.21 to 0.95; CD4 ≥250: HR 0.45, 95% CI: 0.20 to 1.02). Higher nadir CD4 showed a trend toward reduced mortality after adjusting for presenting and treatment variables (HR 0.94, 95% CI: 0.84 to 1.06)., Conclusions: Higher delta CD4 (greater improvement from nadir CD4 to CD4 at cervical cancer diagnosis) is significantly associated with lower mortality. Although not statistically significant, data suggest that higher nadir CD4 may reduce mortality. These results reinforce the importance of early HIV diagnosis and antiretroviral therapy initiation, as their effects influence cervical cancer outcomes years later.

Introduction: We characterized the cervical 16S rDNA microbiome of patients in Botswana with high-grade cervical dysplasia and locally advanced cervical cancer., Methods: This prospective study included 31 patients: 21 with dysplasia and 10 with cancer. The Shannon diversity index was used to evaluate alpha (intra-sample) diversity, while the UniFrac (weighted and unweighted) and Bray-Curtis distances were employed to evaluate beta (inter-sample) diversity. The relative abundance of microbial taxa was compared among samples using linear discriminant analysis effect size., Results: Alpha diversity was significantly higher in patients with cervical cancer than in patients with cervical dysplasia (P<0.05). Beta diversity also differed significantly (weighted UniFrac Bray-Curtis, P<0.01). Neither alpha diversity (P=0.8) nor beta diversity (P=0.19) varied by HIV status. The results of linear discriminant analysis effect size demonstrated that multiple taxa differed significantly between patients with cervical dysplasia vs cancer. Lachnospira bacteria (in the Clostridia class) were particularly enriched among cervical dysplasia patients, while Proteobacteria (members of the Firmicutes phyla and the Comamonadaceae family) were enriched in patients with cervical cancer., Discussion: The results of our study suggest that differences exist in the diversity and composition of the cervical microbiota between patients with cervical dysplasia and patients with cervical cancer in Botswana. Additional studies are warranted to validate these findings and elucidate their clinical significance among women living in sub-Saharan Africa, as well as other regions of the world., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Mycobacterium tuberculosis complex (MTBC) is divided into several major phylogenetic lineages, with differential distribution globally. Using population-based data collected over a three year period, we performed 24-locus Mycobacterial Interspersed Repeat Unit - Variable Number Tandem Repeat (MIRU-VNTR) genotyping on all culture isolates from two districts of the country that differ in tuberculosis (TB) incidence (Gaborone, the capital, and Ghanzi in the Western Kalahari). The study objective was to characterize the molecular epidemiology of TB in these districts. Overall phylogenetic diversity mirrored that reported from neighboring Republic of South Africa, but differences in the two districts were marked. All four major lineages of M. tuberculosis were found in Gaborone, but only three of the four major lineages were found in Ghanzi. Strain diversity was lower in Ghanzi, with a large proportion (38%) of all isolates having an identical MIRU-VNTR result, compared to 6% of all isolates in Gaborone with the same MIRU-VNTR result. This study demonstrates localized differences in strain diversity by two districts in Botswana, and contributes to a growing characterization of MTBC diversity globally., (Published by Elsevier B.V.)

Background: Behavioral intentions (motivational factors), attitudes, subjective norm (social pressures), and perceived behavioral control promote or discourage smoking behavior among adolescents., Objective: To assess students' behavioral intentions, attitudes, subjective norms and perceived behavioral control on smoking using the Theory of Planned Behavior. The prevalence of smoking among the adolescents is also calculated., Methods: In this cross-sectional study, structured self-administered questionnaires were used to collect data from adolescents in primary and secondary schools. Data on demographics, behavioral intentions, attitudes, subjective norms, and perceived behavioral control towards smoking were collected. Pearson product moment correlations and logistic regression models were used to determine factors associated with current smoking., Results: A total sample of 2554 (mean age = 15; Range = 12-18 years) students participated in the study. Twenty-nine percent (n = 728) of the students had tried smoking at least once. Smoking was predicted by attitudes, subjective norms, perceived behavioral control and intention.There was a strong association between having a parent or guardian, caregiver or close friend who smoked (p < 0.001) and being a smoker. The majority of students (57%) conveyed that adults talked to them about the harmful effects of cigarette smoking and 50% had discussed smoking concerns with their friends. Students who had positive attitudes towards smoking like "smoking makes you confident" were more likely to be current smokers (OR: 1.63, 95% CI: 1.03-2.59). The feeling or conviction that they could refuse a cigarette if offered was an impediment from smoking (OR: 0.18, 95% CI: 0.13-0.26)., Conclusions: Attitudes, subjective norms, and perceived behavioral control contributed significantly to the students' smoking. Right attitudes must be cultivated and behavioral control must be strengthened for early effective interventions to curtail smoking among adolescents., Competing Interests: This research was commissioned by Good Business (London) as part of a social marketing programme designed to prevent teenage girls from taking up smoking in Botswana. The commercial affiliation did not play any role in the study." Please note: This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Contact investigation is one public health measure used to prevent tuberculosis by identifying and treating persons exposed to Mycobacterium tuberculosis. Contact investigations are a major tenet of global tuberculosis elimination efforts, but for many reasons remain ineffective. We describe a novel neighbor-based approach to reframe contact investigations.

Tuberculosis caused by concurrent infection with multiple Mycobacterium tuberculosis strains (i.e., mixed infection) challenges clinical and epidemiologic paradigms. We explored possible transmission mechanisms of mixed infection in a population-based, molecular epidemiology study in Botswana during 2012-2016. We defined mixed infection as multiple repeats of alleles at >2 loci within a discrete mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) result. We compared mixed infection MIRU-VNTR results with all study MIRU-VNTR results by considering all permutations at each multiple allele locus; matched MIRU-VNTR results were considered evidence of recently acquired strains and nonmatched to any other results were considered evidence of remotely acquired strains. Among 2,051 patients, 34 (1.7%) had mixed infection, of which 23 (68%) had recently and remotely acquired strains. This finding might support the mixed infection mechanism of recent transmission and simultaneous remote reactivation. Further exploration is needed to determine proportions of transmission mechanisms in settings where mixed infections are prevalent.

Cervical cancer remains a significant cause of morbidity and mortality in women worldwide and is the leading cause of cancer-related death in Botswana. It is well established that women with HIV have a higher risk of persistent HPV infection leading to cervical cancer. We assessed HPV prevalence and genotype distribution in 126 tissue specimens from confirmed invasive cervical cancer cases using Abbott real-time PCR assay. Overall, 88 (69.8%) women were HIV-infected. Fifty-seven (64.8%) of the HIV-infected women had a baseline CD4 + count ≥350 cells/μl, and 82 (93.2%) were on antiretroviral therapy at the time of cervical cancer diagnosis. The median age of HIV-infected patients was significantly younger than that of HIV-uninfected patients (p < 0.001). HPV DNA was detected in all of 126 (100%) of tissues analyzed in our study. The HPV genotypes identified included the HPV-16 (75.4%), HPV-18 (28.6%) and other high-risk (hr) HPV genotypes (16.7%). HIV infection was positively associated with the presence of the HPV-16 genotype (p = 0.036), but not with HPV-18 or with other high-risk (hr)-HPV genotypes. Thirty-three percent of the patients had multiple hr-HPV genotypes, with higher rates in HIV-infected women. These results highlight the importance and potential impact of large-scale HPV vaccination programs covering HPV-16 and HPV-18 genotypes in countries like Botswana with high burden of HIV infection., (© 2019 UICC.)

Multidrug-resistant tuberculosis (TB) is an alarming threat, and targeted deep sequencing (DS) may be an effective method for rapid identification of drug-resistant profiles, including detection of heteroresistance. We evaluated the sensitivity and specificity of targeted DS versus phenotypic drug susceptibility testing (pDST) among patients starting first-line anti-TB therapy in Botswana. Overall, we found high concordance between DS and pDST. Lower sensitivity of DS, which targets established high-confidence resistance variants, was observed for detecting isoniazid resistance among HIV-infected patients., (Copyright © 2019 American Society for Microbiology.)

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.

Background: Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure., Objectives: To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment., Methods: We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies., Results: We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation., Conclusions: Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cancer patients are at higher risk of tuberculosis (TB) infection, especially in hospital settings with high TB/HIV burden. The study was implemented among adult patients admitted to the largest tertiary-level referral hospital in Botswana. We estimated the TB prevalence at admission and the rate of newly diagnosed TB after hospitalization in the medical and oncology wards, separately. Presumptive TB cases were identified at admission through symptom screening and underwent the diagnostic evaluation through GeneXpert. Patients with no evidence of TB were followed-up until TB diagnosis or the end of the study. In the medical and oncology wards, four of 867 admitted patients and two of 240 had laboratory-confirmed TB at admission (prevalence = 461.4 and 833.3 per 100,000, respectively.) The post-admission TB rate from the medical wards was 28.3 cases per 1,000 person-year during 424.5 follow-up years (post-admission TB rate among HIV-positive versus. -negative = 54.1 and 9.8 per 1,000 person-year, respectively [Rate Ratio = 5.5]). No post-admission TB case was detected from the oncology ward. High rates of undetected TB at admission at both medical and oncology wards, and high rate of newly diagnosed TB after admission at medical wards suggest that TB screening and diagnostic evaluation should target all patients admitted to a hospital in high-burden settings., Competing Interests: The authors have declared that no competing interests exist.

Background: Cervical cancer is the leading cause of cancer death in Sub-Saharan Africa. The risk of developing cancer is increased for women living with human immunodeficiency virus (HIV) infection. It is unknown which factors predict the initiation of curative chemoradiotherapy (CRT) in resource-limited settings and whether HIV is associated with initiating curative CRT in settings with a high HIV burden., Methods: All women living with and without HIV infection who were initiating curative and noncurative CRT for locally advanced cervical cancer in Botswana were prospectively enrolled in an observational study. The factors associated with receiving CRT were evaluated in all patients and the subgroup of women living with HIV., Results: Of 519 enrolled women, 284 (55%) initiated CRT with curative intent. The curative cohort included 200 women (70.4%) who were living with HIV and had a median CD4 count of 484.0 cells/μL (interquartile range, 342.0-611.0 cells/μL). In the noncurative cohort, 157 of 235 women (66.8%) were living with HIV and had a median CD4 count of 476.5 cells/μL (interquartile range, 308.0-649.5 cells/μL). HIV status was not associated with initiating curative CRT (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.58-1.56). The factors associated with receiving curative CRT treatment on multivariable analysis in all patients included baseline hemoglobin levels ≥10 g/dL (OR, 1.80; 95% CI, 1.18-2.74) and stage I or II versus stage III or IV disease (OR, 3.16; 95% CI, 2.10-4.75). Women aged >61 years were less likely to receive curative treatment (OR, 0.43; 95% CI, 0.24-0.75). Among women who were living with HIV, higher CD4 cell counts were associated with higher rates of CRT initiation., Conclusions: The initiation of CRT with curative intent does not depend on HIV status. Significant predictors of CRT initiation include baseline hemoglobin level, disease stage, and age., (© 2019 American Cancer Society.)

Cervical cancer is a leading cause of death among women in low- and middle-income countries, and women living with HIV are at high risk for cervical cancer. The objective of this study was to estimate the prevalence and correlates of cervical cancer and pre-cancer lesions and to examine cervical cancer knowledge among women living with HIV receiving antiretroviral therapy in rural Andhra Pradesh, India. We conducted cytology-based screening and administered a standardized questionnaire among 598 HIV-infected women. We found 5 (0.8%), 39 (6.5%), 29 (4.9%), and 4 (0.7%) had atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and squamous cervical carcinoma (SCC), respectively. In multivariable logistic regression analysis, ASCUS/LSIL was independently associated with age >16 years old at first sexual encounter and smokeless tobacco use. We found no factors associated with HSIL/SCC. In total, 101 women (16.9%) had heard of cervical cancer and 28 (27.7%) of them correctly identified HIV infection as a risk factor. In light of the high prevalence of pre-cancer lesions and low level of cervical cancer knowledge in our study population, focused interventions are needed to improve cervical cancer literacy and prevention among rural women living with HIV.

Identification of factors associated with human papillomavirus (HPV) cervical histopathology or recurrence/relapse following loop electrosurgical excision procedure (LEEP) would allow for better management of the disease. We investigated whether gene signatures could (i) associate with HPV cervical histopathology and (ii) identify women with post-LEEP disease recurrence/relapse. Gene array analysis was performed on paraffin-embedded cervical tissue-isolated RNA from two cross-sectional cohorts of antiretroviral therapy (ART)-suppressed HIV+HPV+ coinfected women: (i) 55 women in South Africa recruited into three groups: high risk (HR) (-) (n = 16) and HR (+) (n = 15) HPV without cervical histopathology and HR (+) HPV with cervical intraepithelial neoplasia (CIN) grade 1/2/3 (n = 24), (ii) 28 women in Botswana with CIN2/3 treated with LEEP 12-month prior to recruitment and presenting with (n = 13) and without (n = 15) lesion recurrence/relapse (tissue was analyzed at first LEEP). Three distinct gene expression signatures identified were able to segregate: (i) HR+ HPV and CIN1/2/3, (ii) HR HPV-free and cervical histopathology-free and (iii) HR+ HPV and cervical histopathology-free. Immune activation and neoplasia-associated genes (n = 272 genes; e.g. IL-1A, IL-8, TCAM1, POU4F1, MCM2, SMC1B, CXCL6, MMP12) were a feature of cancer precursor dysplasia within HR HPV infection. No difference in LEEP tissue gene expression was detected between women with or without recurrence/relapse. In conclusion, distinctive gene signatures were associated with presence of cervical histopathology in tissues from ART-suppressed HIV+/HPV+ coinfected women. Lack of detection of LEEP tissue gene signature able to segregate subsequent post-LEEP disease recurrence/relapse indicates additional factors independent of local gene expression as determinants of recurrence/relapse., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Heteroresistant Mycobacterium tuberculosis infections (defined as concomitant infection with drug-resistant and drug-susceptible strains) may explain the higher risk of poor tuberculosis treatment outcomes observed among patients with mixed-strain M. tuberculosis infections. We investigated the clinical effect of mixed-strain infections while controlling for pretreatment heteroresistance in a population-based sample of patients with tuberculosis starting first-line tuberculosis therapy in Botswana., Methods: We performed 24-locus mycobacterial interspersed repetitive unit-variable number tandem-repeat analysis and targeted deep sequencing on baseline primary cultured isolates to detect mixed infections and heteroresistance, respectively. Drug-sensitive, micro-heteroresistant, macro-heteroresistant, and fixed-resistant infections were defined as infections in which the frequency of resistance was <0.1%, 0.1%-4%, 5%-94%, and ≥95%, respectively, in resistance-conferring domains of the inhA promoter, the katG gene, and the rpoB gene., Results: Of the 260 patients with tuberculosis included in the study, 25 (9.6%) had mixed infections and 30 (11.5%) had poor treatment outcomes. Micro-heteroresistance, macro-heteroresistance, and fixed resistance were found among 11 (4.2%), 2 (0.8%), and 11 (4.2%), respectively, for isoniazid and 21 (8.1%), 0 (0%), and 10 (3.8%), respectively, for rifampicin. In multivariable analysis, mixed infections but not heteroresistant infections independently predicted poor treatment outcomes., Conclusions: Among patients starting first-line tuberculosis therapy in Botswana, mixed infections were associated with poor tuberculosis treatment outcomes, independent of heteroresistance.

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis., Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration., Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses., Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition., Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The number and lifespan of individuals living with HIV have increased significantly with the scale-up of antiretroviral therapy. Furthermore, the incidence of breast cancer in women with HIV is growing, especially in sub-Saharan Africa (SSA). However, the association between HIV infection and breast cancer is not well understood., Methods: A literature search was performed to identify articles published in journals pertaining to breast cancer and HIV, with an emphasis on SSA. Selected US-based studies were also identified for comparison., Results: Among the 56 studies reviewed, the largest study examined 314 patients with breast cancer and HIV in the United States. There is no consensus on whether HIV infection acts as a pro-oncogenic or antioncogenic factor in breast cancer, and it may have no relation to breast cancer. A higher incidence of breast cancer is reported in high-income countries than in SSA, although breast cancer in SSA presents at a younger age and at a more advanced stage. Some studies show that patients with breast cancer and HIV experience worse chemotherapy toxicity than do patients without HIV. Data on treatment outcomes are limited. The largest study showed worse treatment outcomes in patients with HIV, compared with their counterparts without HIV., Conclusion: HIV infection has not been associated with different clinical presentation of breast cancer. However, some evidence suggests that concurrent diagnosis of HIV with breast cancer is associated with increased therapy-related toxicity and worse outcomes. Systematic prospective studies are needed to establish whether there is a specific association between breast cancer and HIV.

Background: To synthesize published literature on the association between human immunodeficiency virus (HIV) infection and radiation therapy (RT)-related toxicities. Methods: Two electronic databases, MEDLINE and Embase, were searched to identify studies published before November 2016 comparing RT-related toxicities between HIV-infected and HIV-uninfected patients receiving RT or chemoradiation therapy (CRT) for cancer. A qualitative synthesis of included articles and organ-specific toxicities was then performed. Results: Of the 21 studies included in this review, 15 reported on anal cancer treatment, three on cervical cancer, two on Kaposi sarcoma, and one on prostate cancer. Reports in the pre-antiretroviral therapy (ART) or early ART era tended to identify increased morbidity and mortality with HIV infection. However, modern series incorporating more concurrent chemotherapy, conformal RT techniques, and ART administration result in fewer studies reporting toxicity differences in patients treated for anal and cervical cancers. When statistically significant, HIV-infected patients had higher rates of gastrointestinal toxicity with anal cancer CRT (up to 50%) and higher rates of hematologic toxicity with cervical cancer CRT (up to 31%). Of the 17 studies reporting treatment outcomes, nine suggest HIV-infected patients may have reduced local control and/or survival rates. Conclusions: Overall, RT is likely similarly tolerated between HIV-infected and HIV-uninfected patients, especially with modern RT techniques. HIV-infected patients should continue to receive established standard of care RT and CRT dosing.

Purpose: To prospectively compare survival between human immunodeficiency virus (HIV)-infected versus HIV-uninfected cervical cancer patients who initiated curative chemoradiation therapy (CRT) in a limited-resource setting., Methods and Materials: Women with locally advanced cervical cancer with or without HIV infection initiating radical CRT in Botswana were enrolled in a prospective, observational, cohort study from July 2013 through January 2015., Results: Of 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122 of 143) had stage II/III cervical cancer, and 67% (96 of 143) were HIV-infected. All HIV-infected patients were receiving antiretroviral therapy (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The 2-year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54%-74%) and 66% for HIV-uninfected women (95% CI 49%-79%) (P = .70). Factors associated with better 2-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, P = .003), total radiation dose ≥75 Gy (HR 0.52, 95% CI 0.27-0.97, P = .04), and age <40 years versus 40-59 years (HR 2.17, 95% CI 1.05-4.47, P = .03)., Conclusions: Human immunodeficiency virus status had no effect on 2-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Pyrazinamide is a key drug in the first-line treatment regimen for tuberculosis, with a potent sterilizing effect. Although low pyrazinamide peak serum concentrations (C max ) are associated with poor treatment outcomes, many resource-constrained settings do not have sufficient laboratory capacity to support therapeutic drug monitoring (TDM). The objective of this study was to determine whether a colorimetric test of urine can identify tuberculosis patients with adequate pyrazinamide exposures, as defined by serum C max above a target threshold., Methods: In the derivation study of healthy volunteers, three dose sizes of pyrazinamide were evaluated, and intensive pharmacokinetic blood sampling was performed over an 8-h period, with a timed urine void at 4h post-dosing. Pyrazinamide in urine was isolated by spin column centrifugation with an exchange resin, followed by colorimetric analysis; the absorbance peak at 495nm was measured. The urine assay was then evaluated in a study of 39 HIV/tuberculosis patients in Botswana enrolled in an intensive pharmacokinetic study. Receiver operating characteristics (ROC) curves were used to measure diagnostic accuracy. The guideline-recommended pyrazinamide serum C max target of 35mg/l was evaluated in the primary analysis; this target was found to be predictive of favorable outcomes in a clinical study. Following this, a higher serum C max target of 58mg/l was evaluated in the secondary analysis., Results: At the optimal cut-off identified in the derivation sample, the urine colorimetric assay was 97% sensitive and 50% specific to identify 35 of 39 HIV/tuberculosis patients with pharmacokinetic target attainment, with an area under the ROC curve of 0.81 (95% confidence interval 0.60-0.97). Diagnostic accuracy was lower at the 58mg/l serum C max target, with an area under the ROC curve of 0.68 (95% confidence interval 0.48-0.84). Men were less likely than women to attain either serum pharmacokinetic target., Conclusions: The urine colorimetric assay was sensitive but not specific for the detection of adequate pyrazinamide pharmacokinetic exposures among HIV/tuberculosis patients in a high-burden setting., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major public health threat globally. Several lines of evidence support a role for host genetic factors in resistance/susceptibility to TB disease and MTB infection. However, results across candidate gene and genome-wide association studies (GWAS) are largely inconsistent, so a cohesive genetic model underlying TB risk has not emerged., Recent Findings: Despite the difficulties in identifying consistent genetic associations, genetic studies of TB and MTB infection have revealed a few well-documented loci. These well validated genes are presented in this review, but there remains a large gap in how these genes translate into better understanding of TB. To address this, we present a pathway based extension of standard association analyses, seeding the results with the best validated genes from candidate gene and GWAS studies., Summary: Several pathways were significantly enriched using pathway analyses that may help to explain population patterns of TB risk. In conclusion, we advocate for novel approaches to the study of host genetic analysis of TB that extend traditional association approaches.

Pyrazinamide is the main driver of sterilizing effect in the standard regimen in adults and older children, and this effect is concentration-dependent. Tuberculosis patients co-infected with human immunodeficiency virus (HIV) have an increased risk for poor tuberculosis treatment outcomes and adverse drug events. We sought to determine whether measures of systemic immune activation were related to pyrazinamide pharmacokinetics among HIV/tuberculosis patients. We conducted a prospective cohort study of pyrazinamide pharmacokinetics in HIV/tuberculosis patients in Gaborone, Botswana. Patients underwent intensive pharmacokinetic sampling before and after the initiation of antiretroviral therapy, which can increase immune activation in HIV/tuberculosis. Compartmental pharmacokinetic modeling was performed to determine whether variability in systemic immune activation was related to variability in pyrazinamide pharmacokinetic parameters. Forty HIV/tuberculosis patients completed the first pharmacokinetic sampling visit, and 24 patients returned for a second visit following antiretroviral therapy initiation. The pyrazinamide plasma concentration-versus-time data were best explained by a one-compartment model with first-order elimination, and a combined additive and proportional residual error model. Pyrazinamide clearance was higher in men than women. Expression of CD38 and HLA- DR on CD8+T cells, a measure of HIV-associated immune activation, was inversely related to pyrazinamide clearance, with increasing immune activation associated with decreasing pyrazinamide clearance. Future studies should verify this finding in larger numbers of tuberculosis patients with and without HIV co-infection.

Background: Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients., Patients and Methods: We conducted a prospective cohort study of rifampicin pharmacokinetics in HIV/TB patients in Gaborone, Botswana. We performed two intensively sampled pharmacokinetic visits, before and after ART initiation. Non-linear mixed-effects modelling was performed to determine whether variability in markers of gut damage, microbial translocation or systemic immune activation contributed to variability in rifampicin bioavailability before and after the initiation of ART., Results: We enrolled 40 HIV/TB patients in the first pharmacokinetic visit and 24 patients returned for the second pharmacokinetic visit after initiating ART. Low rifampicin exposure, as defined by the maximum serum concentration, was observed in 40% of patients prior to initiating ART and 46% of patients after initiating ART. In the non-linear mixed-effects model, we did not observe significant covariate effects of markers of gut damage, microbial translocation or immune activation on rifampicin bioavailability before and after ART initiation., Discussion: Markers of intestinal damage, microbial translocation and systemic immune activation did not explain variability in rifampicin bioavailability. The a priori identification of HIV/TB patients at risk for low rifampicin concentrations remains a challenge, supporting a role for therapeutic drug monitoring during HIV/TB therapy., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This study seeks to determine the prevalence and risk factors for smoking among students aged 12-18 years in two cities in Botswana. Using a sample of 2554 students we adapted the Global Youth Tobacco Survey (GYTS) methodology to assess students' smoking practices, knowledge, beliefs and attitudes. Logistic regression models were used to evaluate factors associated with smoking. The results revealed that 10% of students were current tobacco smokers with 29% reporting having tried smoking. Self-image and acceptance by peers were the strongest predictors of smoking overall (adjusted Odds Ratio [aOR]: 3.13, 95%, Confidence Interval [CI]: 2.67-3.66). Intention to smoke or to continue to smoke and perceived norms in conformity with smoking were also independently associated with smoking (aOR: 1.81, 95% CI: 167-2.11 and aOR: 1.31, 95% CI: 1.10-1.57, respectively). Perceived prevalence and exposure to smoking by peers and family and access to tobacco products was stronger among females (aOR: 1.69, 95% CI: 1.52-1.91) compared to males (aOR: 0.93, 95% CI: 0.70-1.24). Our results indicate that anti-tobacco interventions in Botswana should prioritize intra-personal factors associated with smoking. Our findings also suggest that different interventions targeting male and female students should be explored.

Objectives: We determined the performance of a sensor array (an electronic nose) made of 8 metalloporphyrins coated quartz microbalances sensors for the diagnosis and prognosis of pulmonary tuberculosis (TB) using exhaled breath samples., Methods: TB cases and healthy controls were prospectively enrolled. Signals from volatile organic compounds (VOCs) in breath samples were measured at days 0, 2, 7, 14, and 30 of TB therapy and correlated with clinical and microbiological measurements., Results: Fifty one pulmonary TB cases and 20 healthy HIV-uninfected controls were enrolled in the study. 31 (61%) of the 51 pulmonary TB cases were coinfected with HIV. At day 0 (before TB treatment initiation) the sensitivity of our device was estimated at 94.1% (95% confidence interval [CI], 83.8-98.8%) and specificity was 90.0% (95% CI, 68.3-98.8%) for distinguishing TB cases from controls. Time-dependent changes in the breath signals were identified as time on TB treatment progressed. Time-dependent signal changes were more pronounced among HIV-uninfected patients., Conclusion: The identification of VOCs' signals in breath samples using a sensor array achieved high sensitivity and specificity for the diagnosis of TB and allowed following signal changes during TB treatment., (Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Aims: Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid., Methods: We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation. Nonlinear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N-acetyltransferase-2 (NAT-2) genotype and interoccasional variability on clearance (thereby analyzing the PK data before and after ART initiation in a single model)., Results: We enrolled 40 patients in the PK visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a two-compartment model with first-order elimination. After accounting for NAT-2 genotype, increasing levels of CD38 and HLA-DR expression on CD8+ T cells (CD38 + DR + CD8 + ) were associated with decreasing isoniazid clearance., Conclusion: HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events., (© 2016 The British Pharmacological Society.)

During 2012-2015, 10 of 24 patients infected with matching genotypes of Mycobacterium tuberculosis received care at the same hospital in Gaborone, Botswana. Nosocomial transmission was initially suspected, but we discovered plausible sites of community transmission for 20 (95%) of 21 interviewed patients. Active case-finding at these sites could halt ongoing transmission.

Background: Few studies have examined multidrug-resistant (MDR) tuberculosis (TB) treatment outcomes among HIV-infected persons after widespread expansion of antiretroviral therapy (ART). We describe MDR-TB treatment outcomes among HIV-infected and HIV-uninfected patients in Botswana after ART expansion., Methods: We retrospectively reviewed data from patients who started MDR-TB therapy in Botswana during 2006-2013. Multivariable regression models were used to compare treatment outcomes between HIV-infected and HIV-uninfected patients., Results: We included 588 MDR-TB patients in the analysis, of whom, 47 (8.0%) and 9 (1.5%) were diagnosed with pre-extensively drug-resistant (XDR)-TB and XDR-TB, respectively. Of the 408 (69.4%) HIV-infected patients, 352 (86.0%) were on ART or started ART during treatment, and median baseline CD4 T-cell count was 234 cells/mm. Treatment success rates were 79.4% and 73.0% among HIV-uninfected and HIV-infected patients, respectively (P = 0.121). HIV-infected patients with CD4 T-cell count <100 cells/mm were more likely to die during treatment compared with HIV-uninfected patients (adjusted risk ratio = 1.890; 95% CI: 1.098 to 3.254)., Conclusions: High rates of treatment success were achieved with programmatic management of MDR-TB and HIV in Botswana after widespread expansion of ART. However, a 2-fold increase in mortality was observed among HIV-infected persons with baseline CD4 <100 cells/mm compared with HIV-uninfected persons.