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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.

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.

ObjectivesVulvar 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.MethodsWomen 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.ResultsOur 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.ConclusionsThe 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.

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.

IntroductionCombining genomic and geospatial data can be useful for understanding Mycobacterium tuberculosis (Mtb) transmission in high tuberculosis burden settings.MethodsWe performed whole genome sequencing (WGS) on Mtb DNA extracted from sputum cultures from a population-based tuberculosis study conducted in 2012–2016 in Gaborone, Botswana. We used kernel density estimation, spatial K-functions, and created spatial distributions of phylogenetic trees. WGS-based clusters of isolates ≤5 single nucleotide polymorphisms were considered recent transmission, and large WGS-based clusters (≥10 members) were considered outbreaks.ResultsWe analyzed data from 1449 participants with culture-confirmed TB. Among these, 946 (65%) participants had both molecular and geospatial data. A total of 62 belonged to five large outbreaks (10–19 participants each). Geospatial clustering was detected in two of the five large outbreaks, suggesting heterogeneous spatial patterns within the community.ConclusionsIntegration of genomic and geospatial data identified distinct patterns of tuberculosis transmission in a high-tuberculosis burden setting. Targeted interventions in these smaller geographies may interrupt on-going transmission.

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.

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

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.

Comorbidity of tuberculosis (TB) and depression may lead to delayed TB treatment initiation. A cross sectional study was conducted between January and December 2019 to examine the association between depression and delayed TB treatment initiation among newly diagnosed TB patients in Botswana. We used the Patient Health Questionnaire-9 and the ZUNG self-rating anxiety scale to assess depressive and anxiety symptoms, respectively. Delayed TB treatment was defined as experiencing common TB symptoms for more than 2 months before treatment initiation. We used Poisson regression models with robust variance to assess the association between covariates and delayed treatment initiation. Majority of the enrolled 180 study participants were males (n =116, 64.4%). Overall, 99 (55%) were co-infected with HIV; depression and anxiety symptoms were reported by 47.2% and 38.5% of the participants respectively. The prevalence of delayed TB treatment was 42.6% and 18.8% among participants who indicated symptoms of depression and among participants without depression respectively. After adjusting for age, HIV status, gender and anxiety symptoms, depression was still associated with delayed TB treatment (adjusted prevalence ratio [aPR] = 2.09; 95% CI = 1.23–3.57). Integrating management of depressive symptoms during TB treatment may help in improving overall TB treatment outcomes.

IntroductionWe characterized the cervical 16S rDNA microbiome of patients in Botswana with high-grade cervical dysplasia and locally advanced cervical cancer.MethodsThis 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.ResultsAlpha diversity was significantly higher in patients with cervical cancer than in patients with cervical dysplasia (PLachnospira 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.DiscussionThe 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.

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.

Objective:Tuberculosis (TB) remains one of the leading causes of mortality and morbidity among people living with HIV. We sought to estimate the incidence of TB in a national database of HIV-infected patients receiving antiretroviral therapy (ART) in Botswana.Design:A retrospective analysis of HIV-i

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.

BackgroundResearchers have increasingly recognized the adverse effects of smoking on tuberculosis (TB) outcomes. Smoking may be a maladaptive coping mechanism for depression and anxiety among TB patients; however, this association has not yet been investigated.Design/MethodsWe conducted a cross-sectional study among newly diagnosed TB patients between January and December 2019 in Gaborone, Botswana, and evaluated factors associated with cigarette smoking. Using the Patient Health Questionnaire-9 and the Zung Self-Rating Anxiety scale, we collected depression and anxiety scores, respectively; scores of ≥10 indicate depression and scores of ≥36 indicate anxiety. We performed Poisson regression analyses with robust variance to examine whether depression and anxiety were associated with smoking.ResultsOne hundred and eighty participants with TB were enrolled from primary health clinics. Among all enrollees, depression was reported in 46 (27.1%) participants, while anxiety was reported in 60 (44.4%) participants. Overall, 45 (25.0%) participants reported current smoking, and the median number of cigarettes per day was 10. Depressive symptoms were associated with a higher prevalence of smoking (aPR: 1.82; 95% CI = 1.11, 3.01) after adjusting for sex, HIV status, food insecurity, anxiety, and income. The association between anxiety symptoms and cigarette smoking did not reach statistical significance (aPR 1.26; 95% CI: 0.78-2.05).ConclusionsWe found the association between depressive symptoms and smoking among TB patients in Botswana to be significant and the association between anxiety symptoms and cigarette smoking insignificant. Future studies should further investigate these associations when addressing TB care.

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.

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.

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.

PURPOSE/OBJECTIVE(S) To present the stage and outcomes of patients with invasive cervical cancer with all stages in Botswana with or without HIV, and to prospectively evaluate factors associated with survival in this population. MATERIALS/METHODS Between April 2013 and November 2020, women with locally advanced cervical cancer (Stages IA-IVB) living with or without HIV infection were prospectively enrolled in an observational cohort study. Overall survival (OS) was evaluated using the Kaplan-Meier method. Associations with survival were analyzed using Cox proportional hazards modeling. RESULTS Among the 1,034 patients, 69% were women living with HIV (WLWH), 8% (n = 59) had surgery, 84% (n = 603) received radiation (RT), and 55% (n = 391) received chemoradiation (CRT). Median CD4 count at the time of cancer diagnosis in the cohort was 431.5 (245.3-613.8) and 13% had detectable viral load. 94% of patients were on anti-retroviral treatment at the time of cancer diagnosis. Median age of the WLWH was 44 years compared to 61 years in patients living without HIV infection (P < 0.001). Stage distribution in the cohort was as follows: Stage I was 16% (n = 170), Stage II was 37% (n = 384), Stage III was 35% (n = 364), and Stage IV was 8% (n = 86). Median follow up time was 1.95 years. OS at 2 years for Stage I was 95%, Stage II was 89%, Stage III was 54%, and Stage IV was 39%. Combined OS at 2 years was 67%. OS at 5 years for Stage I was 88%, Stage II was 63%, Stage III was 40%, and Stage IV was 32%. Combined OS at 5 years was 56%. WLWH did not show significant differences in OS as compared to those without HIV infection: OS at 2 years was 67% vs. 71% in women WLWH vs. without HIV infection and OS at 5 years was 49% in vs. 60% in women WLWH vs. without HIV infection (P = 0.105). In multivariable cox regression analysis including all patients, OS was associated with baseline hemoglobin (Hb) (HR 0.88, P < 0.001), baseline performance status (HR 1.42, P = 0.004), and disease stage: Stage II (HR 2.71, P = 0.001), Stage III (HR 4.96, P < 0.001), and Stage IV (HR 6.91, P < 0.001). CONCLUSION Among women in Botswana with cervical cancer, HIV status had no effect on OS. Survival was largely associated with patients' disease stage, Hb, and performance status at the time of treatment. Patients with early stage cervical cancer had adequate outcomes regardless of their HIV status. Therefore, for all women it is imperative to optimize their primary care to improve early detection of disease. AUTHOR DISCLOSURE J. George: Independent Contractor; AbbVie. S. Tuli: None. B. Monare: None. K. Lichter: None. D. Ramogola-Masire: None. T. Ralefala: None. A. Seiphetlheng: None. N. Zetola: None. S. Shin: None. L. Bazzett-Matabele: None. S. Grover: None.

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.

ObjectiveCervical 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.MethodsBetween 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.ResultsAmong 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%, pConclusionsAddition 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.

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.

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.

The performance of host blood-based biomarkers for tuberculosis (TB) in HIV-infected patients on antiretroviral therapy (ART) has not been fully assessed. We evaluated the immune phenotype and functionality of antigen-specific T-cell responses in HIV positive (+) participants with TB (n = 12) compared to HIV negative (&minus, ) participants with either TB (n = 9) or latent TB infection (LTBI) (n = 9). We show that the cytokine profile of Mtb-specific CD4+ T-cells in participants with TB, regardless of HIV status, was predominantly single IFN-&gamma, or dual IFN-&gamma, / TNF&alpha, Whilst ESAT-6/CFP-10 responding T-cells were predominantly of an effector memory (CD27&minus, CD45RA&minus, CCR7&minus, ) profile, HIV-specific T-cells were mainly of a central (CD27+CD45RA&minus, CCR7+) and transitional memory (CD27+CD45RA+/&minus, ) phenotype on both CD4+ and CD8+ T-cells. Using receiving operating characteristic (ROC) curve analysis, co-expression of CD38 and HLA-DR on ESAT-6/CFP-10 responding total cytokine-producing CD4+ T-cells had a high sensitivity for discriminating HIV+TB (100%, 95% CI 70&ndash, 100) and HIV&minus, TB (100%, 95% CI 70&ndash, 100) from latent TB with high specificity (100%, 95% CI 68&ndash, 100 for HIV&minus, TB) at a cut-off value of 5% and 13%, respectively. TB treatment reduced the proportion of Mtb-specific total cytokine+CD38+HLA-DR+ CD4+ T-cells only in HIV&minus, TB (p = 0.001). Our results suggest that co-expression of CD38 and HLA-DR on Mtb-specific CD4+ T-cells could serve as a TB diagnosis tool regardless of HIV status.

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

We analyzed 312 drug-resistant genomes of Mycobacterium tuberculosis isolates collected from HIV-coinfected and HIV-negative TB patients from nine countries with a high tuberculosis burden. We found that rifampicin-resistant M. tuberculosis strains isolated from HIV-coinfected patients carried disproportionally more resistance-conferring mutations in rpoB that are associated with a low fitness in the absence of the drug, suggesting these low-fitness rpoB variants can thrive in the context of reduced host immunity.

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.

IntroductionThe global burden of cancer continues to increase in low- and middle-income countries, particularly in sub-Saharan Africa (SSA). Botswana, a middle-income country in SSA, has the second highest prevalence of HIV worldwide and has seen an increase in human papillomavirus (HPV)-associated cervical cancer over the last decade in the setting of improved survival of HIV-infected women. There is an urgent need to understand more clearly the causes and consequences of HPV-associated cervical cancer in the setting of HIV infection. We initiated the Ipabalele (‘take care of yourself’ in Setswana) programme to address this need for new knowledge and to initiate long-term research programme capacity building in the region. In this manuscript, we describe the components of the programme, including three main research projects as well as a number of essential cores to support the activities of the programme.Methods and proceduresOur multidisciplinary approach aims to further current understanding of the problem by implementing three complementary studies aimed at identifying its molecular, behavioural and clinical determinants. Three participant cohorts were designed to represent the early, intermediate and late stages of the natural history of cervical cancer.The functional structure of the programme is coordinated through programmatic cores. These allow for integration of each of the studies within the cohorts while providing support for pilot studies led by local junior investigators. Each project of the Ipabalele programme includes a built-in capacity building component, promoting the establishment of long-lasting infrastructure for future research activities.Ethics and disseminationInstitutional review board approvals were granted by the University of Pennsylvania, University of Botswana and Ministry of Health and wellness of Botswana. Results will be disseminated via the participating institutions and with the help of the Community Advisory Committee, the project’s Botswana advisory group.

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.

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 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.

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 (Cmax) 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 Cmax 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 4 h post-dosing. Pyrazinamide in urine was isolated by spin column centrifugation with an exchange resin, followed by colorimetric analysis; the absorbance peak at 495 nm 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 Cmax target of 35 mg/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 Cmax target of 58 mg/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 58 mg/l serum Cmax 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. Keywords: Tuberculosis, Pyrazinamide, Pharmacokinetics, Human immunodeficiency virus, Point-of-care testing

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. 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. 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.

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.

Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC 0–24 ). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations ( C max ), AUC 0–24 , and trough concentrations. The primary node for failure had two competing variables, C max of 0–24 of 41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R 2 = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin C max of ≥67 mg/liter versus 3/15 (20%) in those with a C max of C max and AUC 0–24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.