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Background: Cancer drug shortages represent a complex global issue with potentially adverse survival outcomes. Up to 98% of oncologists and pharmacists surveyed in North America reported at least 1 drug shortage in the prior year and 66% reported at least one patient who had clinical care impacted by the shortage. In low- and middle-income countries (LMICs), these shortages are even more frequent. No studies to our knowledge have evaluated the impact of chemotherapy stock-out on receipt of standard cancer therapy in LMICs. Aim: Quantify the association between the duration of chemotherapy stock-out and the risk of having a suboptimal therapy delivery event, compared with standard delivery of therapy among cancer patients in Botswana. Methods: Prevalent cohort study of patients with cervical, breast, prostate, esophagus, Kaposi sarcoma, head and neck cancers, lung, uterine, ovarian and colorectal cancers who received any systemic therapy between 01/01/16-12/31/16 at Princess Marina Hospital, Botswana. Primary exposure was stock-out duration per cycle interval calculated by generating a code for the six different patterns for chemotherapy stock-out, using stock data at the Central Medical Stores. Primary outcome was suboptimal therapy delivery defined as a dose reduction, dose delay or switch in intended therapy. We measured statistical associations using two sample t -test and mixed effects univariate and multivariate logistic regression models. Results: 378 patients were identified who met diagnostic criteria and received systemic chemotherapy in 2016. Of these, 293 received commonly prescribed standard regimens who contributed 1452 cycle intervals and were included in our analysis. Majority of the patients (48%) had breast cancer. The mean duration of stock-out for receipt of standard therapy without events was 3.2 days (95% CI: 2.8-3.7) compared with 7.8 days for patients who had a suboptimal therapy delivery event (95% CI: 6.6-9) (P < 0.0001). Male sex, age < 65 and HIV-positive status were also significantly associated with an increased risk of experiencing dose reduction, change in therapy or switch in therapy. Adjusting for these factors in a mixed effects logistic regression, each week of stock-out was independently associated with an 80% increased risk of having a suboptimal therapy delivery event (OR=1.8 (95% CI: 1.6-2.0, P < 0.0001)). Conclusion: Chemotherapy stock-out is independently associated with an 80% increased risk of a patient experiencing dose reduction, change in therapy or delay in therapy. The risk increases with longer duration of stock out. Given prior data showing that these events lead to worse survival outcomes, our further analysis is focusing on quantifying risk of stock-out on survival outcomes in this population. to determine whether interventions promoting standard therapy delivery are warranted to optimize survival outcomes. [ABSTRACT FROM AUTHOR]

Chronic HIV disease is associated with a fivefold increase in albuminuria outside of sub-Saharan Africa. However, very little is known about albuminuria risk among people living with HIV (PLWH) in sub-Saharan Africa. Therefore, we conducted a cross-sectional observational HIV clinic-based study of albuminuria among 1533 adults aged 21 years or older between January 2020 and January 2021 in Gaborone, Botswana. Clinical albuminuria was defined using a sex-based albumin‒creatinine ratio (ACR) of 25-355 mg/g for females and 17-250 mg/g for males. The study population mean age was 48.5 (SD 10.3) years, and 764/1533 (49.7%) were female. The overall prevalence of albuminuria was 20.7% (95% CI 18.7%, 22.8%). A higher proportion of males were more likely to be categorized as having albuminuria than females, 25% (95% CI 22.0, 28.2) versus 16.4% (95% CI 13.8,19.2), P value < 0.001. In the final multivariate models, predictors of albuminuria differed by sex group. Larger longitudinal studies are required to evaluate the impact of albuminuria among PLWH with particular emphasis on the effect of sex on the risk of albuminuria., (© 2024. The Author(s).)

Background: Patients with breast cancer in sub-Saharan Africa (SSA) experience a disproportionate burden of mortality. Fidelity to treatment guidelines, defined as receiving optimal dose and frequency of prescribed treatments, improves survival. We sought to identify patient factors associated with treatment fidelity and how this may differ for people with HIV (PWH) and breast cancer., Methods: We conducted a qualitative study of women who initiated outpatient treatment for stages I-III breast cancer in Botswana, with deviance sampling of high- and low-fidelity patients. One-on-one interviews were conducted using semi-structured guides informed by the Theory of Planned Behavior. The sample size was determined by thematic saturation. Transcribed interviews were double coded with an integrated analytic approach., Results: We enrolled 15 high- and 15 low-fidelity participants from August 25, 2020 to December 15, 2020, including 10 PWH (4 high, 6 low fidelity). Ninety-three percent had stage III disease. Barriers to treatment fidelity included stigma, social determinants of health (SDOH), and health system barriers. Acceptance and de-stigmatization, peer and other social support, increased knowledge and self-efficacy were identified as facilitators. The COVID-19 pandemic amplified existing socioeconomic stressors. Unique barriers and facilitators identified by PWH included intersectional stigma, and HIV and cancer care integration, respectively., Conclusion: We identified multilevel modifiable patient and health system factors associated with fidelity. The facilitators provide opportunities for leveraging existing strengths within the Botswana context to design implementation strategies to increase treatment fidelity to guideline-concordant breast cancer therapy. However, PWH experienced unique barriers, suggesting that interventions to address fidelity may need to be tailored to specific comorbidities., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction. Lack of laboratory capacity hampers consistent national antimicrobial resistance (AMR) surveillance. Chromogenic media may provide a practical screening tool for detection of individuals colonized by extended-spectrum beta-lactamase (ESBL)-producing organisms. Hypothesis. CHROMagar ESBL media represent an adequate screening method for the detection of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE), isolated from rectal swabs. Aim. To evaluate the performance of CHROMagar ESBL media to accurately identify ESCrE isolates from rectal swab samples attained from hospitalized and community participants. Methodology. All participants provided informed consent prior to enrolment. Rectal swabs from 2469 hospital and community participants were inoculated onto CHROMagar ESBL. The performance of CHROMagar ESBL to differentiate Escherichia coli and Klebsiella spp., Enterobacter spp. and Citrobacter spp. (KEC spp.) as well as select for extended-spectrum cephalosporin resistance were compared to matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-TOF-MS) and VITEK-2 automated susceptibility testing. Results. CHROMagar ESBL had a positive and negative agreement of 91.2 % (95 % CI, 88.4-93.3) and 86.8 % (95 % CI, 82.0-90.7) for E. coli and 88.1 % (95 % CI 83.2-92.1) and 87.6 % (95 % CI 84.7-90.2) for KEC spp. differentiation, respectively, when compared to species ID by MALDI-TOF-MS. When evaluated for phenotypic susceptibilities (VITEK-2), 88.1 % (714/810) of the isolates recovered on the selective agar exhibited resistance to third-generation cephalosporins. Conclusion. The performance characteristics of CHROMagar ESBL media suggest that they may be a viable screening tool for the identification of ESCrE from hospitalized and community participants and could be used to inform infection prevention and control practices in Botswana and potentially other low-and middle-income countries (LMICs). Further studies are required to analyse the costs and the impact on time-to-result of the media in comparison with available laboratory methods for ESCrE surveillance in the country.

Background: The epidemiology of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) in low- and middle-income countries (LMICs) is poorly described. Identifying risk factors for ESCrE colonization is critical to inform antibiotic resistance reduction strategies because colonization is typically a precursor to infection., Methods: From 15 January 2020 to 4 September 2020, we surveyed a random sample of clinic patients at 6 sites in Botswana. We also invited each enrolled participant to refer up to 3 adults and children. All participants had rectal swabs collected that were inoculated onto chromogenic media followed by confirmatory testing. Data were collected on demographics, comorbidities, antibiotic use, healthcare exposures, travel, and farm and animal contact. Participants with ESCrE colonization (cases) were compared with noncolonized participants (controls) to identify risk factors for ESCrE colonization using bivariable, stratified, and multivariable analyses., Results: A total of 2000 participants were enrolled. There were 959 (48.0%) clinic participants, 477 (23.9%) adult community participants, and 564 (28.2%) child community participants. The median (interquartile range) age was 30 (12-41) and 1463 (73%) were women. There were 555 cases and 1445 controls (ie, 27.8% of participants were ESCrE colonized). Independent risk factors (adjusted odds ratio [95% confidence interval]) for ESCrE included healthcare exposure (1.37 [1.08-1.73]), foreign travel [1.98 (1.04-3.77]), tending livestock (1.34 [1.03-1.73]), and presence of an ESCrE-colonized household member (1.57 [1.08-2.27])., Conclusions: Our results suggest healthcare exposure may be important in driving ESCrE. The strong links to livestock exposure and household member ESCrE colonization highlight the potential role of common exposure or household transmission. These findings are critical to inform strategies to curb further emergence of ESCrE in LMICs., Competing Interests: Potential conflicts of interest. L. G. reports receiving grant funding for investigating multidrug resistance prevalence in Botswana from the Centers for Disease Control and Prevention (CDC). R. G. reports payment for their salary to Penn from the CDC and National Institutes of Health (NIH) and participation in a data safety monitoring or advisory board with Pfizer. M. M. reports grant funding for their institution from NIH National Heart, Lung, and Blood Institute. K. A., W. B. B., L. L. C., L. C., M. R. G., A. J., E. L., N. B. M., M. M., D. O., G. M. P., K. S., R. S., and A. S. have submitted ICMJE forms and have no conflicts to report. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: The metabolic syndrome, a cluster of inter-related risk factors for cardiovascular diseases is highly prevalent among individuals with obesity and sedentary lifestyle. Chronic psychiatric disorders such as severe mental illness are associated with increased risk for cardiovascular diseases. We aimed to assess the prevalence and correlates of metabolic syndrome among inpatients with severe mental illness in a resource limited setting with high HIV prevalence., Methods: This was a cross-sectional study among adult inpatients at a referral psychiatric hospital in Botswana. We used convenience sampling to enrol participants available at the time of the study. The National Cholesterol Education Program Adult Treatment Panel-III (NCEP-ATP III) criteria was used to define the metabolic syndrome. Data were analysed using descriptive statistics as well as multiple logistic regression modelling., Results: A total of 137 participants were enrolled. Of these, 119 (87%) had complete data for the main analysis. The overall prevalence of metabolic syndrome was 22.6% (95% CI 15.9, 30.6) and did not differ significantly by gender or HIV status. Age was significantly associated with the risk of having the metabolic syndrome while gender, body mass index, HIV status, and days of moderate physical activity were not., Conclusion: There was a moderately high prevalence of metabolic syndrome. Thus, the management of individuals with severe mental illness in resource limited settings should include assessment of cardiovascular risk and target modifiable risk factors in this population. Consideration for the patient's age should be made when rationalizing the limited resources available for assessing metabolic syndrome among patients with severe mental illness., (© 2022. The Author(s).)

Objectives: Although extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) and carbapenem-resistant Enterobacterales (CRE) are a global challenge, data on these organisms in low- and middle-income countries are limited. In this study, we sought to characterize colonization data critical for greater antibiotic resistance surveillance efforts., Methods: This study was conducted in three hospitals and six clinics in Botswana. We conducted ongoing surveillance of adult patients in hospitals and clinics and adults and children in the community. All participants underwent rectal swab sampling to identify ESCrE and CRE., Results: Enrollment occurred from January 15, 2020, to September 4, 2020, but paused from April 2, 2020, to May 21, 2020, because of a countrywide COVID-19 lockdown. Of 5088 individuals approached, 2469 (49%) participated. ESCrE colonization prevalence was 30.7% overall (43% for hospital participants, 31% for clinic participants, 24% for adult community participants, and 26% for child community participants) (P <0.001). A total of 42 (1.7%) participants were colonized with CRE. CRE colonization prevalence was 1.7% overall (6.8% for hospital participants, 0.7% for clinic participants, 0.2% for adult community participants, and 0.5% for child community participants) (P <0.001). ESCrE and CRE prevalence varied substantially across regions and was significantly higher prelockdown versus postlockdown., Conclusions: ESCrE colonization was high in all settings in Botswana. CRE prevalence in hospitals was also considerable. Colonization prevalence varied by region and clinical setting and decreased after a countrywide lockdown., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Cancer drug stockouts occur at high frequencies globally, however, their effects on treatment are understudied in sub-Saharan Africa (SSA). We aimed to determine whether causes of suboptimal cancer treatment prescriptions differed between periods of stockout and full treatment supply., Design: A retrospective cohort study of systemic therapy prescriptions for patients diagnosed with the twelve most common solid tumour cancers treated in 2016., Setting: Princess Marina Hospital in Gaborone, Botswana., Participants: Patients in the retrospective cohort who experienced any suboptimal treatment events, defined as ≥7 days delay or switch from guideline-concordant initiated therapy., Primary and Secondary Outcome Measures: Frequency of delays and patterns of prescription changes for specific regimens and cancer types., Results: 167/378 patients contributed to 320 suboptimal events (115 therapy switches, 167 delays and 38 events with both), over 1452 total chemotherapy cycles received. Events during stockout were 43% delays, 43% switches and 14% both during stockout periods and 67.2% delays, 24.4% switches and 8.4% both during non-stockout periods (p<0.001). Majority of switches involved de-escalation of initially prescribed guideline-recommended regimens in patients with breast cancer, Kaposi sarcoma and patients with colorectal cancer, which occurred more frequently during periods of drug stockouts. Among patients with breast cancer, substitution of docetaxel for paclitaxel event occurred exclusively during paclitaxel drug stockout. Delays of ≥7 days events were most frequent in breast cancer patients receiving paclitaxel during stockout, and combination doxorubicin and cyclophosphamide even during periods of non-stockout., Conclusions: The aetiology of suboptimal events differed during stockout and non-stockout periods. Prescription patterns that involved de-escalation of initiated therapy and substitution of paclitaxel with docetaxel occurred frequently during periods of drug stockout. Further research needs to be conducted to understand the impact of stockout on survival and barriers to maintaining essential cancer medicines supplies in SSA, and the factors driving frequent delays in therapy delivery., Competing Interests: Competing interests: SD, SG, DIS, TBR, PM, LNS and YMM have nothing to disclose. WBB reports personal fees from Genentech, outside the submitted work; Robert Gross reports grants from NIH, during the conduct of the study; personal fees from Pfizer, outside the submitted work; AD reports grants from Pfizer, grants from Novartis, grants from Genentech, grants from Calithera, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Psychological reactance is an aversive response to perceived threats against personal agency. For adolescents receiving HIV treatment in Botswana, we utilized a two-question, medication-specific reactance tool to assess whether: (1) verbal reminders to take medicines made adolescents want to avoid taking them, and, (2) whether adolescents felt anger when reminded to take medicines. Reactant adolescents had 2.05-fold (95% CI 1.23, 3.41) greater odds of treatment failure than non-reactant adolescents (p = 0.03). Adjusted risk of treatment failure was 14% (95% CI 3%, 28%) greater for each point elevation in reactance score (p = 0.016). Autonomy over medication-taking did not modify the association between reactance and treatment failure. Psychological reactance may be a useful interventional target for improving adolescent adherence.

Purpose: This study aimed to determine if disclosure of HIV status to adolescents impacted their medication adherence and how medication autonomy might explain observed effects., Methods: Three hundred adolescents on HIV treatment using electronic medication monitors were followed for 24 months while undergoing routine care. One hundred six of the adolescents were HIV disclosure-naïve and HIV status disclosure in this group was assessed quarterly. Analyses included data from the 75 adolescents who experienced disclosure during the study providing adherence and autonomy data both predisclosure and postdisclosure. Segmented generalized estimating equations were used to examine the trend of adherence and autonomy predisclosure and postdisclosure. Covariates assessed include age at disclosure, sex, and orphan status., Results: Median age at study entry was 12.2 years (interquartile range 11.6-12.9). Incident disclosure occurred in 75 (71%) of the adolescents at a median age of 13.1 years (interquartile range 12.5-13.9). Adherence decreased by 11% (95% confidence interval [CI] 7-15, p < .001) during the predisclosure period and by 22% (95% CI 9-36, p = .001) during the postdisclosure period. Adolescents' autonomy over their medication-taking increased over time, but disclosure did not impact the rate of increase in measured medication-taking autonomy. On a scale of 1-4 assessing autonomy (1 = receiving directly observed therapy and 4 = taking medicines mostly without supervision), autonomy increased by an average of .03 units/month (95% CI .02-.03, p < .001) predisclosure and by .05 units/month (95% CI -.01 to .11, p = .42) postdisclosure., Conclusions: The findings suggest that, among perinatally HIV infected adolescents, HIV status disclosure may adversely impact treatment adherence. Postdisclosure support to HIV infected adolescents should be intensified., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

In adults living with HIV, pharmacy refill data are good predictors of virologic failure (VF). The utility of pharmacy refill data for predicting VF in adolescents has not been reported. We evaluated data from 291 adolescents on antiretroviral therapy. The main outcome measure was VF, defined as two consecutive HIV viral load measurements ≥ 400 copies/mL during 24-months of follow-up. Pharmacy refill non-adherence was defined as two consecutive refill adherence measurements < 95% during the same period. Fifty-three (18%) adolescents experienced VF. One hundred twenty-eight (44%) adolescents had refill non-adherence. Refill non-adherence had poor discriminative ability for indicating VF (receiver operating characteristic AUC = 0.60). Sensitivity and specificity for predicting VF was poor (60% (95% CI 46-74%) and 60% (95% CI 53-66%), respectively). The lack of a viable surrogate for VF in adolescents highlights the urgent need for more access to virologic testing and novel methods of monitoring adolescent treatment adherence.

Purpose: Essential cancer medicine stock outs are occurring at an increasing frequency worldwide and represent a potential barrier to delivery of standard therapy in patients with cancer in low- and middle-income countries. The objective of this study was to measure the impact of cancer medicine stock outs on delivery of optimal therapy in Botswana., Methods: We conducted a retrospective analysis of patients with common solid tumor malignancies who received systemic cancer therapy in 2016 at Princess Marina Hospital, Gaborone, Botswana. Primary exposure was the duration of cancer medicine stock out during a treatment cycle interval, when the cancer therapy was intended to be administered. Mixed-effects univariable and multivariable logistic regression analyses were used to calculate the association of the primary exposure, with the primary outcome, suboptimal therapy delivery, defined as any dose reduction, dose delay, missed cycle, or switch in intended therapy., Results: A total of 378 patients met diagnostic criteria and received systemic chemotherapy in 2016. Of these, 76% received standard regimens consisting of 1,452 cycle intervals and were included in this analysis. Paclitaxel stock out affected the highest proportion of patients. In multivariable mixed-effects logistic regression, each week of any medicine stock out (odds ratio, 1.9; 95% CI, 1.7 to 2.13; P < .001) was independently associated with an increased risk of a suboptimal therapy delivery event., Conclusion: Each week of cancer therapy stock out poses a substantial barrier to receipt of high-quality cancer therapy in low- and middle-income countries. A concerted effort between policymakers and cancer specialists is needed to design implementation strategies to build sustainable systems promoting a reliable supply of cancer medicines.

BACKGROUND AND OBJECTIVE: Efavirenz is commonly used in Africa and is frequently associated with neurocognitive toxicity, which may compromise clinical outcomes. Older individuals are at increased risk for drug toxicity and clinical outcomes may be worse in older age, particularly among those individuals with cytochrome P450 (CYP) 2B6 polymorphisms associated with slower efavirenz metabolism. The aim of this study was to determine if the CYP2B6 polymorphisms differentially impacts loss to care in older people., Methods: We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50 years, was the primary exposure and loss to care at 6 months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care., Results: Older age was associated with loss to care (OR 1.95, 95% CI 1.30-2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38-11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants., Conclusion: Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

Objectives: To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes., Design: Observational cohort study of HIV-infected adults initiating efavirenz-based regimens in Botswana., Methods: The primary endpoint was a composite of death or loss to care or HIV RNA more than 25 copies/ml at 6 months. CYP2B6 516G>T and 983T>C genotyping was done with Taqman Open Array platform. Adverse experiences were measured by using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint., Results: A total of 801 individuals included 406 (51%) men, median age 37 years, median baseline CD4 cell count 195 cells/μl, and plasma HIV RNA 4.9 log10 copies/ml. 288 (36%) reached the endpoint, including 34 (4%) deaths, 151 (19%) lost to care, 11 (1%) lost to the study, but alive and in care, and 92 (11%) with plasma HIV RNA more than 25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences., Conclusion: Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate central nervous system toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.

Background: CYP2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYP2B6 516G>T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana., Setting: We performed a case-control study that included 1338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART). Patients were approached for enrollment during regular visits at one of the outpatient HIV clinics between July 2013 and April 2014., Methods: Cases experienced late HIV failure, defined as plasma HIV RNA >1000 copies/mL after maintaining viral suppression (<400 copies/mL) for at least 6 months. For each case, a total of 4 control patients were randomly sampled from the same population. Controls had plasma HIV RNA <400 copies/mL on ART for at least 6 months. Logistic regression was used to determine the adjusted odds of late HIV failure by 516G>T genotype., Results: After adjustment for the confounding variables age and CD4 count, the CYP2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95% CI: 0.50 to 0.97., Conclusion: The CYP2B6 516 T-allele was protective against late virologic breakthrough in patients with initial (6 month) HIV RNA suppression on EFV-based ART. Future studies are needed to assess long-term viral benefits of identifying and offering EFV containing ART to black African HIV-infected patients with CYP2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.

Psychosocial dysfunction is a risk factor for treatment non-adherence among children and adolescents. A previous study showed that high scores on the Pediatric Symptom Checklist (PSC) were associated with a history of HIV virologic failure. We assessed whether high scores on the PSC could predict virologic failure in HIV-infected youth. Caregivers of 234 adolescents between the ages of 10 and 16 years were asked to complete a PSC at baseline. Elevated PSC scores were associated with virologic failure in the subsequent 6 months. PSC scores may help guide resource utilization when viral load monitoring is limited.

Background: Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation., Methods: We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ(2) tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls., Findings: Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18-0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0-80·0]) and tumour necrosis factor (TNF)α (7·8 [1·1-55·2]). At week 4 after ART initation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2-2·5]) and TNFα (1·5 [1·0-2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3-6·1]), IL-12p40 (1·8 [1·0-3·4]), and IL-15 (2·0 [1·1-3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006)., Interpretation: Distinct immunological profiles before and after ART initiation characterise patients with advanced HIV and tuberculosis who have tuberculosis-associated IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery during ART should be considered in patients co-infected with HIV and tuberculosis., Funding: National Institutes of Health and the Penn Center for AIDS Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Adherence is key to the success of antiretroviral therapy. Enhanced partner support might benefit patients with previous treatment failure. We aimed to assess whether an enhanced partner-based support intervention with modified directly observed therapy would improve outcomes with second-line therapy in HIV-infected patients for whom first-line therapy had failed., Methods: We did a multicentre, international, randomised clinical trial at nine sites in Botswana, Brazil, Haiti, Peru, South Africa, Uganda, Zambia, and Zimbabwe. Participants aged 18 years or older for whom first-line therapy had failed, with HIV RNA concentrations greater than 1000 copies per mL and with a willing partner, were randomly assigned (1:1), via computer-generated randomisation, to receive partner-based modified directly observed therapy or standard of care. Randomisation was stratified by screening HIV RNA concentration (≤10 000 copies per mL vs >10 000 copies per mL). Participants and site investigators were not masked to group assignment. Primary outcome was confirmed virological failure (viral load >400 copies per mL) by week 48. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00608569., Findings: Between April 23, 2009, and Sept 29, 2011, we randomly assigned 259 participants to the modified directly observed therapy group (n=129) or the standard-of-care group (n=130). 34 (26%) participants in the modified directly observed therapy group achieved the primary endpoint of virological failure by week 48 compared with 23 (18%) participants in the standard-of-care group. The Kaplan-Meier estimated cumulative probability of virological failure by week 48 was 25·1% (95% CI 17·7-32·4) in the modified directly observed therapy group and 17·3% (10·8-23·7) in the standard-of-care group, for a weighted difference in standard of care versus modified directly observed therapy of -6·6% (95% CI -16·5% to 3·2%; p=0·19). 36 (14%) participants reported at least one grade 3 or higher adverse event or laboratory abnormality (n=21 in the modified directly observed therapy group and n=15 in the standard-of-care group)., Interpretation: Partner-based training with modified directly observed therapy had no effect on virological suppression. The intervention does not therefore seem to be a promising strategy to increase adherence. Intensive follow-up with clinic staff might be a viable approach in this setting., Funding: AIDS Clinical Trials Group and the National Institute of Allergy and Infectious Diseases, US National Institutes of Health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Study Objectives: Psychosocial factors such as outcome expectancy, perceived stigma, socio-emotional support, consideration of future consequences, and psychological reactance likely influence adolescent adherence to antiretroviral treatments. Culturally-adapted and validated tools for measuring these factors in African adolescents are lacking. We aimed to identify culturally-specific factors of importance to establishing local construct validity in Botswana., Methods: Using in-depth interviews of 34 HIV+ adolescents, we explored how the psychosocial factors listed above are perceived in this cultural context. We evaluated six scales that have been validated in other contexts. We also probed for additional factors that the adolescents considered important to their HIV medication adherence. Analyses were conducted with an analytic framework approach using NVivo9 software., Results: While the construct validity of some Western-derived assessment tools was confirmed, other tools were poorly representative of their constructs in this cultural context. Tools chosen to evaluate HIV-related outcome expectancy and perceived stigma were well-understood and relevant to the adolescents. Feedback from the adolescents suggested that tools to measure all other constructs need major modifications to obtain construct validity in Botswana. The scale regarding future consequences was poorly understood and contained several items that lacked relevance for the Batswana adolescents. They thought psychological reactance played an important role in adherence, but did not relate well to many components of the reactance scale. Measurement of socio-emotional support needs to focus on the adolescent-parent relationship, rather than peer-support in this cultural context. Denial of being HIV-infected was an unexpectedly common theme. Ambivalence about taking medicines was also expressed., Discussion: In-depth interviews of Batswana adolescents confirmed the construct validity of some Western-developed psychosocial assessment tools, but demonstrated limitations in others. Previously underappreciated factors related to HIV medication adherence, such as denial and ambivalence, should be further explored.

Purpose: We aimed to identify modifiable, routinely available patient characteristics associated with adverse experiences potentially attributable to efavirenz-based regimens in patients in Botswana., Methods: HIV-infected treatment naïve individuals starting a standard antiretroviral regimen including two nucleoside analog reverse transcriptase inhibitors and efavirenz in Botswana were enrolled in a prospective cohort. Adverse experiences were measured at 1 and 6 months using the efavirenz checklist, a 35-item instrument developed by the AIDS Clinical Trials Group., Results: We enrolled 232 patients from 11 March 2010 to 17 March 2011. One hundred ninety-six were included in the month 1 analyses. Of the 196 included in the month 1 analyses, 157 (80%) completed the 6-month follow-up. Median efavirenz checklist score was 6 (interquartile range (IQR): 2-15) at month 1 and 1 (IQR: 0-5) at month 6. The median change in efavirenz checklist score from month 1-6 was -4 (IQR: -11 to -1), representing an improvement. Depressive symptoms, low CD4 count and less alcohol use were associated with improvement in adverse experiences over time. Low weight was associated with increased extent of adverse experiences at month 1 and 6. There was no confounding or effect modification., Conclusions: Clinicians may want to consider more intensive and tailored adverse experience education and management in patients based on depressive symptoms, CD4 count, and weight. Further assessment of the mechanism of the effect of alcohol use on adverse experiences, including analysis of CYP2B6 genotype and plasma efavirenz concentrations, is warranted., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: The relationship between antiretroviral therapy (ART) response and early mortality after ART initiation is unknown. We hypothesized that early mortality is associated with decreased early immunologic response to ART., Methods: We prospectively determined the association between changes in plasma human immunodeficiency virus type 1 (HIV-1) RNA and CD4(+) T-cell counts (CD4 count) after 4 weeks of ART and early mortality in adults with pulmonary tuberculosis and pre-ART CD4 counts ≤ 125 cells/µL. Purified protein derivative (PPD)-specific immune recovery was determined by interferon-γ enzyme-linked immunosorbent spot assays. Levels of interleukin 6, C-reactive protein, and soluble CD14 were assessed. Patients with CD4 count and viral load values at baseline and week 4 were analyzed using multiple logistic regression., Results: Early immunologic response, but not pre-ART CD4 counts or virologic response, was related to early mortality (8 [interquartile range {IQR}, -18 to 43] vs 68 [IQR, 24-131] cells/µL, P = .002). In a logistic regression model, every 20 cells/µL increase in the CD4 count from baseline to week 4 was independently associated with a 40% reduction in the odds of death (odds ratio, 0.59 [95% confidence interval, .41-.87]). PPD-specific immune recovery was lower, whereas levels of immune activation were higher, among deaths., Conclusions: Early immunologic failure despite virologic suppression is associated with early mortality after ART initiation in advanced HIV/tuberculosis.

Importance: Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited., Objective: To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment., Design, Setting, and Participants: Retrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana., Main Outcomes and Measures: The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis., Results: With a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses., Conclusions and Relevance: Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.

Background: Data on alcohol abuse as a risk factor for the development of multidrug-resistant tuberculosis (MDR-TB) are scarce., Objective: To describe the patterns of alcohol use in MDR-TB patients and to determine whether alcohol use is associated with the development of MDR-TB in Botswana., Methods: We compared the level of alcohol use among MDR-TB patients against three control groups: 1) non-MDR-TB patients, 2) human immunodeficiency virus (HIV) infected patients without a history of TB, and 3) the general population. Alcohol use and abuse was measured with the Alcohol Use Disorders Identification Test 10 (AUDIT) questionnaire., Results: Of a total national population of 164 MDR-TB cases, 114 (70%) were interviewed. MDR-TB cases had a lifetime prevalence of alcohol use of 35.1%, which was lower than that of all control groups (P < 0.001). MDR-TB cases had higher 1-month prevalence of alcohol dependence symptoms and a lower 1-year period prevalence of alcohol dependence symptoms (P < 0.01 and P = 0.01 respectively). Among patients with TB, alcohol abuse was found to be a risk factor for the development of MDR-TB., Conclusion: MDR-TB patients in Botswana have high rates of alcohol use and abuse. Among TB patients, alcohol abuse is associated with the diagnosis of MDR-TB, and could be an important modifiable factor.

Psychosocial dysfunction in older children and adolescents is common and may lead to nonadherence to HIV treatments. Poor adherence leads to HIV treatment failure and the development of resistant virus. In resource-limited settings where treatment options are typically limited to only one or two available lines of therapy, identification of individuals at highest risk of failure before failure occurs is of critical importance. Rapid screening tools for psychosocial dysfunction may allow for identification of those children and adolescents who are most likely to benefit from limited psychosocial support services targeted at preventing HIV treatment failure. The Pediatric Symptom Checklist (PSC) is used in high resource settings for rapid identification of at-risk youth. In 692 HIV-infected treated children (ages of 8-< 17 years) in Botswana, having a high score on the PSC was associated with having virologic failure (OR 1.7, 95% CI: 1.1-2.6). The PSC may be a useful screening tool in pediatric HIV.

Background: Adverse outcomes occurring early after antiretroviral therapy (ART) initiation are common in sub-Saharan Africa, despite reports of high levels of ART adherence in this setting. We sought to determine the relationship between very early ART adherence and early adverse outcomes in HIV-infected adults in Botswana., Methods: This prospective cohort study of 402 ART-naïve, HIV-infected adults initiating ART at a public HIV clinic in Gaborone, Botswana evaluated the relationship between suboptimal early ART adherence and HIV treatment outcomes in the initial months after ART initiation. Early adherence during the interval between initial ART dispensation and first ART refill was calculated using pill counts. In the primary analysis patients not returning to refill and those with adherence <0.95 were considered to have suboptimal early adherence. The primary outcome was death or loss to follow-up during the first 6 months of ART; a secondary composite outcome included the primary outcome plus incident opportunistic illness (OIs) and virologic failure. We also calculated the percent of early adverse outcomes theoretically attributable to suboptimal early adherence using the population attributable risk percent (PAR%)., Results: Suboptimal early adherence was independently associated with loss to follow-up and death (adjusted OR 2.3, 95% CI 1.1-4.8) and with the secondary composite outcome including incident OIs and virologic failure (adjusted OR 2.6, 95% CI 1.4-4.7). However, of those with early adverse outcomes, less than one-third had suboptimal adherence and approximately two-thirds achieved virologic suppression. The PAR% relating suboptimal early adherence and primary and secondary outcomes were 14.7% and 17.7%, respectively., Conclusions: Suboptimal early adherence was associated with poor outcomes, but most early adverse outcomes occurred in patients with optimal early adherence. Clinical care and research efforts should focus on understanding early adverse outcomes that occur despite optimal adherence.

Background: Although adherence to antiretroviral therapy may be higher in sub-Saharan Africa, knowledge regarding the magnitude of adherence needed to maintain virological suppression in this setting is limited., Methods: A case-control study among HIV-infected individuals initiating highly active antiretroviral therapy (HAART) in Gaborone, Botswana, was performed. Cases were randomly selected from subjects on HAART > or =6 months with plasma HIV-1 RNA levels (viral loads) >1000 copies/mL. Controls were randomly selected from subjects on HAART > or =6 months with all viral loads <400 copies/mL. HAART adherence was determined using pharmacy refill records., Results: In total, 302 individuals were included; 57 cases were compared with 245 controls with respect to adherence levels on nonnucleoside reverse transcriptase inhibitor-based HAART. Median adherence levels, as measured using pharmacy refill patterns, were consistently high but differed among cases and controls (91%, interquartile range 83%-97% for cases vs 97%, interquartile range 91%-100% for controls, P < 0.001, rank-sum test). Adherence <95% was independently associated with virological failure (odds ratio 4.19, 95% confidence interval 2.2 to 8.3)., Conclusions: Very high rates of adherence were present in this setting, yet virological failure occurred nonetheless. Future work should explore other factors that might explain treatment failure in the setting of high levels of adherence.

A large number of HIV-infected patients in sub-Saharan Africa pay out-of-pocket for HAART. This analysis from Botswana indicates that higher median out-of-pocket regimen costs to patients for the initial 30 days of HAART are associated with failure to achieve a viral load< 400 copies/ml [US$32; interquartile range (IQR), 20-84 compared with US$22; (IQR, 17-36), P = 0.001]. HAART costs should be minimized as scale-up efforts in sub-Saharan Africa progress.