<p><strong>BACKGROUND: </strong>Adherence to antiretroviral medication leads to HIV suppression and decreased morbidity and mortality. In resource- limited settings, the dependence on paper medical charts and unstable electronic health records creates a challenge to monitoring medication adherence. A pharmacy-based strategy that utilizes existing cellular phone infrastructure may lead to a more stable system to monitor adherence.</p>

<p><strong>OBJECTIVES: </strong>To develop and evaluate the usability of a smartphone-based software application (app) for tracking antiretroviral medication refill data in a resource-limited setting.</p>

<p><strong>METHODS: </strong>A pharmacy-based smartphone app for tracking HIV medication adherence was developed through a multi-step rapid prototyping process. The usability of the app was assessed during the daily activities of pharmacy dispensers at HIV clinics in and around Gaborone, Botswana using a validated computer usability survey.</p>

<p><strong>RESULTS: </strong>The study demonstrated the effective development of and favorable end-user responses to a pharmacy-based HIV medication adherence app. End users had suggestions for minor changes to improve the app's functionality.</p>

<p><strong>CONCLUSIONS: </strong>In resource-limited settings where electronic health record support is limited, such a system was feasible and appealing. In the future, this system may allow for improved HIV medication adherence tracking and be applied to medications beyond antiretrovirals.</p>

<p>Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G&gt;T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G&gt;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.</p>

<p><strong>AIMS: </strong>To determine alcohol use effect on HIV treatment success and whether alcohol use mediates the relation between male sex and treatment failure.</p>

<p><strong>DESIGN: </strong>Longitudinal cohort study.</p>

<p><strong>SETTING: </strong>Eight HIV clinics in and near Gaborone, Botswana.</p>

<p><strong>PARTICIPANTS: </strong>A total of 938 HIV-infected treatment-naive adults initiating regimens containing the antiretroviral medication efavirenz between June 2009 and February 2013, including 478 (51%) males, median age 38&nbsp;years, and plasma HIV RNA 4.9 logcopies/ml.</p>

<p><strong>MEASUREMENTS: </strong>Primary outcome was a composite of treatment failure over 6&nbsp;months including death, lost to care or plasma HIV RNA &gt; 25 copies/ml. Exposures included alcohol use and gender.</p>

<p><strong>FINDINGS: </strong>Failure in 339 (36%) participants included 40 (4%) deaths, 194 (21%) lost to care and 105 (11%) with HIV RNA&nbsp;&gt;&nbsp;25 copies/ml. Both hazardous alcohol use in the past year [adjusted odds ratio (aOR)&nbsp;=&nbsp;1.4, 95% confidence interval (CI)&nbsp;=&nbsp;1.0, 1.9] and male sex (aOR&nbsp;=&nbsp;2.1, 95% CI&nbsp;=&nbsp;1.5, 2.9) were associated with failure. Hazardous alcohol use in the year prior to enrollment was more common in men (57%) than women (24%), P&nbsp;&lt;&nbsp;0.001. There was no difference in alcohol use effect on failure between sexes (P for interaction&nbsp;&gt;&nbsp;0.5). Controlling for hazardous alcohol use did not change the relation between sex and failure.</p>

<p><strong>CONCLUSION: </strong>Alcohol use among HIV-infected adults in Botswana appears to worsen HIV treatment outcomes. Alcohol use does not appear to have either a mediating or a moderating effect on the relation between gender and HIV treatment outcome failure.</p>

<p><strong>OBJECTIVE: </strong>To identify the prevalence of high HIV transmission potential in a cohort of youth living with HIV (YLWH), and determine the impact of insurance coverage on potential for HIV transmission.</p>

<p><strong>DESIGN: </strong>Retrospective cohort study of antiretroviral therapy (ART)-treated YLWH at a US adolescent HIV clinic, 2002-2015.</p>

<p><strong>METHODS: </strong>The primary exposure was presence or absence of insurance, defined as private, public or pharmacy-only coverage. The primary outcome was high HIV transmission potential, defined as time-concurrent incident bacterial STI (gonorrhea, chlamydia or syphilis) and HIV RNA greater than 1500 copies/ml. Marginal structural models adjusting for baseline demographic covariates, prior history of STI and time-varying retention in care assessed the relationship between insurance status and HIV transmission potential.</p>

<p><strong>RESULTS: </strong>Participants (n = 240) were followed for a median of 22 (IQR 8.1-49) months after ART initiation, and were predominately African-American men and transgender women who have sex with men, with a median age at HIV diagnosis of 19 years (IQR 17-21). We identified 37 (15%) participants with at least one episode of high HIV transmission potential. Insurance coverage was associated with a greater than 50% lower odds of high HIV transmission potential (aOR 0.46, 95% CI 0.26-0.84), and history of STI at or before entry to HIV care conferred more than three-fold higher odds of high transmission potential (aOR 3.21, 95% CI 1.55-6.63).</p>

<p><strong>CONCLUSION: </strong>We found 17% of YLWH to have episodic high HIV transmission potential despite receiving ART. Insurance coverage, including pharmacy-only benefits, was protective against transmission risk, suggesting a pivotal role for universal ART coverage in treatment as prevention.</p>

<p>Correlates of death soon after antiretroviral therapy (ART) initiation remain unclear. We investigated the association between expression of CD39, a novel immune exhaustion marker, and early mortality in patients with human immunodeficiency virus/tuberculosis co-infection. Elevated pre-ART CD39+CD8+ T cell frequency was independently associated with mortality within 6 months of ART initiation.</p>

<p><strong>OBJECTIVES: </strong>To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes.</p>

<p><strong>DESIGN: </strong>Observational cohort study of HIV infected adults initiating efavirenz-based regimens in Botswana.</p>

<p><strong>METHODS: </strong>The primary endpoint was a composite of death or loss to care or HIV RNA&gt;25 copies/ml at 6 months. CYP2B6 516G&gt;T and 983T&gt;C genotyping was done with Taqman Open Array platform. Adverse experiences were measured using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint.</p>

<p><strong>RESULTS: </strong>801 individuals included 406 (51%) males, median age 37 years, median baseline CD4 count 195 cells/mm and plasma HIV RNA 4·9 log10 copies/ml. 277 (35%) reached the endpoint including 34 (4%) deaths, 151 (19%) lost to care, and 92 (11%) with plasma HIV RNA&gt;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.</p>

<p><strong>CONCLUSIONS: </strong>Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate CNS toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.</p>

<p><strong>BACKGROUND: </strong>CYPB2B6 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 CYPB2B6 516G&gt;T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana.</p>

<p><strong>SETTING: </strong>We performed a case-control study that included 1,338 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 7/2013-4/2014.</p>

<p><strong>METHODS: </strong>Cases experienced late HIV failure, defined as plasma HIV RNA &gt;1000 copies/mL after maintaining viral suppression (&lt;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 &lt;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&gt;T genotype.</p>

<p><strong>RESULTS: </strong>After adjustment for the confounding variables age and CD4 count, the CYPB2B6 516 T-allele was protective against late HIV virologic breakthrough, adjusted OR 0.70; 95%CI 0.50-0.97.</p>

<p><strong>CONCLUSION: </strong>The CYPB2B6 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 CYPB2B6 T-alleles, especially given the wider availability of a single pill EFV in this setting.</p>

<p>We hypothesized that longer and more frequent dosing gaps among boys in Botswana taking antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection compared to girls could account for previously seen gender-specific differences in outcomes. We monitored 154 male and 134 female adolescents for 2&nbsp;years with medication event monitoring systems (MEMS). Median adherence was 95.6&nbsp;% for males and 95.7&nbsp;% for females (p&nbsp;=&nbsp;0.40). There were no significant gender differences in the number of ≥7&nbsp;day (p&nbsp;=&nbsp;0.55) and ≥14&nbsp;day (p&nbsp;=&nbsp;0.48) dosing gaps. The median maximal gap was 7.7&nbsp;days for males and 8.0&nbsp;days for females (p&nbsp;=&nbsp;0.47). These findings are not consistent with clinically meaningful gender differences in adherence.</p>

<p><strong>STUDY OBJECTIVES: </strong>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.</p>

<p><strong>METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>DISCUSSION: </strong>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.</p>

<p><strong>BACKGROUND: </strong>Candidemia causes significant morbidity and mortality among children. Removal of a central venous catheter (CVC) is often recommended for adults with candidemia to reduce persistent and metastatic infection. Pediatric-specific data on the impact of CVC retention are limited.</p>

<p><strong>METHODS: </strong>A retrospective cohort study of inpatients &lt;19 years with candidemia at the Children's Hospital of Philadelphia between 2000 and 2012 was performed. The final cohort included patients that had a CVC in place at time of blood culture and retained their CVC at least 1 day beyond the blood culture being positive. A structured data collection instrument was used to retrieve patient data. A discrete time failure model, adjusting for age and the complexity of clinical care before onset of candidemia, was used to assess the association of CVC retention and 30-day all-cause mortality.</p>

<p><strong>RESULTS: </strong>Two hundred eighty-five patients with candidemia and a CVC in place at the time of blood culture were identified. Among these 285 patients, 30 (10%) died within 30 days. Central venous catheter retention was associated with a significant increased risk of death on a given day (odds ratio, 2.50; 95% confidence interval, 1.06-5.91).</p>

<p><strong>CONCLUSIONS: </strong>Retention of a CVC was associated with an increased risk of death after adjusting for age and complexity of care at candidemia onset. Although there is likely persistence of unmeasured confounding, given the strong association between catheter retention and death, our data suggest that early CVC removal should be strongly considered.</p>