Missed Study Visits and Subsequent HIV Incidence Among Women in a Predominantly Sex Worker Cohort Attending a Dedicated Clinic Service in Kampala, Uganda Background: There is limited evidence on the relationship between sustained exposure of female sex workers (FSWs) to targeted HIV programmes and HIV incidence. We investigate the relationship between the number of missed study visits (MSVs) within each episode of 2 consecutively attended visits (MSVs) and subsequent HIV risk in a predominantly FSW cohort. Methods: Women at high risk of HIV are invited to attend an ongoing dedicated clinic offering a combination HIV prevention intervention in Kampala, Uganda. Study visits are scheduled once every 3 months. The analysis included HIV-seronegative women with ≥1 follow-up visit from enrollment (between April 2008 and May 2017) to August 2017. Cox regression models were fitted adjusted for characteristics on sociodemographic, reproductive, behavioral, and sexually transmitted infections (through clinical examination and serological testing for syphilis). Findings: Among 2206 participants, HIV incidence was 3.1/100 (170/5540) person-years [95% confidence interval (CI): 2.6 to 3.5]. Incidence increased from 2.6/100 person-years (95% CI: 2.1 to 3.2) in episodes without a MSV to 3.0/100 (95% CI: 2.2 to 4.1) for 1–2 MSVs and 4.3/100 (95% CI: 3.3 to 5.6) for ≥3 MSVs. Relative to episodes without a MSV, the hazard ratios (adjusted for confounding variables) were 1.40 (95% CI: 0.93 to 2.12) for 1–2 MSVs and 2.00 (95% CI: 1.35 to 2.95) for ≥3 MSVs (P-trend = 0.001). Conclusion: Missing study visits was associated with increased subsequent HIV risk. Although several factors may underlie this association, the finding suggests effectiveness of targeted combination HIV prevention. But exposure to targeted interventions needs to be monitored, facilitated, and sustained in FSWs.

HIV Risk and Prevention Outcomes in a Probability-Based Sample of Gay and Bisexual Men in the United States Background: Although gay and bisexual men (GBM) represent the largest group of HIV-infected individuals in the United States, nearly all evidence on their HIV risk and prevention outcomes derive from nonprobability samples. Setting: A probability-based cohort of GBM (N = 502) from 45 states and Washington, DC. Methods: Cross-sectional survey. Results: Among HIV-negative/unknown/untested GBM, only 6.7% reported using pre-exposure prophylaxis (PrEP) in the past 6 months. Two-thirds (63.3%) of PrEP users reported daily adherence in the past week. Over half (54.2%) of GBM reported not using a condom during anal sex with their most recent male partner; of these men, 93.8% were not on PrEP. Most GBM had been tested for HIV (80.7%) and other sexually transmitted infections (67.1%) in their lifetime, with 45.2% having tested for HIV during the past year. Among those ever tested, 14.1% reported being HIV infected, whereas an additional 8.9% reported testing positive for at least one other sexually transmitted infection after their most recent test. All HIV-positive GBM reported being currently on antiretroviral treatment, and 94.7% reported an undetectable viral load, but nearly one-third (30.4%) reported not taking their medication every day during the past month. A majority of HIV-negative/unknown/untested GBM (64.3%) reported that they had never discussed HIV prevention with their primary health care provider. Conclusions: Our findings present a decidedly mixed picture regarding the success of the US National HIV/AIDS Strategy in meeting its stated goals of addressing HIV risk among the general population of GBM.

Implementation of a Community-Based Hybrid HIV Testing Services Program as a Strategy to Saturate Testing Coverage in Western Kenya Background: Knowledge of HIV status is the entry point for linkage to prevention, care, and treatment, and the first step toward achieving the UNAIDS 90-90-90 targets. Most countries rely on proxies for estimating testing saturation, including periodic population-based sampling and yield (number positive among those tested). We conducted a community-based “Hybrid” HIV testing services (HTS) program to identify persons unaware of their HIV-positive status. Setting: Homa Bay County, Kenya; July–September, 2016. Methods: We conducted community mapping, household census, multi-disease community health campaigns (CHCs), and home-based tracking. HIV testing eligibility was based on 2015 national guidelines. The previously unidentified fraction (PUF) was defined as the proportion of newly identified persons living with HIV (PLWH) out of all previously identified and newly identified PLWH. Results: The Hybrid HTS program reached 28,885 persons in total: 25,340 residents and 3545 nonresidents. There were 19,288 persons reached through CHCs and tracking. Of 11,316 individuals eligible for HIV testing, 9463 (83%) accepted testing, including 1230 (13%) first-time testers. There were 115 newly identified PLWH of 1589 total HIV-positive persons, representing a 7.2% PUF. Of 93 newly identified PLWH at the CHCs, 68% initiated same-day antiretroviral therapy. Conclusion: The Hybrid HTS program identified persons previously unaware of their HIV-positive status, thereby enabling linkage to care and same-day treatment and reducing onward transmission risk. An approach focused on identifying persons unaware of their HIV-positive status in combination with ascertaining the PUF has the potential to better target testing strategies to identify >90% of PLWH in a community.

Brief Report: Diagnostic Accuracy of Oral Mucosal Transudate Tests Compared with Blood-Based Rapid Tests for HIV Among Children Aged 18 Months to 18 Years in Kenya and Zimbabwe Background: Gaps persist in HIV testing for children who were not tested in prevention of mother-to-child HIV transmission programs. Oral mucosal transudate (OMT) rapid HIV tests have been shown to be highly sensitive in adults, but their performance has not been established in children. Methods: Antiretroviral therapy-naive children aged 18 months to 18 years in Kenya and Zimbabwe were tested for HIV using rapid OraQuick ADVANCE Rapid HIV-1/2 Antibody test on oral fluids (OMT) and blood-based rapid diagnostic testing (BBT). BBT followed Kenyan and Zimbabwean national algorithms. Sensitivity and specificity were calculated using the national algorithms as the reference standard. Results: A total of 1776 children were enrolled; median age was 7.3 years (interquartile range: 4.7–11.6). Among 71 children positive by BBT, all 71 were positive by OMT (sensitivity: 100% [97.5% confidence interval (CI): 94.9% to 100%]). Among the 1705 children negative by BBT, 1703 were negative by OMT (specificity: 99.9% [95% CI: 99.6% to 100.0%]). Due to discrepant BBT and OMT results, 2 children who initially tested BBT-negative and OMT-positive were subsequently confirmed positive within 1 week by further tests. Excluding these 2 children, the sensitivity and specificity of OMT compared with those of BBT were each 100% (97.5% CI: 94.9% to 100% and 99.8% to 100%, respectively). Conclusions: Compared to national algorithms, OMT did not miss any HIV-positive children. These data suggest that OMTs are valid in this age range. Future research should explore the acceptability and uptake of OMT by caregivers and health workers to increase pediatric HIV testing coverage.

Brief Report: Association Between Low HIV-1 DNA and Western Blot Reactivity to HIV-1 Pol in Chronically Infected Individuals Background: The aim of the study was to evaluate whether negative HIV-1 pol on Western blot (WB) was associated with low HIV-DNA in adults with chronic HIV-1 infection and suppressive antiretroviral therapy. Methods: Cross-sectional parent study of the APACHE trial, conducted in subjects with chronic infection, HIV-1 RNA <50 copies/mL for ≥10 years, no residual viremia for ≥5 years and CD4+ >500 cells/µL screened for HIV-1 DNA. HIV-1 DNA was quantified in peripheral blood mononuclear cells (PBMCs) by real-time polymerase chain reaction and HIV-1 serostatus was tested by HIV Blot 2.2 WB assay. Multivariate logistic regression was used to determine factors associated with low HIV-1 DNA. Results: We evaluated 96 patients: 78 (81%) and 18 (19%) subjects with HIV-1 DNA ≥100 copies/106 PBMCs and with HIV-1 DNA <100 copies/106 PBMCs, respectively. Median age was 32.5 (25.3–38.9), and 61 (64%) were men; moreover, we reported that nadir CD4+ was 253 (167–339) cells/µL and HIV-RNA <50 copies/mL for 11.7 (10.6–14.0) years. At multivariate analysis, higher nadir CD4+ [adjusted odds ratio (AOR) [95% confidence interval (CI) 1.35 (95% CI: 1.03 to 1.76), P = 0.029], longer years of HIV-1 RNA <50 copies/mL [AOR (95% CI) 2.98 (95% CI: 1.25 to 7.10), P = 0.014], a R5-tropic virus [AOR (R5 vs. non-R5) 0.20 (95% CI: 0.04 to 0.96), P = 0.044], and negative HIV-1 pol [AOR 6.59 (95% CI: 1.47 to 29.54), P = 0.014] were associated with low HIV-1 DNA. Conclusions: In patients with chronic HIV-1 infection and suppressive antiretroviral therapy, negative HIV-1 pol on WB was associated with low HIV-1 DNA as well as higher nadir CD4+, longer years of HIV-1 RNA <50 copies/mL, and a R5-tropic virus.

Extended Prophylaxis With Nevirapine Does Not Affect Growth in HIV-Exposed Infants Background: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial. Methods: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score, length-for-age Z-score, weight-for-length Z-score, and head circumference-for-age Z-score. Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively. Results: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment × time: P > 0.05). However, overall growth declined over time (time effect: P < 0.01) when compared with WHO general population norms. Male sex was associated with higher risk of all adverse growth outcomes (P < 0.05), whereas short BF duration was associated with wasting (P = 0.03). Maternal antiretroviral therapy exposure was protective against underweight (P = 0.02). Zimbabwe tended to have worse growth outcomes especially stunting, compared to South Africa, Uganda and Tanzania (P < 0.05). Conclusions: It is reassuring that prolonged exposure to nevirapine for prevention-of-mother-to-child HIV transmission does not restrict growth. However, targeted interventions are needed to improve growth outcomes among at-risk HEU infants (i.e., male sex, short BF duration, lack of maternal antiretroviral therapy exposure, and resident in Zimbabwe).

Antiretroviral Therapy Adherence Interruptions Are Associated With Systemic Inflammation Among Ugandans Who Achieved Viral Suppression Background: Residual systemic inflammation, which is associated with non-AIDS clinical outcomes, may persist despite viral suppression. We assessed the effect of antiretroviral therapy (ART) adherence interruptions on systemic inflammation among Ugandans living with HIV who were virally suppressed. Setting: We evaluated adults initiating first-line ART at a regional referral hospital clinic in Mbarara, Uganda. Methods: Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble sCD14, sCD163, the kynurenine/tryptophan (K/T) ratio, and CD8+ T-cell activation (HLA-DR+/CD38+ coexpression) were measured at baseline and 6 months after ART initiation among participants who achieved viral suppression (<400 copies/mL) at 6 months. ART adherence was monitored electronically. Time spent in an adherence interruption was computed as the percentage of days when the running average adherence was ≤10%. We fit adjusted linear regressions to evaluate the effect of time spent in an interruption on the log-transformed plasma concentrations of the inflammation biomarkers. Results: Of 282 participants, 70% were women, and the median age was 34 years. At baseline, median CD4 and median log viral load were 135 cells per microliter and 5.1 copies per milliliter, respectively. In the adjusted analysis, a running average adherence of <10% was associated with higher sCD14 (+3%; P < 0.008), sCD163 (+5%; P = 0.002), D-dimer (+10%; P = 0.007), HLA-DR+/CD8+ (+3%; P < 0.025), IL-6 (+14%; P = 0.008), and K:T ratio (+5%; P = 0.002). These findings were largely robust to adjustment for average adherence, as well as higher thresholds of running average adherence, albeit with decreased statistical significance. Conclusions: Increased time spent in adherence interruptions is associated with increased levels of inflammation, despite viral suppression above and beyond average adherence.

Use of Modeling and Simulations to Determine Raltegravir Dosing in Neonates: A Model for Safely and Efficiently Determining Appropriate Neonatal Dosing Regimens: IMPAACT P1110 Background: Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates. Setting: P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection. Methods: P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations. An initial cohort of neonates received 2 single oral doses of raltegravir with standard-of-care therapy for prevention of perinatal transmission—one within 48 hours of birth and a second at 7–10 days of life. Raltegravir concentration data after administration of these doses were combined with data from a previous study of infants aged 4 weeks to 2 years. The combined database was used for population pharmacokinetic modeling and simulations to select a daily dosing regimen for investigation in a second cohort of neonates. Results: Raltegravir concentration data from 6 neonates were combined with data from infants aged 4 weeks to 2 years receiving raltegravir twice daily. The combined data set allowed for successful development of a population pharmacokinetic model with reasonable precision of parameter estimates. Monte Carlo simulations were run to evaluate potential daily dosing regimens from birth to 6 weeks of age, allowing for selection of a regimen to be evaluated in a subsequent cohort of neonates receiving chronic raltegravir dosing. Conclusions: An adaptive design incorporating population pharmacokinetic modeling and simulations was used to select a developmentally appropriate neonatal raltegravir dosing regimen in the first 6 weeks of life.

Hypertension Control and Retention in Care Among HIV-Infected Patients: The Effects of Co-located HIV and Chronic Noncommunicable Disease Care Background: As the noncommunicable disease (NCD) burden is rising in regions with high HIV prevalence, patients with comorbid HIV and chronic NCDs may benefit from integrated chronic disease care. There are few evaluations of the effectiveness of such strategies, especially those that directly leverage and extend the existing HIV care system to provide co-located care for NCDs. Setting: Academic Model of Providing Access to Healthcare, Kenya, provides care to over 160,000 actively enrolled patients in catchment area of 4 million people. Methods: Using a difference-in-differences design, we analyzed retrospective clinical records of 3603 patients with comorbid HIV and hypertension during 2009─2016 to evaluate the addition of chronic disease management (CDM) to an existing HIV care program. Outcomes were blood pressure (BP), hypertension control, and adherence to HIV care. Results: Compared with the HIV standard of care, the addition of CDM produced statistically significant, although clinically small improvements in hypertension control, decreasing systolic BP by 0.76 mm Hg (P < 0.001), diastolic BP by 1.28 mm Hg (P < 0.001), and increasing the probability of BP <140/90 mm Hg by 1.51 percentage points (P < 0.001). However, sustained control of hypertension for >1 year improved by 7 percentage points (P < 0.001), adherence to HIV care improved by 6.8 percentage points (P < 0.001) and retention in HIV care with no gaps >6 months increased by 10.5 percentage points (P < 0.001). Conclusion: A CDM program that co-locates NCD and HIV care shows potential to improve BP and retention in care. Further evaluation of program implementation across settings can inform how to maximize hypertension control among patients with comorbid HIV, and better understand the effect on adherence.

Targeting ABL1 or ARG Tyrosine Kinases to Restrict HIV-1 Infection in Primary CD4+ T‐Cells or in Humanized NSG Mice Background: Previous studies support dasatinib as a potent inhibitor of HIV-1 replication. However, a functional distinction between 2 kinase targets of the drug, ABL1 and ARG, has not been assessed. Setting: We used primary CD4+ T‐cells, CD8-depleted peripheral blood mononuclear cells (PBMCs) from a treatment naïve HIV-1+ patient, and a humanized mouse model of HIV-1 infection. We assessed the roles of ABL1 and ARG during HIV-1 infection and use of dasatinib as a potential antiviral against HIV-1 in humanized mice. Methods: Primary CD4+ T‐cells were administered siRNA targeting ABL1 or ARG, then infected with HIV-1 containing luciferase reporter viruses. Quantitative polymerase chain reaction of viral integration of 4 HIV-1 strains was also assessed. CD8-depleted PBMCs were treated for 3 weeks with dasatinib. NSG mice were engrafted with CD34+ pluripotent stem cells from human fetal cord blood, and infected with Ba-L virus after 19 weeks. Mice were treated daily with dasatinib starting 5 weeks after infection. Results: siRNA knockdown of ABL1 or ARG had no effect on viral reverse transcripts, but increased 2-LTR circles 2- to 4-fold and reduced viral integration 2- to 12-fold. siRNA knockdown of ARG increased SAMHD1 activation, whereas knockdown of either kinase reduced RNA polymerase II activation. Treating CD8-depleted PBMCs from a treatment-naïve patient with 50 nM of dasatinib for 3 weeks reduced p24 levels by 99.8%. Ba-L (R5)-infected mice injected daily with dasatinib showed a 95.1% reduction in plasma viral load after 2 weeks of treatment. Conclusions: We demonstrate a novel nuclear role for ABL1 and ARG in ex vivo infection experiments, and proof-of-principle use of dasatinib in a humanized mouse model of HIV-1 infection.