Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ART.

INTRODUCTION: Monthly intravenous infusion of broadly neutralizing monoclonal antibodies may be an attractive alternative to daily oral antiretroviral treatment for children living with HIV. However, acceptability among caregivers remains unknown. METHODS: We evaluated monthly infusion of dual bNAbs (VRCO1LS and 10-1074) as a treatment alternative to ART among children participating in the Tatelo Study in Botswana. Eligible children aged 2-5 years received 8-32 weeks of bNAbs overlapping with ART, and up to 24 weeks of bNAbs alone as monthly intravenous infusion. Using closed-ended questionnaires, we evaluated caregiver acceptability of each treatment strategy prior to the first bNAb administration visit (pre-intervention) and after the completion of the final bNAb administration visit (post-intervention). RESULTS: Twenty-five children completed the intervention phase of the study, and acceptability data were available from 24 caregivers at both time points. Responses were provided by the child's mother at both visits (60%), an extended family member at both visits (28%), or a combination of mother and an extended family member (12%). Caregiver acceptance of monthly bNAb infusions was extremely high both pre-and post-intervention, with 21/24 (87.5%) preferring bNAbs to ART pre-intervention, and 21/25 (84%) preferring bNAbs post-intervention. While no caregiver preferred ART pre-intervention, 2/25 preferred it post-intervention. Pre-intervention, 3 (13%) caregivers had no preference between monthly bNAbs or daily ART, and 2 (8%) had no preference post-intervention. Pre-intervention, the most common reasons for preferring bNAbs over ART were the perception that bNAbs were better at suppressing the virus than ART (n = 10) and the fact that infusions were dosed once monthly compared to daily ART (n = 9). Post-intervention, no dominant reason for preferring bNAbs over ART emerged from caregivers. CONCLUSIONS: Monthly intravenous bNAb infusions were highly acceptable to caregivers of children with HIV in Botswana and preferred over standard ART by the majority of caregivers. CLINICAL TRIAL NUMBER: NCT03707977.

Adolescence and the risk of ART non-adherence during a geographically focused public health intervention: an analysis of clinic records from Nigeria.

The risk of poor antiretroviral therapy (ART) adherence among adolescents is a challenge to controlling HIV. This study aims to provide guidance for geographically focussed public health interventions to improve adherence. Through clinic records, it investigates adolescents' non-adherence risk and clinic-level differences in regions of Nigeria which were part of PEPFAR's geographical pivot. Records (n = 26,365) were selected using systematic random sampling from all PEPFAR-supported facilities (n = 175) in targeted Local Government Areas across three regions in Nigeria. Adolescents' risk of non-adherence was estimated using region-specific random-effects models accounting for clinic-level variation. These were adjusted for sex, whether a patient had to travel to a different region, clinic location (urban/rural), clinic type (primary, secondary, tertiary). Despite regional variations, adolescents were at higher risk of non-adherence compared to adults. A similar, but weaker, association was found for children. Patients attending tertiary facilities for ART in the South-South region exhibited very high risk of non-adherence. Adolescents and children are at an increased risk of poor ART adherence in rural regions of Nigeria. Regional differences and facility type are critical factors. Future public health programmes focused on the risk of poor adherence targeting "high-prevalence areas" should be sensitive to contextual differences and age-appropriate care.

Predictors of secondary HIV transmission risk in a cohort of adolescents living with HIV in South Africa.

OBJECTIVE: Preventing secondary HIV transmission from adolescents and young people living with HIV (AYPLHIV) to their partners and children is critical to interrupting the HIV infection cycle in sub-Saharan Africa. We investigated predictors of secondary HIV transmission risk (past-year sexual risk combined with past-year viremia) among AYPLHIV in South Africa. DESIGN: A prospective cohort of AYLPHIV in South Africa recruited n = 1046 participants in 2014-2015, 93.6% of whom were followed up in 2016-2017 (1.5% mortality). Questionnaires used validated scales where available and biomarkers were extracted from n = 67 health facilities. METHODS: Multivariate logistic regressions tested baseline factors associated with secondary HIV transmission risk, controlling for covariates, with marginal effect modelling combinations. RESULTS: About 14.2% of AYPLHIV reported high secondary HIV transmission risk. High-risk AYPLHIV were more likely to be sexually infected [adjusted odds ratio (aOR) 2.79, 95% confidence interval (95% CI) 1.66-4.68, P < 0.001], and report hunger (aOR 1.93, 95% CI 1.18-3.14, P = 0.008) and substance use (aOR 2.19, 95% CI 1.19-4.02, P = 0.012). They were more likely to be in power-inequitable relationships (aOR 1.77, 95% CI 1.08-2.92, P = 0.025) and be parents (aOR 4.30, 95% CI 2.16-8.57, P < 0.001). Adolescents reporting none of these factors had a 4% probability of secondary transmission risk, rising to 89% probability with all five identified factors. Older age and early sexual debut were also strongly associated with a higher risk of secondary HIV transmission. CONCLUSION: It is essential to identify and support AYPLHIV at a high risk of secondary transmission. Screening for factors such as mode of infection and parenthood during routine healthcare visits could help identify and provide resources to the most at-risk adolescents.

Clinic and care: associations with adolescent antiretroviral therapy adherence in a prospective cohort in South Africa.

OBJECTIVE: Adolescent antiretroviral treatment (ART) adherence remains critically low. We lack research testing protective factors across both clinic and care environments. DESIGN: A prospective cohort of adolescents living with HIV (sample n = 969, 55% girls, baseline mean age 13.6) in the Eastern Cape Province in South Africa were interviewed at baseline and 18-month follow-up (2014-2015, 2015-2016). We traced all adolescents ever initiated on treatment in 52 government health facilities (90% uptake, 93% 18-month retention, 1.2% mortality). METHODS: Clinical records were collected; standardized questionnaires were administered by trained data collectors in adolescents' language of choice. Probit within-between regressions and average adjusted probability calculations were used to examine associations of caregiving and clinic factors with adherence, controlling for household structure, socioeconomic and HIV factors. RESULTS: Past-week ART adherence was 66% (baseline), 65% (follow-up), validated against viral load in subsample. Within-individual changes in three factors were associated with improved adherence: no physical and emotional violence (12.1 percentage points increase in adjusted probability of adherence, P < 0.001), improvement in perceived healthcare confidentiality (7.1 percentage points, P < 0.04) and shorter travel time to the clinic (13.7 percentage points, P < 0.02). In combination, improvement in violence prevention, travel time and confidentiality were associated with 81% probability of ART adherence, compared with 47% with a worsening in all three. CONCLUSION: Adolescents living with HIV need to be safe at home and feel safe from stigma in an accessible clinic. This will require active collaboration between health and child protection systems, and utilization of effective violence prevention interventions.

The HIV care cascade for adolescents initiated on antiretroviral therapy in a health district of South Africa: a retrospective cohort study.

BACKGROUND: Little evidence exists to comprehensively estimate adolescent viral suppression after initiation on antiretroviral therapy in sub-Saharan Africa. This study examines adolescent progression along the HIV care cascade to viral suppression for adolescents initiated on antiretroviral therapy in South Africa. METHODS: All adolescents ever initiated on antiretroviral therapy (n=1080) by 2015 in a health district of the Eastern Cape, South Africa, were interviewed in 2014-2015. Clinical records were extracted from 52 healthcare facilities through January 2018 (including records in multiple facilities). Mortality and loss to follow-up rates were corrected for transfers. Predictors of progression through the HIV care cascade were tested using sequential multivariable logistic regressions. Predicted probabilities for the effects of significant predictors were estimated by sex and mode of infection. RESULTS: Corrected mortality and loss to follow-up rates were 3.3 and 16.9%, respectively. Among adolescents with clinical records, 92.3% had ≥1 viral load, but only 51.1% of viral loads were from the past 12 months. Adolescents on ART for ≥2 years (AOR 3.42 [95%CI 2.14-5.47], p< 0.001) and who experienced decentralised care (AOR 1.39 [95%CI 1.06-1.83], p=0.018) were more likely to have a recent viral load. The average effect of decentralised care on recent viral load was greater for female (AOR 2.39 [95%CI 1.29-4.43], p=0.006) and sexually infected adolescents (AOR 3.48 [95%CI 1.04-11.65], p=0.043). Of the total cohort, 47.5% were recorded as fully virally suppressed at most recent test. Only 23.2% were recorded as fully virally suppressed within the past 12 months. Younger adolescents (AOR 1.39 [95%CI 1.06-1.82], p=0.017) and those on ART for ≥2 years (AOR 1.70 [95%CI 1.12-2.58], p=0.013) were more likely to be fully viral suppressed. CONCLUSIONS: Viral load recording and viral suppression rates remain low for ART-initiated adolescents in South Africa. Improved outcomes for this population require stronger engagement in care and viral load monitoring.

The effects of decentralising antiretroviral therapy care delivery on health outcomes for adolescents and young adults in low- and middle-income countries: a systematic review.

Background: Decentralisation of antiretroviral therapy has been implemented to scale up HIV care provision for patients in resource-limited countries. Youth living with HIV demonstrate the poorest care outcomes, compared to other age groups. Objectives: To systematically evaluate evidence on the effects of decentralising facility-based HIV care on care outcomes for youth living with HIV in low- and middle-income countries. Methods: A systematic review was conducted through 12 electronic databases of peer-reviewed articles, conference abstracts, and grey literature; contacting relevant experts; and hand-searching references. Records were included if they were published after 1 January 1996 (advent of triple-drug ART) and reported health outcomes for decentralised and centralised care, separately, or evaluated the effect of decentralised care on care outcomes. Two authors independently screened search results. When age-disaggregated data (10-24 years old) were required for inclusion, we contacted study authors for data abstraction. Implementation fidelity of decentralisation, study quality, and risk of bias was assessed using the TIDieR checklist, CASP checklists, and ROBINS-I tool, respectively. Results: Of 11 potentially eligible studies, two studies from sub-Saharan Africa met inclusion criteria after data disaggregation by age. The studies and abstracted data were insufficiently homogenous in implementation and study design to justify meta-analysis. However, evidence suggests the potential for decentralised care to result in at least equivalent attrition-related outcomes (retention in care and mortality) for youth within decentralised HIV care. Limited sample size and significant selection and allocation bias confound clear, generalisable conclusions for youth living with HIV in resource-limited settings. Conclusions: There is a paucity of evidence for the effects of decentralising HIV care for youth living in resource-limited settings, particularly recent evidence reflective of the current HIV care landscape. Further work is required to rigorously analyse the effects of decentralising HIV care to inform policymakers and care providers, particularly as demand for HIV care in this population grows.

Transition Pathways Out of Pediatric Care and Associated HIV Outcomes for Adolescents Living With HIV in South Africa.

BACKGROUND: Research on adolescent transitions out of pediatric HIV care has focused on high-income countries, with limited understanding of transitions in sub-Saharan Africa's public health sector. METHODS: Patient file data were extracted through December 2017 for all 10- to 19-year olds ever initiated on antiretroviral therapy in a health district of the Eastern Cape, South Africa (n = 951). Pathways in HIV care were identified by tracing movements across facility care types and levels. Associations between pathways and viral failure, mortality, loss to follow-up, and viral load change were tested in sequential multivariable regressions. Analyses controlled for sociodemographic and treatment-related variables. Thematic analyses of semistructured health care provider interviews identified transition support at included facilities. RESULTS: Only 57.8% of adolescents had initiated antiretroviral therapy in pediatric care, and 20.4% of the total cohort had transitioned out of pediatric HIV care. Among the 42.2% who had initiated in nonpediatric care, 93.8% remained exclusively in nonpediatric care. Median age at first transition was 14 years. Two main pathways were identified: classical transition to adult HIV care (43.3%) and down referral transition to primary health care clinics (56.7%). Across pathways, 27.3% experienced cyclical transition or repeated movement between pediatric and nonpediatric care. Independent of covariates, adolescents with down referral transition were less likely to demonstrate viral failure (adjusted odds ratio, 0.21; 95% confidence interval: 0.10 to 0.42; P < 0.001). Mortality and loss to follow-up were not associated with either pathway. Median posttransition viral load change was not clinically significant (median, 0.00; interquartile range: 0.00-0.35) or associated with transition pathways. Health care providers described informal "protocols" for mitigating risk of negative posttransition HIV outcomes. CONCLUSIONS: This study proposes a contextually relevant model for transitions out of pediatric HIV care in South Africa. Feasible, scalable "protocols" may mitigate risk of worsening posttransition HIV outcomes.

Sex in the shadow of HIV: A systematic review of prevalence, risk factors, and interventions to reduce sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa.

BACKGROUND: Evidence on sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa is urgently needed. This systematic review synthesizes the extant research on prevalence, factors associated with, and interventions to reduce sexual risk-taking among HIV-positive adolescents and youth in sub-Saharan Africa. METHODS: Studies were located through electronic databases, grey literature, reference harvesting, and contact with researchers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Quantitative studies that reported on HIV-positive participants (10-24 year olds), included data on at least one of eight outcomes (early sexual debut, inconsistent condom use, older partner, transactional sex, multiple sexual partners, sex while intoxicated, sexually transmitted infections, and pregnancy), and were conducted in sub-Saharan Africa were included. Two authors piloted all processes, screened studies, extracted data independently, and resolved any discrepancies. Due to variance in reported rates and factors associated with sexual risk-taking, meta-analyses were not conducted. RESULTS: 610 potentially relevant titles/abstracts resulted in the full text review of 251 records. Forty-two records (n = 35 studies) reported one or multiple sexual practices for 13,536 HIV-positive adolescents/youth from 13 sub-Saharan African countries. Seventeen cross-sectional studies reported on individual, relationship, family, structural, and HIV-related factors associated with sexual risk-taking. However, the majority of the findings were inconsistent across studies, and most studies scored <50% in the quality checklist. Living with a partner, living alone, gender-based violence, food insecurity, and employment were correlated with increased sexual risk-taking, while knowledge of own HIV-positive status and accessing HIV support groups were associated with reduced sexual risk-taking. Of the four intervention studies (three RCTs), three evaluated group-based interventions, and one evaluated an individual-focused combination intervention. Three of the interventions were effective at reducing sexual risk-taking, with one reporting no difference between the intervention and control groups. CONCLUSION: Sexual risk-taking among HIV-positive adolescents and youth is high, with inconclusive evidence on potential determinants. Few known studies test secondary HIV-prevention interventions for HIV-positive youth. Effective and feasible low-cost interventions to reduce risk are urgently needed for this group.

Longitudinal Modeling of Depressive Trajectories Among HIV-Infected Men Using Cocaine.

Cocaine use is prevalent among HIV-infected individuals. While cross-sectional studies suggest that cocaine users may be at increased risk for depression, long-term effects of cocaine on depressive symptoms remain unclear. This is a longitudinal study of 341 HIV-infected and uninfected men (135 cocaine users and 206 controls) ages 30-60 enrolled in the Multicenter AIDS Cohort Study during 1996-2009. The median baseline age was 41; 73% were African-American. In mixed-effects models over a median of 4.8 years of observation, cocaine use was associated with higher depressive symptoms independent of age, education level, and smoking (n = 288; p = 0.02); HIV infection modified this association (p = 0.03). Latent class mixed models were used to empirically identify distinct depressive trajectories (n = 160). In adjusted models, cocaine use was associated with threefold increased odds of membership in the class with persistent high depressive symptoms (95% confidence interval (CI) 1.38-6.69) and eightfold increased odds (95% CI (2.73-25.83) when tested among HIV-infected subjects only. Cocaine use is a risk factor for chronic depressive symptoms, particularly among HIV-infected men, highlighting the importance of integrating mental health and substance use treatments to address barriers to well-being and successful HIV-care.

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.

Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

Hypervolemic hypernatremia in patients recovering from acute kidney injury in the intensive care unit.

BACKGROUND: A high incidence of hypernatremia is often observed in patients recovering from acute kidney injury (AKI) in intensive care units. METHODS: An unselected cohort of 20 adult patients recovering from AKI in the intensive care unit of a single institution during a 1-year period, were investigated. Serum and urine electrolytes, osmolality, urea nitrogen and creatinine were measured in an attempt to determine the cause of the hypernatremia. RESULTS: Eighty-eight percent of patients who could not drink fluids were found to have hypernatremia (serum Na >145 mEq/L). Even though the hypernatremia was mild in most patients (146-160 mEq/L), the average rise in serum sodium concentration was 17.4 mEq/L. The average urine osmolality was 384 mmol/kg of which 47.6 and 32.8 mmol/kg were contributed by sodium and potassium, respectively. The patients had hypervolemia as evidenced by the presence of edema and an average weight gain of 21.5 kg at the onset of the hypernatremia. The rise in serum sodium level coincided with an increase in urine output. CONCLUSION: The hypernatremia is believed to be due to post-AKI diuresis in the face of inability to maximally concentrate the urine because of renal failure. The diuresis caused a disproportionate loss of water in excess of that of sodium in the absence of replenishment of the water loss. Additionally, the patients were hypervolemic due to the retention of large quantities of sodium and water as a result of infusion of substantial volumes of physiological saline prior to the development of hypernatremia.