Cannabinoids and inflammation: implications for people living with HIV Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies. Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons. Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the phytocannabinoids, which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators. CB2 receptor activation has been shown in vitro to reduce CD4+ T-cell infection by CXCR4-tropic HIV and to reduce HIV replication. Studies involving SIV-infected macaques have shown that Δ9-THC can reduce morbidity and mortality and has favourable effects on gut mucosal immunity. Furthermore, Δ9-THC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques. In humans, cannabis use does not induce a reduction in peripheral CD4+ T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokine secretion, all of which are related to HIV disease progression and comorbidities. Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART.

Delayed gastrointestinal-associated lymphoid tissue reconstitution in duodenum compared with rectum in HIV-infected patients initiating antiretroviral therapy Background: We aimed to characterize the impact of antiretroviral therapy (ART) initiation on gastrointestinal-associated lymphoid tissue at various sites along the gastrointestinal site. Methodology: Peripheral blood and duodenal and rectal biopsies were obtained from 12 HIV− to 33 treatment-naive HIV+ participants at baseline and after 9 months ART. Tissue was digested for immunophenotyping. Inflammatory, bacterial translocation and intestinal damage markers were measured in plasma. Results: Twenty-six HIV+ patients completed follow-up. The lowest reconstitution of CD4+ T cells and the lowest CD4+/CD8+ ratio during ART compared with blood were observed in the duodenum with the rectum being either intermediate or approaching blood levels. Regulatory T cells were in higher proportions in the duodenum than the rectum and neither declined significantly during ART. Several correlations with biomarkers of microbial translocation were observed including increases in lipoteichoic acid levels, which reflects Gram-positive bacterial translocation, correlated with increases in %CD4+ T cells in the duodenum (Rho 0.773, P = 0.033), and with decreases in duodenal regulatory T-cell populations (Rho −0.40, P = 0.045). Conclusion: HIV-mediated immunological disruption is greater in the duodenum than rectum and blood before and during ART. Small intestine damage may represent a unique environment for T-cell depletion, which might be attenuated by interaction with Gram-positive bacteria.

HIV-1 genetic diversity to estimate time of infection and infer adherence to preexposure prophylaxis Objective: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) and relate infection with adherence patterns. Design: We used the diversity structure of the virus population at the first HIV RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). Methods: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10–25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. Results: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median = 47 [IQR = 35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90–95% adherence in two, 55% adherence in one, and nonadherence in three. Conclusion: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%.

Better executive function is independently associated with full HIV suppression during combination therapy Objective: HIV-associated neurocognitive impairment continues to be prevalent and clinically relevant. We examined the relationship between neurocognition and full plasma HIV RNA suppression among study participants over a 15-year period at a large research program. Design/methods: We analyzed the combined prospective studies of the HIV Neurobehavioral Research Program at the University of California at San Diego. Participants were eligible for analysis if on three drug combination antiretroviral therapy with comprehensive neuropsychological testing results. Participants who reported recent nonadherence were excluded. The primary outcome was plasma HIV RNA of 50 copies/ml or less. Generalized estimating equation was used to assess for associations with full virologic suppression taking into account longitudinal visits. Results: There were 1943 participants at baseline, of whom 69.4% had plasma HIV RNA of 50 copies/ml or less. Participants with full suppression were slightly older, less likely to abuse cocaine, and had significantly better executive function. Multivariate analysis with incorporation of longitudinal visits (total = 5555) confirmed current cocaine abuse to be strongly associated with lack of virologic suppression (odds ratio = 0.45, 95% confidence interval = 0.31–0.63). In contrast, increasing age, increasing years of HIV infection, and increasing executive function (odds ratio = 1.18 for T score change of 10, 95% confidence interval = 1.07–1.30) were associated with full virologic suppression. Lack of virologic suppression at baseline was associated with a significant subsequent decline in executive function. Conclusion: In a 15-year research cohort of almost 2000 HIV-infected individuals on combination antiretroviral therapy, better executive function was associated with full virologic suppression, possibly as a result rather than a cause.

Comorbidity and polypharmacy among women living with HIV in British Columbia Objective: To characterize comorbid disease and medication burden among women living with HIV (WLWH) in British Columbia (BC), Canada. Design: We examined baseline data from 267 WLWH and 276 HIV-negative women, aged at least 19 years, enrolled in the Children and Women: Antiretrovirals and Markers of Aging (CARMA) cohort. Methods: Self-reported demographic, medical condition, medication, vitamin, and substance exposure data were collected at baseline CARMA study visits. We considered conditions with appropriate concomitant medications to be ‘treated’. Wilcoxon rank-sum and Fisher's exact tests compared continuous and categorical variables between WLWH and HIV-negative women. Number of diagnoses, prescribed medications (excluding HIV/antiretrovirals), vitamins, and prevalence of depression/anxiety/panic disorder were compared using negative binomial and logistic regressions for continuous and binary variables, respectively. Results: WLWH were younger [median, interquartile range (IQR) 39.9, 33.6–46.9 vs. 43.6, 31.8–54.6 years; P = 0.01], attained lower education (40.5 vs. 69.6% college/university; P < 0.001), and more often currently smoked tobacco (47.9 vs. 31.9%; P < 0.001) or had income less than $15 000/year (49.0 vs. 43.1%; P < 0.001). Although younger, and despite omitting HIV infection, WLWH had a greater number of diagnoses (incidence rate ratio, 95% confidence interval 1.58, 1.38–1.81; P < 0.001), and more depression/anxiety/panic disorder vs. controls (odds ratio, 95% CI 1.86, 1.22–2.83; P = 0.004). Our model predicts that with mean BMI (26.3), WLWH and HIV-negative peers would have two comorbid diagnoses by age 30 and 60, respectively. Conclusions: WLWH living in BC have more comorbid illness earlier in life than their HIV-negative peers, and have very high rates of depression/anxiety/panic disorder. Addressing mental health and comorbid conditions is essential to improving health outcomes among WLWH.

Non-AIDS comorbidity burden differs by sex, race, and insurance type in aging adults in HIV care Objective: To understand the epidemiology of non-AIDS-related chronic comorbidities (NACMs) among aging persons with HIV (PWH). Design: Prospective multicenter observational study to assess, in an age-stratified fashion, number and types of NACMs by demographic and HIV factors. Methods: Eligible participants were seen during 1 January 1997 to 30 June 2015, followed for more than 5 years, received antiretroviral therapy (ART), and virally suppressed (HIV viral load <200 copies/ml ≥75% of observation time). Age was stratified (18–40, 41–50, 51–60, ≥61 years). NACMs included cardiovascular disease, cancer, hypertension, diabetes, dyslipidemia, arthritis, viral hepatitis, anemia, and psychiatric illness. Results: Of 1540 patients, 1247 (81%) were men, 406 (26%) non-Hispanic blacks (NHB), 183 (12%) Hispanics/Latinos, 575 (37%) with public insurance, 939 (61%) MSM, and 125 (8%) with injection drug use history. By age strata 18–40, 41–50, 51–60, and at least 61 years, there were 180, 502, 560, and 298 patients, respectively. Median HIV Outpatient Study observation was 10.8 years (range: min-max = 5.0–18.5). Mean number of NACMs increased with older age category (1.4, 2.1, 3.0, and 3.9, respectively; P < 0.001), as did prevalence of most NACMs (P < 0.001). Age-related differences in NACM numbers were primarily due to anemia, hepatitis C virus infection, and diabetes. Differences (all P < 0.05) in NACM number existed by sex (women >men, 3.9 vs. 3.4), race/ethnicity (NHB >non-NHB, 3.8 vs. 3.4), and insurance status (public >private, 4.3 vs. 3.1). Conclusions: Age-related increases existed in prevalence and number of NACMs, with disproportionate burden among women, NHBs, and the publicly insured. These groups should be targeted for screening and prevention strategies aimed at NACM reduction.

Impact of early antiretroviral treatment on sexual behaviour: a randomised comparison Background: Antiretroviral treatment (ART) reduces HIV infectiousness but the effect of early ART on sexual behaviour is unclear. Methods: We assessed, within the START randomized trial that enrolled HIV-positive adults with CD4+ cell count greater than 500 cells/μl, the effect of early (immediate) versus deferred ART on: condomless sex with HIV-serodifferent partners (CLS-D); all condomless sex (CLS); HIV transmission-risk sex (CLS-D-HIV risk, defined as CLS-D and: not on ART or started ART <6 months ago or viral load greater than 200 copies/ml or no viral load in past 6 months), during 2-year follow-up. Month-12 CLS-D (2010–2014) was the primary outcome. Results: Among 2562 MSM, there was no difference between immediate and deferred arms in CLS-D at month 12 [12.6 versus 13.1%; difference (95% CI): −0.4% (−3.1 to 2.2%), P = 0.75] or month 24, or in CLS. Among 2010 heterosexual men and women, CLS-D at month 12 tended to be higher in the immediate versus deferred arm [10.8 versus 8.3%; difference:2.5% (−0.1 to 5.2%), P = 0.062]; the difference was greater at month 24 [9.3 versus 5.6%; difference: 3.7% (1.0 to 6.4%), P = 0.007], at which time CLS was higher in the immediate arm (20.7 versus 15.7%, P = 0.013). CLS-D-HIV risk at month 12 was substantially lower in the immediate versus deferred arm for MSM [0.2 versus 11%; difference: −10.7% (−12.5 to −8.9%), P < 0.001] and heterosexuals [0.6% versus 7.7%; difference: −7.0% (−8.8 to −5.3%), P < 0.001], because of viral suppression on ART. Conclusion: A strategy of early ART had no effect on condomless sex with HIV-serodifferent partners among MSM, but resulted in modestly higher prevalence among heterosexuals. However, among MSM and heterosexuals, early ART resulted in a substantial reduction in HIV-transmission-risk sex, to a very low absolute level.

MicroRNA biomarkers associated with type 1 myocardial infarction in HIV-positive individuals Objective: Individuals with HIV suffer a higher burden of cardiovascular diseases. Traditional cardiovascular risk scores consistently underestimate cardiovascular risk in this population. Subsets of microRNAs (miRNAs) are differentially expressed among individuals with cardiovascular disease and individuals infected with HIV. However, no study has clarified whether specific miRNAs may be biomarkers for cardiovascular disease in individuals with HIV. Design/methods: We compared the miRNA expression profiles of 34 HIV-positive individuals who had experienced clinically adjudicated type I myocardial infarctions (MI) with the profiles of 76 HIV-positive controls matched by traditional cardiovascular risk factors and HIV-specific measures. Using the elastic net algorithm, we selected miRNAs most strongly associated with incident MI and then used conditional Cox proportional hazards regression and cross-validation to evaluate miRNAs and their association with incident MI. We evaluated whether miRNA markers would improve risk classification relative to the Framingham Risk Score. Results: Higher miR-125a-5p and miR-139-5p expression levels were each associated with increased risk of developing MI after adjustment for Framingham Risk Score and HIV-related factors (hazard ratio 2.43, P = 0.018; hazard ratio 2.13, P = 0.048, respectively). Compared with the Framingham Risk Score alone, adding expression levels of miR-125a-5p or miR-139-5p resulted in an integrated discrimination improvement of 10.1 or 5.8%, respectively. Conclusion: MiR-125a-5p and miR-139-5p, transcripts known to be differentially expressed in HIV-positive individuals, may serve as unique biomarkers predictive of cardiovascular disease in these patients and may help clarify processes because of HIV infection that contribute to cardiovascular disorders in this population.

Higher soluble CD14 levels are associated with lower visuospatial memory performance in youth with HIV Objective: HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH). Design: Observational cross-sectional study. Methods: YWH, ages 20–28 years, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation, and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically adjusted z-scores were combined to form indices of attention, motor, executive function, verbal, and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4+ T-cell count, HIV viral load, and ART status. Results: Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (z = −1.59 and −1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, whereas sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels. Conclusion: Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.

Attrition of HIV-positive children from HIV services in low and middle-income countries Introduction: Identification and retention of HIV-positive children in HIV services is essential to ensure optimal health outcomes. This systematic review and meta-analysis examines the magnitude of attrition [loss to follow-up (LTFU) and death) of HIV-positive children from HIV services in low and middle-income countries (LMICs). Methods: We performed a comprehensive multidatabase search of original studies reporting retention/attrition data for HIV-positive children in LMICs through April 2016. Outcomes included LTFU, death, and overall attrition (LTFU + death) at intervals up to 60 months of follow-up. At least two authors determined study eligibility, performed data extraction, and made quality assessments. We used random-effects meta-analytic methods to aggregate effect sizes and perform meta-regression analyses. Results: We identified 3040 unique studies; 91 met eligibility criteria and were included in the analysis. This represents 147 129 HIV-positive children; most were from Africa (83%). LTFU definitions varied widely, with significant variability in outcomes across studies. Most attrition occurred in the first 6 months of follow-up, increasing to 23% by 36 months. HIV-positive children receiving antiretroviral therapy (ART) had significantly better retention in care than those not on ART. Studies that performed case-finding/tracing for those LTFU had better retention in care up to 24 months of follow-up. Conclusions: These findings underscore the high attrition of children from HIV services in LMICs. Early ART initiation and decentralized patient support services (e.g. tracing for those LTFU) have potential to improve retention in care. Implementation research and resources are urgently needed to improve retention among this vulnerable population.