Improved outcomes following gastrointestinal surgery among people living with HIV in the HAART-era: A scoping review.

BACKGROUND: This study aimed to review the varied 1-4 gastrointestinal (GI) system surgical outcomes among people living with Human Immunodeficiency Virus (PLWH) in the HAART-era. METHODS: MEDLINE and EMBASE were searched for primary publications on GI surgery outcomes exclusively in HAART-treated HIV patients. NSQIP-reported complications (NRCs), all-cause complications (ACC) and HIV disease parameters were extracted. RESULTS: 12 studies met study inclusion criteria, examining bowel (4), bariatric (5), cholecystectomy (1), appendectomy (1), and other general abdominal operations (1). The NRC rate was 0%, ≥44.4% and 13.3% in bariatric, bowel and appendix surgeries, respectively. Over half of NRCs were infectious. HAART-treated patients had lower ACC, LOS, and sepsis versus untreated-HIV, and higher ACC, LOS and reoperation rates versus HIV-negative patients. CONCLUSION: HAART use is associated with markedly improved NRC outcomes post GI surgery among PLWH; however, these remained inferior to those documented among HIV uninfected individuals.

Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada.

BACKGROUND: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs. METHODS: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods. RESULTS: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs. CONCLUSIONS: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.

Microbial dysbiosis and the host airway epithelial response: insights into HIV-associated COPD using multi'omics profiling.

BACKGROUND: People living with HIV (PLWH) are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) independent of cigarette smoking. We hypothesized that dysbiosis in PLWH is associated with epigenetic and transcriptomic disruptions in the airway epithelium. METHODS: Airway epithelial brushings were collected from 18 COPD + HIV + , 16 COPD - HIV + , 22 COPD + HIV - and 20 COPD - HIV - subjects. The microbiome, methylome, and transcriptome were profiled using 16S sequencing, Illumina Infinium Methylation EPIC chip, and RNA sequencing, respectively. Multi 'omic integration was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents. A correlation > 0.7 was used to identify key interactions between the 'omes. RESULTS: The COPD + HIV -, COPD -HIV + , and COPD + HIV + groups had reduced Shannon Diversity (p = 0.004, p = 0.023, and p = 5.5e-06, respectively) compared to individuals with neither COPD nor HIV, with the COPD + HIV + group demonstrating the most reduced diversity. Microbial communities were significantly different between the four groups (p = 0.001). Multi 'omic integration identified correlations between Bacteroidetes Prevotella, genes FUZ, FASTKD3, and ACVR1B, and epigenetic features CpG-FUZ and CpG-PHLDB3. CONCLUSION: PLWH with COPD manifest decreased diversity and altered microbial communities in their airway epithelial microbiome. The reduction in Prevotella in this group was linked with epigenetic and transcriptomic disruptions in host genes including FUZ, FASTKD3, and ACVR1B.

People With Human Immunodeficiency Virus Receiving Suppressive Antiretroviral Therapy Show Typical Antibody Durability After Dual Coronavirus Disease 2019 Vaccination and Strong Third Dose Responses.

BACKGROUND: Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) (PLWH), as do initial responses to a third dose. METHODS: We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls. RESULTS: Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. CONCLUSION: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.

Disability-adjusted life years associated with chronic comorbidities among people living with and without HIV: Estimating health burden in British Columbia, Canada.

Life span of people living with HIV (PLWH) has increased dramatically with the advent of modern antiretroviral therapy. As a result, comorbidities have emerged as a significant concern in this population. To describe the burden of chronic comorbidities among PLWH and HIV-negative individuals in British Columbia (BC), Canada, we estimated disability-adjusted life years (DALYs) related to these comorbidities. Based on a population-based cohort in BC, antiretroviral-treated adult PLWH and 1:4 age-sex-matched HIV-negative controls were followed for ≥1 year during 2001-2012. DALYs combined years of life lost to premature mortality (YLLs) and due to disability (YLDs), and were estimated following the Global Burden of Diseases' approaches. DALYs associated with non-AIDS-defining cancers, diabetes, osteoarthritis, hypertension, dementia, cardiovascular (CVD), kidney, liver and chronic obstructive pulmonary diseases were each measured for 2008-2012. Among PLWH, DALYs attributed to non-AIDS-related cancers were also estimated for 2013-2020. We observed that at baseline, our matched cohort consisted of 82% males with a median age of 40 years (25th-75th percentiles: 34-47). During 2008-2012, 7042 PLWH and 30,640 HIV-negative individuals were alive, where PLWH experienced a twofold higher DALYs associated with chronic comorbidities (770.2 years/1000 people [95% credible intervals: 710.2, 831.6] vs. 359.0 [336.0, 382.2]). Non-AIDS-defining cancers and CVD contributed the highest DALYs in both populations, driven by YLLs rather than YLDs. Among PLWH, we estimated increasing DALYs attributable to non-AIDS-defining cancers with 91.7 years/1000 people (77.4, 106.0) in 2013 vs. 97.6 (81.0, 115.2) in 2020. In this study, we showed that PLWH experience a disproportionate burden of chronic comorbidities compared to HIV-negative individuals. The observed disparities may relate to differential health behaviors, residual HIV-related inflammation, and ART-related toxicities. As aging shapes future healthcare needs, our findings highlight the need to enhance prevention and management of comorbidities as part of HIV care.

2021 update to HIV-TRePS: a highly flexible and accurate system for the prediction of treatment response from incomplete baseline information in different healthcare settings.

OBJECTIVES: With the goal of facilitating the use of HIV-TRePS to optimize therapy in settings with limited healthcare resources, we aimed to develop computational models to predict treatment responses accurately in the absence of commonly used baseline data. METHODS: Twelve sets of random forest models were trained using very large, global datasets to predict either the probability of virological response (classifier models) or the absolute change in viral load in response to a new regimen (absolute models) following virological failure. Two 'standard' models were developed with all baseline variables present and 10 others developed without HIV genotype, time on therapy, CD4 count or any combination of the above. RESULTS: The standard classifier models achieved an AUC of 0.89 in cross-validation and independent testing. Models with missing variables achieved AUC values of 0.78-0.90. The standard absolute models made predictions that correlated significantly with observed changes in viral load with a mean absolute error of 0.65 log10 copies HIV RNA/mL in cross-validation and 0.69 log10 copies HIV RNA/mL in independent testing. Models with missing variables achieved values of 0.65-0.75 log10 copies HIV RNA/mL. All models identified alternative regimens that were predicted to be effective for the vast majority of cases where the new regimen prescribed in the clinic failed. All models were significantly better predictors of treatment response than genotyping with rules-based interpretation. CONCLUSIONS: These latest models that predict treatment responses accurately, even when a number of baseline variables are not available, are a major advance with greatly enhanced potential benefit, particularly in resource-limited settings. The only obstacle to realizing this potential is the willingness of healthcare professions to use the system.

The opioid crisis is driving mortality among under-served people living with HIV in British Columbia, Canada.

INTRODUCTION: Universal provision of effective antiretroviral medication has been essential to reduce mortality, increase longevity, and reduce onward transmission of HIV. This study aims to illuminate persistent threats to the health and longevity of under-served PLWH in British Columbia (BC), Canada. METHODS: Between 2007 and 2010, 1000 PLWH across BC were enrolled in the Longitudinal Investigation into Supportive and Ancillary health services (LISA) study and completed a cross-sectional survey on their HIV-care experiences and healthcare engagement. The sample generally reflects an under-served population of PLWH. A linkage to the provincial Vital Statistics registry is used in this analysis in order to examine overall mortality and cause-specific mortality trends; probability of death was modeled using logistic regression for participants with ongoing clinical monitoring (n = 910). RESULTS: By June 2017, 208 (20.8%) participants had died. The majority of deaths 57 (27.4%) were attributed to drug-related complications or overdoses, 39 (18.8%) were attributed to HIV-related complications, and 36 (17.3%) to non-AIDS-defining malignancies. We observed elevated odds of death among PLWH who smoked tobacco (aOR: 2.11, 95% CI: 1.38, 3.23), were older (aOR: 1.06 per one-year increase, 95% CI: 1.04, 1.08), indicated heavy alcohol consumption (aOR: 1.57, 95% CI: 1.11, 2.22), and reported unstable housing (aOR: 1.96, 95% CI: 1.37, 2.80); while higher CD4 cell count was protective (aOR: 0.87 per 100-unit increase, 95% CI: 0.79, 0.94) as was male gender), though non-significant (aOR: 0.73, 95% CI: 0.49, 1.07). CONCLUSIONS: Overdose is - the leading cause of mortality among a cohort of under-served PLWH in BC, Canada. Public health efforts to end the HIV epidemic and support the health and well-being of PLWH are being thwarted by persistent health inequities and the enormous and persistent risks facing people who use drugs. Integrated low-barrier primary care is essential for supporting under-served PLWH, and safe drug supply is needed to support PLWH who use drugs.

Estimation of time of HIV seroconversion using a modified CD4 depletion model.

INTRODUCTION: Several methods have been proposed to estimate the time of HIV seroconversion, including those based on CD4 cell depletion models. However, previous models have failed to consider the heterogeneity that exists in CD4 trajectories among different sub-populations. Our objective was to estimate the time from HIV seroconversion relative to the HIV diagnosis date in a population-based cohort of people living with HIV (PLWH) in the province of British Columbia, Canada. METHODS: We used linked administrative and clinical data from the British Columbia Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) cohort, which contains longitudinal individual-level data on all PLWH ever diagnosed in the province. Eligible participants were aged ≥18 years and diagnosed with HIV between 1989 and 2013. The outcome was pre-antiretroviral treatment CD4 cell count measurements assessed every six months. Models were stratified by age and stage of HIV infection at diagnosis. Several explanatory variables were considered including longitudinal viral load measurements. Longitudinal CD4, square root transformed, was modeled via a non-linear mixed effects model; time was modeled using an exponential decay function. We assumed a Gaussian distribution (identity link), an AR(1) correlation structure, and a random intercept and slope for the longitudinal viral load measurements. Due to the population variation in CD4 count among uninfected individuals, we assumed 500 to 1500 cells/mm3 as the normal range when estimating the time of HIV seroconversion. RESULTS: Longitudinal data on 1,253 individuals were analysed: 80% male, 33% White, and the median age at diagnosis was 38 years (25th-75th percentile [Q1-Q3], 31 to 45). CD4 decay differed by stage of infection at diagnosis and age, with those ≥50 years in Stages 1 and 2 experiencing a faster decline in CD4 over time. The median duration of infection from seroconversion until HIV diagnosis was 6.9 (Q1-Q3, 3.9 to 10.1) years. CONCLUSIONS: Considering the heterogeneity that exists in individual CD4 cell trajectories in a population, we presented a methodology that only relies on routinely collected HIV-related data, which can be further extended to estimate other epidemic measures.

Excess burden of age-associated comorbidities among people living with HIV in British Columbia, Canada: a population-based cohort study.

OBJECTIVES: As people living with HIV (PLWH) live longer, morbidity and mortality from non-AIDS comorbidities have emerged as major concerns. Our objective was to compare prevalence trends and age at diagnosis of nine chronic age-associated comorbidities between individuals living with and without HIV. DESIGN AND SETTING: This population-based cohort study used longitudinal cohort data from all diagnosed antiretroviral-treated PLWH and 1:4 age-sex-matched HIV-negative individuals in British Columbia, Canada. PARTICIPANTS: The study included 8031 antiretroviral-treated PLWH and 32 124 HIV-negative controls (median age 40 years, 82% men). Eligible participants were ≥19 years old and followed for ≥1 year during 2000 to 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: The presence of non-AIDS-defining cancers, diabetes, osteoarthritis, hypertension, Alzheimer's and/or non-HIV-related dementia, cardiovascular, kidney, liver and lung diseases were identified from provincial administrative databases. Beta regression assessed annual age-sex-standardised prevalence trends and Kruskal-Wallis tests compared the age at diagnosis of comorbidities stratified by rate of healthcare encounters. RESULTS: Across study period, the prevalence of all chronic age-associated comorbidities, except hypertension, were higher among PLWH compared with their community-based HIV-negative counterparts; as much as 10 times higher for liver diseases (25.3% vs 2.1%, p value<0.0001). On stratification by healthcare encounter rates, PLWH experienced most chronic age-associated significantly earlier than HIV-negative controls, as early as 21 years earlier for Alzheimer's and/or dementia. CONCLUSIONS: PLWH experienced higher prevalence and earlier age at diagnosis of non-AIDS comorbidities than their HIV-negative controls. These results stress the need for optimised screening for comorbidities at earlier ages among PLWH, and a comprehensive HIV care model that integrates prevention and treatment of chronic age-associated conditions. Additionally, the robust methodology developed in this study, which addresses concerns on the use of administrative health data to measure prevalence and incidence, is reproducible to other settings.

Associations of substance use, psychosis, and mortality among people living in precarious housing or homelessness: A longitudinal, community-based study in Vancouver, Canada.

BACKGROUND: The "trimorbidity" of substance use disorder and mental and physical illness is associated with living in precarious housing or homelessness. The extent to which substance use increases risk of psychosis and both contribute to mortality needs investigation in longitudinal studies. METHODS AND FINDINGS: A community-based sample of 437 adults (330 men, mean [SD] age 40.6 [11.2] years) living in Vancouver, Canada, completed baseline assessments between November 2008 and October 2015. Follow-up was monthly for a median 6.3 years (interquartile range 3.1-8.6). Use of tobacco, alcohol, cannabis, cocaine, methamphetamine, and opioids was assessed by interview and urine drug screen; severity of psychosis was also assessed. Mortality (up to November 15, 2018) was assessed from coroner's reports and hospital records. Using data from monthly visits (mean 9.8, SD 3.6) over the first year after study entry, mixed-effects logistic regression analysis examined relationships between risk factors and psychotic features. A past history of psychotic disorder was common (60.9%). Nonprescribed substance use included tobacco (89.0%), alcohol (77.5%), cocaine (73.2%), cannabis (72.8%), opioids (51.0%), and methamphetamine (46.5%). During the same year, 79.3% of participants reported psychotic features at least once. Greater risk was associated with number of days using methamphetamine (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.05-1.24, p = 0.001), alcohol (aOR 1.09, 95% CI 1.01-1.18, p = 0.04), and cannabis (aOR 1.08, 95% CI 1.02-1.14, p = 0.008), adjusted for demographic factors and history of past psychotic disorder. Greater exposure to concurrent month trauma was associated with increased odds of psychosis (adjusted model aOR 1.54, 95% CI 1.19-2.00, p = 0.001). There was no evidence for interactions or reverse associations between psychotic features and time-varying risk factors. During 2,481 total person years of observation, 79 participants died (18.1%). Causes of death were physical illness (40.5%), accidental overdose (35.4%), trauma (5.1%), suicide (1.3%), and unknown (17.7%). A multivariable Cox proportional hazard model indicated baseline alcohol dependence (adjusted hazard ratio [aHR] 1.83, 95% CI 1.09-3.07, p = 0.02), and evidence of hepatic fibrosis (aHR 1.81, 95% CI 1.08-3.03, p = 0.02) were risk factors for mortality. Among those under age 55 years, a history of a psychotic disorder was a risk factor for mortality (aHR 2.38, 95% CI 1.03-5.51, p = 0.04, adjusted for alcohol dependence at baseline, human immunodeficiency virus [HIV], and hepatic fibrosis). The primary study limitation concerns generalizability: conclusions from a community-based, diagnostically heterogeneous sample may not apply to specific diagnostic groups in a clinical setting. Because one-third of participants grew up in foster care or were adopted, useful family history information was not obtainable. CONCLUSIONS: In this study, we found methamphetamine, alcohol, and cannabis use were associated with higher risk for psychotic features, as were a past history of psychotic disorder, and experiencing traumatic events. We found that alcohol dependence, hepatic fibrosis, and, only among participants <55 years of age, history of a psychotic disorder were associated with greater risk for mortality. Modifiable risk factors in people living in precarious housing or homelessness can be a focus for interventions.

Routine HIV testing in acute care hospitals: Changing practice to curb a local HIV epidemic in Vancouver, BC.

Early treatment of HIV infection increases life expectancy and reduces infectivity; however, delayed HIV diagnosis remains common. Implementation and sustainability of hospital-based routine HIV testing in Vancouver, British Columbia, was evaluated to address a local HIV epidemic by facilitating earlier diagnosis and treatment. Public health issued a recommendation in 2011 to offer HIV testing to all patients presenting to three Vancouver hospitals as part of routine care, including all patients admitted to medical/surgical units with expansion to emergency departments (ED). We evaluated acceptability, feasibility, and effectiveness from 2011 to 2014 and continued monitoring through 2016 for sustainability. Between October 2011-December 2016, 114,803 HIV tests were administered at the three hospitals; an 11-fold increase following implementation of routine testing. The rate of testing was sustained and remained high through 2018. Of those tested, 151 patients were diagnosed with HIV for a testing yield of 0.13%. Review of 12,996 charts demonstrated 4935/5876 (96·9%) of admitted patients agreed to have an HIV test when offered. People diagnosed in hospital were significantly more likely to be diagnosed with acute stage (aOR 1·96, 95% CI 1·19, 3·23) infection, particularly those diagnosed in the ED. This study provides practice-based evidence of the feasibility, acceptability, and effectiveness of implementing a recommendation for routine HIV testing among inpatient and emergency department admissions, as well as the ability to normalize and sustain this change. Routine hospital-based HIV testing can increase diagnoses of acute HIV infection and facilitate earlier initiation of antiretroviral treatment.

Impact of personality disorders on leaving hospital against medical advice among people living with HIV in British Columbia, Canada.

PURPOSE: Leaving hospital against medical advice (AMA) is a significant source of morbidity, mortality, and a major burden to the healthcare system. Studies have indicated that marginalized populations, including people living with HIV (PLHIV) and those living with a personality disorder (PD), experience high hospitalization rates. We sought to identify whether being diagnosed with a PD was associated with leaving hospital AMA among PLHIV in British Columbia (BC), Canada. METHODS: Data were derived from the STOP HIV/AIDS in BC cohort, a provincial-level linkage of a series of surveillance, laboratory, and health administrative databases of all identified PLHIV in BC. Using multivariable generalized estimating equations (GEE), we examined the relationship between diagnoses of PD and premature hospital discharge among PLHIV. RESULTS: Among 8763 PLHIV included in the study sample, 1321 (15%) were diagnosed with a PD. The prevalence of leaving hospital AMA at least once during the study period was 9%. In multivariable GEE analyses, after adjusting for a range of demographic and clinical confounders, there remained a positive association between being diagnosed with a PD and leaving hospital prematurely. Results showed a significant and independent association between a PD diagnosis and leaving AMA among PLHIV. CONCLUSIONS: These findings underscore the importance of identifying and addressing specific PD-related behaviour which negatively impact inpatient treatment completion among this subpopulation of PLHIV. Furthermore, these findings suggest a need to develop novel health system interventions to minimize AMA discharge among this population.

Correlates of opioid and benzodiazepine co-prescription among people living with HIV in British Columbia, Canada: A population-level cohort study.

BACKGROUND: Co-prescribing benzodiazepines and opioids is relatively contraindicated due to the possible overdose risk. However, people living with HIV (PLWH) may have concurrent psychiatric and/or chronic pain diagnoses that may lead to the use of opioids and/or benzodiazepines for symptomatic treatment. Consequently, some PLWH may be at-risk for the health harms associated with the co-prescribing of these medications. Given this, the objectives of this study were to first examine the prevalence of opioids and benzodiazepines co-prescribing, and second, to characterize patient factors associated with the co-prescribing of opioids and benzodiazepines among PLWH in British Columbia (BC), Canada. METHODS: Using data derived from a longitudinal BC cohort, we used bivariable and multivariable generalized estimating equation models to establish the prevalence of a benzodiazepine and opioid co-prescription and determine factors associated with this practice. RESULTS: Between 1996 and 2015, 14 484 PLWH were included in the study and were followed for the entire study period. At baseline, 548 people (4%) were co-prescribed opioids and benzodiazepines, 6593 (46%) were prescribed opioids only, 2887 (20%) were prescribed benzodiazepines only, and 4456 (31%) were prescribed neither medication. A total of 3835 (27%) participants were prescribed both medications at least once during the study period. Factors positively associated with concurrent opioid and benzodiazepine prescribing included: depression/mood disorder [adjusted odds ratio (AOR) = 1.32; 95% confidence interval (CI) = 1.22-1.43] and anxiety disorder (AOR = 1.45; 95% CI = 1.27-1.66), whereas female sex (AOR = 0.76; 95% CI = 0.64-0.91) and substance use disorder (SUD) (AOR = 0.82; 95% CI = 0.74-0.90) were negatively associated with the outcome. CONCLUSION: Our findings indicate that co-prescription of opioids and benzodiazepines was seen at some point during study follow-up in over a quarter of PLWH. Given the known risks associated with this prescribing practice, future research can focus on the outcomes of co-prescribing among this patient population and the development of strategies to reduce the co-prescribing of opioids and benzodiazepines.

Predicting Virological Response to HIV Treatment Over Time: A Tool for Settings With Different Definitions of Virological Response.

OBJECTIVE: Definitions of virological response vary from <50 up to 1000 copies of HIV-RNA/mL. Our previous models estimate the probability of HIV drug combinations reducing the viral load to <50 copies/mL, with no indication of whether higher thresholds of response may be achieved. Here, we describe the development of models that predict absolute viral load over time. METHODS: Two sets of random forest models were developed using 50,270 treatment change episodes from more than 20 countries. The models estimated viral load at different time points following the introduction of a new regimen from variables including baseline viral load, CD4 count, and treatment history. One set also used genotypes in their predictions. Independent data sets were used for evaluation. RESULTS: Both models achieved highly significant correlations between predicted and actual viral load changes (r = 0.67-0.68, mean absolute error of 0.73-0.74 log10 copies/mL). The models produced curves of virological response over time. Using failure definitions of <100, 400, or 1000 copies/mL, but not 50 copies/mL, both models were able to identify alternative regimens they predicted to be effective for the majority of cases where the new regimen prescribed in the clinic failed. CONCLUSIONS: These models could be useful for selecting the optimum combination therapy for patients requiring a change in therapy in settings using any definition of virological response. They also give an idea of the likely response curve over time. Given that genotypes are not required, these models could be a useful addition to the HIV-TRePS system for those in resource-limited settings.

Why Maximizing Quality-Adjusted Life Years, rather than Reducing HIV Incidence, Must Remain Our Objective in Addressing the HIV/AIDS Epidemic.

With efficacious behavioral, biomedical, and structural interventions available, combination implementation strategies are being implemented to combat HIV/AIDS across settings internationally. However, priority statements from national and international bodies make it unclear whether the objective should be the reduction in HIV incidence or the maximization of health, most commonly measured with quality-adjusted life years (QALYs). Building off a model-based evaluation of HIV care interventions in British Columbia, Canada, we compare the optimal sets of interventions that would be identified using HIV infections averted, and QALYs as the primary outcome in a cost-effectiveness analysis. We found an explicit focus on averting new infections undervalues the health benefits derived from antiretroviral therapy, resulting in suboptimal and potentially harmful funding recommendations.

Substance use patterns and HIV-1 RNA viral load rebound among HIV-positive illicit drug users in a Canadian setting.

BACKGROUND: Active illicit drug use can present a barrier to the medical management of HIV infection by complicating adherence to antiretroviral therapy (ART). Plasma HIV-1 RNA viral load (VL) rebound, defined as a period of detectable HIV VL following ART and VL suppression, can lead to the generation of viral resistance and potential treatment failure. We sought to investigate the contribution of substance use patterns on rates of VL rebound. METHODS: We used data from the ACCESS study, a long-running community-recruited prospective cohort of HIV-positive people who use illicit drugs in Vancouver, Canada, a setting of universal no-cost HIV treatment. We analysed time to VL rebound (that is, two consecutive observations ≥1,000 copies/ml) after ART initiation and sustained viral suppression (that is, two consecutive observations <50 copies/ml) using extended Cox regression models with a recurrent events framework. RESULTS: Between May 1996 and November 2013, 564 ART-exposed participants achieved at least one instance of VL suppression and contributed 1,893.8 person-years of observation. Over follow-up, 198 (35.1%) participants experienced ≥ one instance of VL rebound. In adjusted analyses, VL rebound was associated with younger age (adjusted hazard ratio [AHR] =0.97, 95% CI: 0.95, 0.98), heroin injection (≥ daily versus < daily, AHR =1.52, 95% CI: 1.01, 2.30), crack use (≥ daily versus < daily, AHR = 1.73, 95% CI: 1.08, 1.92) and heavy alcohol use (≥ four versus < four drinks/day, AHR =1.97, 95% CI: 1.17, 3.31). CONCLUSIONS: The present study suggests that in addition to heavy alcohol use, high-intensity illicit drug use, particularly ≥ daily heroin injection and ≥ daily crack smoking are risk factors for VL rebound. In addition to the impact of high-intensity drug use on health-care engagement and ART adherence, some evidence exists on the direct impact of psychoactive substances on ART metabolism and the natural progression of HIV disease. At-risk individuals should be provided additional supports to preserve virological control and maintain the benefits of ART.

Decreased microbiome diversity in the HIV small airway epithelium.

BACKGROUND: Persons living with human immunodeficiency virus (PLWH) face an increased burden of chronic obstructive pulmonary disease (COPD). Repeated pulmonary infections, antibiotic exposures, and immunosuppression may contribute to an altered small airway epithelium (SAE) microbiome. METHODS: SAE cells were collected from 28 PLWH and 48 HIV- controls through bronchoscopic cytologic brushings. DNA extracted from SAE cells was subjected to 16S rRNA amplification and sequencing. Comparisons of alpha and beta diversity between HIV+ and HIV- groups were performed and key operational taxonomic units (OTUs) distinguishing the two groups were identified using the Boruta feature selection after Random Forest Analysis. RESULTS: PLWH demonstrated significantly reduced Shannon diversity compared with HIV- volunteers (1.82 ± 0.10 vs. 2.20 ± 0.073, p = 0.0024). This was primarily driven by a reduction in bacterial richness (23.29 ± 2.75 for PLWH and 46.04 ± 3.716 for HIV-, p < 0.0001). Phyla distribution was significantly altered among PLWH, with an increase in relative abundance of Proteobacteria (p = 0.0003) and a decrease in Bacteroidetes (p = 0.0068) and Firmicutes (p = 0.0002). Six discriminative OTUs were found to distinguish PLWH from HIV- volunteers, aligning to Veillonellaceae, Fusobacterium, Verrucomicrobiaceae, Prevotella, Veillonella, and Campylobacter. CONCLUSIONS: Compared to HIV- controls, PLWH's SAE microbiome is marked by reduced bacterial diversity and richness with significant differences in community composition.

Decreased telomere length in the small airway epithelium suggests accelerated aging in the lungs of persons living with human immunodeficiency virus (HIV).

Human immunodeficiency virus (HIV) infection is associated with an increased risk of chronic obstructive pulmonary disease (COPD) independent of cigarette smoke exposure. Previous studies have demonstrated that decreased peripheral leukocyte telomere length is associated with HIV, suggesting an accelerated aging phenomenon. We demonstrate that this process of telomere shortening also occurs in the lungs, with significant decreases in telomere length observed in small airway epithelial cells collected during bronchoscopy. Molecular evidence of accelerated aging in the small airway epithelium of persons living with HIV may be one clue into the predisposition for chronic lung disease observed in this population.

HIV Serostatus and Having Access to a Physician for Regular Hepatitis C Virus Care Among People Who Inject Drugs.

BACKGROUND: People who inject drugs (PWIDs) and who are living with HIV and hepatitis C virus (HCV) infection are vulnerable to a range of health-related harms, including liver cirrhosis, hepatocellular carcinoma, and death. There is limited evidence describing how HIV serostatus shapes access to a physician for regular HCV care among PWID. SETTING: Data were collected through the Vancouver Injection Drug Users Study (VIDUS), the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS), and the At-Risk Youth Study (ARYS), 3 prospective cohorts involving people who use illicit drugs in Vancouver, Canada, between 2005 and 2015. METHODS: Using generalized estimating equations, we examined the relationship between HIV-seropositivity and having access to a physician for regular HCV care. We conducted a mediation analysis to examine whether this association was mediated by increased frequency of engagement in health care. RESULTS: In total, 1627 HCV-positive PWID were eligible for analysis; 582 (35.8%) were HIV-positive at baseline; and 31 (1.9%) became HIV-positive during follow-up. In multivariable analyses, after adjusting for a range of confounders, HIV serostatus [adjusted odds ratio = 1.99; 95% confidence interval: 1.77 to 2.24] was significantly associated with having access to HCV care. Approximately 26% of the effect was due to mediation. CONCLUSION: Our results demonstrate a positive relationship between HIV-seropositivity and having access to a physician for regular HCV care, which is partially explained through increased frequency of engagement in health care. These findings highlight the need to address patterns of inequality in access to HCV care among PWID.

Cannabis use is associated with lower rates of initiation of injection drug use among street-involved youth: A longitudinal analysis.

INTRODUCTION AND AIMS: Street-involved youth are known to be at elevated risk of initiating injection drug use. However, the impact of so-called 'gateway' drugs, such as cannabis, on injection initiation is unknown. The objective of this study was to examine the association between cannabis use and initiation of injection drug use among a prospective cohort of street-involved youth in Vancouver, Canada. DESIGN AND METHODS: Data for this study were collected from the At-Risk Youth Study. From September 2005 to May 2015, participants aged 14-26 who reported illicit drug use were recruited into this open prospective cohort study. An extended Cox regression model with time-updated covariates was used to identify factors independently associated with injection initiation. RESULTS: During the study period, 481 street-involved youth were included in this study. Of these, 228 (47.4%) reported at least daily cannabis use, and 103 (21.4%) initiated injection drug use. In a multivariable analysis, ≥daily cannabis use was associated with slower rates of injection initiation (adjusted relative hazard 0.66, 95% confidence interval 0.45-0.98; P = 0.038). Sub-analyses revealed that cannabis use was negatively associated with initiation of injection stimulants but not initiation of injection opioids. DISCUSSION AND CONCLUSIONS: Given the expansion of cannabis legalisation throughout North America, it is encouraging that cannabis use was associated with slower time to initiation of injection drug use in this cohort. This finding challenges the view of cannabis as a gateway substance that precipitates the progression to using harder and more addictive drugs.