Prevalence and Correlates of Reporting Difficulty Taking Antiretroviral Treatment Among HIV-Positive Illicit Drug Users in Vancouver, Canada: A Longitudinal Analysis.

People living with HIV who use illicit drugs continue to experience high rates of suboptimal treatment outcomes from antiretroviral therapy (ART). Although previous studies have identified important behavioural, social and structural barriers to ART adherence, the effects of patient-level factors have not been fully evaluated. Thus, we sought to investigate the prevalence and correlates of reporting ART was difficult to take among a cohort of illicit drug users in Vancouver, Canada. We accessed data from the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS), an ongoing prospective cohort of HIV-positive illicit drug users linked to comprehensive HIV clinical monitoring records. We used generalized linear mixed-effects modeling to identify factors longitudinally associated with periods in which individuals reported they found ART difficult to take. Between December 2005 and May 2014, 746 ART-exposed illicit drug users were recruited and contributed at least one study interview. Finding ART hard to take was reported by 209 (28.0%) participants at baseline, and 460 (61.7%) participants throughout the study period. Patients ingesting a greater daily pill count (adjusted odds ratio [AOR] = 1.12 per pill, 95% confidence interval [CI] 1.08-1.17) and experiencing barriers to healthcare (AOR = 1.64, 95% CI 1.34-2.01) were more likely to report difficulty taking ART. Patients less likely to report satisfaction with their HIV physician (AOR = 0.76, 95% CI 0.58-1.00) and achieve a non-detectable HIV viral load (AOR = 0.62, 95% CI 0.51-0.74) were more likely to report finding ART hard to take. In this community-recruited cohort of ART-exposed illicit drug users, a substantial proportion reported they found HIV treatment hard to take, which was clearly linked to higher dissatisfaction with healthcare experiences and, most importantly, a lower likelihood of experiencing optimal virologic outcomes. Our findings reveal a number of opportunities to improve HIV treatment experiences and outcomes for people who use illicit drugs, including the use of treatment regimens with lower pill burdens, as well as reducing barriers to healthcare access.

Drug use and phylogenetic clustering of hepatitis C virus infection among people who use drugs in Vancouver, Canada: A latent class analysis approach.

This study estimated latent classes (ie, unobserved subgroups in a population) of people who use drugs in Vancouver, Canada, and examined how these classes relate to phylogenetic clustering of hepatitis C virus (HCV) infection. HCV antibody-positive people who use drugs from two cohorts in Vancouver, Canada (1996-2012), with a Core-E2 sequence were included. Time-stamped phylogenetic trees were inferred, and phylogenetic clustering was determined by time to most common recent ancestor. Latent classes were estimated, and the association with the phylogenetic clustering outcome was assessed using an inclusive classify/analyse approach. Among 699 HCV RNA-positive participants (26% female, 24% HIV+), recent drug use included injecting cocaine (80%), injecting heroin (70%), injecting cocaine/heroin (ie, speedball, 38%) and crack cocaine smoking (28%). Latent class analysis identified four distinct subgroups of drug use typologies: (i) cocaine injecting, (ii) opioid and cocaine injecting, (iii) crack cocaine smoking and (iv) heroin injecting and currently receiving opioid substitution therapy. After adjusting for age and HIV infection, compared to the group defined by heroin injecting and currently receiving opioid substitution therapy, the odds of phylogenetic cluster membership was greater in the cocaine injecting group (adjusted OR [aOR]: 3.06; 95% CI: 1.73, 5.42) and lower in the crack cocaine smoking group (aOR: 0.06; 95% CI: 0.01, 0.48). Combining latent class and phylogenetic clustering analyses provides novel insights into the complex dynamics of HCV transmission. Incorporating differing risk profiles associated with drug use may provide opportunities to further optimize and target HCV treatment and prevention strategies.

A single untimed plasma drug concentration measurement during low-level HIV viremia predicts virologic failure.

Suboptimal untimed plasma drug levels (UDL) have been associated with lower rates of virologic suppression and the emergence of drug resistance. Our aim was to evaluate whether UDL among patients with low-level viremia (LLV) while receiving highly active antiretroviral therapy (HAART) can predict subsequent virologic failure (plasma viral load ≥1000 copies/mL) and emergence of resistance. The first documented LLV episode of 328 consenting patients was analysed in terms of drug levels, viral load and resistance, which were monitored while patients were on a consistent HAART regimen. UDL of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), were categorized as 'therapeutic' or 'subtherapeutic' based on predefined target trough concentrations. Drug resistance genotype was assessed using the Stanford algorithm. Time to virologic failure was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. We found 78 of 328 patients (24%) with subtherapeutic drug levels at time of first detectable LLV, while 19% harboured drug-resistant virus. Both subtherapeutic UDL and drug resistance independently increased the risk of subsequent virologic failure (p <0.001 and p 0.04, respectively). In a multivariable model, variables associated with LLV and virologic failure included subtherapeutic UDL, elevated plasma viral load, and drug resistance. Patients with subtherapeutic UDL accumulated further drug resistance faster during follow-up (p 0.03). Together, resistance and UDL variables can explain a higher proportion of virologic failure than either measure alone. Our results support further prospective evaluation of UDL in the management of low-level viremia.

Cancer incidence among HIV-positive women in British Columbia, Canada: Heightened risk of virus-related malignancies.

OBJECTIVES: We used population-based data to identify incident cancer cases and correlates of cancer among women living with HIV/AIDS in British Columbia (BC), Canada between 1994 and 2008. METHODS: Data were obtained from a retrospective population-based cohort created from linkage of two province-wide databases: (1) the database of the BC Cancer Agency, a province-wide population-based cancer registry, and (2) a database managed by the BC Centre for Excellence in HIV/AIDS, which contains data on all persons treated with antiretroviral therapy in BC. This analysis included women (≥ 19 years old) living with HIV in BC, Canada. Incident cancer diagnoses that occurred after highly active antiretroviral therapy (HAART) initiation were included. We obtained a general population comparison of cancer incidence among women from the BC Cancer Agency. Bivariate analysis (Pearson χ(2) , Fisher's exact or Wilcoxon rank-sum test) compared women with and without incident cancer across relevant clinical and sociodemographic variables. Standardized incidence ratios (SIRs) were calculated for selected cancers compared with the general population sample. RESULTS: We identified 2211 women with 12 529 person-years (PY) of follow-up who were at risk of developing cancer after HAART initiation. A total of 77 incident cancers (615/100 000 PY) were identified between 1994 and 2008. HIV-positive women with cancer, in comparison to the general population sample, were more likely to be diagnosed with invasive cervical cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma and Kaposi's sarcoma and less likely to be diagnosed with cancers of the digestive system. CONCLUSIONS: This study observed elevated rates of cancer among HIV-positive women compared to a general population sample. HIV-positive women may have an increased risk for cancers of viral-related pathogenesis.

Non-HIV-related health care utilization, demographic, clinical and laboratory factors associated with time to initial retention in HIV care among HIV-positive individuals linked to HIV care.

OBJECTIVES: The aim of the study was to explore non-HIV-related health care service (NHRHS) utilization, demographic, clinical and laboratory factors associated with timely initial "retention" in HIV care among individuals "linked" to HIV care in British Columbia (BC), Canada. METHODS: We conducted a Weibull time-to-initial-retention analysis among BC Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) cohort participants linked in 2000-2010, who had ≥ 1 year of follow-up. We defined "linked" as the first HIV-related service accessed following HIV diagnosis and "retained" as having, within a calendar year, either: (i) at least two HIV-related physician visits/diagnostic tests or (ii) at least two antiretroviral therapy (ART) dispensations, ≥ 3 months apart. Individuals were followed until they were retained, died, their last contact date, or until 31 December 2011, whichever occurred first. RESULTS: Of 5231 linked individuals (78% male; median age 39: (Q1-Q3: 32-46) years], 4691 (90%) were retained [median time to initial retention of 9 (Q1-Q3: 5-13) months] by the end of follow-up and 540 (10%) were not. Eighty-four per cent of not retained and 96% of retained individuals used at least one type of NHRHS during follow-up. Individuals who saw a specialist for NHRHS during follow-up had a shorter time to initial retention than those who did not [adjusted hazard ratio (aHR) 2.79; 95% confidence interval (CI): 2.47-3.16]. However, those who saw a general practitioner (GP) for NHRHS (aHR 0.79; 95% CI: 0.74-0.84) and those admitted to the hospital for NHRHS (aHR 0.60; 95% CI: 0.54-0.67), versus those who did/were not, respectively, had longer times to initial retention, as did female patients, people who inject drugs (PWID) and individuals < 40 years old. CONCLUSIONS: Overall, 84% of not retained individuals used some type of NHRHS during follow-up. Given that 71% of not retained individuals used GP NHRHS, our results suggest that GP-targeted interventions may be effective in improving time to initial retention.

The 'Expanded HIV care in opioid substitution treatment' (EHOST) cluster-randomized, stepped-wedge trial: A study protocol.

The public health response to HIV/AIDS has turned its focus onto optimizing health care system delivery to maximize case identification, access and sustained engagement in antiretroviral treatment (ART). Opioid Agonist Treatment (OAT) provides a critical opportunity for HIV testing and linkage to ART. The EHOST study is a cluster-randomized, stepped-wedge trial to evaluate a prescriber-focused intervention to increase HIV testing rates, and optimize ART engagement and retention outcomes among individuals engaged in OAT. The study will encompass all drug treatment clinics currently admitting patients for the treatment of opioid use disorder across the province of British Columbia, encompassing an estimated 90% of the OAT caseload. The trial will be executed over a 24-month period, with groups of clinics receiving the intervention in 6-month intervals. Evaluation of the proposed intervention's effectiveness will focus on three primary outcomes: (i) the HIV testing rate among those not known to be HIV positive; (ii) the rate of ART initiation among those not on ART; and (iii) the rate of ART continuation among those on ART. A difference-in-differences analytical framework will be applied to estimate the intervention's effect. This approach will assess site-specific changes in primary outcomes across clusters while adjusting for potential residual heterogeneity in patient case mix, volume, and quality of care across clinics. Statistical analysis of outcomes will be conducted entirely with linked population-level administrative health datasets. Facilitated by established collaborations between key stakeholders across the province, the EHOST intervention promises to optimize HIV testing and care within a marginalized and hard-to-reach population.

Social and Structural Factors Shaping High Rates of Incarceration among Sex Workers in a Canadian Setting.

In light of the emphasis on enforcement-based approaches towards sex work, and the well-known negative impacts of these approaches on women's health, safety and well-being, we conducted a study to investigate the prevalence and correlates of recent incarceration among a cohort of women sex workers in Vancouver, Canada. Data were obtained from an open prospective community cohort of female and transgender women sex workers, known as An Evaluation of Sex Workers' Health Access (AESHA). Bivariate and multivariable logistic regression analyses, using generalized estimating equations (GEE), were used to model the effect of social and structural factors on the likelihood of incarceration over the 44-month follow-up period (January 2010-August 2013). Among 720 sex workers, 62.5 % (n = 450) reported being incarcerated in their lifetime and 23.9 % (n = 172) being incarcerated at least once during the study period. Of the 172 participants, about one third (36.6 %) reported multiple episodes of incarceration. In multivariable GEE analyses, younger age (adjusted odds ratio [AOR] = 1.04 per year younger, 95 % confidence interval [CI] 1.02-1.06), being of a sexual/gender minority (AOR = 1.62, 95 % CI 1.13-2.34), heavy drinking (AOR = 1.99, 95 % CI 1.20-3.29), being born in Canada (AOR = 3.28, 95 % CI 1.26-8.53), living in unstable housing conditions (AOR = 4.32, 95 % CI 2.17-8.62), servicing clients in public spaces (versus formal sex work establishments) (AOR = 2.33, 95 % CI 1.05-5.17) and experiencing police harassment without arrest (AOR = 1.82, 95 % CI 1.35-2.45) remain independently correlated with incarceration. This prospective study found a very high prevalence and frequency of incarceration among women sex workers in Vancouver, Canada, with the most vulnerable and marginalized women at increased risk of incarceration. Given the well-known social and health harms associated with incarceration, and associations between police harassment and incarceration in this study, our findings further add to growing calls to move away from criminalized and enforcement-based approaches to sex work in Canada and globally.

Predictors of unstructured antiretroviral treatment interruption and resumption among HIV-positive individuals in Canada.

OBJECTIVES: Sustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration. METHODS: cART-naïve individuals ≥ 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as ≥ 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI. RESULTS: A total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count ≥ 350 vs. <200 cells/µL: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/µL at cART initiation. CONCLUSIONS: Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART.

Successes and gaps in uptake of regular, voluntary HIV testing for hidden street- and off-street sex workers in Vancouver, Canada.

Despite evidence globally of the heavy HIV burden among sex workers (SWs) as well as other poor health outcomes, including violence, SWs are often excluded from accessing voluntary, confidential and non-coercive health services, including HIV prevention, treatment, care and support. This study therefore assessed the prevalence and association with regular HIV testing among street- and off-street SWs in Vancouver, Canada. Cross-sectional baseline data were used from a longitudinal cohort known as "An Evaluation of Sex Worker's Health Access" (AESHA; January 2010-July 2012). This cohort included youth and adult SWs (aged 14+ years). We used multivariable logistic regression to assess the relationship between explanatory variables and having a recent HIV test (in the last year). Of the 435 seronegative SWs included, 67.1% reported having a recent HIV test. In multivariable logistic regression analysis, having a recent HIV test remained significantly independently associated with elevated odds of inconsistent condom use with clients [adjusted (multivariable) odds ratios, AOR: 2.59, 95% confidence intervals [95% CIs]: 1.17-5.78], injecting drugs (AOR: 2.33, 95% CIs: 1.17-4.18) and contact with a mobile HIV prevention programme (AOR: 1.76, 95% CIs: 1.09-2.84) within the last six months. Reduced odds of having a recent HIV test was also significantly associated with being a migrant/new immigrant to Canada (AOR: 0.33, 95% CIs: 0.19-0.56) and having a language barrier to health care access (AOR: 0.26, 95% CIs: 0.09-0.73). Our results highlight successes of reaching SWs at high risk of HIV through drug and sexual pathways. To maximize the effectiveness of including HIV testing as part of comprehensive HIV prevention and care to SWs, increased mobile outreach and safer-environment interventions that facilitate access to voluntary, confidential and non-coercive HIV testing remain a critical priority, in addition to culturally safe services with language support.

Cost-effectiveness analysis along the continuum of HIV care: how can we optimize the effect of HIV treatment as prevention programs?

The cascade of HIV care has been proposed as a useful tool to monitor health system performance across the key stages of HIV care delivery to reduce morbidity, mortality, and HIV transmission, the focal points of HIV Treatment as Prevention campaigns. Interventions to improve the cascade at its various stages may vary substantially in their ability to deliver health value per amount expended. In order to meet global antiretroviral treatment access targets, there is an urgent need to maximize the value of health spending by prioritizing cost-effective interventions. We executed a literature review on economic evaluations of interventions to improve specific stages of the cascade of HIV care. In total, 33 articles met the criteria for inclusion in the review, 22 (67 %) of which were published within the last 5 years. Nonetheless, substantial gaps in our knowledge remain, particularly for interventions to improve linkage and retention in HIV care in developed and developing-world settings and generalized and concentrated epidemics. We make the case here that the attention of scientists and policymakers needs to turn to the development, implementation, and rigorous evaluation of interventions to improve the various stages of the cascade of HIV care.

Criminalisation of clients: reproducing vulnerabilities for violence and poor health among street-based sex workers in Canada-a qualitative study.

OBJECTIVES: To explore how criminalisation and policing of sex buyers (clients) rather than sex workers shapes sex workers' working conditions and sexual transactions including risk of violence and HIV/sexually transmitted infections (STIs). DESIGN: Qualitative and ethnographic study triangulated with sex work-related violence prevalence data and publicly available police statistics. SETTING: Vancouver, Canada, provides a unique opportunity to evaluate the impact of policies that criminalise clients as the local police department adopted a sex work enforcement policy in January 2013 that prioritises sex workers' safety over arrest, while continuing to target clients. PARTICIPANTS: 26 cisgender and 5 transgender women who were street-based sex workers (n=31) participated in semistructured interviews about their working conditions. All had exchanged sex for money in the previous 30 days in Vancouver. OUTCOME MEASURES: Thematic analysis of interview transcripts and ethnographic field notes focused on how police enforcement of clients shaped sex workers' working conditions and sexual transactions, including risk of violence and HIV/STIs, over an 11-month period postpolicy implementation (January-November 2013). RESULTS: Sex workers' narratives and ethnographic observations indicated that while police sustained a high level of visibility, they eased charging or arresting sex workers and showed increased concern for their safety. However, participants' accounts and police statistics indicated continued police enforcement of clients. This profoundly impacted the safety strategies sex workers employed. Sex workers continued to mistrust police, had to rush screening clients and were displaced to outlying areas with increased risks of violence, including being forced to engage in unprotected sex. CONCLUSIONS: These findings suggest that criminalisation and policing strategies that target clients reproduce the harms created by the criminalisation of sex work, in particular, vulnerability to violence and HIV/STIs. The current findings support decriminalisation of sex work to ensure work conditions that support the health and safety of sex workers in Canada and globally.

A comparison of computational models with and without genotyping for prediction of response to second-line HIV therapy.

OBJECTIVES: We compared the use of computational models developed with and without HIV genotype vs. genotyping itself to predict effective regimens for patients experiencing first-line virological failure. METHODS: Two sets of models predicted virological response for 99 three-drug regimens for patients on a failing regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and one nonnucleoside reverse transcriptase inhibitor in the Second-Line study. One set used viral load, CD4 count, genotype, plus treatment history and time to follow-up to make its predictions; the second set did not include genotype. Genotypic sensitivity scores were derived and the ranking of the alternative regimens compared with those of the models. The accuracy of the models and that of genotyping as predictors of the virological responses to second-line regimens were compared. RESULTS: The rankings of alternative regimens by the two sets of models were significantly correlated in 60-69% of cases, and the rankings by the models that use a genotype and genotyping itself were significantly correlated in 60% of cases. The two sets of models identified alternative regimens that were predicted to be effective in 97% and 100% of cases, respectively. The area under the receiver-operating curve was 0.72 and 0.74 for the two sets of models, respectively, and significantly lower at 0.55 for genotyping. CONCLUSIONS: The two sets of models performed comparably well and significantly outperformed genotyping as predictors of response. The models identified alternative regimens predicted to be effective in almost all cases. It is encouraging that models that do not require a genotype were able to predict responses to common second-line therapies in settings where genotyping is unavailable.

Modelling clinical progression and health care utilization of HIV-positive patients in British Columbia prior to death.

OBJECTIVES: The extent to which clinical progression of HIV-positive patients leads to an increase in health care utilization, especially prior to their death, is unknown. Thus, we modelled trends in CD4 cell count and emergency department utilization and the likelihood of an emergency department visit leading to a transfer to an acute care-level facility prior to a patient's death from nonaccidental causes. METHODS: Eligible patients initiated highly active antiretroviral therapy (HAART) in British Columbia between August 1996 and June 2006 (n = 457). Patients were followed until their death, which occurred on or before 30 June 2007 (period in which the emergency department visit data were available). Trends were modelled using generalized mixed effects. RESULTS: Patients experienced a significantly steep decline in CD4 cell count and a corresponding increase in the number of emergency department visits and transfers to acute-level facilities in the 5 years prior to death. For every 6-month interval prior to death, the CD4 cell count decreased by 13.22 cells/µL, the risk of experiencing an emergency department visit increased by 9%, and among those ever admitted, the odds ratio of being transferred to an acute care-level facility increased by 3%. CONCLUSIONS: We showed that patients experienced a steep decline in CD4 cell count, which was associated with an increase in health care utilization prior to their death. These findings highlight the substantial residual avoidable burden that unsuccessfully managed HIV disease poses, even in the HAART era. Further strategies to enhance sustained and successful engagement in care are urgently needed to mitigate high health care utilization.

Performance of HIV-1 drug resistance testing at low-level viremia and its ability to predict future virologic outcomes and viral evolution in treatment-naive individuals.

BACKGROUND: Low-level viremia (LLV; human immunodeficiency virus [HIV-1] RNA 50-999 copies/mL) occurs frequently in patients receiving antiretroviral therapy (ART), but there are few or no data available demonstrating that HIV-1 drug resistance testing at a plasma viral load (pVL) <1000 copies/mL provides potentially clinically useful information. Here, we assess the ability to perform resistance testing by genotyping at LLV and whether it is predictive of future virologic outcomes in patients beginning ART. METHODS: Resistance testing by genotyping at LLV was attempted on 4915 plasma samples from 2492 patients. A subset of previously ART-naive patients was analyzed who achieved undetectable pVL and subsequently rebounded with LLV (n = 212). A genotypic sensitivity score (GSS) was calculated based on therapy and resistance testing results by genotyping, and stratified according to number of active drugs. RESULTS: Eighty-eight percent of LLV resistance assays produced useable sequences, with higher success at higher pVL. Overall, 16 of 212 (8%) patients had pretherapy resistance. Thirty-eight of 196 (19%) patients without pretherapy resistance evolved resistance to 1 or more drug classes, primarily the nucleoside reverse transcriptase (14%) and/or nonnucleoside reverse transcriptase (9%) inhibitors. Patients with resistance at LLV (GSS <3) had a 2.1-fold higher risk of virologic failure (95% confidence interval, 1.2- to 3.7-fold) than those without resistance (P = .007). Progressively lower GSS scores at LLV were associated with a higher increase in pVL over time (P < .001). Acquisition of additional resistance mutations to a new class of antiretroviral drugs during LLV was not found in a subset of patients. CONCLUSIONS: Routine HIV-1 genotyping of LLV samples can be performed with a reasonably high success rate, and the results appear predictive of future virologic outcomes.

Characteristics and determinants of T-cell phenotype normalization in HIV-1-infected individuals receiving long-term antiretroviral therapy.

OBJECTIVES: Although combination antiretroviral therapy (cART) can restore CD4 T-cell numbers in HIV infection, alterations in T-cell regulation and homeostasis persist. We assessed the incidence and predictors of reversing these alterations with cART. METHODS: ART-naïve adults (n = 4459) followed within the Canadian Observational Cohort and exhibiting an abnormal T-cell phenotype (TCP) prior to cART initiation were studied. Abnormal TCP was defined as having (1) a low CD4 T-cell count (< 532 cells/µL), (2) lost T-cell homeostasis (CD3 < 65% or > 85%) or (3) CD4:CD8 ratio dysregulation (ratio < 1.2). To thoroughly evaluate the TCP, CD4 and CD8 T-cell percentages and absolute counts were also analysed for a median duration of 3.14 years [interquartile range (IQR) 1.48-5.47 years]. Predictors of TCP normalization were assessed using adjusted Cox proportional hazards models. RESULTS: At baseline, 96% of pateints had CD4 depletion, 32% had lost homeostasis and 99% exhibited ratio dysregulation. With treatment, a third of patients had normalized CD4 T-cell counts, but only 85 individuals (2%) had normalized their TCP. In a multivariable model adjusted for age, measurement frequency and baseline regimen, higher baseline CD4 T-cell counts and time-dependent viral suppression independently predicted TCP normalization [hazard ratio (HR) for baseline CD4 T-cell count = 1.42 (1.31-1.54) per 100 cells/µL increase; P ≤ 0.0001; HR for time-dependent suppressed viral load = 3.69 (1.58-8.61); P-value ≤ 0.01]. CONCLUSIONS: Despite effective cART, complete TCP recovery occurred in very few individuals and was associated with baseline CD4 T-cell count and viral load suppression. HIV-induced alterations of the TCP are incompletely reversed by long-term ART.

Computational models can predict response to HIV therapy without a genotype and may reduce treatment failure in different resource-limited settings.

OBJECTIVES: Genotypic HIV drug-resistance testing is typically 60%-65% predictive of response to combination antiretroviral therapy (ART) and is valuable for guiding treatment changes. Genotyping is unavailable in many resource-limited settings (RLSs). We aimed to develop models that can predict response to ART without a genotype and evaluated their potential as a treatment support tool in RLSs. METHODS: Random forest models were trained to predict the probability of response to ART (≤400 copies HIV RNA/mL) using the following data from 14 891 treatment change episodes (TCEs) after virological failure, from well-resourced countries: viral load and CD4 count prior to treatment change, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. Models were assessed by cross-validation during development, with an independent set of 800 cases from well-resourced countries, plus 231 cases from Southern Africa, 206 from India and 375 from Romania. The area under the receiver operating characteristic curve (AUC) was the main outcome measure. RESULTS: The models achieved an AUC of 0.74-0.81 during cross-validation and 0.76-0.77 with the 800 test TCEs. They achieved AUCs of 0.58-0.65 (Southern Africa), 0.63 (India) and 0.70 (Romania). Models were more accurate for data from the well-resourced countries than for cases from Southern Africa and India (P < 0.001), but not Romania. The models identified alternative, available drug regimens predicted to result in virological response for 94% of virological failures in Southern Africa, 99% of those in India and 93% of those in Romania. CONCLUSIONS: We developed computational models that predict virological response to ART without a genotype with comparable accuracy to genotyping with rule-based interpretation. These models have the potential to help optimize antiretroviral therapy for patients in RLSs where genotyping is not generally available.

Relationship of chronic hepatitis C infection to rates of AIDS-defining illnesses in a Canadian cohort of HIV seropositive individuals receiving highly active antiretroviral therapy.

BACKGROUND: The influence of chronic hepatitis C virus (HCV) infection on the risk, timing, and type of AIDS-defining illnesses (ADIs) is not well described. To this end, rates of ADIs were evaluated in a Canadian cohort of HIV seropositive individuals receiving highly active antiretroviral therapy (HAART). METHODS: ADIs were classified into 6 Centers for Disease Control and Prevention (CDC)-defined etiological subgroups: non-Hodgkin lymphoma, viral infection, bacterial infection, HIV-related disease, protozoal infection, and mycotic infection. Generalized estimating equation (GEE) Poisson regression models were used to estimate the effect of HCV on rates of ADIs after adjusting for covariates. RESULTS: Among 2,706 HAART recipients, 768 (28%) were HCV coinfected. Rates of all ADIs combined and of bacterial infection, HIV-related disease, and mycotic infection were increased in HCV-coinfected persons and among those with CD4 counts <200 cells/mm3 HCV was associated with an increased risk of ADIs (rate ratio [RR], 1.38; 95% CI, 1.01-1.88) and a 2-fold increased risk of mycotic infections (RR, 2.21; 95% CI, 1.35-3.62) in univariate analyses and after adjusting for age, baseline viral load, baseline CD4 count, and region of Canada. However, after further adjustment for HAART interruptions, HCV was no longer associated with an increased rate of ADIs overall (RR, 1.13; 95% CI, 0.80-1.59), but remained associated with an increased rate of mycotic infections (RR, 1.97, 95% CI, 1.08-3.61). CONCLUSION: Although HCV coin-fected individuals are at increased risk of developing ADIs overall, our analysis suggests that behavioral variables associated with HCV (including rates of retention on HAART), and not biological interactions with HCV itself, are primarily responsible.

Increases in the availability of prescribed opioids in a Canadian setting.

BACKGROUND: The nonmedical use of prescribed opioids (POs) has increased across North America over the past decade. Our objective was to identify changes in the availability of POs and other illicit drugs among drug users in a Canadian setting. METHODS: Information on the availability of illicit drugs was collected in standardized interviews from a large observational research program involving illicit drug users in Vancouver, British Columbia from 2006 to 2010. The primary outcome was the perceived availability of a set of six POs (aspirin/oxycodone, hydromorphone, oxycodone, morphine, acetaminophen/codeine and methadone) among individuals reporting ever using POs. Availability was measured in three levels: not available, delayed availability (available ≥10 min), and immediate availability (available <10 min). Multivariate ordinal logistic regression models were executed to estimate the trend in PO availability, controlling for individual characteristics hypothesized to influence availability. RESULTS: 1871 individuals were followed during the study period (2006-2010), including 583 (31.2%) women. The availability of POs increased over time, regardless of changes in the characteristics of cohort entrants. These increases were observed while the availability of traditional drugs of abuse (e.g., heroin and cocaine) remained constant. The adjusted odds of delayed availability vs. unavailability were between 34% (hydromorphone) and 71% (acetaminophen/codeine) greater in each calendar year. DISCUSSION: The availability of POs among drug users in a Canadian setting increased markedly over a relatively short timeframe, despite persistent and high availability of heroin and cocaine. Further study is required to determine the context of use of POs, associated harms, as well as policy responses to increasing availability.