Silvia Guillemi

Methadone maintenance therapy promotes initiation of antiretroviral therapy among injection drug users

AIMS Despite proven benefits of antiretroviral therapy (ART), many human immunodeficiency virus (HIV)-infected injection drug users (IDU) do not access treatment even in settings with free health care. We examined whether methadone maintenance therapy (MMT) increased initiation and adherence to ART among an IDU population with free health care. DESIGN We examined prospectively a cohort of opioid-using antiretroviral-naive HIV-infected IDU and investigated factors associated with initiation of antiretroviral therapy as well as subsequent adherence. Factors associated independently with time to first initiation of antiretroviral therapy were modelled using Cox proportional hazards regression. FINDINGS Between May 1996 and April 2008, 231 antiretroviral-naive HIV-infected opioid-using IDU were enrolled, among whom 152 (65.8%) initiated ART, for an incidence density of 30.5 [95% confidence interval (CI): 25.9-35.6] per 100 person-years. After adjustment for time-updated clinical characteristics and other potential confounders, use of MMT was associated independently with more rapid uptake of antiretroviral therapy [relative hazard = 1.62 (95% CI: 1.15-2.28); P = 0.006]. Those prescribed methadone also had higher rates of ART adherence after first antiretroviral initiation [odds ratio = 1.49 (95% CI: 1.07-2.08); P = 0.019]. CONCLUSION These results demonstrate that MMT contributes to more rapid initiation and subsequent adherence to ART among opioid-using HIV-infected IDU. Addressing international barriers to the use and availability of methadone may increase dramatically uptake of HIV treatment among this population.

Dose-response Effect of Incarceration Events on Nonadherence to HIV Antiretroviral Therapy Among Injection Drug Users

BACKGROUND Although some studies have identified impressive clinical gains for incarcerated HIV-seropositive injection drug users (IDUs) undergoing antiretroviral therapy (ART), the effect of incarceration on adherence to ART remains undetermined. METHODS We used data from a long-term community-recruited cohort of HIV-seropositive IDUs, including comprehensive ART dispensation records, in a setting where HIV care is free. We estimated the relationship between the cumulative burden of incarceration, measured longitudinally, and the odds of < 95% adherence to ART, with use of multivariate modeling. RESULTS From 1996 through 2008, 490 IDUs were recruited and contributed 2220 person-years of follow-up; 271 participants (55.3%) experienced an incarceration episode, with the number of incarcerations totaling 1156. In a multivariate model, incarceration had a strong dose-dependent effect on the likelihood of nonadherence to ART: 1-2 incarceration events (adjusted odds ratio [AOR], 1.49; 95% confidence interval [95% CI], 1.03-2.05), 3-5 events (AOR, 2.48; 95% CI, 1.62-3.65), and > 5 events (AOR, 3.11; 95% CI, 1.86-4.95). CONCLUSIONS Among HIV-seropositive IDUs receiving ART, an increasing burden of incarceration was associated with poorer adherence in a dose-dependent fashion. Our findings support improved adherence support for HIV-seropositive IDUs experiencing incarceration.

Homelessness as a Structural Barrier to Effective Antiretroviral Therapy Among HIV-Seropositive Illicit Drug Users in a Canadian Setting

Despite the advent of effective antiretroviral therapy (ART), HIV-seropositive injection drug users (IDU) continue to suffer from elevated levels of morbidity and mortality. Evidence is needed to identify social- and structural-level barriers to effective ART. We investigated the impact of homelessness on plasma HIV RNA response among illicit drug users initiating ART in a setting with free and universal access to HIV care. We accessed data from a long-running prospective cohort of community-recruited IDU linked to comprehensive HIV clinical monitoring and ART dispensation records. Using Cox proportional hazards with recurrent events modeling, we estimated the independent effect of homelessness on time to plasma HIV viral load suppression. Between May 1996 and September 2009, 247 antiretroviral naïve individuals initiated ART and contributed 1755 person-years of follow-up. Among these individuals, the incidence density of plasma HIV RNA suppression less than 500 copies/mm(3) was 56.7 (95% confidence interval [CI]: 46.9-66.0) per 100 person-years. In unadjusted analyses, homelessness was strongly associated with lower rates suppression (hazard ratio = 0.56, 95% CI: 0.40-0.78, p = 0.001), however, after adjustment for adherence this association was no longer significant (adjusted hazard ratio = 0.79, 95% CI: 0.56-1.11, p = 0.177). Homelessness poses a significant structural barrier to effective HIV treatment. However, since this relationship appears to be mediated by lower levels of ART adherence, interventions to improve adherence among members of this vulnerable population are needed.

Female gender predicts lower access and adherence to antiretroviral therapy in a setting of free healthcare

BackgroundBarriers to HIV treatment among injection drug users (IDU) are a major public health concern. However, there remain few long-term studies investigating key demographic and behavioral factors - and gender differences in particular - that may pose barriers to antiretroviral therapy (ART), especially in settings with universal healthcare. We evaluated access and adherence to ART in a long-term cohort of HIV-positive IDU in a setting where medical care and antiretroviral therapy are provided free of charge through a universal healthcare system.MethodsWe evaluated baseline antiretroviral use and subsequent adherence to ART among a Canadian cohort of HIV-positive IDU. We used generalized estimating equation logistic regression to evaluate factors associated with 95% adherence to antiretroviral therapy estimated based on prescription refill compliance.ResultsBetween May 1996 and April 2008, 545 IDU participants were followed for a median of 23.8 months (Inter-quartile range: 8.5 - 91.6), among whom 341 (63%) were male and 204 (37%) were female. Within the six-month period prior to the baseline interview, 133 (39%) men and 62 (30%) women were on ART (p = 0.042). After adjusting for clinical characteristics as well as drug use patterns measured longitudinally throughout follow-up, female gender was independently associated with a lower likelihood of being 95% adherent to ART (Odds Ratio [OR] = 0.70; 95% Confidence Interval: 0.53-0.93).ConclusionsDespite universal access to free HIV treatment and medical care, female IDU were less likely to access and adhere to antiretroviral therapy, a finding that was independent of drug use and clinical characteristics. These data suggest that interventions to improve access to HIV treatment among IDU must be tailored to address unique barriers to antiretroviral therapy faced by female IDU.

Social and Environmental Predictors of Plasma HIV RNA Rebound Among Injection Drug Users Treated With Antiretroviral Therapy

IntroductionEvidence is needed to improve HIV treatment outcomes for individuals who use injection drugs (IDU). Although studies have suggested higher rates of plasma viral load (PVL) rebound among IDU on antiretroviral therapy (ART), risk factors for rebound have not been thoroughly investigated. MethodsWe used data from a long-running community-recruited prospective cohort of IDU in Vancouver, Canada, linked to comprehensive ART and clinical monitoring records. Using proportional hazards methods, we modeled the time to confirmed PVL rebound above 1000 copies per milliliter among IDU on ART with sustained viral suppression, defined as 2 consecutive undetectable PVL measures. ResultsBetween 1996 and 2009, 277 individuals had sustained viral suppression. Over a median follow-up of 32 months, 125 participants (45.1%) experienced at least 1 episode of virologic failure for an incidence of 12.6 [95% confidence interval (CI): 10.5 to 15.0] per 100 person-years. In a multivariate model, PVL rebound was independently associated with sex-trade involvement [adjusted hazard ratio (AHR) = 1.40, 95% CI: 1.08 to 1.82) and recent incarceration (AHR = 1.83, 95% CI: 1.33 to 2.52). Methadone maintenance therapy (AHR = 0.79, 95% CI: 0.66 to 0.94) was protective. No measure of illicit drug use was predictive. ConclusionsIn this setting of free ART, several social and environmental factors predicted higher risks of viral rebound among IDU, including sex-trade involvement and incarceration. These findings should help inform efforts to identify individuals at risk of viral rebound and targeted interventions to treat and retain individuals in effective ART.

Young age predicts poor antiretroviral adherence and viral load suppression among injection drug users.

Previous studies of adherence to antiretroviral therapy (ART) for HIV among young injection drug users (IDU) have been limited because financial barriers to care disproportionately affect youth, thus confounding results. This study examines adherence among IDU in a unique setting where all medical care is provided free-of-charge. From May 1996 to April 2008, we followed a prospective cohort of 545 HIV-positive IDU of 18 years of age or older in Vancouver, Canada. Using generalized estimating equations (GEE), we studied the association between age and adherence (obtaining ART≥95% of the prescribed time), controlling for potential confounders. Using Cox proportional hazards regression, we also studied the effect of age on time to viral load suppression (<500 copies per milliliter), and examined adherence as a mediating variable. Five hundred forty-five participants were followed for a median of 23.8 months (interquartile range [IQR]=8.5-91.6 months). Odds of adherence were significantly lower among younger IDU (adjusted odds ratio [AOR]=0.76 per 10 years younger; 95% confidence interval [CI], 0.65-0.89). Younger IDU were also less likely to achieve viral load suppression (adjusted hazard ratio [AHR]=0.75 per 10 years younger; 95% CI, 0.64-0.88). Adding adherence to the model eliminated this association with age, supporting the role of adherence as a mediating variable. Despite absence of financial barriers, younger IDU remain less likely to adhere to ART, resulting in inferior viral load suppression. Interventions should carefully address the unique needs of young HIV-positive IDU.

Emergent drug resistance with integrase strand transfer inhibitor-based regimens

Objectives: To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs. Design: Retrospective cohort study. Methods: Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir or dolutegravir in British Columbia, Canada in 2012–2014 and were followed to 31 December 2015. Emergent resistance was defined as new mutations conferring intermediate-high level NRTI or INSTI resistance (score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1). First-year resistance rates and 95% confidence intervals (95% CI) were estimated for ‘any’ (INSTI or NRTI) resistance using Poisson regression. The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards. Results: There were 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons who were predominantly male (77%), antiretroviral therapy (ART)-experienced (81%), with low prevalence of preexisting drug resistance (16%). INSTI and NRTI resistance emerged in both ART-experienced and ART-naive persons (including dolutegravir-treated ART-naive), with no statistically significant differences in ‘any’ resistance rates (95% CI) between INSTIs: raltegravir 3.80 (1.90, 7.60), elvitegravir 2.37 (1.06, 5.27) and dolutegravir 1.48 (0.62, 3.55)/100 person-years. The strongest factors associated with emergent resistance were CD4+ less than 200 cells/&mgr;l, adjusted hazard ratio (95% CI) 10.46 (4.67, 23.41) and less than 80% adherence to the INSTI regimen hazard ratio 2.52 (1.11, 5.71). Conclusion: Incident drug resistance rates were low with ‘real-world’ use of INSTI-based regimens. However, incomplete ART adherence and low CD4+ cell count were associated with increased resistance rates regardless of which INSTI was prescribed. Provide adherence support and monitor for drug resistance.

Patterns of heroin and cocaine injection and plasma HIV-1 RNA suppression among a long-term cohort of injection drug users

BACKGROUND Previous studies suggest that active drug use may compromise HIV treatment among HIV-positive injection drug users (IDU). However, little is known about the differential impacts of cocaine injection, heroin injection, and combined cocaine and heroin injection on plasma HIV-1 RNA suppression. METHODS Data were derived from a longstanding open prospective cohort of HIV-positive IDU in Vancouver, Canada. Kaplan-Meier methods and Cox proportional hazards regression were used to examine the impacts of different drug use patterns on rates of plasma HIV-1 RNA suppression. RESULTS Between May 1996 and April 2008, 267 antiretroviral (ART) naïve participants were seen for a median follow-up duration of 50.6 months after initiating ART. The incidence density of HIV-1 RNA suppression was 65.2 (95%CI: 57.0-74.2) per 100 person-years. In Kaplan-Meier analyses, compared to those who abstained from injecting, individuals injecting heroin, cocaine, or combined heroin/cocaine at baseline were significantly less likely to achieve viral suppression (all p<0.01). However, none of the drug use categories remained associated with a reduced rate of viral suppression when considered as time-updated variables (all p>0.05). CONCLUSIONS Active injecting at the time of ART initiation was associated with lower plasma HIV-1 RNA suppression rates; however, there was no difference in suppression rates when drug use patterns were examined over time. These findings imply that adherence interventions for active injectors should optimally be applied at the time of ART initiation.

Absolute Leukocyte Telomere Length in HIV-Infected and Uninfected Individuals: Evidence of Accelerated Cell Senescence in HIV-Associated Chronic Obstructive Pulmonary Disease

Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT) imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p<0.001); however, the slopes of aTL vs. age were not different (p=0.469). Patients with longer known durations of HIV infection (p=0.019) and lower nadir CD4 cell counts (p=0.023) had shorter aTL. Shorter aTL were also associated with older age (p=0.026), smoking (p=0.005), reduced forced expiratory volume in one second (p=0.030), and worse CT emphysema severity score (p=0.049). HIV-infected subjects demonstrate advanced cellular aging, yet in a cART-treated cohort, the relationship between aTL and age appears no different from that of HIV-uninfected subjects.

Increased prevalence of controlled viremia and decreased rates of HIV drug resistance among HIV-positive people who use illicit drugs during a community-wide Treatment-as-Prevention initiative

BACKGROUND Although treatment-as prevention (TasP) is a new cornerstone of global human immunodeficiency virus (HIV)-AIDS strategies, its effect among HIV-positive people who use illicit drugs (PWUD) has yet to be evaluated. We sought to describe longitudinal trends in exposure to antiretroviral therapy (ART), plasma HIV-1 RNA viral load (VL) and HIV drug resistance during a community-wide TasP intervention. METHODS We used data from the AIDS Care Cohort to Evaluate Exposure to Survival Services study, a prospective cohort of HIV-positive PWUD linked to HIV clinical monitoring records. We estimated longitudinal changes in the proportion of individuals with VL <50 copies/mL and rates of HIV drug resistance using generalized estimating equations (GEE) and extended Cox models. RESULTS Between 1 January 2006 and 30 June 2014, 819 individuals were recruited and contributed 1 or more VL observation. During that time, the proportion of individuals with nondetectable VL increased from 28% to 63% (P < .001). In a multivariable GEE model, later year of observation was independently and positively associated with greater likelihood of nondetectable VL (adjusted odds ratio = 1.20 per year; P < .001). Although the proportion of individuals on ART increased, the incidence of HIV drug resistance declined (adjusted hazard ratio = 0.78 per year; P = .011). CONCLUSIONS We observed significant improvements in several measures of exposure to ART and virologic status, including declines in HIV drug resistance, in this large long-running community-recruited cohort of HIV-seropositive illicit drug users during a community-wide ART expansion intervention. Our findings support continued efforts to scale up ART coverage among HIV-positive PWUD.