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Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV coinfected patients
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active IDU associated with immune activation.....current IDUs are at even greater risk for immune activation & inflammation & onset for & perhaps early, accelerated & premature comorbidities
Understanding the Relative Contributions of IDU and HCV on Systemic Immune Activation...... .....HCV should be aggressively treated in current IDUs even more if HIV and/or HCV positive - (04/4/16)
"aim of this study was to examine the association between injection cocaine use and chronic renal impairment (CRI) among HIV-HCV coinfected patients receiving clinical care.......Cocaine itself has been associated with rhabdomyolysis and acute kidney injury, and is a known nephropathic drug....It is estimated that 5-11% of people living with HIV have mild to moderately reduced kidney function....In conclusion, we found evidence to suggest that cumulative exposure and frequent cocaine use are associated with CRI progression among HIV-HCV coinfected patients. The role of substance use in contributing to renal disease in coinfection has been underappreciated and should be taken into consideration when evaluating impaired renal function in this setting.
injection cocaine increased the risk of CRI, independent of chronic HCV infection, ART use, and other traditional kidney disease risk factors. Furthermore, frequent injection cocaine use of three or more times per week was associated with rapid progression to CRI. We also found that regular use of injection cocaine was associated with CRI progression. Relative effect estimates for cocaine use in this analysis were large. For example, past injection cocaine use was associated with an approximately two-fold greater risk of prevalent CRI. Similar associations were also observed for frequent and cumulative injection and noninjection cocaine in the incident cohort. We also found important clinical differences in annual rates of change in eGFR between injection cocaine users and nonusers. Given that the prevalence of injection drug use in this population is high, cocaine use may be an important modifiable risk factor for CKD among coinfected patients [22]. These results support that screening guidelines for CKD among HIV-infected populations should be expanded to include cocaine users as a high-risk group for kidney disease, as has previously been suggested [34,35].
Consistent with findings from an assessment of the effect of cumulative ART exposure, past use of lopinavir and atazanavir, two protease inhibitors, and current atazanavir use were also associated with CRI in this study.....Increasing age, female sex, past tenofovir, lopinavir, and atazanavir use were also associated with CRI in the multivariate analysis
Cocaine is known to have strong vasoconstrictive effects on smooth muscle tissue, which may accelerate hypertensive nephrosclerosis. Furthermore, kidney epithelial cells exposed to cocaine experienced a reduction in intracellular glutathione, an antioxidant and important component of cellular homeostasis, increasing oxidative stress, and may reduce normal kidney function [24]. Results of our analysis were appreciably similar for noninjection cocaine use, suggesting the nephropathic potential of cocaine is drug-specific and not related to route of administration.
Overall, most participants had initially healthy kidney function, with a median eGFR of 104 ml/min per 1.73 m2 (IQR 94, 112). Two hundred and eighty-seven participants (27%) reported recent injection cocaine use in the past 6 months prior to the index visit. Of these, 61 participants (21%) reported using injection cocaine on average of at least 3 days/week. Four hundred and twenty participants (40%) reported using injection cocaine at least once during follow-up. Compared to those participants who did not develop CRI, those with CRI were older, more likely to be women, had a lower income and CD4+ cell count, were more likely to be on atazanavir or lopinavir-based regimens, and were more likely to have hypertension and ESLD.
The median eGFR of those at the time of CRI was 63 ml/min per 1.73 m2 (IQR 57, 67). The majority of patients with CRI (89%) never recovered eGFR above 70 ml/min per 1.73 m2 and 42% progressed to eGFR below 60 ml/min per 1.73 m2."
Depression and Social Isolation Mediate Effect of HIV Stigma on Women's ART Adherence - (02/26/16)....."findings suggest that potential predictors of adherence may operate differently by race.....contribute to our understanding of different rates of adherence and health outcomes by race among women living with HIV.....also suggest that interconnected psychosocial mechanisms affect ART adherence.....internalized stigma was a significant predictor of sub-optimal adherence
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Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV coinfected patients
AIDS June 1 2016
Rossi, Carmine; Cox, Joseph; Cooper, Curtis; Martel-Laferrière, Valerie; Walmsley, Sharon; Gill, John; Sapir-Pichhadze, Ruth; Moodie, Erica E.M.; Klein, Marina B.; for the Canadian Co-infection Cohort Investigators
aMcGill University, Department of Epidemiology, Biostatistics and Occupational Health, Montreal, Quebec
bThe Ottawa Hospital-General Campus, Ottawa, Ontario
cCentre Hospitalier de l'Universite de Montreal - Notre-Dame, Montreal, Quebec
dUniversity Health Network, University of Toronto, Toronto, Ontario
eSouthern Alberta HIV Clinic, Calgary, Alberta
fMcGill University, Division of Nephrology and Multi-Organ Transplant Program, Department of Medicine, Montreal, Quebec
gChronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada.
Abstract
Objective: To examine the association between injection cocaine use, hepatitis C virus (HCV) infection, and chronic renal impairment (CRI).
Design: Prospective observational cohort study of HIV-HCV coinfected patients.
Methods: Data from 1129 participants in the Canadian Co-Infection Cohort with baseline and follow-up serum creatinine measurements between 2003 and 2014 were analyzed. Prevalent and incident cohorts were created to examine the association between self-reported past, current, and cumulative cocaine use and chronic HCV with CRI. CRI was defined as an estimated glomerular filtration rate below 70 ml/min per 1.73 m2. Multivariate logistic regression was used to calculate odds ratios, and discrete-time proportional-hazards models were used to calculate hazard ratios for cocaine use, in the two respective cohorts, adjusted for HCV RNA and important demographic, HIV disease stage, and comorbidity confounders.
Results: Eighty-seven participants (8%) had prevalent CRI.
Past injection cocaine use was associated with a two-fold greater risk of prevalent CRI [odds ratio 2.03, 95% confidence interval (CI) 0.96, 4.32].
During follow-up, 126 of 1061 participants (12%) developed incident CRI (31 per 1000 person-years).
Compared to nonusers, heavy (≥ 3 days/week) and frequent injection cocaine users (≥75% of follow-up time) experienced more rapid progression to CRI (hazard ratio 2.65, 95% CI 1.35, 5.21; and hazard ratio 1.82, 95% CI 1.07, 3.07, respectively).
There was no association between chronic HCV and CRI in either cohort.
Conclusion: After accounting for HCV RNA, frequent and cumulative injection cocaine abuse was associated with CRI progression and should be taken into consideration when evaluating impaired renal function in HIV-HCV coinfection.
Introduction
Chronic kidney disease (CKD) is a prevalent comorbidity among HIV-infected persons [1,2]. It is estimated that 5-11% of people living with HIV have mild to moderately reduced kidney function [3-5], increasing their risk of cardiovascular disease and premature mortality [6,7]. HIV-associated nephropathy (HIVAN), which is associated with rapid progression to end-stage renal disease (ESRD), is the classic kidney disease presentation among HIV patients, particularly in African Americans [8]. With the introduction of antiretroviral therapy (ART), which has been effective in the prevention and treatment of HIVAN [9,10], the spectrum of CKD among HIV-infected persons has changed. Of late, the increasing CKD burden among HIV-infected persons has been attributed to aging, metabolic changes associated with a greater prevalence of diabetes and hypertension, and direct nephrotoxic complications from prolonged ART use [1,11].
Hepatitis C virus (HCV) coinfection has also been implicated as an important risk factor for CKD and ESRD among HIV patients [12-16]. Because of shared routes of transmission, approximately 25% of people living with HIV are also coinfected with HCV [17].
Membranoproliferative glomerulonephritis (MPGN) is more common in HCV coinfected compared to HIV monoinfected patients [18,19]. MPGN is associated with type II mixed cryoglobulinemia, which may represent a pathway by which HCV affects the kidney [20]. A recent epidemiologic study, however, found no association between HCV RNA and CKD, suggesting that the excess risk associated with HCV infection may be attributable to other exposures in this population [21].
Injection drug use (IDU), the primary route of HCV infection, remains a common behavior for many coinfected individuals [22]. Cocaine itself has been associated with rhabdomyolysis and acute kidney injury, and is a known nephropathic drug [23,24]. However, there is little epidemiological evidence about the role that cocaine has on renal function or whether its use may explain the observed association between HCV and CKD. The aim of this study was to examine the association between injection cocaine use and chronic renal impairment (CRI) among HIV-HCV coinfected patients receiving clinical care.
Discussion
In this prospective study of HIV-HCV coinfected patients, past injection cocaine increased the risk of CRI, independent of chronic HCV infection, ART use, and other traditional kidney disease risk factors. Furthermore, frequent injection cocaine use of three or more times per week was associated with rapid progression to CRI. We also found that regular use of injection cocaine was associated with CRI progression. Relative effect estimates for cocaine use in this analysis were large. For example, past injection cocaine use was associated with an approximately two-fold greater risk of prevalent CRI. Similar associations were also observed for frequent and cumulative injection and noninjection cocaine in the incident cohort. We also found important clinical differences in annual rates of change in eGFR between injection cocaine users and nonusers. Given that the prevalence of injection drug use in this population is high, cocaine use may be an important modifiable risk factor for CKD among coinfected patients [22]. These results support that screening guidelines for CKD among HIV-infected populations should be expanded to include cocaine users as a high-risk group for kidney disease, as has previously been suggested [34,35].
This is the first cohort study to examine the effect of injection cocaine use, a known nephropathic drug [23,24,36], on renal function among HIV or coinfected populations. Previous research in non-HIV-infected populations has been limited by small sample sizes, poor exposure ascertainment, and the use of nonlongitudinal study designs, which have led to inconsistent results. For example, in a case-control study of recreational drug use and ESRD, cocaine use was not associated with being on dialysis; however, the effect estimate lacked precision as the population controls reported no past illicit drug use [37]. In a cohort of 647 hypertensive men, past cocaine use was strongly associated with mild increases in SCr concentrations [38]. However, because of the retrospective cohort design, drug use may have occurred after follow-up time in the analysis began for many participants. Results from this study are similar to results from a longitudinal analysis of acute kidney disease among a cohort of 367 HCV-infected patients, which have characteristics comparable to our coinfected cohort [39]. Garg et al.[39] reported that recent injection or noninjection cocaine use was associated with a two-fold greater risk of a concomitant rise in SCr, which may be a marker for future chronic disease. Our study supports that elevations in creatinine associated with cocaine use are not transient, but rather lead to chronic kidney dysfunction because the vast majority of those developing CRI never returned to normal renal function.
Results from this study are consistent with clinical studies that demonstrate pathogenic effects of cocaine on the kidney [40]. Cocaine is known to have strong vasoconstrictive effects on smooth muscle tissue, which may accelerate hypertensive nephrosclerosis. Furthermore, kidney epithelial cells exposed to cocaine experienced a reduction in intracellular glutathione, an antioxidant and important component of cellular homeostasis, increasing oxidative stress, and may reduce normal kidney function [24]. Results of our analysis were appreciably similar for noninjection cocaine use, suggesting the nephropathic potential of cocaine is drug-specific and not related to route of administration.
It is notable that in our analysis, chronic HCV infection was not associated with an increased risk of CRI. As HCV has been associated with specific glomerular diseases, such as MPGN, it has been hypothesized that patients with a chronic HCV infection may be at a greater risk for CKD, compared to those who have spontaneously cleared the virus or developed a sustained virologic response to HCV treatment [41]. Indeed, in studies of patients enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) and Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) trials, and the EuroSIDA cohort, the coinfected patients with HCV viral loads at least 800 000 and 500 000 IU/ml, respectively, had larger CKD incidence rates compared to those with resolved HCV infections [42,43]. In the larger North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohort, however, rates of incident CKD did not differ between coinfected patients with any quantifiable or undetectable HCV viral load [21]. None of these studies accounted for cocaine use. It is therefore possible that some or much of the effect attributed to HCV may instead be related to cocaine abuse rather than to HCV itself. Due to the lack of quantitative measures for all participants, we were unable to determine if HCV RNA levels may impact risk of renal impairment at higher thresholds. Among the subset of participants with available quantitative HCV RNA measures, the median HCV RNA was high (median 1.3 million IU/ml) and there was no evidence that cocaine use was associated with level of HCV RNA, suggesting our findings were not confounded by HCV viremia.
As reported previously, past exposure to tenofovir was associated with prevalent CRI [13,44]. Consistent with findings from an assessment of the effect of cumulative ART exposure, past use of lopinavir and atazanavir, two protease inhibitors, and current atazanavir use were also associated with CRI in this study [26]. We found no evidence of interaction between any of these nephrotoxic ART agents and injection cocaine use, suggesting that renal safety of these medications is not affected by cocaine use.
The study has several important strengths. First, the cohort collected detailed, time-updated information on the use of specific illicit drugs, and their frequency of use. This information is typically not recorded in clinical databases used for other HIV cohort studies on CKD. Previous studies have also ascertained drug exposure retrospectively or at only one time point. Second, with regular HCV RNA testing, this study isolated the effect of HCV viremia from the effect of specific injection drug use, which has not previously been done in HIV-infected cohorts. Finally, we used a validated kidney function equation to measure eGFR and required two consecutive measurements, at least 3 months apart, to confirm incident CRI and rule out acute kidney injury.
Our study has also several potential limitations. First, although data were obtained from a large cohort of coinfected patients, study power was limited to detect smaller effect sizes and interactions between exposure and covariates. Therefore, we only considered CRI as our outcome rather than traditional CKD (eGFR <60 ml/min per 1.73 m2), as there were few CKD events. Whereas it is possible that risk factors for CRI may differ from CKD, there is increasing interest in identifying patients at earlier risk for CKD, so interventions and modifications of treatment can be implemented [26]. Our analysis of CRI may help to achieve this aim. Second, drug history was measured by self-report and may result in misclassification if some patients failed to report drug use. We do not expect the degree of misclassification to be biased, however, as drug use history was collected independently of objective serum creatinine measures. Third, as only 3% of the study participants were black, we were unable to adequately evaluate race as a confounder or effect modifier. Finally, HCV viremia was measured using a combination of qualitative and quantitative molecular assays. As a result, we were unable to assess a dose-response relationship between viremia and CRI as we classified all those with any detectable HCV viral load as being viremic.
In conclusion, we found evidence to suggest that cumulative exposure and frequent cocaine use are associated with CRI progression among HIV-HCV coinfected patients. The role of substance use in contributing to renal disease in coinfection has been underappreciated and should be taken into consideration when evaluating impaired renal function in this setting.
Methods
Study population>
Data were obtained from the Canadian Co-Infection Cohort (CCC). This study has been described previously [25]. Briefly, after providing informed consent, all eligible participants at least 16 years of age with a confirmed HIV infection and serologic evidence of HCV exposure completed a baseline questionnaire to provide sociodemographic information and self-reported injection drug histories. Medical records were abstracted to obtain ART treatment histories, and AIDS, liver disease, and other comorbidities. Standard laboratory analyses were used to measure CD4+ T-cell counts, HIV viral load, and HCV viremia, using qualitative or quantitative molecular HCV RNA assays. A serum biochemistry panel was also performed, which included measurement of serum creatinine (SCr). All information was updated at bi-annual follow-up visits. The study was approved by the community advisory committee of the Canadian Institutes of Health Research (CIHR) - Canadian HIV Trials Network - and by all institutional ethics boards of participating centers.
We included 1366 CCC participants enrolled between January 2003 and October 2014, who had at least one SCr measurement. The first study visit with an available SCr measurement was defined as the index visit; 98% of participants had their first SCr measurement at enrollment. The study population was divided into prevalent and incident cohorts for two separate analyses (Fig. 1). For the prevalent cohort, we included all participants who enrolled after February 2007, the date after which study questionnaires introduced a question on injection drug histories. For the incident cohort, we included all participants without CRI (see definition below) at the index visit and who were followed for at least two study visits. No exclusion based on the older questionnaire was used for the incident cohort because questions on current injection use were available on all questionnaires.
Chronic renal impairment
Prevalent CRI was defined as an estimated glomerular filtration rate (eGFR) below 70 ml/min per 1.73 m2 at the index visit. For those who did not have CRI at the index visit, incident CRI was defined as two consecutive eGFR values of less than 70 ml/min per 1.73 m2[26]. We calculated eGFR using the 2009 SCr-based CKD-epidemiology (EPI) equation [27]. This equation has been validated in HIV-infected populations [28,29]. A confirmed eGFR decline to less than 70 ml/min per 1.73 m2 was chosen to maximize study power, but it is also clinically relevant as renal interventions can be initiated to prevent kidney disease progression [30].
Exposure and covariate definitions
For the prevalent cohort, past injection cocaine use was defined as any self-reported use prior to the index visit. For the incident cohort, current injection cocaine use was defined as any self-reported use in the past 6 months. Frequency of injection cocaine use was categorized as: no use in the past month (referent), occasional use (<1 day/week), regular use (1 or 2 days/week), or heavy use (≥3 days/week). Cumulative exposure to injection cocaine was defined using the proportion of total follow-up time when a participant self-reported using any amount of the drug by injection. The following categories were used: no use during follow-up (referent), low (≥1% to <33% of follow-up time), moderate (≥33% to <75%), and high (≥75%). All injection cocaine exposures in the incident cohort analysis were time-updated.
Hepatitis C virus viremia was measured with either a qualitative (e.g. Amplicor HCV Test v2.0) or quantitative molecular HCV RNA assay (e.g. Abbott Real Time PCR) according to study center-specific laboratory standards. Any participant with detectable HCV viremia from a qualitative or quantitative assay was considered to have a chronic HCV infection.
On the basis of low-income cut-offs from Statistics Canada, annual income was dichotomized at 24 000 Canadian dollars [31]. Hypertension was defined by clinical diagnosis, SBP above 140 mmHg or DBP above 90 mmHg, or the use of any antihypertensive drug. Diabetes was defined by clinical diagnosis or the use of insulin or any oral hypoglycemic agents. End-stage liver disease (ESLD) was defined by any diagnosis of cirrhosis, ascites, varices, spontaneous bacterial peritonitis, portal hypertension, encephalopathy, or hepatocellular carcinoma. In the incident cohort, hypertension and ESLD were coded as time-updated ever diagnosed variables. AIDS was defined as a diagnosis of any opportunistic infection or AIDS-related illness, regardless of CD4+ cell count.
Statistical analysis
Prevalent cohort
Logistic regression was used to calculate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between past injection cocaine use and prevalent CRI. The multivariate model was adjusted for age, sex, income, chronic HCV infection, detectable HIV viral load (>50 copies/ml), any past tenofovir, ritonavir-boosted or unboosted atazanavir, and lopinavir use, and prevalent hypertension. Covariates were selected a priori based on their plausibility as confounders for the past injection cocaine and kidney disease relationship. Missing data were imputed using fully conditional specification multiple imputation (FCS-MI) [32]. Continuous covariates were imputed using linear regression, and dichotomous variables were imputed using logistic regression. The imputation model included all covariates in the multivariate model and an indicator for CRI. We created 10 imputed data sets and combined regression results using Rubin's rules [32].
Incident cohort
Participants were followed from the index visit until they developed incident CRI, died, were lost to follow-up, or had their last visit prior to 1 October 2014. Person-time was censored for participants not developing CRI at their last visit. Discrete-time proportional-hazards models were used to estimate crude and adjusted hazard ratios and 95% CIs for CRI [33]. Three separate models were fit for current injection cocaine use, current frequency of use, and cumulative exposure to injection cocaine. All multivariate models were adjusted for age, sex, income, chronic HCV infection, CD4+ cell count, detectable HIV viral load, tenofovir, atazanavir and lopinavir use, AIDS diagnosis in the past 6 months, and prevalent hypertension, and ESLD, using time-updated covariates. We tested for interaction between the three injection cocaine exposures and all covariates. Missing longitudinal data were also imputed. STATA version 13.1 (College Station, Texas, USA) was used for all analyses.
Supplemental analyses
In a supplemental analysis, we modeled continuous eGFR using generalized estimating equations (GEEs) to compare longitudinal rates of change in eGFR per year between injection cocaine users and nonusers. To examine if any observed association was related to cocaine and not the injection route of administration, we also considered the role of current and cumulative exposure to noninjection cocaine and CRI using discrete-time proportional-hazards models.
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