Original article Risk of cardiovascular disease associated with HCV and HBV coinfection among antiretroviral-treated HIV-infected individuals

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1 Antiviral Therapy 2014; 19: (doi: /IMP2724) Original article Risk of cardiovascular disease associated with HCV and HBV coinfection among antiretroviral-treated HIV-infected individuals Jennifer Gillis 1, Marek Smieja 2, Angela Cescon 3, Sean B Rourke 4,5,6, Ann N Burchell 5,7, Curtis Cooper 8, Janet M Raboud 1,7 *, the OHTN Cohort Study Group 1 Toronto General Research Institute, University Health Network, Toronto, ON, Canada 2 Department of Pathology & Molecular Medicine, McMaster University, Hamilton, ON, Canada 3 British Columbia Centre for Excellence in HIV/AIDS, St Paul s Hospital, Vancouver, BC, Canada 4 Department of Psychiatry, University of Toronto, Toronto, ON, Canada 5 Ontario HIV Treatment Network, Toronto, ON, Canada 6 St Michael s Hospital, Toronto, ON, Canada 7 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada 8 University of Ottawa, The Ottawa Hospital Research Institute, Ottawa, ON, Canada *Corresponding author janet.raboud@uhnresearch.ca These authors contributed equally as senior authors A list of the OHTN Cohort Study Group members can be found via Additional file 1 Background: The increased risk for cardiovascular disease (CVD) in HIV is well established. Despite high prevalence of viral hepatitis coinfection with HIV, there are few studies on the risk of CVD amongst antiretroviral therapy (ART)-treated coinfected patients. Methods: Ontario HIV Treatment Network Cohort Study participants who initiated ART without prior CVD events were analysed. HBV and HCV coinfection were identified by serology and RNA test results. CVD was defined as any of: coronary artery disease including atherosclerosis, chronic ischaemic heart disease and arteriosclerotic vascular disease; myocardial infarction; congestive heart failure; cerebrovascular accident or stroke; coronary bypass; angioplasty; and sudden cardiac death. The impact of HBV and HCV coinfection on time to CVD was assessed using multivariable competing risk models accounting for left truncation between ART initiation and study enrolment. Results: A total of 3,416 HIV-monoinfected, 432 HIV HBV- and 736 HIV HCV-coinfected individuals were followed for a median (IQR) of 2.32 years ( ). Over the study period, 167 CVD events and 613 deaths were documented. After adjustment for age, gender, race, year initiating ART, weight and smoking status, HBV was not associated with time to CVD onset (ahr=1.05, 95% CI [0.63, 1.74]; P=0.86). There was an elevated risk of CVD for HCV-coinfected individuals, which approached statistical significance (ahr=1.44, 95% CI [0.97, 2.13]; P=0.07). Conclusions: Our results are consistent with a moderate increase of CVD among individuals with HIV HCV coinfection relative to those with HIV infection alone, lending support to consideration of initiation of HCV antiviral treatment. Introduction The risk for cardiovascular disease (CVD) in HIV-positive individuals has been widely studied [1 3]. Although complex, the pathophysiology appears to be influenced by high rates of traditional risk factors for CVD in HIV-positive populations (for example, smoking, alcohol and substance use) and the viral infection itself (for example, creating of a proinflammatory immune environment that may favour endothelial injury). The use of virologically suppressive antiretroviral therapy (ART) interrupts immunological decay and leads to normalization of the proinflammatory cytokine milieu, which is thought to ameliorate the risk of CVD, compared with untreated HIV infection [2]. However, these medications may also impact CVD risk through creation of abnormal lipid profiles, increased occurrence 2014 International Medical Press (print) (online) 309

2 J Gillis et al. of central obesity and metabolic syndromes, and potential effects on the endothelium [2 4]. Viral hepatitis coinfection is common in HIV with 30% HCV and 10% HBV coinfection rates globally [5]. In the context of HIV infection, HCV, and to a lesser extent HBV, have been shown to decrease hyperlipidaemia and hypercholesterolemia associated with ART [6 9]. In contrast to this positive impact on lipid profiles, HCV coinfection increases insulin resistance in HIV-positive individuals treated with ART [10,11] and likely increases the risk of type 2 diabetes [10]. Data on the association between HCV coinfection and subclinical CVD within HIV-positive populations are inconsistent. While the prevalence of carotid plaques has been shown to be higher among HCV-coinfected individuals than individuals infected with HIV alone [12], carotid intima-media thickness was not significantly increased in the presence of HCV coinfection [12 14]. Associations of HCV coinfection with endothelial function are mixed [11,14]. Clinical CVD outcomes in the context of HIV viral hepatitis coinfection have been evaluated in few studies. Freiberg et al. [15] found a significant association between HCV coinfection and self-reported CVD in a cohort of HIV-positive individuals with past or current excess alcohol consumption. In a study of 19,424 HIV-infected individuals, HCV coinfection was found to increase the risk of cerebrovascular disease, but only a trend towards increased risk of acute myocardial infarction was identified [16]. The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort found no association between HCV or HBV coinfection and myocardial infarction or stroke [17]. Little data exist on the association of coinfection with HBV on the risk of CVD in the context of HIV infection. These studies demonstrate a lack of consensus on the association of viral hepatitis coinfection with the risk of CVD in HIV-positive individuals undergoing therapy. To address this uncertainty, we evaluated the impact of viral hepatitis coinfection on the incidence of new CVD in HIV-positive individuals treated with ART, adjusting for common CVD risk factors and competing causes of death. Methods Study population and setting We studied participants enrolled in the Ontario HIV Treatment Network (OHTN) Cohort Study (OCS), a voluntary clinic-based cohort at 11 HIV care sites in Ontario, Canada [18]. The OCS was initiated in 2007 and includes new enrolees and participants from the HIV Ontario Observational Database (HOOD), the predecessor cohort study to the OCS, who consented to continue their enrolment or who had either died or were lost to follow-up. The study follow-up period was from January 1995, the time of the first enrolment into the OCS, to January 2011, the time of the last follow-up. Data are collected from multiple sources including electronic medical charts and manual chart abstraction, linkages to laboratory databases and completion of questionnaires. Clinical and laboratory data are extracted every 6 months and include CD4 + T-cell counts, viral load measurements, hospitalizations and adverse events. HBV and HCV viral load, serology and genotype data were obtained from the Public Health Ontario Laboratories (PHOL), through which virtually all confirmatory HCV diagnostic testing in the province is conducted. Socio-behavioural and demographic data are collected from annually interviewer administered questionnaires. Classification of hepatitis status Individuals were classified as having HBV if a positive laboratory test for HBV surface antigen or HBV viral load was ever present. Individuals were classified as HCV-infected if they were ever HCV antibody, viral load or genotype positive. All others were classified as HIV-monoinfected. Outcome measures The outcome of interest was the time to first CVD event, which was defined as the number of years from ART initiation to the occurrence of any of coronary artery disease including atherosclerosis, chronic ischaemic heart disease and arteriosclerotic vascular disease; myocardial infarction; congestive heart failure; cerebrovascular accident or stroke; coronary bypass; angioplasty; and sudden cardiac death. Details about CVD events were abstracted from medical charts and classified according to ICD9 codes. For inclusion in the current analyses, participants had to have initiated ART and have not been diagnosed with CVD prior to ART initiation. Death from non-cvd causes was considered as a competing risk. Deaths for which cause was unknown were considered to be non-cvd-related since only 5% of deaths were CVD-related. Individuals who did not experience a CVD event or death from competing cause were censored on their last date of contact with the OCS. Statistical methods Demographic and clinical characteristics were summarized using frequencies and percentages for categorical variables and medians and IQR for continuous variables. The demographic and clinical characteristics of HIV HBV and HIV HCV-coinfected individuals were compared with HIV-monoinfected individuals using c 2 tests and Wilcoxon rank-sum tests, as appropriate. Incidence rates of CVD events and death were calculated for HIV-monoinfected, HIV HBV and HIV HCV-coinfected individuals International Medical Press

3 HIV viral hepatitis coinfection and risk of CVD The time origin of interest, ART initiation, occurred prior to cohort enrolment for some individuals. While death is necessarily left truncated between the time origin and enrolment into the cohort, the availability of retrospective administrative data on comorbid conditions provided data on CVD events during this period. To our knowledge, no methods are currently available to handle differential left truncation in the context of time to event regression modelling. As such, data were left truncated between the time of ART initiation and enrolment in the OCS for those individuals who initiated ART prior to enrolment, and CVD events that occurred prior to enrolment were excluded from the analysis. Predictors of progression to CVD were explored using cumulative incidence function plots and univariable Fine and Gray models [19] accounting for the competing risk of non-cvd death. A multivariable Fine and Gray model was used to examine the impact of HBV and HCV coinfection after adjusting for factors known a priori to be associated with progression to CVD including age, sex, race, weight centered on average weight of males and females accordingly, baseline smoking status and year of ART initiation. Imputation of missing smoking status at ART initiation Multiple imputation methods were used to impute missing smoking status at ART initiation [20]. Univariable cumulative logit models for smoking status and univariable logistic regression models were used to determine which covariates were significantly associated with baseline smoking status and missingness, respectively. Those covariates that were significant in the univariable left-truncated Fine and Gray models were also considered for inclusion in the imputation model. The final imputation model included HBV and HCV status, age, sex, race, risk factors for HIV acquisition, education, year of ART initiation, baseline regimen, previous CVD-related events (diabetes diagnosis, hypertension, dyslipidaemia, angina and peripheral vascular disease), CVD event or death and OCS site. Results Of the 5,644 individuals who were enrolled in the OCS as of December 2010, 4,501 had initiated ART with no prior history of CVD and came from sites providing sufficient baseline demographic and clinical data. During the study period, 3,852/4,501 (86%) of participants were tested at least once for HCV. Of the 720 participants with at least one positive antibody result, 367 (51%) had confirmatory RNA testing. An additional 16 participants had only RNA-positive results, for a total of 736 HCV-positive individuals. 85% of the participants were tested at least once during the study period for HBV. In total, 349 participants were HIV HBV-coinfected, 653 were HIV HCV-coinfected and 83 were HIV HBV HCV tri-infected. Demographic and clinical characteristics at ART initiation of HIV HBV and HIV HCV-coinfected individuals were compared with HIV-monoinfected individuals (Table 1). In Table 1, tri-infected individuals were included in both of the HIV HBV- and HIV HCV-infected groups. HIV HBV- and HIV HCVcoinfected individuals were more likely to have been infected with HIV through injection drug use, had lower education and income, were smokers at initiation of ART, and had been diagnosed with HIV longer than HIV-monoinfected individuals. Smoking status at ART initiation was imputed for 692 (15%) of the study population. The proportion of individuals with missing smoking data was similar by coinfection status and CVD outcome (data not shown). A total of 167 CVD events and 613 non-cvd deaths were documented during the study period after enrolment into the OCS with a median (IQR) time of followup of 2.32 years ( ). An additional 46 CVD events were excluded from the analysis because they occurred after ART initiation but prior to enrolment. The numbers of CVD events excluded from the analysis because they occurred prior to enrolment were 39, 4 and 4 for HIV, HIV HCV and HIV HBV, which was 25%, 10% and 18% of the CVD events for each group, respectively. Since the proportion of events excluded from the analysis due to left truncation was slightly higher among HIV-monoinfected individuals, exclusion of these events may have biased our findings slightly towards the null. Of the 46 patients with events that were excluded due to left-truncation, 4 had a subsequent CVD event during the study period. CVD event type is tabulated by coinfection status in Table 2. 25% and 16% of CVD events were attributed to myocardial infarction and cerebrovascular accident (stroke), respectively. 11% of the CVD events were cardiac procedures of coronary bypass and angioplasty. Coronary artery disease, congestive heart failure and sudden cardiac death respectively contributed 29%, 12% and 9% of events. The incidence (95% CI) of CVD (events per 1,000 person-years follow-up) was 8.70 (4.68, 12.7) for HIV HBV, 9.62 (6.38, 12.9) for HIV HCV-coinfected individuals and 7.59 (6.22, 8.96) for HIV-monoinfected individuals. The incidence (95% CI) of the competing risk, death (events per 1,000 person-years followup), was 40.3 (31.6, 48.9) for HIV HBV, 34.9 (28.7, 41.1) for HIV HCV-coinfected individuals and 27.3 (24.6, 29.9) for HIV-monoinfected individuals. Figure 1 depicts the cumulative incidence functions of CVD events and non-cvd death for HIV HBV- and HIV HCV-coinfected individuals. Antiviral Therapy

4 J Gillis et al. Table 1. Demographic and clinical characteristics at initiation of antiretroviral therapy by viral hepatitis coinfection status a Variables HIV (n=3,416) HIV HBV (n=432) P-value HIV HCV (n=736) P-value Demographics Age, years 36 (31 43) 36 (31 42) (31 42) 0.22 Sex Male 2,887 (85) 405 (94) < (81) 0.01 Race White 2,228 (69) 285 (71) (74) < Black 460 (14) 50 (12) 38 (5) Aboriginal 226 (7) 26 (6) 106 (15) Other 316 (10) 42 (10) 41 (6) Country of origin Canada 2,259 (69) 281 (69) (86) < Low prevalence country 544 (17) 83 (20) 68 (9) High prevalence country b 455 (14) 44 (11) 30 (4) HIV risk factor (not hierarchical) Men who have sex with men 2,413 (73) 320 (76) (38) < Injection drug use 162 (5) 74 (18) < (54) < High prevalence country 455 (14) 44 (10) (4) < Heterosexual contact 499 (15) 53 (13) (46) < Medical/blood contact 258 (8) 37 (9) (20) < Education Less than high school 348 (11) 62 (16) <0.001 c 222 (31) < c Completed high school 498 (16) 74 (19) 129 (18) Some college/university 594 (19) 71 (19) 142 (20) Completed college/university 1281 (42) 143 (38) 181 (26) Post-graduate education 342 (11) 30 (8) 32 (5) Household gross yearly income <$20, (33) 123 (46) <0.001 c 288 (63) < c $20,000 $30, (14) 32 (12) 48 (11) $30,000 $40, (10) 27 (10) 26 (6) $40,000 $60, (20) 36 (13) 47 (10) >$60, (23) 51 (19) 48 (11) Smoking status Non-smoker 1,083 (38) 106 (29) < (17) < Past smoker 392 (14) 44 (12) 46 (7) Current smoker 1,402 (49) 213 (59) 486 (76) Missing 539 (16) 69 (16) 97 (13) Clinical Year of HIV-positive test < (20) 123 (29) < c 185 (25) < c (27) 128 (30) 199 (27) (21) 79 (18) 174 (24) (18) 63 (15) 108 (15) > (13) 37 (9) 64 (9) Year of ART initiation < (4) 20 (5) <0.001 c 22 (3) 0.37 c (22) 122 (28) 150 (20) ,135 (33) 136 (31) 300 (41) (18) 81 (19) 111 (15) > (23) 73 (17) 153 (21) Baseline CD4 + T-cell count, cells/mm 3d 250 ( ) 234 ( ) ( ) <0.001 Baseline HIV RNA, log 10 copies/ml e 4.7 ( ) 4.7 ( ) ( ) 0.36 Previous CVD-related event f 841 (25) 93 (22) (16) < Diabetes g 178 (5) 20 (5) (5) 0.72 a Results are reported as frequency (%) or median (IQR). b High prevalence countries are those with HIV prevalence >1% and the predominant mode of transmission is heterosexual contact. c Cochrane Armitage test for trend. d Missing for 1,300 participants. e Missing for 2,264 participants. f Previous cardiovascular disease (CVD)-related events include diabetes diagnosis, hypertension, dyslipidaemia, angina and peripheral vascular disease. g During the study period International Medical Press

5 HIV viral hepatitis coinfection and risk of CVD Table 1. Continued Variables HIV (n=3,416) HIV HBV (n=432) P-value HIV HCV (n=736) P-value Hypertension g 378 (11) 46 (11) (6) < Dyslipidaemia g 451 (13) 39 (9) (6) < Weight, kg Female 67 (58 80) 64 (56 72) (55 74) <0.01 Male 74 (66 83) 73 (66 81) (65 81) <0.01 Table 2. First cardiovascular disease event by viral hepatitis coinfection a Cardiovascular disease event HIV (n=3,416) HIV HBV (n=432) HIV HCV (n=736) Myocardial infarction, n (%) 33 (28) 3 (17) 6 (18) Cerebrovascular accident (stroke), n (%) 17 (14) 1 (6) 8 (24) Coronary artery disease, n (%) 33 (28) 8 (44) 7 (20) Congestive heart failure, n (%) 14 (12) 2 (11) 5 (15) Coronary procedures (angioplasty or bypass), n (%) 15 (13) 2 (11) 1 (3) Sudden cardiac death, n (%) 6 (5) 2 (11) 7 (20) Total number of CVD events, n Participants with 1 event, n a Percentage of cardiovascular disease (CVD) events. Figure 1. Cumulative incidence function plots of CVD events and non-cvd mortality A 1.0 B 1.0 Cumulative incidence Cumulative incidence Years since ARV initiation Years since ARV initiation CVD events: HBV- CVD events: HBV+ CVD events: HCV- CVD events: HCV+ Non-CVD mortality: HBV- Non-CVD mortality: HBV+ Non-CVD mortality: HCV- Non-CVD mortality: HCV+ Cumulative incidence function plots of cardiovascular disease (CVD) events and non-cvd mortality by (A) hepatitis B status (B) hepatitis C status. +, positive; -, negative. In univariable Fine and Gray models accounting for left truncation and the competing risk of non- CVD death, male sex, initiation of ART prior to 1990, past or current smoking status at ART initiation, and older age were associated with increased risk of CVD (Table 3). HIV HBV coinfection was not associated with progression to CVD in either the univariable model (HR=1.04, 95% CI [0.64, 1.69]; P=0.89) or multivariable models adjusting for age, sex, race, year of ART initiation, weight and baseline smoking status (HR=1.05, 95% CI [0.63, 1.75]; P=0.86). Similarly, HIV HCV coinfection was not significantly Antiviral Therapy

6 J Gillis et al. Table 3. Univariable and multivariable left truncated Fine and Gray models of time from ART initiation to development of cardiovascular disease Univariable Multivariable Hazard ratio 95% CI P-value Hazard ratio 95% CI P-value HBV coinfection 1.04 (0.64, 1.69) (0.63, 1.74) 0.86 HCV coinfection 1.23 (0.84, 1.79) (0.97, 2.13) 0.07 Age per 10 years 1.81 (1.57, 2.09) < (1.69, 2.33) < Male sex 1.92 (1.07, 3.46) (0.92, 4.34) 0.08 Race (reference Caucasian) African/Black 0.42 (0.18, 0.94) (0.28, 1.46) 0.29 Aboriginal 0.80 (0.44, 1.44) (0.54, 1.79) 0.95 Other 0.92 (0.51, 1.67) (0.66, 2.18) 0.56 Weight per 5 kg 0.98 (0.94, 1.02) (0.98, 1.10) 0.16 Smoking status (reference non-smoker) Past 1.68 (0.99, 2.85) (0.78, 2.33) 0.29 Current 1.48 (1.01, 2.16) (1.00, 2.26) 0.05 Year of ART Initiation (reference <1990) (0.25, 0.78) < (0.18, 0.58) (0.21, 0.69) < (0.14, 0.46) < (0.12, 0.63) < (0.07, 0.38) < > (0.12, 0.85) (0.08, 0.58) Baseline CD4 + T-cell count 0.97 (0.88, 1.04) 0.43 per 100 cells/mm 3 IDU 1.17 (0.75,1.81) 0.50 ART, antiretroviral therapy; IDU, intravenous drug use. associated with progression to CVD in the univariable model. However, we observed an elevation of risk for CVD among HIV HCV-coinfected individuals that approached statistical significance in the multivariable model (ahr=1.44, 95% CI [0.97, 2.13]; P=0.07). In these models, tri-infected individuals had values of 1 for both binary variables indicating HBV and HCV coinfection. Age, baseline smoking status and year of ART initiation remained significantly associated with progression to CVD. Findings were consistent among models with imputed smoking data and complete case analyses and no significant interaction between HBV and HCV status was observed (data not shown). Discussion In this cohort of HIV-positive participants attending primary and tertiary care centres in Ontario, Canada, there was an increased estimated risk of CVD among HIV HCV-coinfected individuals relative to those infected with HIV alone, which approached statistical significance. HBV coinfection was not found to increase the risk of CVD. While a number of studies have examined the impact of viral hepatitis on lipid profile and subclinical CVD outcomes in HIV-positive individuals [6 14], few have examined the association of hepatitis coinfection with CVD events [15 17]. Results from these studies are mixed. A cross-sectional analysis of 400 participants with former or current alcohol dependency and median age 42 from the HIV-Longitudinal Interrelationships of Viruses and Ethanol (HIV-LIVE) cohort reported significantly higher prevalence of self-reported past CVD, including peripheral vascular disease, stroke and myocardial infarction, amongst HCV-coinfected individuals (OR=4.65, [95% CI=1.70, 12.71]) [15] compared with those infected with HIV alone. Because of the small number of events, analyses examining the association of various factors with CVD adjusted for age only. HCV coinfection was found to be significantly associated with time to development of cerebrovascular disease (transient ischaemic attacks or strokes; HR=1.20, [95% CI 1.04, 1.38]) in a predominantly male cohort of 19,424 HIV-positive individuals, median age 46, of which 31% were HCVcoinfected [16]. A trend towards an increased risk of acute myocardial infarction was also observed among HIV HCV-coinfected individuals (HR=1.25 [95% CI 0.98, 1.59]). The risks of myocardial infarction and stroke were not increased in either HIV HBV- or International Medical Press

7 HIV viral hepatitis coinfection and risk of CVD HIV HCV-coinfected individuals enrolled in the D:A:D study between December 1999 and February 2007 [17]. There are a number of possible explanations for the differences in findings among studies. Classification of coinfection with HCV varied from HCV RNA testing on all participants to HCV RNA or antibody test results on a subset of patients according to individual physician practice patterns. The median age of participants also varied among the studies; studies with older participants observed higher incidence rates of CVD. The ability of individual studies to adjust for confounders varied with the sample size of the study and availability of data on CVD risk factors such as body mass index (BMI) and family history of CVD. Study designs varied, with some examining prevalence [15] and others examining incidence [16,17]. The time origin also varied among incidence studies. Our study used the date of ART initiation while others used the date of entry into the cohort [16,17]. Furthermore, study populations varied with some comprising a specific risk group [15], almost all men [16] or with a more diverse population [17]. The choice of cardiovascular end point varied from self-reported CVD [15] and adjudicated myocardial infarction [17] to composite end points of a number of CVD events, as in the present study. Procedures including bypass surgery and angioplasty are often pursued to reduce the risk for myocardial infarction and stroke. With this in mind, we developed broad inclusion criteria for CVD in an effort to fully document the effect of hepatitis coinfection on CVD risk. The studies by Bedimo et al. [16] and the D:A:D cohort [17] focused their investigations on myocardial infarction and stroke. In our cohort, only 25% and 16% of the events observed were attributed to these specific events, respectively, and 11% to coronary angioplasty and bypass procedures. In addition, the proportion of specific CVD events differed by coinfection status. HBV- and HCVcoinfected individuals were less likely to experience myocardial infarction than HIV-monoinfected individuals (17% and 18% of events, respectively, versus 28% in monoinfected individuals). These data, along with the literature on the pathogenesis of CVD in HIV HCV coinfection, suggest that a broad look at the clinical manifestation of CVD may be preferable when exploring the potential impact of viral hepatitis coinfection on cardiovascular health. Sudden cardiac death was identified as a cardiovascular disease event in 5% of HIV-monoinfected, 11% of HIV HBV-coinfected and 20% of HIV HCV-coinfected cohort participants. This level of risk has been described elsewhere [21]. Acknowledging the small sample size, these results suggest a possible increase in sudden cardiac death in HIV HCV coinfection. There is a heavier burden of substance abuse and overdose in HIV HCV-coinfected individuals, which contributes to the risk of sudden cardiac death [22,23]. Furthermore, concurrently used medications in this population may produce QTc interval prolongation thereby increasing the risk of sudden cardiac death [24]. Methadone has been implicated as a potential contributing factor via this mechanism [25,26]. Vallecillo et al. [25] also identified being antiretroviral-naive and cirrhosis as independent risk factors for QTc interval prolongation. HIV coinfection is a risk factor for more rapid progression to cirrhosis in those with HCV infection, which may put this population at increased risk for sudden cardiac death. Serial EKG monitoring has been suggested in HIV-infected patients [25]. However, the effectiveness of this has not been established. Finally, HCV coinfection is associated with increased risk for insulin resistance [10] and decreased lipid levels [6 9]. It is unclear how this influences overall CVD risk in this population. Therefore, the association between HCV coinfection and myocardial infarction or stroke, whether protective or detrimental, may have also been attenuated through the inclusion of previous myocardial infarction or stroke, diabetes, and lipid profiles as covariates in the aforementioned studies. Strengths of our study include the use of a comprehensive definition of CVD attained from medical charts, relatively complete data on smoking status, and a diverse population of individuals enrolled in a long-standing cohort within a universal health care setting. Limitations of the study include incomplete data on cholesterol, lipid levels, BMI and family history of CVD at the time of ART initiation. Data on injection drug use during follow-up was limited for the majority of the cohort, and therefore we were unable to adjust for on-going injection drug use. Cardiovascular events were obtained through chart review and were not validated. Incomplete data on HCV RNA limited our investigation of the impact of chronic HCV infection. Further, limited methodology for use of time-updated variables in competing risks with left-truncated data may have led to time-dependent bias associated with HCV status. Increasing incidence of HCV acquisition after ART initiation and clearance of the virus spontaneously or through treatment may contribute to this bias. As such, the harm associated with HCV positivity may have been underestimated [27] within our Fine and Gray models. HIV HCV coinfection may increase the risk of CVD in HIV-positive individuals after accounting for confounding variables and competing causes of death. Since traditional modifiable CVD risk factors remain one of the largest contributors to increased risk in this population, it is pertinent to continue with focused interventions and encouragement to decrease smoking, Antiviral Therapy

8 J Gillis et al. drug and alcohol use and to improve diet and activity levels within HCV-coinfected individuals and those at risk of acquiring the virus. It is plausible that successful treatment of HCV infection with HCV antivirals may be another strategy to reduce the risk of CVD in the HIV HCV-coinfected population. Specific evaluation of this question is warranted. Acknowledgements We gratefully acknowledge all of the people living with HIV who volunteered to participate in the OHTN Cohort Study and the work and support of the past and present members of the OCS Governance Committee: Darien Taylor, Evan Collins, Greg Robinson, Shari Margolese, Patrick Cupido, Tony Di Pede, Rick Kennedy, Michael Hamilton, Ken King, Brian Finch, Lori Stoltz, Ahmed Bayoumi, Clemon George, Curtis Cooper, Troy Grennan, Adrian Betts, Tracey Conway and Colleen Price. We thank all the interviewers, data collectors, research associates and coordinators, nurses and physicians who provide support for data collection and extraction. The authors wish to thank the OHTN staff and their teams for data management and IT support (Mark Fisher, Director, IT) and OCS project coordination (Samantha Robinson, Project Coordinator). The OHTN Cohort Study is supported by the Ontario Ministry of Health and Long-Term Care. Three investigators are the recipients of salary support from the Ontario HIV Treatment Network (JR and CC) and the Canadian Institutes for Health Research (AB). Disclosure statement The authors declare no competing interests. Additional file Additional file 1: A list of the members of the OHTN Cohort Study Group can be found at intmedpress.com/uploads/documents/2963_gillis_ Additionalfile1.pdf References 1. Kamin DS, Grinspoon SK. Cardiovascular disease in HIVpositive patients. AIDS 2005; 19: Palella FJ, Phair JP. 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9 HIV viral hepatitis coinfection and risk of CVD 26. Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A community-based evaluation of sudden death associated with therapeutic levels of methadone. Am J Med 2008; 121: Beyersmann J, Wolkewitz M, Schumacher M. The impact of time-dependent bias in proportional hazards modelling. Stat Med 2008; 27: Accepted 24 October 2013; published online 16 January 2014 Antiviral Therapy