Miller, Cari L. MSc*; Wood, Evan PhD*†; Spittal, Patricia M.*†; Li, Kathy MSc*; Frankish, James C. PhD†; Braitstein, Paula MSc*; Montaner, Julio S. G. MD*; Schechter, Martin T. MD, PhD*†
HIV and hepatitis C virus (HCV) coinfection is a growing concern in North America, particularly among injection drug users (IDUs), in whom the majority of coinfections are concentrated. 1,2 It has been estimated that approximately 40% of individuals living with HIV are also coinfected with HCV, and among HIV-positive IDUs, the estimate is between 50% and 90%. 1 Although the impact of HCV infection on HIV disease progression remains unclear, 3–6 evidence suggests that coinfection has been associated with more rapid HCV progression. 7 In addition, some of the antiretroviral therapy used to ward off HIV disease progression has been shown to be associated with liver toxicity. 8 Thus, coinfection among IDUs is a growing concern in terms of public health as well as HCV and HIV treatment. 9
The age of individuals becoming infected with HIV and HCV in North America is decreasing. 10,11 Studies of IDUs have suggested that youth and recent initiates were at higher risk for both HIV 12 and HCV 13,14 infection. HIV infections among IDUs in North America have been concentrated among marginalized populations; African Americans in the United States and aboriginals in Canada have been disproportionately affected by the epidemic. 15,16 Given the evidence suggesting higher morbidity and mortality among coinfected individuals, there is an urgent need to document the incidence and prevalence of coinfection to understand the magnitude of the epidemic and to characterize target populations for intervention programs and future treatment strategies. Young IDUs provide an important opportunity to examine the incidence of coinfection due to more recent initiation into injection drug use, lower baseline infection(s), and increased risk for seroconversion.
Since 1996, Vancouver, British Columbia, has experienced an explosive and ongoing epidemic of HIV among IDU populations. 17 The public health response to the epidemic has focused on enforcement-based interventions, whereas drug treatment and other HIV and HCV prevention measures have remained desperately underfunded. Vancouver youth who use injection drugs have not been spared. We have documented an HIV incidence rate of 4.37 per 100 person-years 18 and an HCV incidence rate of 37.3 per 100 person-years 19 among IDUs aged 24 or younger. We undertook the current study to estimate the prevalence of coinfection and the time to HIV and HCV coinfection among IDUs aged 29 or younger and to characterize sociodemographic characteristics and risk factors for coinfection.
Data were collected within a prospective open cohort study of IDUs, the Vancouver Injection Drug Users Study (VIDUS). A description of this study has been published. 20 The VIDUS has recruited more than 1400 Vancouver area IDUs since May 1996. The study office is located in a store-front in the Downtown Eastside (DTES) of Vancouver. The DTES is Vancouver's poorest neighborhood, where an estimated 5000 IDUs reside in an area of approximately 10 city blocks and inexpensive housing in the form of hotels and single-room occupancies (SROs) abounds. The DTES is the epicenter of illicit drug-related activity in Vancouver.
Eligibility criteria included residing in the city of Vancouver and surrounding municipalities and having injected in the previous month before enrollment. Participants must be aged 14 years or older to enroll. Participants were administered a questionnaire by trained nurses and interviewers and were eligible to return for follow-up every 6 months. At each visit, eligible participants were tested for HIV and HCV antibodies through a venous blood sample. This study was approved by the St. Paul's Hospital Committee on Human Experimentation.
The VIDUS questionnaire elicits information regarding sociodemographic, sexual, and drug risk characteristics. Behavioral variables were elicited in reference to the previous 6 months before the interview. This includes the variables of sex trade work, frequency of injection, neighborhood, sexual behaviors, needle sharing, and methadone. Sex trade was defined as trading sex for money, drugs, or shelter.
For the purposes of this study, young injectors were defined as those aged 29 years or less at the time of recruitment. Young injectors identified at baseline as HIV- and HCV-negative or monoinfected with 1 virus were compared with those who were baseline HIV and HCV coinfected using contingency table analysis. χ2 and Fisher exact tests were used to compare categoric variables, and the Wilcoxon rank sum test was used to compare continuous variables. All relevant sexual and risk variables available through the VIDUS survey were examined in univariate analysis. All variables significant at the P < 0.05 level were reported in the tables as well as variables of significance from the literature. All multivariate models described were fit using the same protocol of adjusting for all variables that were significant (P < 0.05) in univariate analysis. All reported probability values were 2-sided.
Youth who became HIV and HCV coinfected during the study period were compared with youth who remained mono-infected or negative and had at least 1 follow-up visit. The date of seroconversion for a secondary infection was estimated using the midpoint between the last negative test result and the first positive test result. Cumulative incidence rates of coinfection were calculated using Kaplan-Meier methods. In these analyses, time 0 was defined as the date of enrollment. Participants who entered the study and remained seronegative or monoinfected were considered to be right-censored at the time of their most recent negative test result. Annual rates of seroconversion for the secondary infection were calculated using actuarial methods. Relative risks (RRs) and 95% confidence intervals (CIs) were obtained for variables of interest. Adjusted and unadjusted time-dependent Cox regression models were used to identify associations with seroconversion to coinfected status among the young participants. All probability values reported are 2-sided.
In addition, we undertook a Cochran-Armitage trend test to profile trends between 3 groups of youth: HIV- and HCV-negative, monoinfected, and coinfected youth. For this analysis, baseline prevalent youth and those who became coinfected during the study period were combined. Ordinal logistic regression of the trichotomous-dependent variable (no infection, monoinfection, or coinfection) was undertaken simultaneously to adjust the associations of a number of sociodemographic and risk factors with infection status. For all models, the proportional odds assumption was tested by the score test. For the trend test, infection status (not infected, monoinfected, or coinfected) was assessed at the latest follow-up visit for each participant. All reported probability values are 2-sided.
Of the 1478 participants enrolled in the VIDUS, 479 were aged ≤29 years at baseline (median age = 24 years). Of the young participants, 78 (16%) were HCV and HIV coinfected and 401 (84%) were either monoinfected (211 [53%] were HCV-positive and 12 [3%] were HIV-positive) or negative 178 (44%) at baseline. The median age of coinfected youth was 26 (interquartile range [IQR]: 24–28) years, and they had been injecting for a median duration of 7 (IQR: 5–11) years. The median age of monoinfected or negative youth was 24 (IQR: 20–26) years, and they had been injecting for a median of 3 (IQR: 1–7) years.
Table 1 compares baseline sociodemographic, drug, and sexual risk variables between coinfected versus monoinfected and negative youth. Baseline coinfected youth were more likely to be female (62% vs. 42%; P = 0.002), to be of aboriginal ancestry (45% vs. 22%; P = <0.001), to have a history of sexual abuse (53% vs. 38%; P = 0.014), to reside in the IDU epicenter (69% vs. 46%; P = <0.001), to be engaged in sex trade work (63% vs. 38%; P = <0.001), to have had greater than 100 lifetime sexual partners (59% vs. 31%; P = <0.001), to inject cocaine (63% vs. 38%; P = <0.001) and speedballs (28% vs. 16%; P = 0.012) at least daily, and to use condoms always with clients (47% vs. 28%; P = <0.001). There was no difference between the 2 groups with respect to injecting heroin at least daily (45% vs. 53%; P = 0.170), requiring help to inject (42% vs. 47%; P = 0.458), borrowing needles (37% vs. 40%; P = 0.595), and always using condoms with regular (17% vs. 18%; P = 0.825) and casual (15% vs. 23%; P = 0.117) sexual partners.
Independent associations with baseline coinfection (data not shown) included being female (odds ratio [OR] = 1.18, CI: 1.07, 1.31), being of aboriginal ancestry (OR = 2.44, CI: 1.41, 4.25), older age (OR = 1.18, CI: 1.07, 1.31), a greater number of years injecting (OR = 1.17, CI: 1.05, 1.21), and living in the IDU epicenter (OR = 1.87, CI: 1.06, 3.28).
Among the monoinfected or negative youth, there were a total of 297 (112 both HIV- and HCV-negative, 178 HCV-positive, and 7 HIV-positive) youth who had follow-up data and 104 who were lost to follow-up. There was no difference between the youth who returned for follow-up and those who did not with respect to HIV serostatus, female gender, being engaged in sex trade work, age, years injecting, or types of drugs used. Aboriginal youth were significantly more likely than nonaboriginal youth to return for follow-up visits. Baseline HCV-positive youth were significantly more likely to return for follow-up than HCV-negative youth (42% vs. 56%; P = 0.014).
In total, there have been 45 youth with follow-up data who seroconverted to a secondary infection during the study period (infected with both HCV and HIV [27%], HCV only [9%], or HIV only [64%]). The incidence rate for coinfection among VIDUS youth was 5.2 (CI: 3.8, 6.9) per 100 person-years. The median age of the seroconverters was 24 years, they had been injecting for a median of 3 years, 25 (55%) were female, and 20 (45%) were of aboriginal ancestry.
Table 2 presents the results of our Cox regression model. There were no differences between those who became HIV and HCV coinfected and those who remained negative or monoinfected with respect to female gender (RR = 1.12, CI: 0.61, 2.05) and requiring help to inject (RR = 1.92, CI: 0.94, 3.91). Unadjusted only associations with seroconversion were detected in those youth residing in the IDU epicenter (RR = 1.98, CI: 1.03, 3.82), of aboriginal ancestry (RR = 1.99, CI: 1.08, 3.64), and those injecting heroin (RR = 3.46, CI: 1.83, 6.52) and speedball (RR = 3.86, CI: 2.05, 7.25) greater than once daily. Unadjusted only associations with seroconversion were independently associated with seroconversion. In addition, accessing methadone maintenance therapy in the previous month (RR = 0.23, CI: 0.09, 0.59) was protective in the final model.
Of the 479 youth in the VIDUS, including baseline prevalent and study period incidence, there were a total of 123 (26%) youth coinfected with HIV and HCV. Table 3 presents the results of our Cochran-Armitage trend test comparing sociodemographic and risk variables between HIV- and HCV-negative youth, monoinfected youth, and coinfected youth. There were clear trends across the 3 categories ranging from no infection to coinfected youth for increasing age (median = 22, 24, 25; P = <0.001), greater number of years injecting (median = 3, 5, 7; P = <0.001), female gender (37%, 43%, 59%; P = <0.001), aboriginal ethnicity (10%, 24%, 45%; P = <0.001), greater than 100 lifetime partners (20%, 34%, 55%; P = <0.001), living in the IDU epicenter (33%, 47%, 71%; P = <0.001), daily cocaine (18%, 44%, 62%; P = <0.001) and speedball (3%, 22%, 26%; P = <0.001) injection, sex trade work (23%, 42%, 63%; P = <0.001), history of sexual abuse (32%, 41%, 47%; P = 0.014), and always using condoms with clients (18%, 29%, 47%; P = <0.001). There were no statistical differences between the 2 groups with respect to daily heroin injection (38%, 61%, 49%; P = 0.110), borrowing needles (38%, 44%, 35%; P = 0.675), and always using condoms with regular (23%, 15%, 17%; P = 0.204) and casual (26%, 23%, 16%; P = 0.072) sexual partners.
Table 4 presents the results of our ordinal logistic regression model comparing risk association covariates across the 3 categories of no infection, monoinfection, and coinfection. Adjusted risk associations for coinfection among the youth were increased age (RR = 1.12, CI: 1.06, 1.19), greater number of years injecting (RR = 1.07, CI: 1.02, 1.13), aboriginal ancestry (RR = 2.89, CI: 1.83, 4.31), residing in the IDU epicenter (RR = 1.85, CI: 1.27, 2.69), daily cocaine injection (RR = 2.15, CI: 1.46, 3.17), and being female (RR = 1.54, CI: 1.06, 2.25).
The number of youth HIV and HCV coinfected identified in this study is concerning. Alarming was the finding that the median age of youth becoming coinfected was 24 years and that they had been injecting for a median of only 3 years. Coinfection was concentrated among young female and aboriginal youth engaged in sex trade work and living in the IDU epicenter. These findings do not bode well for the future of coinfection without the immediate implementation of a comprehensive evidence-based prevention strategy for high-risk youth. Additionally, attention must to be given to working with female and aboriginal IDUs to facilitate the initiation of treatment and begin addressing access- and adherence-related issues among youth who are already living with coinfection.
Baseline Coinfection Among Young Injection Drug Users
There were a number of associations with baseline coinfection identified among youth at enrollment. Youth identified as being coinfected at baseline were older, had been injecting a greater number of years, and were more likely to be female and aboriginal. The finding that the burden of infection lies with female and aboriginal people was consistent with the findings of other studies conducted on HIV prevalence and incidence in this cohort. 16,17,20 These findings were more pronounced among the youth, however, where more than 60% of the coinfections were among female subjects and more than 45% were among aboriginal populations. Additionally, 63% of the youth infected were involved in the sex trade. These findings beg the question why, given the overwhelming vulnerability of young women involved in the sex trade, there are not resources available such as 24-hour services to access clean needles, inject safely, and seek care.
Incidence of Coinfection Among Young Injection Drug Users
Youth particularly vulnerable to acquiring coinfection were frequent cocaine injectors and those who borrowed needles. Cocaine injection has been associated with HIV and HCV incidence in a number of studies, including in our setting in Vancouver, likely because of the more frequent patterns of injection characterizing cocaine use. 13,21 Not surprising was the finding that the use of methadone maintenance therapy in the previous 6 months was protective. In our experience, youth at highest risk for blood-borne infections are females engaged in sex trade work and who use cocaine as well as other drugs frequently. 22 These findings suggest that there is a need for more research on how to make methadone and other forms of substitution therapy more accessible for youth and how to improve harm reduction services such as needle exchange programs to improve access to health care and drug treatment as well as injection safety programs.
When we combined the prevalent and study period incidence of coinfected youth and looked at trends in risk across the 3 categories of no infection, monoinfection, and coinfection, we found several increasing levels of risk associated with coinfection. Confirmed was increasing prevalence among female and aboriginal youth and sex trade across the 3 categories. Additionally, there were clear sexual- and drug-related trends in risk, whereby a history of sexual abuse, a high number of lifetime sexual partners, and greater than once-daily cocaine and speedball injection all increased with the level of infection. Young people, particularly female youth, who have histories of sexual abuse, who face continued predation through sex trade work, and who engage in polydrug use are consistently at high-risk for blood-borne infections in our setting and others. 22–24 Sexual abuse, sex trade work, and drug risk appear to be interrelated with blood-borne infections among youth, suggesting that there is a need for a continuum of care for vulnerable youth that includes sex abuse counseling within drug intervention programs.
In most of our analysis of coinfection among the youth, residing in the DTES, Vancouver's IDU epicenter, was associated with coinfection. In fact, more than 70% of the coinfected youth lived in the IDU epicenter. This is likely related to the higher prevalence of infection among the contacts of study participants residing there. A series of poor public policy decisions have led to the concentration of the epidemic in the DTES. 25 The ongoing public health emergency is not surprising, given that a recent study found that 95% of Canada's drug strategy is directed to law enforcement, 26 despite the fact that there is no study indicating that law enforcement is an effective strategy for dealing with health problems related to addiction. The positive aspect of having communities with IDU epicenters is that high-risk drug-using practices are concentrated in a small area, thus facilitating the implementation of evidence-based public health intervention strategies.
There are several limitations that should be noted with regard to this study. We have included cross-sectional data of the baseline coinfected youth to characterize young IDUs who may be most at risk for coinfection and the types of behaviors they may be engaged in; however, causal inference based on cross-sectional data needs to be interpreted with care. Furthermore, the results may be diluted by combining monoinfected and negative youth; however, despite this potential limitation, there were a number of strong associations found.
Another important limitation was that young IDUs who were HCV-positive at baseline were more likely to return for follow-up, suggesting that youth included in our time to analysis may have been a higher risk group than other populations of young IDUs. As in other observational studies with voluntary recruitment, however, our study may have limited potential for generalization. Although our results are likely not applicable to general populations, despite the loss to follow-up, they likely reflect urban centers experiencing high prevalence of injection drug use and blood-borne infections among these populations. We know of no difference in sampling for the VIDUS project that may have selected for any specific youth characteristics differing from those of other young IDUs. An additional limitation of the present study is that there were insufficient numbers of HIV-monoinfected individuals to explore rates of coinfection among this group. Consequently, we were unable to discern differences between sexual- and drug-related risk between monoinfected to incident HIV- and HCV-coinfected youth. Exploring these issues in future studies would provide significant contributions to the literature.
There are several important issues identified in terms of medical care for this young population. To begin with, identifying such a young coinfected population whose median age is 24 years at the time of infection raises concerns about the morbidity and mortality related to disease progression that these individuals may face over time. 27,28 Studies on treating HIV and coinfection are usually conducted in older populations; thus, little is known about treatment early in disease progression. There is some evidence to suggest that treating HCV before starting HIV therapies may be important for coinfected individuals. 3 Furthermore, IDUs are less likely to receive antiretroviral therapies, especially female and young IDUs, even when such therapies are distributed free of charge. 29,30 Looking at trends in AIDS, less likely to receive therapy are aboriginal and African-American populations, who make up proportionally more of the IDU population in North America. 15,30 Hence, in terms of treating coinfection, young IDUs, particularly marginalized populations, will become increasingly important.
The number of people in this study identified as HIV and HCV coinfected was alarming, particularly in light of their young age. Regardless of differences in transmissibility, the similarity in transmission routes between HIV and HCV may make coinfection a universal phenomenon for high-risk youth living in HIV and HCV endemic areas unless immediate preventative action occurs. Given the scientific uncertainty surrounding appropriate treatment of coinfection and the interaction between the 2 infections, the future life expectancy and quality of life for these youth are under severe threat. The data from this study suggest that this is no small problem and that coinfection may become ubiquitous for young IDUs living in endemic areas.
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