Injection Drug Use and the Hepatitis C Virus: Considerations for a Targeted Treatment Approach--The Case Study of Canada

Journal of Urban Health: Bulletin of the New York Academy of Medicine, Vol. 81, No. 3,  The New York Academy of Medicine 2004; all rights reserved. doi:10.1093/jurban/jth128 Injection Drug Use and the Hepatitis C Virus: Considerations for a Targeted Treatment Approach—The Case Study of Canada Benedikt Fischer, Emma Haydon, Jürgen Rehm, Mel Krajden, and Jens Reimer ABSTRACT Infection with the hepatitis C virus (HCV) is a major public health burden in Canada and globally. The literature shows that injection drug use is currently the primary transmission route for HCV, and that a majority of injection drug users (IDUs) are currently infected with HCV in Canada. This article first reviews the burden of HCV within IDU populations and the transmission risks and the treatment implications specific to IDUs. Traditionally, IDUs have been excluded from HCV treatment unless abstaining from illicit drug use. However, recent research suggests that categorical exclusion is not medically necessary. A series of key questions about the feasibility of offering HCV treatment to IDUs in the specific Canadian context are considered, including concerns related to the motivation of treatment for IDUs, treatment delivery, treatment side effects, HCV reinfection, and the social environment. The article concludes that treatment of HCV-infected illicit drug users is both feasible and may be necessary to reduce transmission and adverse outcomes in this high-risk population. KEYWORDS Canada, Hepatitis C, Injection drug use, Prevention, Treatment. INTRODUCTION Infection with the hepatitis C virus (HCV) and related disease consequences constitute a major health burden in Canada as well as globally.1–3 This situation is aggravated by the fact that the major health consequences of HCV infection—including liver cirrhosis and hepatocellular carcinoma—do not, in many cases, materialize until years or decades after infection. Among the various risk factors for HCV in Canada, injection drug use has emerged as the primary transmission route. Furthermore, the majority of injection drug users (IDUs) appear to be infected with HCV, and the majority of new HCV infections can be attributed to injection drug use.4,5 In this article, we first give a brief overview of HCV risk and epidemiology as it relates to IDUs in the Canadian context. We then outline HCV transmission risk factors within populations of IDUs, followed by a discussion of treatment implications and barriers. Finally, we outline a set of questions and challenges specific to the Drs. Fischer and Rehm are with the Department of Public Health Sciences, University of Toronto, Ontario, Canada; Drs. Fischer and Rehm and Ms. Haydon are with Public Health and Regulatory Policy Research Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Dr. Krajden is with British Columbia Hepatitis Services, and with Pathology and Laboratory Medicine, University of British Columbia, both in Vancouver, British Columbia, Canada; and Dr. Reimer is with the Center for Interdisciplinary Addiction Research, Hamburg, Germany. Correspondence: Dr. Benedikt Fischer, Centre for Addiction and Mental Health, 33 Russell Street, Room 2035, Toronto, ON M5S 2S1, Canada. (E-mail: benedikt_fischer@camh.net) 428 INJECTION DRUG USE AND HEPATITIS C 429 target population of IDUs that will need to be addressed to facilitate much-needed targeted HCV treatment options. THE HEPATITIS C VIRUS BURDEN General Population About 170 million persons worldwide (3% of the global population) are infected with the HCV.6 If not treated, the infection becomes chronic in 50% to 85% of individuals; 10% to 20% of infected persons develop liver cirrhosis within 10–20 years of infection, and 5% to 10% of those with cirrhosis develop hepatocellular carcinoma.7,8 In Canada, it is estimated that 0.8%–1.0% of the total population, or 250,000– 315,000 persons, are HCV infected.1,9 Regional variations exist, with peak HCV prevalence rates in the three largest provinces (British Columbia, Ontario, Quebec).1 Prediction models of the future HCV-related burden of illness in Canada suggest that approximately 4,000 new HCV infection cases are expected each year.10 Estimates propose that the number of patients with HCV-related cirrhosis, liver failure, and hepatocellular carcinoma will likely double by the year 2008; simultaneously, it is expected that the number of HCV-related liver deaths would more than double in that period.1,9,10 The HCV-related health care costs have been estimated at $500 million per annum in Canada to date; by 2010, this cost burden is expected to reach $1 billion (M. Krajden, personal communication, 2002). Similar proportions of the burden of illness related to HCV exists for the United States, where 2.7 million persons have chronic HCV infection; for the period 2010–2019, estimates predict 165,000 deaths from liver disease, 27,000 deaths from hepatocellular carcinoma, $10.7 billion in direct medical expenditures, and societal costs of $75.5 billion in lost productivity related to HCV.11 Injection Drug User Populations IDUs are at particular risk of HCV exposure and infection, related in large part to the method of drug administration that defines the population. For the purposes of this article, injection drug use refers to the injection of any illicit drug, mainly opiates, cocaine, crack, and amphetamines, although IDUs can employ variable routes of drug administration.12 Although the drugs used by IDUs may be different, there are certain HCV transmission-related risks and characteristics that appear regardless of the drug injected. The two major transmission routes responsible for the majority of previous and existing HCV infections in Canada have been therapeutic blood receipt and injection drug use.4 As detection of HCV infection in donated blood and tissue samples has improved substantially and prevention measures have been established, injection drug use remains the single major risk factor for HCV transmission. Between one half and two thirds of HCV infections in Canada are thought to be caused by injection drug use.4,5 A small proportion of the remaining cases of HCV transmission are thought to be attributable to sexual transmission, needle-stick accidents, and tattooing.3,13,14 Although discussion of drug use as a risk for HCV transmission is usually limited to “injection,” other forms of drug administration involving the exchange of blood (intranasal cocaine use and crack smoking) have been identified as possible transmission routes.13–16 Even in light of the evidence pointing toward injection drug use as the primary risk factor for HCV transmission, IDUs remain a relatively understudied population of those with chronic HCV infection.17 Within the high-risk population of IDUs in other Western countries, numerous studies18 have demonstrated anti-HCV positivity rates of 60% to 95%. One of the 430 FISCHER ET AL. strongest predictors of anti-HCV positivity is the duration of injection drug use.19–28 In an ongoing cohort study of untreated illicit opiate users in five cities across Canada, saliva tests indicated 61% anti-HCV positivity.29 Other evidence of the high rates of anti-HCV comes from specific Canadian cities. For example, a cohort of 1,345 injection drug users in Vancouver (Vancouver cohort study of IDUs, VIDUS) demonstrated that 81.6% were anti-HCV positive at recruitment; over a 3-year follow-up period (1996–1999), the originally seronegative cases demonstrated an incidence rate of over 16 per 100 person-years.30 An open cohort of IDUs in Montreal indicated a 70% antiHCV prevalence rate,31 and a Toronto cohort of untreated illicit opiate users selfreported a 56% anti-HCV positivity rate.32 A cohort of drug injecting youth in Vancouver indicated 46% anti-HCV prevalence at baseline,33 and injection drug user populations in Calgary and Winnipeg have indicated anti-HCV prevalence rates of 56% and 60%, respectively.34 INJECTION DRUG USERS AS A DISTINCT HIGH-RISK GROUP FOR HEPATITIS C VIRUS Direct and indirect characteristics and determinants render IDUs a distinct population from the perspective of HCV transmission risk and treatment implications. The determinants related to the high risk of HCV transmission for IDUs are presented in the next section. This is followed by a review of injection drug use–specific HCV treatment challenges. Canadian data are reported if applicable and/or available. Hepatitis C Virus Transmission Risk Overall, IDUs are a distinct risk population for HCV because they have chronic exposure to the virus, are engaged in specific risk behaviors facilitating HCV transmission, and are in a particular social context that increases risk of transmission. Drug Use and Injection Risks Because blood-to-blood contact is the main mode of transmission for HCV infection, a variety of distinct risk factors exists for IDUs in relation to the route of drug administration: injection. The main risk factor for HCV transmission has been shown to be the sharing of contaminated needles and other drug use paraphernalia; front- and backloading, communal mixing and drawing into syringes from the same bags, as well as “booting” and “jacking” (drawing blood into a syringe before injecting) also increase the possibility of blood-to-blood contact.2,3,35–38 HCV may be transmitted more efficiently than human immunodeficiency virus (HIV) as it exhibits higher infectivity,39 increasing the risks of sharing contaminated injection equipment.37,40 Although not all IDUs share needles, the practice is quite common; in one study, 33% of untreated illicit opiate users in Toronto reported having shared needles, and 41% of respondents had shared other works in the last year.32 In VIDUS, of 776 participants who reported active injection drug use in the 6 months before the most recent follow-up, during the period January 1999 to October 2000, there were 27% who reported sharing needles during the 6-month period.41 Daily injection, sharing needles, cocaine injection (which is typically more frequent), and a history of drug treatment have been shown to be significantly correlated with anti-HCV positivity.42 Sharing of injection equipment other than needles is also an important risk factor because blood particles are contained in both syringes and other injection paraphernalia.27 One study found that 54% of HCV infections in IDUs who did not share needles were attributable to cooker/cotton sharing.27 INJECTION DRUG USE AND HEPATITIS C 431 Skin infections related to injection, including abscesses and other open wounds, are also common in IDUs.12 Open wounds on the skin may enhance the transmission of HCV through direct contact with infected blood. Also, IDUs who engage in crack smoking can develop oral sores from burns or cuts,43 which may increase HCV transmission risk through oral crack use paraphernalia. Especially among cocaine-using IDUs, the number of injections per day can be very high, with up to 30 injection episodes during “binge” days; therefore, their risk of blood contact is likely higher than for heroin or amphetamine injectors.38,44 The VIDUS study in Vancouver found that frequent cocaine injection was also associated with needle sharing.41 Cocaine use, injection, and the use of needleexchange programs were key factors associated with the seroconversion to antiHCV-positive status of IDUs in a Vancouver cohort.30 Frequent injection, together with the above-described injection risks, increases the probability of blood contact, thereby enhancing HCV transmission risks. However, knowledge of serostatus may alter injection and drug use risk behaviors. A recent study found that 61% of the sample of 197 out-of-treatment IDUs in Denver, CO, were unaware that they were anti-HCV positive. Participants who were unaware of their anti-HCV-positive status were more likely to share equipment, inject with used needles, and report unsafe injection practices.45 Biological Risks A number of possible immunological determinants that increase HCV transmission risk are present in populations of IDUs. IDUs, especially those also involved in cocaine/crack and polydrug use may be significantly affected by decreased immunocompetence.42,46–49 Increased stress and blood cortisol levels— related to injection drug use behaviors—have been recognized as variables compromising immunity in IDUs.50,51 Decreased immunocompetence may have an impact on the body’s ability to act against exposure to HCV, which is important in light of the high rate of exposure of IDUs to HCV-contaminated blood. However, there are also indications that IDUs may exhibit decreased susceptibility to HCV52 because of their repeated exposure to the virus, although the evidence on this is still unclear.18,53,54 Possible relevant interactions between HCV and other infectious virological diseases have been suggested to occur, with many infectious diseases more common among those with HCV infection in comparison to those without HCV infection.55 Interactions with HIV have been shown to occur on the immunological level, with HIV-infected individuals exhibiting accelerated adverse outcomes and the possibility of increased risk of HCV infection in the presence of HIV.43,56,57 Also, HCV infection is more prevalent in alcoholics,58,59 and alcohol dependence is common in illicit drug users60; thus, IDUs consuming alcohol are at increased risk. There are thus a number of biological factors, most relating to immunosuppression, that may lead to enhanced HCV infectivity in IDUs. Physical Health Risks IDUs, especially those with a long-term drug use history, in general tend to display a poorer health status.12 In a Toronto cohort of untreated illicit opiate users, with a majority of IDUs, 54% of participants reported that they were currently experiencing severe health problems, and 33% reported having been hospitalized in the last 12 months.32 Studies of illicit drug user populations across Canada reported disproportionately high frequencies of medical visits to emergency rooms or physicians; conversely, illicit drug users report a high frequency of medical emergency situations in which required medical help was not 432 FISCHER ET AL. available or accessible.32,61,62 Disproportionate levels of compromised physical health of IDUs may be related in part to greater susceptibility of HCV infection and thus the high rate of HCV within populations of IDUs. Sexual Risks Another risk factor for HCV infection common in IDUs is the disproportionate involvement of the this population in sex trade work and high-risk sexual activities. Although risk for HCV through sexual transmission is low, HCV can be transmitted through high-risk sexual activities, such as unprotected sex, and is exacerbated by sexual contact with multiple partners4; such individuals are also at increased risk of acquiring sexually transmitted infections.63 A study of patients (N = 6,668) of sexually transmitted disease clinics in Edmonton found that engaging in prostitution or trading sex for drugs and not using condoms were significant risk factors for anti-HCV positivity.64 IDUs have also been reported to be more likely than noninjecting drug users to engage in sex trading.65 One study also found a correlation between receiving money for sex and anti-HCV positivity in a sample of IDUs in Harlem, New York28; similarly, selling sex was reported as an independent risk factor for anti-HCV seroconversion in a sample of young IDUs in San Francisco, California.37 In the Toronto sample of untreated illicit opiate users mentioned here, 31% had engaged in unprotected vaginal or anal intercourse in the past year.32 In a sample of IDUs in Toronto, respondents always used condoms more often with clients (53%) than with casual sexual partners (30%).66 Illegal shooting galleries and crack houses often have areas set aside for sexual activities,67 which may further exacerbate the risk of sexually transmitted infections and HCV. Ethnographic data have observed how some IDUs will beg with offers of sex for small amounts of drugs.38 This practice enhances the risk of HCV because the individual may engage in unprotected sex, and the drug received in return may be what was left over after the drug “giver” had already done his or her injection. Highrisk sexual activities are also documented in crack users, specifically involving multiple partners, trading sex for money or drugs, and inconsistent use of condoms.60,68,69 Social Factors Poor health, lack of social integration, poverty, gender issues, and inadequate access to health services are important risk factors for disease in the general population,70 and these risk dynamics are further exacerbated in populations of IDUs.71 In a cocaine-using sample in Vancouver, those with unstable housing conditions were significantly more likely to use emergency room services,62 suggesting a poorer health status for those more economically disadvantaged. Social marginalization—as is, for example, reflected by poverty and poor housing frequent among IDUs in Canada and worldwide61,72,73—is correlated with higher prevalence of HCV risks or infection.2 For example, economic disadvantage has also been suggested as contributing to continued drug use,74,75 and there is evidence that economic deprivation leads to sharing behaviors vis-à-vis syringes, other equipment, and drugs.76,77 The pooling of money to purchase drugs has been found to correlate with HCV seropositivity.37 A few studies have also suggested that unstable housing or lack of a “home” or safe private space is correlated with injection risk and public injection.32,78,79 Many subjects in the study of illicit opiate users in Toronto had injected in outdoor or semipublic areas (including streets, cars, and alleyways).32 Outdoor injection has been shown to be correlated with the reuse of needles not cleaned by bleach,80 although the utility of bleach cleaning in the prevention of HCV transmission is still unclear. INJECTION DRUG USE AND HEPATITIS C 433 Certain sociodemographic variables have also been suggested to influence risk in IDUs, including gender (women more at risk of sharing because of the nature of their social relationships)77,81 and racial or ethnic status.79,82,83 TREATMENT IMPLICATIONS Although the pharmacotherapeutic treatment of HCV in general populations has made great progress in recent years,84,85 there are still a number of key dynamics and characteristics of HCV treatment that are specifically relevant for IDUs and need to be considered to ensure feasibility of HCV treatment in this population. One important consideration is the differential treatment duration and response, which are dependent on the infecting HCV genotype. There are at least six major HCV genotypes and several subtypes, which differ in their geographic distribution.86 Genotypes 1, 2, and 3 are the most common in North America.86,87 Genotypes 1 and 3 are more prevalent in IDUs,35,88–90 although different patterns are observed worldwide.22,91 Although HCV genotypes are generally not related to disease severity,87–89,92 they do affect treatment duration and response. Genotype 1 requires a 48-week course of pegylated interferon/ribavirin therapy with a 40%– 46% probability of sustained viral clearance; in contrast, genotypes 2 and 3 require 24 weeks of therapy, and approximately 76%–82% of treated people respond.46,93–95 Therefore, knowledge of genotype is required to guide treatment duration and response. Potential drug interactions also need to be considered. For example, it has been suggested96 that interferon and pegylated interferon (peginterferon) can lead to an increase in serum methadone levels, especially in the presence of alcohol. This is especially important for illicit opiate users who may begin HCV treatment in the context of a methadone program. Also, there is evidence that alcohol use decreases treatment response rates to interferon therapy.97 Psychiatric comorbidity status and susceptibility are also key concerns for possible HCV treatment, primarily focusing on the frequent and often severe neuropsychiatric (mostly depression, but also psychosis) side effects of interferon therapy regimes. Psychiatric comorbidity (i.e., depression, anxiety disorders, and psychosis) is disproportionately prevalent in drug user populations.98–104 In fact, many illicit drug users have been shown to engage in substance use as a form of self-medication for psychiatric conditions.105–107 HCV treatment and its potential psychiatric side effects may thus initiate a vicious cycle exacerbating drug use and its related risks in this population.108 Although IDUs may disproportionately seek or access certain health care services (particularly emergency services), they also experience barriers to adequate preventive and nonemergency care, including issues of trust and stigma in relation to health care providers, fear of detection of illicit drug use and punitive consequences, and the inability to enter the health care system without a primary physician.32,71 In Australia, HCV-related dynamics of discrimination within the health care system have been recognized as a barrier to HCV treatment access for IDUs and other illicit drug users.109,110 A study of Seattle, Washington, IDUs found that HCV reporting to public health services for the sample was extremely low, and the authors suggested the reasons for this were related in part to the poor access of IDUs to the health care system.111 Thus, a number of treatment issues specific to IDU populations will need to be addressed if HCV treatment is to be provided in an effective manner. 434 FISCHER ET AL. Previous State of Hepatitis C Virus Treatment for Injection Drug Users Until recently, both Canada and the United States suggested that HCV treatment for illicit drug users was not recommended.112 In the United States, for example, it was advocated113 that “[HCV] treatment of patients . . . who are actively using illicit drugs should be delayed until these habits are discontinued for at least 6 months” (p. 24). In Canada, a guide to HCV treatment supported by the Canadian Medical Association114 stated that “[c]ontinued use of injected . . . street drugs will permit re-infection with hepatitis C, so there is no point going for therapy until this habit has been stopped” (p. 69). In an urban population of HIV and HCV co-infected patients in Boston, Massachusetts, assessed for suitability for interferon treatment, 70% were deemed ineligible by infectious disease and hepatology staff in a medical clinic, with active drug or alcohol use cited as one of the main reasons.115 Although the exclusion of illicit drug users from HCV treatment has been rationalized for the most part by specific “contraindications” relating to active drug use, psychiatric comorbidity, and concerns with adherence,108,1156 the categorical barring of illicit drug users from HCV treatment is being questioned.84,116 Rather, it can be argued that stigma and systemic and ideological factors may reflect a populationspecific form of discrimination117 that leads to IDUs being denied treatment.112,118 New Hepatitis C Virus Treatment: The Chance for Hepatitis C Virus Treatment for Injection Drug Users? Over recent years, the new generation of pharmacotherapeutic treatments—specifically peginterferon in combination with ribavirin—has become established as a substantively improved form of therapy for HCV.119,120 The treatment regimes have already been described in the section relating to treatment implications for IDUs. Pegylated interferon by injection can be administered once a week, thus easing compliance and medical visit requirements.84 Psychiatric side effects of this therapy have also been reduced in severity.121 The fact that sustained virological responders clear the virus completely from the body has led to the optimistic conclusion that HCV has become a “curable disease.”122 Therefore, treatment should be made widely available and accessible to those infected to reduce individual and social burden related to HCV infection. Interferon-plus-ribavirin therapy for HCV has also been determined to be a cost-effective approach to treating chronic HCV.123–125 A few encouraging HCV treatment studies have been successfully conducted with the special target population of IDUs. The Table provides data regarding the evaluation of HCV treatment in a selection of studies with samples of illicit drug users. Positive results were found in an experimental HCV treatment study of drug users, with a 36% sustained viral response rate when treated with interferon or interferon/ribavirin combination therapy, regardless of success in the substance use detoxification program.126,127 An Italian study of newly detoxified heroin users (within 2–4 weeks of detoxification treatment) found an enhanced response to interferon alfa-n2b treatment (8 weeks of treatment) for the user group in comparison to controls without a history of drug addiction, although there were no data on sustained virological response.128 An evaluation study of the safety, tolerability, and efficacy of interferon/ribavirin combination therapy in HCV-infected illicit opiate injector patients engaged in methadone maintenance treatment found that the end-of-treatment response rate was similar to that of patients without a history of illicit drug use.129 Researchers in Munich conducted a study of treatment with interferon alfa plus ribavirin for TABLE. Summary of published studies on treatment of chronic hepatitis C in injection drug users Reference Treatment setting Antiviral treatment Number treated 126, 127 128 131 In-/outpatient detoxification Inpatient detoxification Outpatient methadone substitution and unspecific Interferon or interferon/ribavirin combination Interferon Interferon/ribavirin combination 50 47 42 130 Outpatient methadone maintenance Interferon/ribavirin combination 50 Sustained virological response (percentage of patients) 36% Not determined 43% in the methadone substitution group 28% in the former addiction group 54% 435 436 FISCHER ET AL. psychiatric risk groups (n = 81), including psychiatric patients, methadone treatment clients, patients with former addictions, and a control group.130 Virological response of those with drug use histories was comparable to that of the psychiatric and the control groups, although the former addiction group did have significantly higher dropout rates. A Norwegian study131 provided 5-year follow-up data on 27 IDUs treated successfully (sustained virological response) for chronic HCV infection with interferon alpha with or without ribavirin, with all but one remaining HCV-RNA (ribonucleic acid) negative at the follow-up point of 5 years after treatment. However, this study required patients to be illicit drug use free for at least 6 months prior to HCV treatment and did not provide follow-up data on the viral nonresponders. Although the data for these studies are encouraging, the small sample sizes make conclusions on widespread feasibility and effectiveness of HCV treatment for drug users premature. Given that IDUs are currently the major risk population for HCV infection and related disease, the crucial questions are whether these advances in HCV treatment can be generalized into an opportunity for broad-scale HCV treatment for IDUs as well as whether, subsequent to the initiation of treatment, ways can be found to reduce HCV transmission risk in this target population. It indeed seems that the time has come for a targeted and proactive HCV treatment approach for IDUs, and that it is feasible and desirable from a public health perspective. However, the complexity of the problem as well as particular characteristics and needs of the target population of drug users—regarding HCV treatment as well as posttreatment prevention—leave some key challenges for wide-scale operationalization as well as knowledge gaps that require addressing for a fully evidencebased HCV treatment campaign for IDUs. In the following, we outline and discuss key challenges and issues relating to HCV treatment of IDUs: Are IDUs Interested in and Motivated for Hepatitis C Virus Treatment? One cannot categorically assume that HCV-infected IDUs are interested in and motivated for HCV treatment even if it were widely available and accessible. First, many IDUs are not aware of their HCV status45 or are not interesting in knowing. Second, the lives of IDUs are chaotic and described by short-term existential needs and concerns,132 including the need to obtain drugs and funds to buy drugs, being at risk of death or disease from multiple causes, being in conflict with the law, and frequently lack of shelter. HCV treatment may be a low priority for IDUs, especially if there is a lack of acute symptoms related to their HCV status, because it can be many years before more tangible and severe disease consequences materialize. Also, to date there has been no systematic ranking of HCV-related health consequences in the assessment of the global burden of disease, as this has been done for HIV.133 It is therefore difficult to gauge the rank order of HCV in relation to other health consequences related to injection drug use. A crucial research effort would be to address this area to further inform the need and motivation for HCV treatment in IDUs. However, in an ongoing multisite cohort study of untreated users of illicit opiates, the majority of whom are injectors, in sites across Canada (N = 455 at preliminary analysis), 36.9% listed HCV infection and its related complications when asked for their “primary physical health problem.”29 This figure clearly indicates that HCV infection represents a real and tangible health problem in populations of illicit drug users. On the other hand, there is evidence that a considerable proportion of drug users may not be interested in HCV treatment. INJECTION DRUG USE AND HEPATITIS C 437 In Rhode Island, a survey of 306 former IDUs currently in a methadone maintenance program were asked about their willingness to receive interferon HCV treatment. After being informed of the risks and benefits of treatment, the number of treatment injections required, probability of successful therapy, treatment side effects, and the need for liver biopsy, only 53% indicated that they would definitely or probably enter treatment.134 A Swiss study reported the reasons for nonparticipation in HCV treatment for drug users deemed eligible for treatment.116 Among the 28.3% of patients who refused the HCV treatment offered, the main reasons stated for refusal were side effects, the need to have blood drawn, and the need to come in for regular office visits during treatment. On the basis of the above, more information is required to gauge IDUs’ interest and readiness for HCV treatment. How Would Hepatitis C Virus Treatment Best Be Delivered to IDUs? Treatment for HCV in IDUs should be initiated through an individualized approach,118 as for all HCV infected people,112 and there should be no automatic or implicit exclusion of IDUs from treatment.135 Important principles to consider in the operationalization of treatment are the need for effective access and support and a trusting provider environment.136,137 These treatment environment qualities may best be accomplished by utilizing community organizations familiar with and adapted for the special profiles and needs of drug user clienteles. In Canada, the relatively broad availability of needle-exchange and methadone treatment programs,138,139 especially in the urban centers, could provide for some of the supporting infrastructure. A related challenge for effective HCV treatment is attaining maximum adherence to the treatment regime because treatment effectiveness is directly correlated with adherence.140 Although there are widespread assumptions that illicit drug users are not capable of adherence to long-term pharmacotherapeutic treatment regimes, experience regarding treatment of other infectious diseases of drug users (e.g., HIV and tuberculosis) has demonstrated the possibility of comparably “normal” or good compliance rates.141,142 For the most marginalized injection drug use patients, the possibility of peginterferon monotherapy (no ribavirin) may be considered. This treatment regime does not require the daily ribavirin component and may be considered especially in patients with genotypes 2 and 3, for which response rates are as high as 40%, although it is still not as effective as pegylated interferon/ribavirin treatment.120 Embedding HCV treatment into other comprehensive programs of social, health, addiction, or treatment services that drug users trust, need, and frequent regularly (e.g., methadone treatment or needle-exchange program) may facilitate treatment acceptance and adherence; individualized therapy plans and reward systems (e.g., the possibility of methadone “take-homes”) may reinforce desired effects. HCV treatment demonstration projects for illicit drug users in Europe and the United States using a combination of the above strategies have shown positive initial results, with adherence rates of 80% and more.126,129 How Could Treatment Side Effects Be Managed? One of the most problematic side effects of interferon-based treatment for HCV is psychiatric symptoms, primarily depression or anxiety.95,143,144 It has been reported that interferon treatment has initiated such psychiatric episodes in patients with no prior psychiatric history, as well as aggravated symptoms in people for whom they previously existed. As discussed, a disproportionately high number of illicit drug users demonstrate psychiatric comorbidities.145 438 FISCHER ET AL. Self medication dynamics of drug use105–107 were discussed in this article in relation to IDUs and psychiatric status. IDUs may experience novel or aggravated depression symptoms as an HCV treatment side effect and attempt to compensate for these depression effects with more of the “remedy” that exposed them to HCV in the first place (i.e., drug use and its anticipated self-medicating effect). This may undermine the ability for treatment efficacy and adherence and also heighten the chances of HCV reinfection because of drug injection and related risks. The fact that a few experimental HCV treatment studies with psychiatrically comorbid patients have concluded that treatment is possible, safe, and acceptable for such patients when properly monitored129,146 and that antiviral treatment does not per se lead to increased risk of psychiatric side effects130 is encouraging. However, the challenges and range of potential consequences of psychiatric side effects in IDUs are complex. Currently, interferon-related mild-to-moderate depression can be managed with selective serotonin reuptake inhibitors,147 although there is no agreement in the field whether preventive medication therapy is advisable or if the use of antidepressants should be limited to those with symptoms.148 Many psychiatric side effects of interferon therapy are also dose related, so individualized therapy may affect clinical manifestations.144 A thorough assessment of other nonpsychiatric side effects of HCV treatment is also required, including more investigation into the interactions among methadone, alcohol, and interferon.96 How to Prevent Hepatitis C Virus Reinfection of IDUs During or After Treatment? Possible reinfection with HCV is one of the great challenges potentially undermining the long-term success and value of HCV treatment. In IDU patients, this is a particular challenge because the habits of IDUs related to drug use may persist during and even after successful treatment. It is certainly desirable that IDUs will undergo addiction treatment in parallel to HCV treatment, with abstinence from drug use—bearing the main risks of HCV transmission—the possible outcome. However, given that addiction has been recognized as a chronic disease,149 it is unlikely that this result will or can be accomplished in all, or even a majority, of IDUs who are ready to undergo HCV treatment. For a comprehensive HCV treatment strategy for IDUs to work and be worthwhile, it therefore must be part of broad secondary HCV prevention strategies targeting IDUs who are at risk for continued drug use and thus possible HCV reinfection. A small HCV treatment study with IDUs observed rather low HCV reinfection rates by utilizing targeted prevention.131 Comprehensive HCV reinfection prevention strategies aimed at IDUs must build on known and existing prevention measures (i.e., comprehensive risk education, needle exchange, peer outreach programs).150–152 Such programs should also include injection drug use risk interventions that are currently under discussion in Canada, including supervised injection facilities.153,154 Increasing knowledge of HCV for users, as delivered by targeted peer and outreach programs, may also serve to reduce risk behaviors.155 Finally, a further important measure is that the range and diversity of available addiction treatments, including opiate maintenance treatment for opiate-using IDUs, which has been shown to reduce infectious disease risk and transmission.156,157 How to Improve the Social Environment for Effective Hepatitis C Virus Treatment for Injection Drug Users? The role of social determinants and environment in health has been evidenced,70,158,159 and it is widely documented that IDUs are subject INJECTION DRUG USE AND HEPATITIS C 439 to numerous counterproductive socioenvironmental factors that negatively influence their health status. An HCV treatment strategy for IDUs must take into consideration the broad determinants of health to address clinical therapeutic needs. The lack of stable housing, poverty, and lack of access to proper health and social care all contribute to the systemic marginalization of IDUs and represent a powerful barrier barring IDUs from effective prevention and treatment in the Canadian context.71 One critical factor is the criminalization of most IDUs, which hinders many from accessing care because of stigma and other systemic obstacles and may lead to contact with an environment recognized as conducive to HCV transmission: correctional facilities.160 One final factor, with both sociocultural and ethical implications, relates to the social status of drug users and their “deservingness” of receiving expensive medical treatment. In ethical, medical, and general social circles, strong resistance has been expressed against providing drug users with treatment, especially for a disease they were seen as having brought on themselves through their “immoral” drug use behavior.161–163 Specifically, the categorical exclusion of illicit drug users from HCV treatment, as it was proclaimed and practiced until recently,113,114 seems neither medically tenable nor necessary112,116,163; thus, a process of innovative education and acculturation in professional and societal arenas must begin and be translated into everyday attitudes and practice. An interdisciplinary focus is required to share expertise from numerous areas, including hepatology, addiction medicine, and social services.112 CONCLUSIONS The prevalence of HCV among illicit drug users presents a substantial and increasing disease burden of HCV, with significant downstream public health consequences and an ongoing source of HCV transmission. A targeted and proactive approach to address the availability and effectiveness of HCV treatment for IDUs in Canada is urgently needed to determine if this can improve HCV control measures on the population level given the recent feasibility of pharmacological cure. In this article, we have outlined what some of the challenges and needs are for IDUs in the Canadian context. Experimental HCV treatment studies abroad have demonstrated that HCV treatment of illicit drug users is feasible, that it can produce similar outcomes as with non-drug-using patients, that side effects are controllable in this population, and that secondary prevention or treatment programs may be an appropriate and effective vehicle of delivering HCV treatment to drug users. Recently, the NIH Consensus Development Conference on the Management of Hepatitis C,122 declared in the final statement: Recent, albeit limited, experience has demonstrated the feasibility and effectiveness of treating chronic HCV in people who use illicit injection drugs. . . . Thus, it is recommended that treatment of active [IDUs] is considered on a case-by-case basis, and that active [injection drug use] in and of itself not be used to exclude such patients from antiviral therapy. (p. 23) This new consensus statement explicitly underlines the eligibility and need of IDUs for HCV treatment and should be operationalized and evaluated in the Canadian context. The new knowledge coming from treatment studies of IDUs must be further 440 FISCHER ET AL. developed and assessed to determine the utility of treatment as an instrument of reducing the HCV disease burden. However, it is clear that HCV treatment must be part of a comprehensive harm reduction program focusing on HCV itself as well as the wider harms of injection drug use. Other countries have chosen to lead the way with experimental and targeted HCV treatment initiatives for IDUs. From both a public health and an individual welfare perspective, the time is right to combine scientific knowledge and professional action into a targeted and proactive HCV treatment approach for IDUs in Canada. ADDENDUM In the interest of most up-to-date information published in this journal, we would like to refer the reader to two scientific developments that have occurred since the above manuscript was accepted. First, Dr. Robert Remis’ recent comprehensive estimation of HCV prevalence and incidence in Canada in 2002164 essentially confirmed the primary epidemiological contribution of illicit drug use to the HCV burden described in our paper. 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