According to the World Health Organization (WHO), approximately 170 million people are infected with the hepatitis C virus (HCV) throughout the world [1]. The annual incidence rate is 3 to 4 million cases, 80% of whom develop chronic hepatitis C. Injection drug users (IDUs, which include both intravenous drug users and those who inject subcutaneously) are the largest group of individuals with established HCV infection; they also have the greatest risk of acquiring the virus. Since HCV-related mortality is estimated to triple by 2030, it is imperative to implement successful strategies to control hepatitis C in IDUs [2].
Since 1992, blood supply screening for HCV antibody (and subsequently for HCV-RNA) has nearly eliminated transfusion-related HCV infections in the developed world. Preventing HCV transmission among IDUs, however, has proved to be more of a challenge. Although strategies to control HCV infection in IDUs have been modestly successful, in most locations they have been implemented inconsistently or not at all. Successful HCV prevention efforts focus on preventing exposure to the virus (by reducing injection drug use), preventing infection among users, and treating HCV with the goal of reducing the pool of infected persons and preventing the consequences of the disease (see Table 1).
This article summarizes interventions designed to reduce morbidity and mortality from hepatitis C among IDUs, the largest population in which the HCV epidemic continues to spread in developed countries. It provides a framework for the implementation of these interventions and recommends important areas for further research.
 | TABLE 1. Strategies to decrease HCV transmission in IDUs |
EPIDEMIOLOGY
Recent studies of IDUs have found HCV incidence rates as high as 25.1 cases/100 person-years in Vancouver and 41.8 cases/100 person-years in London, two cities where large-scale prevention programs for IDUs are in use [3,4]. HCV seroprevalence ranged from 80% to 90% among IDUs in the United States who began injecting before the introduction of human immunodeficiency virus (HIV) prevention measures in the late 1980s and 1990s [5-7]. However, the reported prevalence among younger IDUs who are new to injection drug use is generally < 50% [3,4,8,9], suggesting that HIV prevention measures such as improved access to sterile syringes have also reduced HCV transmission. Data from the United States National Health and Nutrition Examination Survey (NHANES) show that HCV prevalence has remained stable at 1.6 - 1.8% of the non-institutionalized, non-homeless civilian population of the United States during the periods 1988-1994 and 1999-2002. The survey identified injection drug use as the strongest risk factor for HCV acquisition [10]. Because NHANES excluded homeless and incarcerated populations, 2 groups with large proportions of HCV-infected individuals, true prevalence rates are probably underestimated. If homeless and incarcerated persons are included, at least 5 million individuals in the United States are HCV-positive [11]. Currently in the United States, the annual costs related to medical care and work-related absenteeism due to HCV are estimated at $600 million [12]. As well, the direct medical cost of HCV, as extrapolated from economic models, is predicted to increase to $10.7 billion for the 10-year period from 2010 through 2019 [12].
The primary route of HCV acquisition among IDUs is injecting with a syringe previously used by an infected person. Other factors associated with increased HCV risk include a higher frequency and duration of injection drug use, and cocaine use [5,13-15]. Several recent studies have found associations between HCV infection and the sharing of not only syringes but drug solution containers, "cookers", filters, "cottons", and mixing water, suggesting that these items likely also play a role in HCV transmission [8,16,17]. The common practice of giving and receiving injections with the attendant opportunities for direct blood contact has also been suggested as a possible route of HCV transmission [16,18,19]. Other than syringe sharing, however, the exact behaviors that result in HCV transmission are as yet unknown.
PREVENTION OF EXPOSURE BY REDUCING INJECTION DRUG USE
Effective strategies for preventing drug use among youth include educating and training parents, strengthening families, providing alternative venues for building skills and confidence, mobilizing and empowering communities, and other structural approaches [20]. Because HCV can be rapidly acquired after the onset of injection drug use, early interventions that prevent transitioning to that practice is an important facet of HCV control. Such measures include targeting social networks to impact norms and practices, facilitating psycho-social stabilization by addressing unmet needs such as housing and mental health conditions, and providing ready access to effective treatments for substance use, particularly opioid substitution therapy [21,22]. The current inadequate capacity of substance use treatment programs should be expanded to meet existing demands as a crucial strategy to reduce exposure to HCV among both non-injection and injection drug users, particularly adolescents and young adults, who are at highest risk for HCV infection when they start to inject drugs.
PREVENTION OF INFECTION
Most IDUs in the United States who began injecting in the 1980s or earlier became HCV-infected within their first year of drug use [23]. More recent studies conducted in locations where HIV prevention measures, such as streetbased outreach, counseling and testing and needle exchanges have been implemented, have suggested that this window is lengthening with an average time to seroconversion of 3-5 years [24]. Consequently, the time to implement transmission-modifying interventions has increased contemporaneously.
Implementing harm reduction strategies for IDUs such as those outlined above can decrease the risk of acquiring and transmitting HCV. Harm reduction is a model for policy and service delivery with the primary objective of reducing the risk of negative health outcomes in circumstances where complete elimination of risk is not a realistic expectation. Such efforts help reduce high risk behaviors without imposing unrealistic demands for complete change. For people who are unlikely to discontinue injection drug use, interventions with practical objectives can and should be taken to help reduce the harmful consequences of continued drug use. Harm reduction is based on the recognition that people must set their own agenda for behavior change and the observation that drug users take steps to improve their health and well-being when barriers to healthier behaviors are removed [25]. The following paragraphs discuss a variety of interventions to prevent HCV transmission.
HIV prevention efforts
Since HIV and HCV are both blood-borne pathogens, integrating HCV prevention into already existing HIV prevention programs is cost-effective, because it uses existing resources and expertise [26]. To date, HIV prevention programs appear to have had a substantial impact on reducing HCV transmission although further measures are needed to reduce transmission to acceptable levels [27]. Because HCV can be acquired shortly after beginning injection drug use, interventions to prevent HCV acquisition should target IDUs who have recently begun to inject.
Community-based outreach
Community-based outreach programs are effective in helping drug users reduce behaviors that place them at risk for acquiring blood-borne viral infections [28]. Outreach programs train and employ community health care workers, some of whom may be peers, to visit places where IDUs congregate and speak to them about their current health status and general preventive heath measures. Outreach programs should provide education on how to avoid acquiring and transmitting HCV infection, offer safer injection supplies, and provide links to services, including HCV testing and care for infected persons.To prevent HCV transmission, it is particularly important that programs be designed specifically for young IDUs and those who have recently begun injecting.
Access to sterile syringes
Persons who inject drugs need access to sterile injection equipment to avoid acquiring and transmitting HCV and other blood-borne infections [29]. Three steps are required to provide meaningful access. First, lawmakers must repeal paraphernalia and prescription laws that prohibit public health workers and pharmacists from making syringes available and that leave IDUs who legally acquire them at risk for arrest [30]. Second, syringe exchange and distribution programs must be expanded [29,31]. Third, physicians, pharmacists, and the public should understand that providing access to sterile syringes is a lifesaving intervention for IDUs [32-34].
Needle exchange programs (NEPs)
First introduced in Amsterdam in 1984, NEPs have served as an effective means to provide sterile syringes and to dispose of used ones. As well, they link IDUs to other vital services such as primary health care, mental health services, and substance abuse treatment programs. NEPs are found throughout the world and accumulating evidence supports their utility [31]. Evidence demonstrates that HIV prevalence is significantly lower in cities with NEPs compared to those in which they do not exist [35]. As of 2002, the number of programs in the United States had increased to 178 sites in 36 states, Puerto Rico, and Washington, D.C. [36]. Studies of NEP users have demonstrated reduced rates of sharing among HIV negative and positive injectors, decreased rates of re-use, lower incidence rates of HIV, hepatitis B virus (HBV), and HCV as well as higher rates of entry into substance abuse treatment programs. Other services offered at some programs include HIV and HCV testing, HBV and hepatitis A virus vaccination, naloxone (opiate antagonist) distribution, and training to respond to drug overdose.
Local pharmacies
The local pharmacy offers an ideal venue for primary HCV prevention. Pharmacies have the advantage of being more ubiquitous than NEPs or community-based organizations, and their hours of operation are considerably longer. At present, pharmacies in 46 states in the United States (and most of Europe) may legally sell syringes without prescription, because these states either do not have laws requiring prescription for syringes [30,37] or have recently amended them [38-41]. In a few states, legal restrictions prevent pharmacists from dispensing syringes [30]. When the New York State legislature legally expanded syringe access programs in 2001 to enable pharmacists to dispense syringes without prescriptions, IDUs began purchasing syringes from pharmacies and thus significantly reduced their reliance on used syringes [42].
Safe injection facilities (SIFs)
Although NEPs and pharmacies offer venues for obtaining sterile syringes and disposing of used ones, SIFs may provide more comprehensive on-site care than NEPs. SIFs currently operate in the Netherlands, Switzerland, Germany, Australia, and Canada. SIFs are supervised by physicians who oversee the proper use of sterile equipment and manage potential drug overdoses. Among enrollees, modification of high-risk behaviors such as needle and drug paraphernalia sharing, accelerated entry into medical and substance abuse treatment, and reduction of unsafe syringe disposal are some of the proven benefits [43]. In an IDU cohort in British Columbia, the following factors were highly correlated with a desire to visit a site: a) difficulty in obtaining sterile syringes, b) inability to selfinject, c) heroin use greater than once daily, and d) drug use in public places [43]. In 2004-2005, Vancouver's SIF, the only program operating in North America, successfully registered 4764 individuals, referred 2171 (37%) individuals for addiction counseling, and treated 273 drug overdoses without a single death [44].
Health care professionals
Physicians and other health care providers can play vital roles in HCV prevention. Health care providers should become familiar with resources for substance abuse treatment in their communities and be able to refer patients to competent programs when appropriate. They should refer patients who are currently injecting to syringe exchange programs, teach them safe injection techniques, and prescribe syringes to those without safe alternatives [32-34]. IDUs should be instructed not to use syringes, cookers, cottons, or mixing water that have been used by another person. They also should be encouraged to wash their hands and clean the injection site before injecting, and to wash their hands before and after giving injections, because fingers often become contaminated with blood during injection and can transmit HCV. Health care workers should recognize that these interventions are potential lifesavers. Patients who inject drugs should be given biohazard sharps containers or instructed to safely dispose of injection equipment in puncture-resistant containers.
Correctional facilities
Correctional facilities provide an unparalleled opportunity to provide prevention services to a large number of persons at risk for HCV infection. These services are particularly important because injection drug use and HIV transmission are known to occur in prisons. Therefore, preventing HCV transmission in these facilities is especially important. Education on HCV transmission and prevention, testing, and counseling should be offered to all inmates in correctional facilities. Providing clean injection equipment to prison inmates is now politically unacceptable in the United States and is prohibited in most jurisdictions [45], but has been used in Germany and Switzerland since 1998 [46-48].
DISEASE PREVENTION
The high prevalence of HCV in IDUs suggests that the burden of HCV disease will continue to escalate unless interventions designed to avert the consequences of infection are implemented. Screening, HCV therapy and substance abuse treatment are paramount to successful prevention of disease.
Screening
Screening is effective in the prevention of both infection and disease. All patients (and inmates in correctional facilities) should be asked about past and current illicit drug use, and those with a history of illicit drug injection or intranasal cocaine use should be screened for HCV antibody. All illicit drug users and prisoners should be screened for HCV annually, or at intervals commensurate with their risk. A cross-sectional study of Canadian prisoners found that inmates with a history of IDU or incarceration in federal facilities were at a greater risk of continued injection drug use while in prison [49]. HCV-seropositive individuals who have detectable HCV-RNA should be offered anti-viral therapy and substance abuse treatment if medically indicated.
HCV Treatment
Anti-HCV therapy may slow or entirely prevent the development of complications resulting from HCV infection, including cirrhosis and hepatocellular carcinoma (HCC). Unfortunately however, pegylated interferon alpha (PEG-IFNα) and ribavirin, the current standard treatment for chronic hepatitis C, are associated with several side effects [50,51]. HCV treatment in individuals with substance abuse and psychiatric disorders can be successful by effectively integrating providers across multiple disciplines with expertise in hepatitis C treatment, psychiatry, and substance use (see Figures 1 and 2). For example, a study in which IDUs were simultaneously treated for HCV and substance abuse had 36% of patients achieving sustained virological responses (SVR), defined as absence of detectable HCV-RNA 24 weeks after completion of a regimen of standard interferon in combination with ribavirin. There was no difference in response rate between IDUs who relapsed to drug use compared with those who did not [52]. The strongest predictor of achieving an SVR was attending at least two-thirds of scheduled appointments during PEF-IFNα/ribavarin combination therapy [52]. Another study illustrated that IDUs and non-IDUs did not differ significantly in either failure to attend the end-oftreatment (8.2 versus 6.8%, respectively) or SVR (46.6% versus 36.6%) [53]. In addition, re-infection occurred infrequently among those patients who achieved an SVR [54]. Effective HCV treatment also prevents the likelihood of viral transmission to other IDUs.
 | Figure 1. Interventions required for the prevention of infection, disease or both. |
 | Figure 2. Diagram illustrating the management of hepatitis C virus, substance abuse, and psychiatric comorbidities among injection drug users. |
Role of substance abuse treatment in control of HCV
HCV screening and treatment should be incorporated into all types of drug treatment programs. Substance abuse treatment programs vary widely by modality, including detoxification, drug-free outpatient programs, inpatient rehabilitation programs, 12-step programs, therapeutic community programs, methadone maintenance treatment programs (MMTPs) and others. Screening and evaluation for HCV can occur in most settings. Providing HCV treatment in highly structured drug treatment programs such as MMTPs may be optimal because of the high prevalence of HCV among attendees and because the existing infrastructure includes frequent visits in a medical setting, toxicology screening, counseling, and case management. Directly observed therapy (DOT) for hepatitis C treatment may be a practical option because many patients enrolled in MMTPs attend on a daily basis. An estimated 500,000 individuals receive methadone for heroin addiction worldwide and approximately 200,000 are present in more than 1000 United States programs, in spite of the fact that MMTPs in the United States are encumbered by onerous federal regulations, and the total treatment capacity is sufficient for only approximately 10%15% of those in need [55]. Since PEG-IFNα/ribavirin is associated with significant adverse effects [50,51], the structure afforded by MMTPs can play an important role in HCV treatment adherence through DOT and ongoing support, thereby increasing the likelihood of achieving an SVR.
The prevalence of HCV infection among individuals enrolled in MMTPs ranges from 64% to 88% depending upon location and population characteristics [56]. Methadone offers a viable substitute for those with chronic illicit opioid dependency [57,58]. Currently, methadone treatment is often unaccompanied by other health care services; it is also stigmatized, and often viewed as suspect by the public. Nonetheless, methadone treatment reduces the rate of death from drug overdose, HIV infection, and other consequences of heroin use, even in patients who continue to use illicit drugs [59]. Individuals participating in MMTPs are often able to cease heroin and other illicit opioid use and resume normal life activities. In the United States, the recent approval of buprenorphine, a sublingual µ receptor partial agonist that is used alone or in combination with naloxone, has enhanced access to opiate replacement therapy and offers a promising alternative to methadone because it can be prescribed by any physician who has completed a short training course [60].
Treatment strategies (staff training)
It is vital to ensure proper training of substance abuse treatment staff on the prevention and treatment of HCV infection. PEG-IFNα/ribavirin can exacerbate pre-existing psychiatric disorders and substance use. Frequent side effect and sensitivity assessments are required. Staff must also assess MMTP patients for drug relapse and the need for methadone dose adjustments. Patients may be more receptive to the regimented structure when it is coupled with patient-centered care [61]. Specialized training can sensitize substance abuse staff and other health professionals to negative attitudes and behaviors that drug users may encounter when seeking care for co-morbid medical conditions. Regular case conferences and other presentations can also foster stronger subspecialty staff collaboration [62]. Additionally, personnel should be able to identify and triage problems such as extreme fatigue, transient rashes, or bruising. These symptoms and signs can occur as a direct consequence of PEG-IFNα/ribavirin [63], or indirectly because they may be indicative of an underlying condition.
Treatment of psychiatric and substance abuse symptoms during therapy
Side effects of PEG-IFNα/ribavirin include neuropsychiatric symptoms such as fatigue, depression, anxiety, panic attacks, insomnia, aggression and mania in patients with or without preexisting mental illness or substance use disorders [64]. Because of these concerns, treatment guidelines up until 2002 recommended against HCV treatment in individuals with these comorbidities. However, several subsequent studies have shown that individuals with psychiatric and substance abuse disorders can be successfully treated with PEG-IFNα/ribavirin in combination with psychotropic medications with few complications [65]. Symptoms such as fatigue and anorexia, which are frequent manifestations of depression, should be assessed and treated when indicated. While depression may respond to selective serotonin reuptake inhibitors (SSRIs), fatigue may be more amenable to psycho-stimulants, such as methylphenidate or modifinal [66]. Effective management of depression and anxiety as well as prevention of drug relapse include the use of atypical antipsychotics quetiapine, olanzapine and ziprasidone; SSRIs; and benzodiazepines. Alcohol dependence can be treated using naltrexone or acamprosate. Careful patient monitoring is necessary to identify the emergence of hypomanic or mixed mood states that can occur in patients treated with PEG-IFNα/ribavirin in combination with SSRIs.These conditions can be treated successfully with atypical antipsychotics [67-69]. Peer support and group counseling based on a flexible curriculum, including issues related to stigmatization and the ethos of drug abuse, are invaluable to effectively treat substance abuse. Twelve-step programs, outpatient rehabilitation services, group treatment, or individual psychotherapy according to the patient's individual needs, should be encouraged to assist IDUs who want to stop drug use. When possible, integration of support systems including family and friends into the treatment plan can help clients address problems that reinforce problematic substance use [70].
Correctional facilities
Correctional facilities also provide an unprecedented opportunity to safely and effectively treat a large number of persons with HCV infection in a setting where barriers to adherence can be eliminated or minimized [71]. Federal, state, and local correctional departments should be provided the resources to enable the prescription of PEGIFNα/ribavirin and prevention services to prisoners. Treatment for substance use in prison, with opiate replacement therapy, for example, can also be very beneficial for those inmates who need it. Referrals of inmates to MMTPs upon release from prison will facilitate the likelihood of remaining substance-free [72]. For example, among parolees who were untreated for substance abuse while incarcerated, 60-75% relapsed to drug use within 3 months of release [72]. A parallel rise in criminal activity, overdose, re-incarceration, and death occurs when IDUs recommence drug use upon release [72]. Hepatitis C treatment can be facilitated with treatment for concurrent substance abuse, thus helping to avert drug use relapse and its consequences.
BENEFITS OF CONTROLLING HCV
Tremendous individual and societal advantages can accrue through control of HCV transmission among IDUs. For the individual, long-term complications of cirrhosis, such as ascites, variceal bleeding, encephalopathy, liver failure, and HCC can potentially be averted. Furthermore, HCV can have a strong impact on quality of life: approximately 45% of HCV-infected individuals experience worsening fatigue and 39% are unable to perform activities of daily living and maintain employment [73]. Additional evidence of the effect of HCV on quality of life comes from a cohort study of welfare recipients in Texas, where only 25% of seropositive welfare recipients remained employed after 1 year of follow-up versus 45% of seronegative recipients [74]. Besides HCV seropositivity, these patients may also have had other issues, such as mental illness or drug or alcohol dependence, which might have interfered with employment. These findings justify a multidisciplinary approach to HCV treatment.
On a societal level, enrolling individuals with hepatitis C into governmental assistance programs, such as welfare or disability initiatives that provide access to treatment for both hepatitis and substance abuse can have a positive effect in controlling HCV transmission, thereby decreasing the number of infected people and potentially resulting in cost savings. Substance abuse treatment should be intimately linked to HCV treatment, and IDUs should have the opportunity to avail themselves of both types of treatment at the same time.
FUTURE DIRECTIONS
As the HCV epidemic continues to increase, prevention and treatment strategies to effectively control HCV transmission among IDUs are increasingly important. In addition to improving quality of life for individuals, these strategies have the potential to diminish the anticipated future burden on health care systems, especially those that treat IDUs or prisoners.
Public health authorities should fund proven health initiatives that reduce HCV transmission such as those discussed in this article [25]. Legislative bodies should fund and implement the interventions discussed here and remove legal barriers to safe syringe access such as those prohibiting needle exchange, distribution, and possession. HCV prevention and treatment programs must be tailored to the specific needs of IDUs, as all programs will not necessarily benefit all individuals. More research is needed to elucidate the natural history of HCV in IDUs and to develop methods to prevent HCV among first-time injectors [25]. Research is needed on methods of treating active IDUs for hepatitis C to better define the critical elements of successful programs and to increase the proportion of patients who can be effectively treated. With regard to correctional facilities, studies are needed to determine the effectiveness of HCV prevention education programs and the optimal methods to treat HCV among incarcerated individuals. As well, research is required to determine rates of re-infection among IDUs previously treated successfully for HCV and to evaluate the impact of societal efforts to reduce substance abuse, relapse, and infection [25]. Multidisciplinary methods that encourage integration, cooperation, and communication among hepatologists, substance abuse specialists, and psychiatrists have the highest likelihood of successfully controlling HCV among IDUs.
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