The prevalence of hepatitis C virus (HCV) among HIV-infected injection drug users (IDU) is approximately 50–70% [1–4]. Recently revised guidelines for HCV treatment state that patients are candidates for HCV therapy regardless of HIV co-infection and ongoing substance abuse . HCV treatment success is defined as viral clearance 6 months after completion of therapy (sustained virological response; SVR) and occurs in approximately 40–50% of those receiving the current standard of care, pegylated interferon plus ribavirin (PEG IFN/RBV) . Recent data from controlled clinical trials among HIV/HCV-co-infected patients suggest decreased but still reasonable response rates (10–40% achieve SVR) among co-infected individuals receiving PEG IFN/RBV [7–10]. It is likely that success rates will improve as existing treatments are optimized and new therapies are developed.
In general, HCV treatment is rarely received by IDU, who represent the largest reservoir of HCV infection. The proportion of HIV/HCV-co-infected IDU who have been treated is even lower [11–13]. The provision of HCV treatment among IDU is affected by many factors beyond the complexity and duration of the regimen, including determinants that affect treatment eligibility and additional factors that impact the need for treatment, the likelihood of success and anticipated tolerability as well as the acceptability of treatment to the IDU. The impact of these medical factors and barriers may be different among HCV-mono-infected and HIV/HCV-co-infected IDU. We propose a framework for understanding factors that affect the utilization of and adherence to HCV therapy for mono-infected and co-infected IDU. Understanding these barriers is crucial to identifying which IDU are most likely to benefit from treatment and which intervention strategies are likely to improve access, utilization and response to HCV therapy.
Hepatitis C virus treatment
Before discussing the factors that affect treatment, it is important to define HCV treatment. Treatment is only one component of management, which also includes counselling to reduce transmission and disease progression. When referring to HCV treatment, we refer to the use of weekly pegylated interferon alfa injections coupled with the daily ingestion of oral ribavirin (PEG IFN/RBV). We refer to this regimen as ‘HCV treatment’ because it is the most effective of the US Food and Drug Administration approved treatments, and consequently is considered the standard of care [5,6,14,15].
The decision as to whether to treat HCV infection involves a calculation of the relative risks and benefits, a calculation that involves a number of factors, some of which fluctuate over time. Collectively, these factors determine a gradient of treatment eligibility, advisability and acceptability (Fig. 1).
Determining hepatitis C virus treatment eligibility
Some individuals are clearly not eligible for treatment . These individuals have absolute or non-modifiable contraindications to treatment. In some cases, this is because there would be no benefit to treatment (e.g. individuals without detectable HCV RNA, indicating viral clearance or life expectancy less than 2 years). In other cases, the risks of treatment are too high (e.g. those with decompensated liver disease).
There are additional contraindications that preclude treatment but are potentially modifiable. Examples of modifiable contraindications include hematological disease (anemia, thrombocytopenia or neutropenia), renal insufficiency, poor adherence to medical care, severe depression with suicidal ideation, and pregnancy or unwillingness to use contraception . It is important to note that these therapy indicators may change over time, and, for that reason, treatment eligibility and risk/benefit assessment should be a dynamic process. Changing eligibility for treatment means that individuals must be carefully monitored because treatment may become less risky for someone for whom treatment was once considered inadvisable, for example, if depression becomes well controlled.
Treatment eligibility by HIV serostatus
Eligibility for HCV treatment may be different for HIV/HCV-co-infected compared with HCV-mono-infected individuals. HIV/HCV-co-infected individuals are more likely to have ongoing HCV infection, and thus detectable HCV RNA. Whereas approximately 20% of HCV-mono-infected patients clear HCV RNA from their blood naturally, HCV clearance occurs in only 5–10% of co-infected patients and is even less frequent in those with low CD4 cell counts [16–18]. On the other hand, the risk of treatment may be greater among HIV/HCV-co-infected individuals because of the increased prevalence of decompensated liver disease, anemia, thrombocytopenia, neutropenia and renal disease [19–27]. Antiretroviral therapy may ameliorate some of these conditions , once again reinforcing the fact that HCV treatment eligibility is dynamic.
In one study that examined treatment eligibility among 144 HIV/HCV-co-infected patients (predominantly IDU) referred for care to an urban health center , 105 (70%) were considered ineligible for therapy. However, only some of the eligibility criteria were absolute contraindications, such as decompensated liver disease (12%) and medical comorbidities (8%). Other eligibility criteria used in that and other studies represent modifiable barriers, including non-adherence to medical visits (23%), active drug or alcohol use (23%) and advanced HIV disease (13%). Even some patients who were excluded because of psychiatric disease might have had moderate, treatable depression .
Modifying medical factors
The potential benefits of treatment are largely determined by medical factors that conceptually can be grouped as those that affect treatment need and those that affect treatment success (advisability).
Assessing treatment need requires a reliable indicator of disease stage, ideally a screening test that can be widely used. Unfortunately, although CD4 cell counts serve this function for HIV infection, no such test exists to stage HCV infection. The best existing measure of the stage of HCV-related liver disease is the liver biopsy. Accordingly, it remains the standard of care to predicate treatment decisions based on the information from the biopsy [5,15]. However, liver biopsies are difficult to obtain, rarely performed on IDU outside of research studies, are expensive, and can lead, albeit infrequently, to serious complications . In addition, there is significant measurement error [31,32]. For these reasons, there are vigorous efforts underway to find alternative ways to stage liver disease.
Other markers, including the results of blood testing for liver enzymes, serum bilirubin and others biochemical markers have recently been investigated (both individually and in combination) with some success as surrogates for liver biopsy [33,34]. Fibrosis markers represent a valuable tool especially for this population in which biopsies may be difficult to obtain because of the cost and risk.
Naturally, information on the stage of disease affects treatment decisions most clearly when disease is either severe or minimal. For example, treatment can reasonably be deferred for individuals with no fibrosis on liver biopsy, whereas it is recommended most for those with severe fibrosis (but not end-stage liver disease, see above) [5,15]. For many individuals the stage of liver diseases is judged to be intermediate, and other factors play a major role in determining treatment advisability.
In most cases, HIV/HCV co-infection has been associated with accelerated progression of liver disease, so the disease stage and subsequent treatment need is likely to be greater in HIV/HCV-co-infected IDU compared with HCV-mono-infected IDU .
The likelihood of treatment success is also an important factor in determining treatment advisability. Success is chiefly determined by the eradication of HCV RNA from the blood by the end of treatment and 6 months after treatment is stopped, an outcome defined as an SVR. With existing HCV treatment, approximately half of the individuals with mono-infection enrolled in clinical studies achieve SVR [6,14]. Response likelihood can be anticipated with greater precision for individuals based on a number of factors, chiefly HCV genotype and viral load [6,14]. For example, response rates are significantly lower among individuals with genotype 1 infection compared with those infected with other genotypes. In controlled trials, SVR rates for PEG IFN/RBV were approximately 40% among individuals infected with genotype 1 compared with more than 70% in those infected with other genotypes [6,14]. Similarly, response rates are lower among those with high pretreatment viral loads  and among African Americans [35,36]. Finally, other co-morbid conditions including diabetes mellitus, hypertension and other co-infections may also affect the likelihood of treatment success.
Although SVR is the stated objective of treatment, it is possible that there could be additional benefit in retarding liver disease progression in individuals who do not achieve an SVR [6,37]. However, this benefit is harder to factor into treatment advisability discussions because long-term studies have not been completed. Further complicating the risk benefit calculation is the fact that the patients most likely to respond to treatment appear to be those least likely to develop serious liver disease . For example, HIV co-infection accelerates HCV disease progression, but reduces treatment success [39,40].
In general, compared with HCV-mono-infected individuals, those with HIV/HCV co-infection have lower treatment response rates, with SVR rates for genotype I reaching only 10% [7,8]. Furthermore, factors described above that influence response are likely to be more prevalent among HIV/HCV-co-infected individuals. For example, HCV-RNA levels are higher in HIV co-infected individuals compared with those that are HCV mono-infected [41,42].
Barriers to care
Important barriers to care exist beyond medical advisability that are likely to impact the acceptability of HCV treatment to IDU. None of these factors preclude an individual from treatment, but they may shift the risk/benefit calculation away from treatment. Some of these barriers exist at the level of the individual, others at the level of the provider, and finally some are structural or environmental barriers. Again, the relative importance of these barriers may be different among HCV-mono-infected compared with HIV/HCV-co-infected IDU.
Low patient motivation
One potential explanation for the limited uptake of HCV treatment by IDU is low patient motivation to undergo a potentially toxic treatment that requires injections and will not always result in cure. IDU are probably not aware of the long-term consequences of HCV infection and may not understand their own risk of progression. Even patients who are aware of these consequences might perceive the risk as being remote because complications are not likely to manifest for many years. Treatment of HCV infection requires the delayed gratification perspective because most will not be feeling sick from their HCV, and other competing priorities, including HIV infection and other health conditions, drug use, unstable housing and income, may take precedence. However, recent data suggest that IDU are willing to undergo therapy in spite of all these factors [43,44].
Willingness to undergo therapy has been examined among groups of HCV-mono-infected IDU as well as HIV/HCV-co-infected IDU. In a multi-center study among HCV-mono-infected treatment-naive young IDU in Baltimore, Seattle and New York City, 82% reported being interested in receiving therapy for HCV. Interest was greatest for individuals who had a higher perceived threat of progressive liver disease and had been told by their physician that they were at high risk of progressing to cirrhosis or liver cancer . Another study that included both mono-infected and co-infected IDU among methadone maintenance participants from Providence, Rhode Island, observed that more than 50% of participants reported that they would definitely or probably be willing to undergo therapy given the success rate of 20%, the requirement for thrice weekly injections, the potential for side-effects and the requirement of a liver biopsy. The study was conducted when patients were primarily being treated with interferon monotherapy, and probably represents conservative estimates now that PEG IFN/RBV therapy is available. Willingness to take therapy was higher for HIV-negative (60%) compared with HIV-positive (36%) individuals, perhaps reflecting previous experience with HIV medication burden or side-effects . It is important to note that in both of the studies, estimates reflect patient intentions based on survey questions and not the proportion actually entering into clinical care. In both of the studies, despite high levels of willingness, very few mono-infected and co-infected IDU actually entered into care.
In one study that specifically examined treatment initiation rates among 44 HIV/HCV-co-infected IDU who were referred for care by their primary healthcare provider and deemed eligible for therapy , the majority (64%) opted not to undergo therapy. The primary reasons for not starting therapy were concerns about potential side-effects, unstable social circumstances and worry about relapsing into injecting again. Of note was the fact that the majority of individuals who refused therapy because of concerns about side-effects had minimal fibrosis . Treatment initiation rates might have been different among patients with more severe liver disease.
Even among IDU who are willing to undergo therapy, there are issues of competing priorities and instability that may impede treatment initiation and success. Addiction is a dynamic process and IDU probably vacillate between periods of heavy drug and potentially alcohol use and periods of more stability in which they may actually be drug free and enrolled in methadone maintenance or other drug treatment programmes or simply abstinent on their own. The nature of their addiction lends itself to living under social stress and instability. Factors such as inconsistent income, unstable housing and frequent incarceration are common, and deprivation of basic essentials of life including housing, meals, medications or transportation all contribute to a general sense of chaos. Even among IDU who want to be on treatment, it can be difficult to prioritize and adhere to treatment for HCV in light of all of these more acute problems.
In a study of predictors of adherence to antiretroviral therapy among HIV-infected IDU in Baltimore, MD, many of whom were HIV/HCV co-infected, the strongest predictor of non-adherence was eating less than two meals per day . In another study of young IDU in Baltimore, homelessness was associated (although not independently) with being less willing to receive HCV therapy . Finally, in a study of HIV-infected IDU, the lack of social stability (defined on the basis of employment status, stable relationships, incarceration and housing) was the only significant predictor of non-adherence to antiretroviral therapy among ex-IDU .
Active injection drug use
Active injection drug use was previously considered to be an absolute contraindication to therapy , primarily because of concerns of compliance among those actively using drugs and a presumed high risk of re-infection. For this reason, pivotal clinical trials of HCV treatment excluded individuals who were actively injecting [6–8,14]. Even IDU enrolled in methadone maintenance were not initially included in clinical trials because there were concerns about relapse into drug use. Although these concerns are to some extent valid, there is now evidence to suggest that some IDU, even those who are not completely abstinent from drug use can successfully complete treatment for HCV .
A number of recent studies have demonstrated the successful treatment of IDU in drug abuse treatment, even when they were not completely abstinent from drug use [11,12]. In a study from Germany , 50 IDU in drug treatment were given interferon or interferon plus ribavirin and 36% achieved SVR. In another study of methadone maintenance patients in California , 78% of 50 patients completed a 6–12 month course of treatment and 64% had an end of treatment virological response. Compared with other treated non-IDU populations, these patients were older, had a longer duration of HCV infection, a higher prevalence of comorbid psychiatric illness and higher rates of liver fibrosis. It is noteworthy that despite these factors, all of which would predispose against virological response, the end-of-treatment response rate was comparable to other trials.
There have recently been attempts to extend HCV therapy to IDU outside of drug treatment settings. In a tertiary care university hospital in Chicago, 120 HCV-infected IDU with a history of recent or current drug use were treated with interferon mono-therapy and 33% achieved SVR . This was not statistically different from the SVR of 37% among non-IDU. Only 43% of the IDU were enrolled in methadone maintenance during the study. Of note was the fact that IDU in that study had high rates of alcohol abuse, pre-existing psychiatric disease and hepatitis B virus anti-core antibodies, all of which might diminish the response to IFN. Compliance and attendance at follow-up visits were over 90% in both groups; 102 of 120 IDU (85%) completed the study, which was not significantly different from the controls (93%). However, it is important to note that IDU were treated overall for longer periods of time because it took them longer to become consistently HCV-RNA negative. Only seven of the IDU in the study (6%) were HIV co-infected and 36% achieved an SVR, which is not significantly different from other groups .
Alcohol use was also a reason for exclusion from clinical trials of HCV treatment, including those among HIV/HCV-co-infected patients [6,9,47]. Heavy alcohol use is associated with more rapid progression of chronic hepatitis C [18,48] and is a common problem among IDU, with anywhere from 30 to 50% reporting heavy alcohol use, alcohol abuse or dependence [38,49,50].
However, in some recent studies, IDU reporting a history of heavy alcohol use have been treated successfully. In one study in which 53% had a history of alcohol abuse, the end of treatment response rate for those who reported a history of alcohol abuse (56%) was not significantly different from that among those who did not (49%, P = 0.26) . In that study, it was not known whether any of the individuals were drinking alcohol at the time of treatment.
Both severe and moderate depression are common among IDU [51,52]. This is further complicated by the fact that interferon treatment for HCV can exacerbate pre-existing depressive symptoms, can result in new depressive symptoms, and in some cases, even give rise to suicidal ideation [53,54]. It is not known whether depression is more common among HIV/HCV-co-infected compared with HCV-mono-infected IDU. Although a few studies have suggested that depression or suicide are more common among IDU who are co-infected with HIV [55,56], the majority of evidence suggests that the frequency of depressive symptoms and suicide attempts are comparable among HCV-mono-infected and HIV/HCV-co-infected IDU [52,57–60]. Among HIV-infected IDU receiving highly active antiretroviral therapy (HAART), depression has been associated with non-adherence , but recent studies have suggested that depression among HIV-infected individuals actually improves while on HAART [62,63].
A handful of recent studies have demonstrated that interferon therapy can actually be safely administered to patients with psychiatric disease. In a study of 50 methadone patients receiving HCV treatment, 62% reported a history of psychiatric diagnosis, the majority being depression or anxiety. Forty-one (88%) were receiving some psychiatric medication by the end of treatment (28 were receiving psychiatric medications before starting HCV treatment and 13 initiated new medications while on HCV treatment). Fifty-four per cent of these 50 treated were end-of-treatment responders, which is comparable to other trials. The rate of treatment discontinuation was 24%, which approximates that of pivotal HCV treatment trials, despite the high prevalence of pre-existing psychiatric disease .
In addition to these individual-level barriers, there are barriers that exist at the level of the provider that would also impact on the acceptability of treatment to both the IDU and the provider. Providers, especially those with limited experience with IDU, may be reluctant to prescribe treatment primarily because of concerns regarding toxicities, perceived adherence and the presumed risk of re-infection. Providers may be even more reluctant to prescribe or refer HIV/HCV-co-infected patients for treatment because of perceptions that treatment may be burdensome and ineffective in these patients and may compromise their HIV treatment . Moreover, IDU may not always have a trusting relationship with their provider, and primary care physicians who often represent the first point of healthcare contact may have limited experience managing patients with HCV infection (especially drug-using patients) and may not provide appropriate referrals. Stigma and discrimination related to drug users can affect medical decision making, even extending to former users who have organized their lives, as has been noted for HIV treatment .
HCV therapy is complicated, requires once weekly injections and is associated with debilitating side-effects. Providers may be reluctant to prescribe HCV therapy to IDU because of their own perceptions of low levels of adherence among IDU. There are few data with respect to adherence and HCV therapy, but there is evidence that drug users can adhere to other medical treatments. Rates of adherence to HAART among IDU in a number of studies ranged from 50 to 90% [66–69], and adherence rates tended to be higher when programmes were specifically tailored to drug users [70,71]. Moreover, a number of studies have suggested that clinicians are not able to predict adherence accurately at an individual level [72,73]. Although there are few data on adherence to HCV therapy, it is possible that adherence rates to HCV treatment would be even higher among those co-infected with HIV, perhaps because of previous experience with HIV treatment or the selection of more compliant patients.
Perceptions of re-infection
Providers may also be reluctant to treat IDU, especially those who are actively using, because of a perceived high risk of re-infection. Data on HCV re-infection rates among treated IDU are limited, primarily because few have been treated. In one study from Germany , among 50 patients who were treated for HCV while undergoing drug treatment, 80% relapsed into drug use after leaving the inpatient detoxification unit. However, none of the patients who relapsed to injection became re-infected within 6 months after completing treatment. In another study of 27 IDU who had been successfully treated for HCV , nine (33%) relapsed into injecting over 5 years of follow-up, but only one became re-infected with HCV. These low rates of re-infection despite high rates of relapse into drug use suggest that counselling received during treatment on safe injection practices may have had an impact.
There is also some evidence to suggest that even IDU who become re-infected may be protected from developing persistent infection because of some immunity acquired from the previous infection. In a study of IDU from Baltimore, MD , the rate of re-infection among 98 IDU who had naturally cleared HCV infection was 12%. However, compared with individuals infected for the first time, HIV-uninfected individuals who became re-infected were 20 times less likely to develop persistent infection. Of note was the fact that clearance rates after re-infection were substantially lower among HIV-positive individuals. Although it is not known if the same immunity is likely to exist after treatment-associated clearance, these findings suggest that the risk of re-infection and subsequent viral persistence may not be as high as previously thought among IDU who clear HCV after treatment.
Recent studies have suggested that young IDU who have been counselled by their provider are more likely than those not counselled regarding the potential long-term effects of HCV infection to want therapy . Appropriate counselling may be less likely to be given to IDU who only have contact with their primary care physician and are not referred to a specialist. Studies have sometimes suggested a conservative management style by primary healthcare providers of patients with HCV infection [76–78]. For example, it has also been observed that providers are most likely to refer patients with elevated alanine aminotransferase (ALT) levels to gastroenterologists . Although data on treating individuals with normal ALT levels is inconsistent, the revised treatment guidelines do not recommend against treating individuals with normal ALT levels . Moreover, ALT levels fluctuate among individuals with chronic HCV , so one ALT measurement is not sufficient to make a decision about treatment, and even a substantial proportion of individuals with persistently normal ALT levels can have histological evidence of liver disease .
There are environmental or system-level barriers that make it difficult for IDU to access care even when individual or provider-level barriers do not exist. A lack of access to basic needs, including housing, transportation, child care, a primary healthcare physician or health insurance all represent major obstacles to care.
It has often been suggested that low rates of HCV treatment stem from a lack of access to primary healthcare. IDU often use emergency rooms as their primary point of healthcare, and many may not have a primary care physician . For these IDU, there may be limited opportunities for entry into HCV care. However, even among some populations who have primary care providers, HCV treatment rates are low. For example, among 182 HIV/HCV-co-infected homeless or marginally housed individuals in San Francisco, 79% of whom had a history of IDU, 94% were in primary medical care and 43% were on HAART (with 40% having > 70% adherence to HAART). Twenty-eight of these patients (21%) were referred to a gastroenterologist, 21 (12%) underwent liver biopsy and only seven (4%) received treatment for HCV infection. Overall, 68% were aware that treatment was available and 42% had actually discussed treatment with their provider. Among those who had discussed treatment with their provider, treatment was not started predominantly either because of patient refusal or deferment by the provider. Ten individuals reported active treatment for depression or substance abuse in preparation for treatment, 37% reported alcohol use, 11% had severe depression, and 35% had mild depression .
Even among IDU who have some source of healthcare, many do not have health insurance. Treatment for HCV infection is expensive and there are currently no mechanisms for third-party reimbursement for HCV therapy. Taking into account stopping treatment for week 24 non-responders, actual drug usage with discontinuation or dose reduction for adverse events (based on clinical trial data), and healthcare resource utilization, including office visits, laboratory tests and contraception, 48 weeks of combination therapy should cost approximately US$12 000 per patient, which is comparable to the cost of one year of therapy for HIV infection . Health insurance should theoretically be less of an issue for HIV/HCV-co-infected patients who can receive HCV treatment free of charge under the Ryan White Care act, which was passed in 1990 for HIV-infected individuals to overcome financial barriers to access medical care. However, as eligibility criteria are set by each state, many working poor without health insurance are ineligible and the utilization of HCV treatment even among co-infected IDU remains low, presumably because of other individual-level barriers described above .
Treatment of HCV infection is available and can result in cure in some who receive a full course. However, even among IDU who are eligible for treatment, there are a number of challenges that will affect the advisability and acceptability of HCV treatment. The relative importance of these factors may be different for HCV-mono-infected IDU and HIV/HCV-co-infected IDU. Whereas HCV care should be made available to all IDU regardless of HIV co-infection, decisions actually to undergo treatment are best made on an individual basis after careful consideration of these issues by the provider and patient. The data collectively suggest a need for novel strategies to identify the group of HCV-mono-infected and HIV/HCV-co-infected IDU who most need treatment, combined with a multifaceted approach to deliver care successfully to this group of IDU.
Although the sheer magnitude of HCV-infected IDU who have not had treatment initially appears daunting, the actual number who need immediate treatment may not be as high as previously thought. The first step is to find individuals who are eligible for treatment. Among those with absolute non-modifiable contraindications, there is little that can be done in terms of treatment, so the focus for these individuals should remain on preventing disease progression, transmission and improving quality of life. It is important to recognize, however, that among those with modifiable absolute contraindications, treatment eligibility can change over time and should be continually monitored.
Among those who are eligible for treatment, there is a pressing need to develop novel, accurate alternatives to the liver biopsy in order to identify the group of IDU who need treatment the most. Access and willingness to undergo liver biopsy are likely to remain low in this population, so research related to alternatives such as non-invasive fibrosis marker panels for the diagnosis of liver fibrosis should be continued and expanded.
Among individuals in whom treatment need may not be imminent, it is important to weigh the risks/benefits of treatment by taking into account many of the factors described above. Addressing these other barriers in turn will improve the likelihood of treatment acceptability and success. Any intervention to overcome barriers to care should include education of IDU. The data do suggest that knowledge of disease stage and the long-term consequences of chronic liver disease may be associated with better treatment uptake. Educating IDU on short and long-term consequences of HCV infection and informing them of their disease will help to guide informed decisions about whether or not to undergo treatment.
The simultaneous education of primary care providers is also needed. There is a need for educational initiatives and guidelines among primary healthcare providers so that IDU can be referred to gastroenterologists, hepatologists and infectious disease specialists for HCV management at an early enough disease stage at which HCV treatment can still be beneficial. Moreover, education related to treating IDU in general will help to maximize adherence and subsequent treatment response. Whereas provider concerns regarding compliance and the risk of re-infection are valid, it is critical that these issues do not globally exclude all IDU from treatment as there is ample evidence that some IDU can adhere to treatment and reduce their risk behavior. The data suggest that perceived adherence is not always accurate so it is not a good idea to exclude someone from treatment because of presumed poor adherence. Perhaps a surrogate measure such as return for clinic follow-up can be used instead as an indicator of compliance. In addition, compliance can change over time, so it is important that it be reassessed at regular intervals.
Drug use, alcohol use and depression all represent major challenges to treatment success among IDU, and it is important that those who need and are ready for treatment for drug addiction, alcoholism and depression have access to it. This can be difficult because IDU may need treatment for more than one of these, suggesting the need for prioritization and individualized decision making.
Treating hepatitis C among those who are actively injecting drugs will remain challenging, although there are data to suggest that this may be possible. More importantly, it is imperative that former IDU not be stigmatized as drug users when being considered for treatment. The data collectively suggest there is at the very least a group of ‘functional IDU’ who can benefit from therapy. Integrating HCV treatment into methadone programmes is one strategy that might increase treatment uptake and success. In general, it is well known that methadone maintenance can help to stabilize IDU [83,84]. Higher levels of treatment adherence are probable among methadone patients because they have to consult with their physician at least once a week (and sometimes as often as once a day), and the evidence demonstrates that treatment in this setting can be successful [11,12]. Unfortunately, methadone treatment programmes can accommodate only 15–20% of the estimated heroin users in the United States, and less than 50% of IDU have a history of IDU treatment [85–87] so other strategies need to be considered.
With recent Food and Drug Administration approval in the USA for buprenorphine as drug abuse therapy, directly observed therapy for HCV in an office-based setting in combination with buprenorphine could provide treatment in the same stabilizing atmosphere as methadone maintenance. The success of linking antiviral therapy to buprenorphine has been demonstrated in the context of HIV treatment, in which HAART adherence improved among individuals receiving buprenorphine . Similarly, linking primary care with needle exchange programmes might be another approach. Correctional facilities represent another potential setting for the delivery of HCV treatment, where clinic visit attendance would not be a factor. It has been estimated that one-third of HCV-infected individuals pass through prisons annually, and the average length of stay is 2 years , which would be sufficient for administering a full course of therapy. A recent study  demonstrated that 46% of 98 individuals, most of whom had a history of IDU, achieved SVR after treatment with PEG IFN/RBV. Finally, for HIV/HCV-co-infected IDU, linking HCV treatment services with HIV care is another feasible option.
Another challenge in treating HCV among IDU are the high rates of depression. However, whereas severe depression with suicidal ideation is an absolute contraindication to HCV therapy, those with moderate depression can be treated . Depression and other mental health issues can be assessed before beginning treatment, and a number of studies have demonstrated the successful treatment of IDU receiving concomitant medication for depression .
Structural barriers such as the lack of a primary healthcare physician and health insurance are additional challenges that need to be addressed. The cost of therapy remains high and is prohibitive for those without insurance. One method to decrease cost would be to treat patients for an initial 12 weeks, stopping therapy if a virological response is not seen.
Perhaps the greatest barrier and most difficult to address in this population is the lack of social stability. Even among individuals who have access to primary healthcare and do not face some of the aforementioned barriers, the chaos resulting from unstable housing, frequent incarceration, unemployment and inconsistent income remains a major obstacle to care. Interventions to increase the utilization of HCV treatment among IDU must work to address some of these issues before treatment will be successful in this population. A multidimensional approach that includes not only concomitant treatment for HIV, drug and alcohol use and depression, but also case management to address the broader issues including unstable housing and unemployment is needed.
In conclusion, HCV treatment for IDU is most likely to be successful in a setting in which programmes are specifically tailored to drug users. This will require collaboration between hepatitis and substance abuse experts so that challenges such as adherence, re-infection, depression and substance abuse and the monitoring of toxicities can be effectively addressed. Integrating HCV treatment into substance abuse programmes and other health or social service settings is likely to be successful if these settings provide the requisite expertise, because it offers an opportunity to provide HCV treatment and social stability simultaneously. Moreover, to prevent re-infection, drug users should be counselled and supported to avoid risky injection behavior. Most importantly, marginalized populations that have HCV infection should not be barred from treatment, but should have knowledgeable clinicians provide ongoing care to address this major public health problem. We have proposed a framework that may be useful for guiding therapeutic decisions among IDU populations. An evaluation of this framework is needed to determine its applicability and feasibility.
Sponsorship: This study was partly supported by Public Health Service Grants DA 16078, DA 04334 and DA12568.
1. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis 2002; 34:831–837.
2. Sulkowski MS. Hepatitis C virus infection in HIV-infected patients. Curr Infect Dis Rep 2001; 3:469–476.
3. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199–206.
4. Thomas DL, Vlahov D, Solomon L, Cohn S, Taylor E, Garfein R, et al
. Correlates of hepatitis C virus infections among injection drug users. Medicine 1995; 74:212–220.
5. National Institutes of Health. Consensus statement on management of hepatitis C. 2002. NIH Consens State Sci Statements
6. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al
. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358:958–965.
7. Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al
. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351:451–459.
8. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A, et al
. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438–450.
9. Neau D, Trimoulet P, Winnock M, Rullier A, Le Bail B, Lacoste D, et al
. Comparison of 2 regimens that include interferon-alpha-2a plus ribavirin for treatment of chronic hepatitis C in human immunodeficiency virus-coinfected patients. Clin Infect Dis 2003; 36:1564–1571.
10. Sulkowski MS, Felizarta F, Smith C, Slim J, Berggren R, Goodman R, et al
. Daily versus thrice-weekly interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected persons: a Multicenter Randomized Controlled Trial. J Acquir Immune Defic Syndr
11. Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of hepatitis C infection in injection drug users. Hepatology 2001; 34:188–193.
12. Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend 2002; 67:117–123.
13. Neri S, Bruno CM, Abate G, Ierna D, Mauceri B, Cilio D, et al
. Controlled clinical trial to assess the response of recent heroin abusers with chronic hepatitis C virus infection to treatment with interferon alpha-n2b. Clin Ther 2002; 24:1627–1635.
14. Fried MW, Shiffman ML, Reddy RK, Marino G, Goncales F, Haeussinger D, et al
. Pegylated (40 kDa) interferon alfa-2a (PEGASYS) in combination with ribavirin: Efficacy and safety results from a phase II randomized, actively controlled, multicenter study [Abstract]. Gastroenterology 2001; 120:A55.
15. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39:1147–1171.
16. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999; 29:908–914.
17. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, et al
. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992; 327:1899–1905.
18. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al
. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000; 284:450–456.
19. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al
. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–569.
20. Belperio PS, Rhew DC. Prevalence and outcomes of anemia in individuals with human immunodeficiency virus: a systematic review of the literature. Am J Med 2004; 116(Suppl. 7A):27S–43S.
21. Semba RD, Shah N, Strathdee SA, Vlahov D. High prevalence of iron deficiency and anemia among female injection drug users with and without HIV infection. J Acquir Immune Defic Syndr 2002; 29:142–144.
22. Burbano X, Miguez MJ, Lecusay R, Rodriguez A, Ruiz P, Morales G, et al
. Thrombocytopenia in HIV-infected drug users in the HAART era. Platelets 2001; 12:456–461.
23. Scaradavou A. HIV-related thrombocytopenia. Blood Rev 2002; 16:73–76.
24. Coyle TE. Hematologic complications of human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Med Clin North Am 1997; 81:449–470.
25. Israel DS, Plaisance KI. Neutropenia in patients infected with human immunodeficiency virus. Clin Pharm 1991; 10:268–279.
26. Monahan M, Tanji N, Klotman PE. HIV-associated nephropathy: an urban epidemic. Semin Nephrol 2001; 21:394–402.
27. Abbott KC, Hypolite I, Welch PG, Agodoa LY. Human immunodeficiency virus/acquired immunodeficiency syndrome-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival in the pre highly active antiretroviral therapy era. J Nephrol 2001; 14:377–383.
28. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: a 12-year cohort study. AIDS 2004; 18:541–546.
29. Fleming CA, Craven DE, Thornton D, Tumilty S, Nunes D. Hepatitis C virus and human immunodeficiency virus coinfection in an urban population: low eligibility for interferon treatment. Clin Infect Dis 2003; 36:97–100.
30. Poynard T, Ratziu V, Bedossa P. Appropriateness of liver biopsy. Can J Gastroenterol 2000; 14:543–548.
31. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38:1449–1457.
32. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al
. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97:2614–2618.
33. Myers RP, Benhamou Y, Imbert-Bismut F, Thibault V, Bochet M, Charlotte F, et al
. Serum biochemical markers accurately predict liver fibrosis in HIV and hepatitis C virus co-infected patients. AIDS 2003; 17:721–725.
34. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001; 357:1069–1075.
35. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004; 39:1702–1708.
36. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350:2265–2271.
37. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al
. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339:1485–1492.
38. Van Thiel DH, Anantharaju A, Creech S. Response to treatment of hepatitis C in individuals with a recent history of intravenous drug abuse. Am J Gastroenterol 2003; 98:2281–2288.
39. Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al
. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:492–497.
40. Monga HK, Rodriguez-Barradas MC, Breaux K, Khattak K, Troisi CL, Velez M, et al
. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 33:240–247.
41. Eyster ME, Fried MW, Di Bisceglie AM, Goedert JJ. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study. Blood 1994; 84:1020–1023.
42. Thomas DL, Astemborski J, Vlahov D, Strathdee SA, Ray SC, Nelson KE, et al
. Determinants of the quantity of hepatitis C virus RNA. J Infect Dis 2000; 181:844–851.
43. Strathdee S, Latka M, Campbell J, O'Driscoll PT, Golub ET, Kapadia F, et al
. Factors associated with interest in injecting treatment for hepatitis C virus (HCV) among young HCV-infected injection drug users. Clin Infect Dis
2005; 15(Suppl. 5)
44. Stein MD, Maksad J, Clarke J. Hepatitis C disease among injection drug users: knowledge, perceived risk and willingness to receive treatment. Drug Alcohol Depend 2001; 61:211–215.
45. Gebo KA, Keruly J, Moore RD. Association of social stress, illicit drug use, and health beliefs with nonadherence to antiretroviral therapy. J Gen Intern Med 2003; 18:104–111.
46. Bouhnik AD, Chesney M, Carrieri P, Gallais H, Moreau J, Moatti JP, et al
. Nonadherence among HIV-infected injecting drug users: the impact of social instability. J Acquir Immune Defic Syndr 2002; 31(Suppl. 3):S149–S153.
47. National Institutes of Health. Consensus Development Conference Panel statement: management of hepatitis C. Hepatology
1997; 26(Suppl. 1)
48. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349:825–832.
49. Crum RM, Galai N, Cohn S, Celentano DD, Vlahov D. Alcohol use and T-lymphocyte subsets among injection drug users with HIV-1 infection: a prospective analysis. Alcohol Clin Exp Res 1996; 20:364–371.
50. Campbell JV, Hagan H, Latka M, Garfein RS, Golub ET, Kapadi F, et al
. Alcohol use among hepatitis C virus antibody positive injection drug users in three US cities.
In: 2nd International Conference on Urban Health
. October 15–18 2003, New York, NY. [Abstract]
51. Golub ET, Latka M, Hagan H, Havens JR, Hudson SM, Kapadia F, et al
. Screening for Depressive Symptoms Among HCV-Infected Injection Drug Users: Examination of the Utility of the CES-D and the Beck Depression Inventory. J Urban Health 2004; 81:278–290.
52. Malbergier A, de Andrade AG. Depressive disorders and suicide attempts in injecting drug users with and without HIV infection. AIDS Care 2001; 13:141–150.
53. Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB, et al
. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987; 147:1577–1580.
54. Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C, Clemens J. Suicidal ideation with IFN-alpha and ribavirin in a patient with hepatitis C. Psychosomatics 2001; 42:365–367.
55. Cochand P, Bovet P. HIV infection and suicide risk: an epidemiological inquiry among male homosexuals in Switzerland. Soc Psychiatry Psychiatr Epidemiol 1998; 33:230–234.
56. Turrina C, Fiorazzo A, Turano A, Cacciani P, Regini C, Castelli F, et al
. Depressive disorders and personality variables in HIV positive and negative intravenous drug-users. J Affect Disord 2001; 65:45–53.
57. Grassi L, Mondardini D, Pavanati M, Sighinolfi L, Serra A, Ghinelli F. Suicide probability and psychological morbidity secondary to HIV infection: a control study of HIV-seropositive, hepatitis C virus (HCV)-seropositive and HIV/HCV-seronegative injecting drug users. J Affect Disord 2001; 64:195–202.
58. Davis RF, Metzger DS, Meyers K, McLellan AT, Mulvaney FD, Navaline HA, et al
. Long-term changes in psychological symptomatology associated with HIV serostatus among male injecting drug users. AIDS 1995; 9:73–79.
59. Kelly B, Raphael B, Judd F, Perdices M, Kernutt G, Burnett P, et al
. Suicidal ideation, suicide attempts, and HIV infection. Psychosomatics 1998; 39:405–415.
60. Richardson J, Barkan S, Cohen M, Back S, FitzGerald G, Feldman J, et al
. Experience and covariates of depressive symptoms among a cohort of HIV infected women. Soc Work Health Care 2001; 32:93–111.
61. Starace F, Ammassari A, Trotta MP, Murri R, De Longis P, Izzo C, et al
. Depression is a risk factor for suboptimal adherence to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 31(Suppl. 3):S136–S139.
62. Judd FK, Cockram AM, Komiti A, Mijch AM, Hoy J, Bell R. Depressive symptoms reduced in individuals with HIV/AIDS treated with highly active antiretroviral therapy: a longitudinal study. Aust NZ J Psychiatry 2000; 34:1015–1021.
63. Alciati A, Starace F, Scaramelli B, Campaniello M, Adriani B, Mellado C, et al
. Has there been a decrease in the prevalence of mood disorders in HIV-seropositive individuals since the introduction of combination therapy? Eur Psychiatry 2001; 16:491–496.
64. Fultz SL, Justice AC, Butt AA, Rabeneck L, Weissman S, Rodriguez-Barradas M. Testing, referral, and treatment patterns for hepatitis C virus coinfection in a cohort of veterans with human immunodeficiency virus infection. Clin Infect Dis 2003; 36:1039–1046.
65. Celentano DD, Vlahov D, Cohn S, Shadle VM, Obasanjo O, Moore RD. Self-reported antiretroviral therapy in injection drug users. JAMA 1998; 280:544–546.
66. Lucas GM, Cheever LW, Chaisson RE, Moore RD. Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection. J Acquir Immune Defic Syndr 2001; 27:251–259.
67. Bangsberg DR, Hecht FM, Charlebois ED, Zolopa AR, Holodniy M, Sheiner L, et al
. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS 2000; 14:357–366.
68. Bamberger JD, Unick J, Klein P, Fraser M, Chesney M, Katz MH. Helping the urban poor stay with antiretroviral HIV drug therapy. Am J Public Health 2000; 90:699–701.
69. Moatti JP, Carrieri MP, Spire B, Gastaut JA, Cassuto JP, Moreau J. Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment. The Manif 2000 study group. AIDS 2000; 14:151–155.
70. Broers B, Morabia A, Hirschel B. A cohort study of drug users’ compliance with zidovudine treatment. Arch Intern Med 1994; 154:1121–1127.
71. Samet JH, Libman H, Steger KA, Dhawan RK, Chen J, Shevitz AH, et al
. Compliance with zidovudine therapy in patients infected with human immunodeficiency virus, type 1: a cross-sectional study in a municipal hospital clinic. Am J Med 1992; 92:495–502.
72. Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al
. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133:21–30.
73. Bangsberg DR, Hecht FM, Clague H, Charlebois ED, Ciccarone D, Chesney M, et al
. Provider assessment of adherence to HIV antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 26:435–442.
74. Dalgard O, Bjoro K, Hellum K, Myrvang B, Skaug K, Gutigard B, et al
. Treatment of chronic hepatitis C in injecting drug users: 5 years’ follow-up. Eur Addict Res 2002; 8:45–49.
75. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, et al
. Protection against persistence of hepatitis C. Lancet 2002; 359:1478–1483.
76. Shehab TM, Orrego M, Chunduri R, Lok AS. Identification and management of hepatitis C patients in primary care clinics. Am J Gastroenterol 2003; 98:639–644.
77. Shehab TM, Sonnad SS, Lok AS. Management of hepatitis C patients by primary care physicians in the USA: results of a national survey. J Viral Hepat 2001; 8:377–383.
78. Shehab TM, Sonnad SS, Jeffries M, Gunaratnum N, Lok AS. Current practice patterns of primary care physicians in the management of patients with hepatitis C. Hepatology 1999; 30:794–800.
79. Inglesby TV, Rai R, Astemborski J, Gruskin L, Nelson KE, Vlahov D, et al
. A prospective, community-based evaluation of liver enzymes in individuals with hepatitis C after drug use. Hepatology 1999; 29:590–596.
80. Haber MM, West AB, Haber AD, Reuben A. Relationship of aminotransferases to liver histological status in chronic hepatitis C. Am J Gastroenterol 1995; 90:1250–1257.
81. Solomon L, Frank R, Vlahov D, Astemborski J. Utilization of health services in a cohort of intravenous drug users with known HIV-1 serostatus. Am J Public Health 1991; 81:1285–1290.
82. Hall CS, Charlebois ED, Hahn JA, Moss AR, Bangsberg DR. Hepatitis C virus infection in San Francisco's HIV-infected urban poor. J Gen Intern Med 2004; 19:357–365.
83. Gronbladh L, Ohlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990; 82:223–227.
84. Marsch LA. The efficacy of methadone maintenance interventions in reducing illicit opiate use. HIV risk behavior and criminality: a meta-analysis. Addiction 1998; 93:515–532.
85. Vlahov D, Anthony JC, Munoz A, Margolick J, Nelson KE, Celentano DD, et al
. The ALIVE study, a longitudinal study of HIV-1 infection in intravenous drug users: description of methods and characteristics of participants. NIDA Res Monogr 1991; 109:75–100.
86. Watters JK. Impact of HIV risk and infection and the role of prevention services. J Subst Abuse Treat 1996; 13:375–385.
87. Hammett TM, Harmon MP, Rhodes W. The burden of infectious disease among inmates of and releasees from US correctional facilities, 1997. Am J Public Health 2002; 92:1789–1794.
88. Allen SA, Spaulding AC, Osei AM, Taylor LE, Cabral AM, Rich JD. Treatment of chronic hepatitis C in a state correctional facility. Ann Intern Med 2003; 138:187–190.