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Addiction. Author manuscript; available in PMC 2013 October 28.
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PMCID: PMC3810138

Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patients



Hepatitis C virus (HCV) infection is a common chronic complication of injection drug use. Methadone maintenance programs contain large numbers of patients infected with HCV. This paper reviews HCV infection with emphasis on the medical care of HCV-infected, or HCV and human immunodeficiency virus co-infected, patients on methadone or buprenorphine maintenance.


Literature searches using PubMed, PsycINFO and SocINDEX were used to identify papers from 1990–present on antiviral therapy for HCV in methadone maintenance patients and on liver transplantation in methadone maintenance patients.


Injection drug use is the most significant risk factor for HCV infection in most western countries. The prevalence of HCV antibody is high in injection drug users (53–96%) and in patients enrolled in methadone maintenance programs (67–96%). Studies of antiviral therapy for HCV in methadone maintenance patients show rates of sustained virological response (SVR), defined as negative HCV-RNA 24 weeks after the end of treatment, of 28–94%. In studies with contrast groups, no significant differences in SVR between methadone and contrast groups were found. Excellent completion rates of antiviral therapy (72–100%) were found in five of six studies. There are many barriers to methadone maintenance patients’ receiving antiviral therapy, and research on overcoming barriers is discussed. Liver transplantation has been successful in methadone maintenance patients but has not been utilized widely.


High quality medical care for all aspects of HCV infection can be provided to methadone maintenance patients. The literature supports the effectiveness of such services, but the reality is that most patients do not receive them.

Keywords: Antiviral therapy, buprenorphine, hepatitis C, injection drug use, liver transplantation, medical care, methadone maintenance


Hepatitis C virus (HCV) infection is a common and potentially serious chronic complication of injection drug use [1]. For patients who self-administer heroin or other illicitly used opiates and who have developed tolerance, methadone maintenance will be the most effective treatment [2,3]; buprenorphine/naloxone is also effective [4,5]. Methadone maintenance treatment prevents narcotic withdrawal, reduces or eliminates heroin or other opioid self-administration by people addicted to opioids and facilitates social rehabilitation. Methadone maintenance programs contain large numbers of patients infected with HCV. This paper reviews HCV infection with emphasis on the data that are most important for the medical care of HCV-infected methadone maintenance patients and includes a detailed analysis of published reports on antiviral therapy of HCV infection and liver transplantation in these patients.


Specific searches were conducted on antiviral therapy and methadone maintenance, and liver transplantation and methadone maintenance, in January, June, October and December 2007. Searches were also conducted for antiviral therapy and injection drug use because papers on this subject may include methadone maintenance patients. Search terms used were: hepatitis C, HCV, methadone, methadone maintenance, antiviral therapy, interferon, ribavirin, injection drug use, IDU and liver transplantation.

All searches were limited to the English language and were made using PubMed (; in October 2007 the searches were also conducted on PsycINFO and SocINDEX. Searches included reports from 1990–present.

We found 11 papers containing data on antiviral therapy for HCV infection in methadone maintenance patients [616]. We excluded one study in which some methadone maintenance patients were included in a larger group of injection drug users without delineation of specific results in methadone maintenance patients [8], two papers which were retrospective [11,12] and one [16] which did not have as a stated aim [17] the study of methadone maintenance patients. Two of the papers reported on the same patients [6,10] (the earlier study [6] reported preliminary results due to the urgent need to document feasibility of antiviral treatment in methadone maintenance patients) and are considered together. Six papers [7,9,10,1315] were evaluated for quality items that were derived from other publications [17,18]— documentation of inclusion and exclusion criteria [17,18]; similarity of comparison groups at baseline [18]; intention-to-treat (ITT) analysis used [18]; and withdrawals and dropouts described [18]—or developed by us—comparison of methadone maintenance patients with and without a sustained virological response (SVR), defined as a negative HCV-RNA 24 weeks after the end of treatment; or a prolonged follow-up to assess for re-infection with HCV. Quality items were graded as present, partial or absent. For liver transplantation, all studies showing results of transplantation in methadone maintenance patients are included.


Hepatitis C virus (HCV) is a RNA virus which is related closely to the flaviviruses but is unrelated to other hepatitis viruses [19,20]. A hallmark of HCV is genetic variability, manifested as differences in genotypes and quasispecies. Genotypes of HCV are major genetic groups which can have sequence variability as great as 35% [20]. There are six genotypes and more than 50 subtypes [20,21]. In Vienna, Austria, the prevalences of HCV genotypes 1, 2, 3, 4 and 5 in 250 patients (30% injection drug users) were 74.8%, 2.8%, 16%, 5.2% and 0.4%, respectively [22]. In 438 patients from 10 centers in the United States (24% injection drug users), the proportions of patients with genotypes 1, 2, 3 and 4 were 71.5%, 13.5%, 5,5% and 1.1%, respectively [23]. In a study of injection and non-injection drug users from Flanders, Belgium, 48.7% had genotype 1, 1.4% had genotype 2, 41.2% had genotype 3 and 8.8% had genotype 4 [24]. Genotypes have a major impact on response rates to antiviral therapy for HCV infection, with genotypes 2 and 3 responding more often and with shorter treatment duration than genotypes 1 and 4. The distribution of genotypes is therefore of great importance in interpreting studies of antiviral therapy [20].

Quasispecies are a mixed population of HCV sequences within a given individual [20]. They are closely related but not identical. Quasispecies may contribute to the chronicity of HCV infection, the response or lack thereof to antiviral therapy and the difficulties in HCV vaccine development [20].

Injection drug use is by far the most significant risk factor for HCV infection in most developed countries. In an analysis of the 1999–2002 National Health and Nutrition Examination Survey (NHANES) from the United States [25], the adjusted odds ratio for the association of injection drug use with the presence of antibody to HCV (anti-HCV) was 148.9 [95% confidence interval (CI) 44.9–494]. In contrast, the adjusted odds ratio for blood transfusions before 1992 (the year that HCV screening of transfused blood was fully implemented) was 2.6 (95% CI 0.9–7.3). and for 20 or more life-time sexual partners it was 5.2 (95% CI 1.5–18.2) [25]. The prevalence of anti-HCV in the United States was found in this study to be 1.6%, corresponding to 4.1 million people. The prevalence of HCV-RNA-positivity, reflecting viremia and chronic infection, was 1.3%, corresponding to 3.2 million people. The true prevalence of chronic HCV infection may be higher, as the NHANES study did not include homeless or institutionalized people [25]. Also, the association of anti-HCV with injection drug use may be even stronger, as the memory of experimentation with drug injection may be suppressed, forgotten or withheld at the interview [26].

Sexual transmission of HCV is possible but inefficient. Within antibody-discordant couples, sexual transmission of HCV is rare [2729]. In studies from the United States and Europe that used genotyping, the prevalence of the same genotype in non-injecting heterosexual partners of people with HCV-associated chronic liver disease is 2–3% [29]. In studies of injection drug users, sexual practices did not correlate with HCV infection [28,30,31]. Sexual transmission of HCV is much more likely, however, with co-infection with HCV and human immunodeficiency virus (HIV) [32,33].

Injection drug users have very high prevalences of anti-HCV, ranging from 53 to 96% [3440]. Lower prevalences, 27–46%, are seen in younger patients [41,42]. HCV can be acquired rapidly by injection drug users, with 65% positive for anti-HCV after 1 year or less of injection drug use [35] and 77% positive after 1–2 years [30]. Among people injecting for 10 or more years 94% were positive for anti-HCV [30], and in current or former injection drug users with biopsy-proven chronic liver disease, 98% were positive [43]. Data from the early 2000s have revealed declines in the prevalence of HCV infection among injection drug users, attributed to increased awareness of risk factors for HIV and HCV infections, syringe exchange programs and availability of methadone maintenance treatment [44,45].

Studies in methadone maintenance programs conducted after initial enrollment reveal seroprevalences ranging from 67 to 96% [31,4650]. Methadone maintenance treatment reduces and often eliminates heroin injection, and it therefore could prevent acquisition of HCV in those who are seronegative at the time they enter treatment [2,51]. Seroconversions to HCV during methadone maintenance treatment are due to injection of heroin or other drugs, often as a result of inadequate methadone dose or interruption of treatment [36,48,52].

Acquisition of HCV infection is subclinical in most patients [53]. Acute HCV infection is diagnosed infrequently, but as anti-HCV does not confer protective immunity more than one episode may occur in a person with multiple exposures [54]. Fulminant HCV infection is very rare [55].

Chronic HCV infection occurs in 55–85% of any group of exposed people [56,57]. HCV infection is characterized by continuous viral replication and rarely resolves spontaneously [53]. Serum transaminases are normal or mildly elevated and may fluctuate over time. Transaminase abnormalities with minimal or no symptoms are often the initial finding. Chronic HCV infection leads usually to hepatic necroinflammation and fibrosis, assessment of which requires liver biopsy. Transaminase levels correlate poorly with liver biopsy findings. Some patients with normal transaminases have significant liver fibrosis [58,59]. In most United States methadone clinics, routine testing is only with liver transaminases for cost containment, and cases of HCV infection are missed [60].

After 20–30 years of chronic HCV infection, 5–20% of persons will progress to cirrhosis [59]. Hepatocellular carcinoma may develop in patients with cirrhosis and HCV infection at a rate of 1–4% per year [53]. Cirrhosis from chronic HCV is the most common indication for liver transplantation [61]. Hepatic cirrhosis has been found to be more common in users of both alcohol and drugs by injection compared with users of alcohol alone or drugs by injection alone [62,63]. Many studies have shown that liver fibrosis in chronic HCV infection progresses more rapidly in patients with significant use of alcohol [6467]. Even moderate drinking (20–50 g alcohol daily) may increase the rate of liver fibrosis in chronic HCV infection [64,68]. Alcohol use reduces responsiveness to antiviral therapy for HCV infection [66,69]. A safe level of alcohol intake for patients with HCV infection has not been established [66,67], and abstinence from alcohol is the best advice for patients with this disorder. Age greater than 50 years at the onset of HCV and male gender are also important factors in fibrosis progression [70]. In HCV-infected patients who also have chronic hepatitis B virus infection, there may be more severe chronic liver disease and an increased risk of hepatocellular carcinoma [71].


Antiviral therapy of chronic HCV infection is improving. Interferon monotherapy was the earliest regimen followed in the late 1990s by combination treatment with interferon and ribavirin. Recent advances have involved pegylated interferons. The attachment of polyethylene glycol to the interferon molecule results in reduced clearance and prolonged half-life, allowing once-weekly dosing [72]. In addition, the wide fluctuations in plasma levels seen with standard interferon are avoided.

The primary endpoint of antiviral therapy for HCV infection is the SVR, defined as undetectable HCV-RNA 24 weeks after the end of treatment. The efficacy of treatment is also assessed using the rapid virological response, defined as undetectable HCV-RNA after 4 weeks of treatment, and the early virological response (EVR), defined as undetectable HCV-RNA or a decrease in HCV-RNA level of 2-log or greater at 12 weeks [73].

The currently recommended treatment is peginterferon α-2a 180 µg subcutaneously weekly or α-2b 1.5 µg/kg subcutancously weekly, plus oral ribavirin, 1000–1200 mg daily based on body weight. In a large clinical trial of 48 weeks of treatment, peginterferon α-2b plus ribavirin yielded a SVR of 54%, compared with 47% for interferon α-2b plus ribavirin [74]. Among genotype 1-infected patients, 42% responded to peginterferon α-2b and ribavirin versus 33% to interferon and ribavirin [74]. A study of peginterferon α-2a plus ribavirin given for 48 weeks showed a SVR of 56% in all patients and 46% in genotype 1 patients, results significantly better than in the comparison groups [75].

Some patients have improvement in liver histology after peginterferon treatment for chronic HCV infection despite failure to achieve SVR [74,76,77]. Also, pooled data in 3010 recipients of antiviral therapy for chronic hepatitis C who had pre- and post-treatment liver biopsies showed that treatment reduced the rate of progression of fibrosis and the incidence of cirrhosis [78]. This effect was most common in patients who had a SVR, but also occurred in others. In patients with cirrhosis on their initial biopsy, improvement in fibrosis (‘reversal of cirrhosis’) was seen in 49% [78]. Only one-third of those had a SVR.

Patients with genotype 1 should receive 48 weeks of therapy for HCV as long as they achieve an EVR. Discontinuation of antiviral therapy should be considered strongly if EVR is not achieved, but more prolonged treatment may be helpful [73] for those with cirrhosis or bridging fibrosis (liver biopsy showing connective tissue bridges that link portal tracts with other portal tracts or central veins, but no regenerative nodules indicating cirrhosis) [79]. Patients with genotypes 2 or 3 can be treated with 24 rather than 48 weeks of peginterferon and ribavirin and a lower dose of ribavirin, 800 mg daily [80]. A SVR rate of 84% has been reported with this regimen [80]. Extensive research is in progress to develop new and improved therapies [57,59]. Recent studies have suggested that treatment efficacy may be enhanced by prolonging antiviral therapy to 72 weeks in genotype 1 patients who have detectable HCV-RNA at 4 or 12 weeks but none at 24 weeks [73,81,82].

Side effects of peginterferon and ribavirin include flu-like symptoms, anemia, neutropenia and thrombocytopenia [83]. The flu-like symptoms caused by interferon may resemble opiate withdrawal. Methadone disposition is not altered significantly by peginterferon α-2a [84] or α-2b [85,86]. Peginterferon can cause psychiatric symptoms, including malaise, irritability and depression [83]. Family members and opioid treatment program personnel can be enlisted to help monitor for these symptoms, Rarely, acute psychosis, suicide attempts or completed suicides have occurred in patients without addictive diseases receiving interferon products. Severe psychiatric symptoms necessitate discontinuation of therapy, but milder ones can be managed with antidepressants and possible peginterferon dose reduction. Psychiatric consultation is not mandatory in all cases of depression, but will often be helpful [87]. Ribavirin is contraindicated in pregnancy, and males should not father children while taking the drug and for 6 months following treatment.

Although one study suggested that superinfection with hepatitis A virus may increase the risk of fulminant hepatitis in patients with chronic HCV infection [88], others have not confirmed this [89]. Hepatitis A [89] and B [90] vaccinations of susceptible HCV-infected patients are recommended.

In June 2002, the US National Institutes of Health (NIH) convened a Consensus Development Conference on hepatitis C [58]. The conference report recommended increased consideration for antiviral therapy of patients in methadone maintenance treatment, injection drug users who are likely to comply with therapy, and patients with co-infection with HCV and HIV. All patients are potential candidates for treatment, but those with little or no fibrosis may reasonably choose observation.

Table 1 shows the results of treatment of HCV-infected methadone maintenance patients with interferon or peginterferon and ribavirin. Two studies included some buprenorphine-maintained patients [13,14]. The rates of SVR in maintenance patients in these reports ranged from 28 to 94%. Three studies assessed the statistical significance of the SVR rate in methadone maintenance patients versus contrast groups, and all found no difference [7,9,15]. In one report [9], methadone maintenance patients had a higher rate of discontinuation of antiviral therapy in the first 8 weeks but not subsequently. In the other five studies, 72–100% of maintenance patients completed antiviral therapy. None of the three papers with contrast groups showed an increase in psychiatric side effects in methadone maintenance patients [7,9,15]. Sylvestre et al. reported a modest decrease in SVR rate in patients with a pre-existing psychiatric history [10].

Table 1
Prospective studies of antiviral therapy for chronic hepatitis C virus infection in methadone maintenance patients.

The quality of this published work on antiviral therapy of HCV in methadone maintenance patients is variable. As Mauss et al. indicate, a randomized trial comparing HCV treatment in patients on, versus not on, opioid maintenance, is not feasible [9]. Five of the papers listed in Table 1 provided inclusion and exclusion criteria, and one did so partially [13]. In two [7,1 5] of the three studies with contrast groups there were some baseline differences between the methadone and contrast groups. Mauss et al. matched control patients for sex, age, HCV genotype and HCV-RNA [9]. Five of the six studies used an ITT analysis. One group from Norway planned to study all genotypes but decided later to publish data only on genotype 3, the predominant genotype there, because only three non-genotype-3 patients were enrolled [14]. Four reports described withdrawals and dropouts adequately, one did so partially [15] and one had no dropouts [14]. Three studies compared methadone patients with and without SVR [9,10, 15]. None address the issue of HCV re-infection after SVR; a few studies of this in drug users who continue to inject describe a low incidence [91,92].

We conclude that the literature strongly supports the feasibility of antiviral therapy in methadone maintenance patients with HCV infection. This treatment can be effective, but additional studies with larger numbers would allow stronger conclusions regarding efficacy. Future studies should ideally be prospective; should have the study of methadone patients as a specific aim; should include data on the numbers of patients who were evaluated, were eligible for the treatment and who actually entered the study; should compare patients with and without SVR; and should have a prolonged follow-up. There is no scientific or clinical reason to withhold antiviral therapy from methadone or buprenorphine maintenance patients. Three groups have reviewed antiviral therapy for HCV infection in current or former injection drug users, and all support increased efforts to treat such patients [87,93,94].


Injection drug use is a major route of transmission of both HIV and HCV. Overall, about 15–30% of HIV-positive individuals are co-infected with HCV [95,96]. In methadone maintenance patients, the prevalence of HIV and HCV co-infection will be significantly higher because, as discussed previously, 67–96% of methadone maintenance patients are infected with HCV [31,4650]. A small number of patients with HIV infection may be seronegative for anti-HCV despite having HCV infection with HCV-RNA positivity [97]. Compared with HCV alone, HIV and HCV co-infection is associated with higher HCV-RNA levels [98,99] and a more rapid progression to cirrhosis [98100]. Co-infected patients who are treated with antiretroviral therapy are living longer and arc thus more likely to develop complications of, and mortality from, HCV-associated liver cirrhosis [101].

Several of the antiretroviral medications used to treat HIV infection may cause hepatotoxicity, which may be manifested as asymptomatic elevations of liver transaminases or, less frequently, clinical hepatitis [102]. Nevirapine commonly causes clinical hepatitis, and some cases may be part of a hypersensitivity syndrome including rash, fever and eosinophilia [102]. Nucleoside reverse transcriptase inhibitors used to treat HIV infection can cause a syndrome of lactic acidosis and hepatic steatosis that has a high mortality [102,103]. In HIV-infected patients receiving protease inhibitors, co-infection with HCV is associated with an increased risk of hepatoxicity which is thought to be secondary to toxic metabolites [104,105] or immune reconstitution from effective HIV therapy [102]. Several of the medications used to treat HIV infection have significant interactions with methadone; these have been comprehensively reviewed elsewhere [106108].

Antiviral therapy for HCV can be effective in patients with HIV/HCV co-infection. In three studies of 48 weeks of treatment, peginterferon α-2a or α-2b plus ribavirin was superior to interferon plus ribavirin in patients infected with HIV and HCV [109111]. In genotypes 2 and 3, a full 48 weeks of antiviral therapy is recommended for HIV/HCV co-infection [109,112]. Antiviral therapy of HCV infection may be discontinued in co-infected patients who do not achieve an EVR [113]. Control of HIV disease is generally maintained during treatment of HCV infection with peginterferon and ribavirin.

For most patients with HIV/HCV co-infection, treatment of HIV with effective antiretroviral therapy will be the first priority. A recent study suggests that enrollment in methadone maintenance treatment can lead to improved adherence to antiretroviral therapy [114]. In early HIV infection, or when there is no HIV viremia, therapy for HCV infection may be initiated. Patients with HIV/HCV co-infection and CD4 counts under 100 × 106/1 should not be treated with antiviral therapy for HCV infection because interferon-induced myelosuppression may cause further decreases in CD4 counts leading to opportunistic infections [115]. In co-infected patients who receive peginterferon and ribavirin, clinicians will need to watch for drug interactions and overlapping toxicities. Ribavirin inhibits phosphorylation of zidovudine and stavudine in vitro [102,112,116], and these combinations are best avoided. Caution is recommended with the combination of ribavirin and didanosine because of increased mitochondrial toxicity (lactic acidosis and hepatic steatosis or chronic hyperlactatemia) [103,111,112]. In one study of HIV/HCV co-infection, peginterferon monotherapy was found to be more effective than standard interferon plus ribavirin [109], and this may be considered in selected patients in whom avoidance of ribavirin is desirable.


Liver transplantation may be the only treatment option for patients with end-stage cirrhosis. In 2000, Koch & Banys surveyed liver transplantation programs in the United States and found that although 56% accept methadone maintenance patients, another 32% require that methadone be discontinued prior to transplantation [117]. This practice has been criticized appropriately in editorials in transplantation journals [118,119]. Such a requirement would enhance the likelihood of relapse to heroin use [52,120] and should be discontinued. Thirty-nine programs had transplanted one or more methadone maintenance patients, with a total of 180 patients transplanted, but only nine programs had transplanted more than five such patients [117].

Small numbers of liver transplantations in methadone maintenance patients [121124] have been reported (Table 2). Liu et al. described 36 such patients, all but one of whom had HCV infection [122]. Postoperatively the methadone dose had to be increased in 15 and decreased in four [122]. Four patients experienced single episodes of relapse to heroin use, and the methadone dose was increased in two of these. Nine patients died (median follow-up 999 days, range 208–2561), but none of the deaths were associated with heroin use or methadone treatment. Patient and graft survivals were comparable to national averages at 1, 3 and 5 years [122]. Weinrieb et al. described 10 methadone maintenance patients who were transplanted, and they found that these patients required significantly higher doses of intraoperative anesthesia and postoperative analgesia than transplanted patients not receiving methadone [123]. Their paper includes detailed recommendations on effective analgesia for methadone maintenance patients in the transplant setting [123], Methadone doses were increased in 50% of their patients, and the average dose increase was 60%. Two of the 10 patients had post-transplant substance abuse, one with alcohol and one with cocaine. Kanchana et al. describe serious postoperative complications in four of five patients, but none relapsed to substance use [121].

Table 2
Liver transplantation in methadone maintenance patients.

Chronic hepatitis C almost always recurs in liver transplant recipients [125,126]. Infection of the new liver is associated with rapid progression of chronic hepatitis, with a median time to cirrhosis of 8–10 years, and antiviral therapy is often tolerated poorly [125,126]. The two larger studies of liver transplantation in methadone maintenance patients [122,123] describe severe recurrent HCV disease (Table 2). A methadone maintenance patient who was treated successfully for HCV which recurred after liver transplantation has been reported [124].

A liver transplantation program from Barcelona, Spain, has reported selection criteria for HIV-infected patients with end-stage liver disease from HCV or hepatitis B which indicate that methadone maintenance patients are being accepted [127,128]. A consensus document supporting the policies of this program has been published [127].

These data suggest that successful liver transplantation is achievable in methadone maintenance patients. It is likely that many methadone maintenance patients in the developed countries with end-stage cirrhosis are not being referred for liver transplantation, and further research is therefore indicated. The roles of antiviral therapy [129] and re-transplantation [130] for all transplanted patients with HCV need further clarification.


Methadone maintenance treatment has been an effective treatment for heroin addiction for more than 40 years [131] and has shown to be non-hepatotoxic [132] and safe when administered up to 15 years or longer [133], Long-term methadone maintenance can normalize several parameters of cellular immunity which become abnormal during injection drug use [134]. Methadone disposition is not altered significantly in moderate [135] and most cases of severe [136] chronic liver disease. This is attributed to a balance between damage to hepatic drug-metabolizing systems and damage to the storage and release functions of the liver regarding methadone [135,136]. The optimal methadone dose (80–1 50 mg) need not be changed in patients with stable chronic liver disease, including advanced cirrhosis. Higher doses of methadone (> 120 mg) in maintenance treatment are probably safe, but have not been studied prospectively. Doses of 120–150 mg have been used extensively world-wide: some groups use doses >150 mg. Optimal management of patients with doses >120 mg includes measurement of plasma methadone levels and monitoring of the corrected QT interval [137].

Buprenorphine with naloxone can be an effective treatment for opioid dependence [45]. Sullivan el al. compared patients entering buprenorphine treatment with and without prior methadone maintenance and found that the latter had fewer years of opioid dependence and thus a lower prevalence of anti-HCV [138]. They suggest that buprenorphine treatment may attract some patients with more recent narcotic use, allowing for prevention of some cases of HCV infection.

We have described the high quality of medical care, and the support in the medical literature thereof, which can be provided to methadone maintenance patients with HCV infection. The current reality for most patients falls far short of the treatment we have reviewed. There are many barriers to treatment of HCV infection in current or former injection drug users [87,139145]. Patients may have incomplete knowledge and understanding of HCV disease and may not know of available resources for HCV treatment [139,145]. They may be unaware of their personal status regarding HCV, HIV or other health issues [139,145]. Other medical or psychiatric conditions, use of illicit drugs or alcohol, lack of adequate housing or legal difficulties may reduce interest in, or adherence to antiviral therapy [87,141143]. Other patient-related barriers include distrust of the health-care system, difficulties with transportation to treatment sites, fear of adverse effects and penalties for missed visits [140,143,144]. The cost of testing, including multiple quantitative HCV-RNA determinations, medications and medical services, including liver biopsy, can be a major barrier [60,144]. Brown et al. analyzed the availability of services for HCV in a network of treatment programs in the United States that participate in a National Institute on Drug Abuse program to improve addiction treatment [60]. They found that only 74.1% offered patient education on HCV, 34.4% of programs offered HCV testing, 58.9% offered HCV counseling and 28.9% offered HCV treatment [60].

Notwithstanding the dedicated and capable physicians and staff involved with addiction and HCV patients, some providers may have negative attitudes regarding treatment of drug users or may be inexperienced in such treatment [87,143,144]. They may believe that current or former drug users will adhere to treatment poorly [143,144]. Finally, despite a United Nations position paper [146] and a National Institutes of Health Consensus Conference [147] supporting expansion of methadone maintenance or buprenorphine/naloxone treatment in areas of need, such treatment is not consistently available.

Some research has been conducted on overcoming barriers to HCV treatment in current or former injection drug users. Hallinan el al. studied patients with chronic HCV on opioid replacement therapy with methadone or buprenorphine in Australia [148]. Using personnel trained in HCV, they found that 27 of 43 (63%) patients referred to a liver clinic had attended it, despite multiple barriers. Moirand et al. found that among 378 patients with a history of injection drug use, enrollment in methadone maintenance was associated with initiation of anti-HCV therapy [149]. Sylvestre et al. treated 76 methadone-maintained patients at two drug-treatment facilities which provide comprehensive primary care for medical and psychiatric problems [10]. Prior to antiviral treatment, 36 (47%) were taking antidepressants compared with 65 (86%) at the end of treatment. They conclude that HCV treatment can be successful in methadone patients in a setting that can address their special medical and psychiatric needs. Sylvestre & Clements reported that adding new psychiatric medications improved HCV treatment adherence [150]. Schaefer et al. found that 67% of patients on methadone maintenance received antidepressants during HCV treatment [15]. Their study utilized an interdisciplinary team and thorough pretreatment medical and psychiatric evaluations. In Norway, provision of psychosocial support and a multi-disciplinary team resulted in 100% adherence to antiviral therapy; however, all patients had genotype 3 and therefore needed only 24 weeks of therapy [14]. Watson et al. found that a structured alcohol brief intervention was acceptable to opioid maintenance patients with HCV and alcohol misuse [151].

Overcoming the barrier of inadequate funding is a challenge in many countries. Mauss et al. found that most methadone patients who discontinued antiviral therapy did so within the first 8 weeks, limiting the cost of unsuccessful treatment [9]. A study of methadone maintenance patients in New Zealand indicates that peginterferon and ribavirin for HCV are cost-effective under varying assumptions of rate of disease progression and adherence to treatment [152].


We conclude that antiviral therapy for HCV can be provided to methadone maintenance patients with acceptable rates of adherence and SVR. When one considers the multiple barriers to such treatment, including underlying psychiatric disorders, the available results compare favorably to those of the initial drug trials, in which methadone patients were excluded. Data suggest that effective treatment of psychiatric disorders, a multi-disciplinary team and a treatment site that is acceptable to methadone maintenance patients (often but not necessarily the site of methadone treatment) will improve results. Controlled studies to prove conclusively that these measures are effective are not likely to be forthcoming. Liver transplantation can be effective in methadone maintenance patients with advanced liver disease and should be utilized more widely. Advances are needed in financial support, greater access to addiction treatment, additional research on outcomes of antiviral therapy and liver transplantation, data on immunological and genetic aspects affecting response and development of a HCV vaccine. This review is most applicable to the developed countries. Studies are needed in less developed countries in which methadone maintenance is being introduced for the treatment of addiction and to reduce the incidence of HIV and HCV infection.


Dr Kreek is supported by NIH-NIDA K05-DA00049, NIH-NIDA P60-DA05130, NIH-NIMH R01-MH79880 and the New York State OASAS. We gratefully acknowledge assistance from Patrizia Farci, Ann Ho, Andrew H. Talal, Brenda Ray, Elizabeth Ducat, Cassandra Williamson, Susan Russo and the Medical Library Staff of Kettering Medical Center and The Rockefeller University.


1. Novick DM, Haverkos HW, Teller DW. The medically ill substance abuser. In: Lowinson JM, Ruiz P, Millman RB, Langrod JG, editors. Substance Abuse: A Comprehensive Textbook. 3rd edn. Baltimore: Williams & Wilkins; 1997. pp. 534–550.
2. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. In: O’Brien CP, Jaffe JH, editors. Addictive States. New York: Raven Press; 1992. pp. 205–230.
3. Kreek MJ, LaForge S, Butelman E. Pharmacotherapy of addictions. Nat Rev Drug Discov. 2002;1:710–726. [PubMed]
4. Kreek MJ. Long-term pharmacotherapy for opiate (primarily heroin) addiction: opioid antagonists and partial agonists. In: Schuster CR, Kuhar MJ, editors. Pharmacological Aspects of Drug Dependence: Toward an Integrated Neurobehavioral Approach. Berlin: Springer-Verlag; 1996. pp. 563–598.
5. Buprenophine: an alternative to methadone. Med Lett Drug Ther. 2003;45:13–15. [PubMed]
6. Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend. 2002;67:117–123. [PubMed]
7. Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G, Schindlbeck N, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology. 2003;37:443–451. [PubMed]
8. 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. [PubMed]
9. Mauss S, Berger F, Goelz J, Jacob B, Schmutz G. A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance. Hepatology. 2004;40:120–124. [PubMed]
10. Sylvestre DL, Litwin AH, Clements BJ, Gourevitch MN. The impact of barriers to hepatitis C virus treatment in recovering heroin users maintained on methadone. J Subst Abuse Treat. 2005;29:159–165. [PubMed]
11. Matthews G, Kronborg IJ, Dore GJ. Treatment for hepatitis C virus infection among current injection drug users in Australia. Clin Infect Dis. 2005;40:S325–S329. [PubMed]
12. Robaeys G, Van Vlierberghe H, Mathei C, Van Ranst M, Bruckers L, Buntinx F. Similar compliance and effect of treatment in chronic hepatitis C resulting from intravenous drug use in comparison with other infection causes. Eur J Gastroenterol Hepatol. 2006;18:159–166. [PubMed]
13. Belfiori B, Chiodera A, Ciliegi P, Tosti A, Baldelli F, Stagni G, et al. Treatment for hepatitis C virus in injection drug users on opioid replacement therapy: a prospective multicentre study. Eur J Gastroenterol Hepatol. 2007;19:731–732. [PubMed]
14. Krook AL, Stokka D, Heger B, Nygaard E. Hepatitis C treatment of opioid dependants receiving maintenance treatment: results of a Norwegian pilot study. Eur Addict Res. 2007;13:216–221. [PubMed]
15. Schaefer M, Hinzpeter A, Mohmand A, Janssen G, Pich M, Schwaiger M, et al. Hepatitis C treatment in ‘difficult-to-treat’ psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects. Hepatology. 2007;46:991–998. [PubMed]
16. Grebely J, Raffa JD, Meagher C, Duncan F, Genoway KA, Khara M, et al. Directly observed therapy for the treatment of hepatitis C virus infection in current and former injection drug users. J Gastroenterol Hepatol. 2007;22:1519–1525. [PubMed]
17. Scheinmann R, Hagan H, Lelutiu-Weinberger C, Stern R, Des Jarlais DC, Flom PL, et al. Non-injection drug use and hepatitis C virus: a systematic review. Drug Alcohol Depend. 2007;89:1–12. [PMC free article] [PubMed]
18. Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation. [accessed 1 November 2007];Health Technol Assess. 2004 8:1–140. Available at: [PubMed]
19. Robertson B, Myers G, Howard C, Brettin T, Bukh J, Gaschen B, et al. Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses: proposals for standardization. Arch Virol. 1998;143:2493–2503. [PubMed]
20. Farci P, Purcell RH. Clinical significance of hepatitis C virus genotypes and quasispecies. Semin Liver Dis. 2000;20:103–126. [PubMed]
21. Simmonds P, Holmes EC, Cha T-A, Chan S-W, McOmish F, Irvine B, et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol. 1993;74:2391–2399. [PubMed]
22. Haushofer AC, Kopty C, Hauer R, Brunner H, Halbmayer W-M. HCV genotypes and age distribution in patients of Vienna and surrounding areas. J Clin Virol. 2001;20:41–47. [PubMed]
23. Lau JYN, Davis GL, Prescott LE, Maertens G, Lindsay KL, Qian K, et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Ann Intern Med. 1996;124:868–876. [PubMed]
24. Matheï C, Wollants E, Verbeeck J, Van Ranst M, Robaeys G, Van Damme P, et al. Molecular epidemiology of hepatitis C among drug users in Flanders, Belgium: association of genotype with clinical parameters and with sex- and drug-related risk behaviours. Eur J Clin Microbiol Infect Dis. 2005;24:514–522. [PubMed]
25. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–714. [PubMed]
26. Dienstag JL. Hepatitis C: a bitter harvest. Ann Intern Med. 2006;144:770–771. [PubMed]
27. Tahan V, Karaca C, Yildirim B, Bozbas A, Ozaras A, Demir K, et al. Sexual transmission of HCV between spouses. An J Gastroenterol. 2005;100:821–824. [PubMed]
28. McMahon JM, Pouget ER, Tortu S. Individual and couple-level risk factors for hepatitis C infection among heterosexual drug users: a multilevel dyadic analysis. J Infect Dis. 2007;195:1572–1581. [PubMed]
29. Hahn JA. Sex, drugs, and hepatitis C virus. J Infect Dis. 2007;195:1556–1559. [PubMed]
30. 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 (Balt) 1995;74:212–220. [PubMed]
31. Chetwynd J, Brunton C, Blank M, Plumridge E, Baldwin D. Hepatitis C seroprevalence amongst injecting drug users attending a methadone program. NZ Med J. 1995;108:364–366. [PubMed]
32. Gabrielli C, Zannini A, Corradini R, Gafa S. Spread of hepatitis C virus among sexual partners of HCVAb positive intravenous drug users. J Infect. 1994;29:17–22. [PubMed]
33. Soto B, Rodrigo L, Garcia-Bengoechea M, Sanchez-Quijano A, Riestra S, Arenas JI, et al. Heterosexual transmission of hepatitis C virus and the possible role of coexistent human immunodeficiency virus infection in the index case: a multicentre study of 423 pairings. J Intern Med. 1994;236:515–519. [PubMed]
34. Woodfield DG, Harness M, Rix-Trott K. Hepatitis C virus infections in oral and injectable drug users. NZ Med J. 1993;106:332–334. [PubMed]
35. Garfein RS, Vlahov D, Galai N, Doherty MC, Nelson KE. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health. 1996;86:655–661. [PubMed]
36. Thiede H, Hagan H, Murrill CS. Methadone treatment and HIV and hepatitis B and C risk reduction among injectors in the Seattle area. J Urban Health: Bull NY Acad Med. 2000;77:331–345. [PMC free article] [PubMed]
37. Cook PA, McVeigh J, Syed Q, Mutton K, Bellis MA. Predictors of hepatitis B and C infection in injecting drug users both in and out of drug treatment. Addiction. 2001;96:1787–1797. [PubMed]
38. Rhodes T, Platt L, Maximova S, Koshkina E, Latishevskaya N, Hickman M, et al. Prevalence of HIV, hepatitis C and syphilis among injecting drug users in Russia: a multi-city study. Addiction. 2006;101:252–266. [PubMed]
39. Faye-White E, Garfein RS, Brouwer KC, Lozada R, Ramos R, Firestone-Cruz M, et al. Prevalence of hepatitis C virus and HIV infection among injection drug users in two Mexican cities bordering the U.S. Salud Publica Mex. 2007;49:165–172. [PMC free article] [PubMed]
40. Peles E, Rados V, Adelson M. Characterization of former heroin addict patients with hepatitis C virus antibodies in a methadone maintenance treatment (MMT) clinic in Israel. Subst Use Misuse. 2007;42:1477–1484. [PubMed]
41. Thorpe LE, Bailey SL, Huo D, Monterroso ER, Ouellet LJ. Injection-related risk behaviors in young urban and suburban injection drug users in Chicago (1997–1999) J Acquir Immune Defic Syndr. 2001;27:71–78. [PubMed]
42. Miller CL, Johnston C, Spittal PM, Li K, LaLiberté N, Montaner JSG, et al. Opportunities for prevention: hepatitis C prevalence and incidence in a cohort of young injection drug users. Hepatology. 2002;36:737–742. [PubMed]
43. Novick DM, Reagan KJ, Croxson TS, Gelb AM, Stenger RJ, Kreek MJ. Hepatitis C virus serology in parenteral drug users with chronic liver disease. Addiction. 1997;92:167–171. [PubMed]
44. Des Jarlais DC, Perlis T, Arasteh K, Torian LV, Hagan H, Beatrice S, et al. Reductions in hepatitis C virus HIV infections among injecting drug users in New York City, 1990–2001. AIDS. 2005;19:S20–S25. [PubMed]
45. van de Laar TJW, Langendam MW, Bruisten SM, Welp EAE, Verhaest I, van Ameijden EJC, et al. Changes in risk behavior and dynamics of hepatitis C virus infections among young drug users in Amsterdam, the Netherlands. J Med Virol. 2005;77:509–518. [PubMed]
46. Chamot E, de Saussure P, Hirschel B, Deglon JJ, Perrin LH. Incidence of hepatitis C hepatitis B and HIV infections among drug users in a methadone-maintenance programme. AIDS. 1992;6:430–431. [PubMed]
47. Selvey LA, Denton M, Plant AJ. Incidence and prevalence of hepatitis C among clients of a Brisbane methadone clinic: factors influencing hepatitis C serostatus. Aust NZ J Public Health. 1997;21:102–104. [PubMed]
48. Crofts N, Nigra L, Oman K, Stevenson E, Sherman J. Methadone maintenance and hepatitis C virus infection among injecting drug users. Addiction. 1997;92:999–1005. [PubMed]
49. McCarthy JJ, Flynn N. Hepatitis C in methadone maintenance patients: prevalence and public policy implications. J Addict Dis. 2001;20:19–31. [PubMed]
50. Piccolo P, Borg L, Lin A, Melia D, Ho A, Kreek MJ. Hepatitis C virus and human immunodeficiency virus-1 co-infection in former heroin addicts in methadone maintenance treatment. J Addict Dis. 2002;21:55–66. [PubMed]
51. Novick DM, Joseph H, Croxson TS, Salsitz EA, Wang G, Richman BL, et al. Absence of antibody to human immunodeficiency virus in long-term, socially rehabilitated methadone maintenance patients. Arch Intern Med. 1990;150:97–99. [PubMed]
52. Dole VP. Implications of methadone maintenance for theories of narcotic addiction. JAMA. 1988;260:3025–3029. [PubMed]
53. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52. [PubMed]
54. Lai ME, Mazzoleni AP, Argiolu F, De Virgilis S, Balestrieri A, Purcell RH, et al. Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet. 1994;343:388–390. [PubMed]
55. Farci P, Alter HJ, Shimoda A, Govindarajan S, Cheung LC, Melpolder JC, et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med. 1996;335:631–634. [PubMed]
56. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21–S29. [PubMed]
57. Wong W, Terrault N. Update on chronic hepatitis C. Clin Gastroenterol Hepatol. 2005;3:507–520. [PubMed]
58. Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C 2002 (June 10–12, 2002) Gastroenterology. 2002;123:2082–2099. [PubMed]
59. Kadam JS, Talal AH. Changing treatment paradigms: hepatitis C virus in HIV-infected patients. AIDS Patient Care STDS. 2007;21:154–168. [PubMed]
60. Brown LS, Kritz SA, Goldsmith RJ, Bini EJ, Rotrosen J, Baker S, et al. Characteristics of substance abuse treatment programs providing services for HIV/AIDS, hepatitis C virus infection, and sexually transmitted infections: the National Drug Abuse Treatment Clinical Trials Network. J Subst Abuse Treat. 2006;30:315–321. [PMC free article] [PubMed]
61. Belle SH, Beringer KC, Detre KM. Recent findings concerning liver transplantation in the United States. In: Cecka JM, Terasaki PI, editors. Clinical Transplants. 1st edn. Los Angeles: UCLA Tissue Typing Laboratory; 1997. pp. 15–29.
62. Novick DM, Enlow RW, Gelb AM, Stenger RJ, Fotino M, Winter JW, et al. Hepatic cirrhosis in young adults: association with adolescent onset of alcohol and parenteral heroin abuse. Gut. 1985;26:8–13. [PMC free article] [PubMed]
63. Novick DM, Stenger RJ, Gelb AM, Most J, Yancovitz SR, Kreek MJ. Chronic liver disease in abusers of alcohol and parenteral drugs: a report of 204 consecutive biopsyproven cases. Alcohol Clin Exp Res. 1986;10:500–505. [PubMed]
64. Pessione F, Degos F, Marcellin P, Duchatelle V, Njapoum C, Martinot-Peignoux M, et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology. 1998;27:1717–1722. [PubMed]
65. Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28:805–809. [PubMed]
66. Safdar K, Schiff ER. Alcohol and hepatitis C. Semin Liver Dis. 2004;24:305–315. [PubMed]
67. Hutchinson SJ, Bird SM, Goldberg DJ. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clin Gastroenterol Hepatol. 2005;3:1150–1159. [PubMed]
68. Hezode C, Lonjon I, Roudot-Thoraval F, Pawlotsky J-M, Zafrani ES, Dhumeaux D. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C and specific influence of steatosis: a prospective study. Aliment Pharmacol Ther. 2003;17:1031–1037. [PubMed]
69. Chang A, Skole K, Gautam M, Schmutz J, Black M, Thomas R, et al. The impact of past alcohol use on treatment response rates in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2005;22:701–706. [PubMed]
70. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates and risk factors of liver fibrosis in patients with chronic hepatitis C. J Hepatol. 2001;34:730–739. [PubMed]
71. Sterling RK, Sulkowski MS. Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection. Semin Liver Dis. 2004;24:61–68. [PubMed]
72. Glue P, Fang JWS, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, et al. Pegylated interferon-α2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther. 2000;68:556–567. [PubMed]
73. Yee HS, Currie SL, Darling JM, Wright TL. Management and treatment of hepatitis C viral infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 2006;101:2360–2378. [PubMed]
74. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiftman 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. [PubMed]
75. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982. [PubMed]
76. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai M-Y, Gane E, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343:1666–1672. [PubMed]
77. Heathcote EJ, Shiffman ML, Cooksley WGE, Dusheiko GM, Lee SS, Balart L, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med. 2000;343:1673–1680. [PubMed]
78. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122:1303–1313. [PubMed]
79. Batts KP, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417. [PubMed]
80. Hadziyannis SJ, Sette H, Morgan TJ, Balan V, Diago M, Marcellin P, et al. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C. Ann Intern Med. 2004;140:346–355. [PubMed]
81. Berg T, von Wagner M, Nasser S, Sarrazin C, Heintges T, Gerlach T, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology. 2006;130:1086–1097. [PubMed]
82. Sánchez-Tapias JM, Diago M, Escartín P, Enríquez J, Romero-Gómez M, Bárcena R, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology. 2006;131:451–460. [PubMed]
83. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology. 2002;36:S237–S244. [PubMed]
84. Sulkowski M, Wright T, Rossi S, Arora S, Lamb M, Wang K, et al. Peginterferon alfa-2a does not alter the pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy. Clin Pharmacol Ther. 2005;77:214–224. [PubMed]
85. Berk SI, Litwin AH, Arnsten JH, Du E, Soloway I, Gourevitch MN. Effects of pegylated interferon alfa-2b on the pharmacokinetic and pharmacodynamic properties of methadone: a prospective, nonrandomized, crossover study in patients coinfected with hepatitis C and HIV receiving methadone maintenance treatment. Clin Ther. 2007;29:131–138. [PubMed]
86. Gupta SK, Sellers E, Somoza E, Angles L, Kolz K, Cutler DL. The effect of multiple doses of peginterferon alfa-2b on the steady-state pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy. J Clin Pharmacol. 2007;47:604–612. [PubMed]
87. Dore GJ, Thomas DL. Management and treatment of injection drug users with hepatitis C virus (HCV) infection and HCV/human immunodeficiency virus coinfection. Semin Liver Dis. 2005;25:18–32. [PubMed]
88. Vento S, Garofano T, Renzini C, Cainelli F, Casali F, Ghironzi G, et al. Fulminant hepatitis associated with hepatitis A superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338:286–290. [PubMed]
89. Deterding K, Tegtmeyer B, Cornberg M, Hadem J, Potthoff A, Böker KHW, et al. Hepatitis A virus infection suppresses hepatitis C replication and may lead to clearance of HCV. J Hepatol. 2006;45:770–778. [PubMed]
90. Bart G, Piccolo P, Zhang L, Jacobson I, Schaefer R, Kreek MJ. Markers for hepatitis A, B, and C in methadone maintained patients: an unexpectedly high coinfection with silent hepatitis B. Addiction. 2008;103:681–686. [PMC free article] [PubMed]
91. Dalgard O, Bjøro 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. [PubMed]
92. Backmund M, Meyer K, Edlin BR. Infrequent reinfection after successful treatment for hepatitis C virus infection in injection drug users. Clin Infect Dis. 2004;39:1540–1543. [PMC free article] [PubMed]
93. Schaefer M, Heinz A, Backmund M. Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules? Addiction. 2004;99:1167–1175. [PubMed]
94. Robaeys G, Buntinx F. Treatment of hepatitis C viral infections in substance abusers. Acta Gastroenterol Belg. 2005;68:55–67. [PubMed]
95. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA. 2002;288:199–206. [PubMed]
96. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med. 2003;138:197–207. [PubMed]
97. George SL, Gebhardt J, Klinzman D, Foster MB, Patrick KD, Schmidt WN, et al. Hepatitis C virus viremia in HIV-infected individuals with negative HCV antibody tests. J Acquir Immune Defic Syndr. 2002;31:154–162. [PubMed]
98. Serfaty L, Costagliola D, Wendrum D, Picard O, Meyohas M-C, Girard P-M, et al. Impact of early-untreated HIV infection on chronic hepatitis C in intravenous drug users: a case-control study. AIDS. 2001;15:2011–2016. [PubMed]
99. Di Martino V, Rufat P, Boyer N, Renard P, Degos F, Martinot-Peignoux M, et al. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology. 2001;34:1193–1199. [PubMed]
100. Bruno R, Sacchi P, Puoti M, Soriano V, Filice G. HCV chronic hepatitis in patients with HIV: clinical management issues. Am J Gastroenterol. 2002;97:1598–1606. [PubMed]
101. 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. [PubMed]
102. Dybul M, Fauci A, Bartlett JG, Kaplan JE, Pau AK. Guidelines for using antiviral agents among HIV-infected adults and adolescents. Ann Intern Med. 2002;137:381–433. [PubMed]
103. Montessori V, Harris M, Montaner JSG. Hepatotoxicity of nucleoside reverse transcriptase inhibitors. Semin Liver Dis. 2003;23:167–171. [PubMed]
104. Savès M, Raffi F, Clevenburgh P, Marchou B, Waldner-Combernoux A, Morlat P, et al. Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic cytolysis after initiation of a protease inhibitor-containing anti-retroviral regimen in human immunodeficiency virus-infected patients. Antimierob Agents Chemother. 2000;44:3451–3455. [PMC free article] [PubMed]
105. Sherman KE, Peters M, Koziel MJ. HIV and liver disease forum: conference proceedings. Hepatology. 2007;45:1566–1577. [PMC free article] [PubMed]
106. McCance-Katz EF. Treatment of opioid dependence and coinfection with HIV and hepatitis C virus in opioid-dependent patients: the importance of drug interactions between opioids and antiviral agents. Clin Infect Dis. 2005;41:S89–S95. [PubMed]
107. Bruce RD, Altice FL, Gourevitch MN, Friedland GH. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. J Acquir Immune Defic Sijndr. 2006;41:563–572. [PubMed]
108. Maas BM, Kerr T, Fairbairn N, Montaner J, Wood E. Pharmacokinetic interactions between HIV antiretroviral therapy and drugs used to treat opioid dependence. Expert Opin Drug Metab Toxicol. 2006;2:533–543. [PubMed]
109. Torriani FJ, Rodriquez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. New Engl J Med. 2004;351:438–450. [PubMed]
110. Chung RT, Anderson 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. [PMC free article] [PubMed]
111. Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b. plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839–2848. [PubMed]
112. Manns MR, Wedemeyer H. Treatment of hepatitis C in HIV-infected patients: significant progress but not the final step. JAMA. 2004;292:2909–2913. [PubMed]
113. Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med. 2007;356:1445–1454. [PMC free article] [PubMed]
114. Palepu A, Tyndall MW, Joy R, Kerr T, Wood E, Press N, et al. Antiretroviral adherence and HIV treatment outcomes among HIV/HCV co-infected drug users: the role of methadone maintenance therapy. Drug Alcohol Depend. 2006;84:188–194. [PubMed]
115. Gonzalez SA, Talal AH. Hepatitis C virus in human immunodeficiency virus-infected individuals: an emerging comorbidity with significant implications. Semin Liver Dis. 2003;23:149–166. [PubMed]
116. Baba M, Pauwels R, Balzarini J, Herdewijn P, De Clercq E, Desmyter J. Ribavirin antagonizes inhibitory effects of pymimidine 2′,3′-dideoxynucleosides but enhances inhibitory effects of purine 2′,3′-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 1987;31:1613–1617. [PMC free article] [PubMed]
117. Koch M, Banys P. Liver transplantation and opioid dependence. JAMA. 2001;285:1056–1058. [PubMed]
118. Koch M, Banys P. Methadone is a medication, not an addiction. Liver Transpl. 2002;8:783–786. [PubMed]
119. Di Martini A, Weinrieb R. Liver transplantation for methadone-maintained opiate dependents: making the case for cautious optimism. Am J Transpl. 2003;3:1183–1184. [PubMed]
120. Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT): a review of historical and clinical issues. Mt Sinai J Med. 2000;67:347–364. [PubMed]
121. Kanchana TP, Kaul V, Manzarbeitia C, Reich DJ, Hails KC, Munoz SJ, et al. Liver transplantation for patients on methadone maintenance. Liver Transpl. 2002;8:778–782. [PubMed]
122. Liu LU, Schiano TD, Lau N, O’Rourke M, Min AD, Sigal SH, et al. Survival and risk of recidivism in methadone-dependent patients undergoing liver transplantation. Am J Transpl. 2003;3:1273–1277. [PubMed]
123. Weinrieb RM, Burnett R, Lynch KG, DePiano M, Atanda A, Olthoff KM. A matched comparison study of medical and psychiatric complications and anesthesia and analgesia requirements in methadone-maintained liver transplant recipients. Liver Transpl. 2004;10:97–106. [PubMed]
124. Hancock MM, Prosser CC, Ransibrahmanakul K, Lester L, Craemer E, Bourgeois JA, et al. Liver transplant and hepatitis C in methadone maintenance therapy: a case report. [accessed 18 June 2007];Subst Abuse Treat Prevent Policy. 2007 2:5. Available at: [PMC free article] [PubMed]
125. Terrault NA, Berenguer M. Treating hepatitis C in liver transplant recipients. Liver Transpl. 2006;12:1192–1204. [PubMed]
126. Kotlyar DS, Campbell MS, Reddy KR. Recurrence of diseases following orthotopic liver transplantation. Am J Gastroenterol. 2006;101:1370–1378. [PubMed]
127. Miró JM, Torre-Cisnero J, Moreno A, Tuset M, Quereda C, Laguno M, et al. GESIDA/GESITRA-SEIMC, PNS and ONT consensus document on solid organ transplant (SOT) in HIV-infected patients in Spain (March 2005) Enferm Infecc Microbiol Clin. 2005;23:353–362. [PubMed]
128. Miró JM, Laguno M, Moreno A, Rimola A. Hospital Clinic OLT in HIV Working Group. Management of end stage liver disease (ESLD): what is the current role of orthotopic liver transplantation (OLT)? J Hepatol. 2006;44:S140–S145. [PubMed]
129. Sharma P, Marrero JA, Fontana RJ, Greenson JK, Conjeevaram H, Su GL, et al. Sustained virological response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence. Liver Transpl. 2007;13:1100–1108. [PubMed]
130. McCashland T, Watt K, Lyden E, Adams L, Charlton M, Smith AD, et al. Retransplantation for hepatitis C: results of a U.S multicenter retransplant study. Liver Transpl. 2007;13:1246–1253. [PubMed]
131. Dole VP, Nyswander ME, Kreek MJ. Narcotic blockade. Arch Intern Med. 1966;118:304–309. [PubMed]
132. Kreek MJ, Dodes L, Kane S, Knobler J, Martin R. Long-term methadone maintenance therapy: effect on liver function. Ann Intern Med. 1972;77:598–602. [PubMed]
133. Novick DM, Richman BL, Friedman JM, Friedman JE, Fried C, Wilson JP, et al. The medical status of methadone maintenance patients in treatment for 11–18 years. Drag Alcohol Depend. 1993;33:235–245. [PubMed]
134. Novick DM, Ochshorn M, Ghali V, Croxson TS, Mercer WD, Chiorazzi N, et al. Natural killer cell activity and lymphocyte subsets in parenteral heroin abusers and long-term methadone maintenance patients. J Pharmacol Exp Thar. 1989;250:606–610. [PubMed]
135. Novick DM, Kreek MJ, Fanizza AM, Yancovitz SR, Gelb AM, Stenger RJ. Methadone disposition in patients with chronic liver disease. Clin Pharmacol Ther. 1981;30:353–362. [PubMed]
136. Novick DM, Kreek MJ, Arns PA, Lau LL, Yancovitz SR, Gelb AM. Effect of severe alcoholic liver disease on the disposition of methadone in maintenance patients. Alcohol Clin Exp Res. 1985;9:349–354. [PubMed]
137. Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients—a cross-sectional study. Addiction. 2007;102:289–300. [PubMed]
138. Sullivan LE, Chawarski M, O’Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Drug Alcohol Depend. 2005;79:113–116. [PubMed]
139. 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. [PubMed]
140. Edlin BR. Prevention and treatment of hepatitis C in injection drug users. Hepatology. 2002;36:S210–S219. [PMC free article] [PubMed]
141. Kresina TF, Seeff LB, Francis H. Hepatitis C infection and injection drug use: the role of hepatologists in evolving treatment efforts. Hepatology. 2004;40:516–519. [PubMed]
142. Sylvestre DL, Loftis JM, Hauser P, Genser S, Cesari H, Borek N, et al. Co-occurring hepatitis C, substance use, and psychiatric illness: treatment issues and developing integrated models of care. J Urban Health: Bull NY Acad Med. 2004;81:719–434. [PMC free article] [PubMed]
143. Edlin BR, Kresina TF, Raymond DB, Carden MR, Gourevitch MN, Rich JD, et al. Overcoming barriers to prevention, care, and treatment of hepatitis C in illicit drug users. Clin Infect Dis. 2005;40:S276–S285. [PMC free article] [PubMed]
144. Taylor LE. Delivering care to injection drug users coinfected with HIV and hepatitis C. Clin Infect Dis. 2005;40:S355–S361. [PubMed]
145. Strauss SM, Astone-Twerell J, Munoz-Plaza CE, Des Jarlais DC, Gwadz M, Hagan H, et al. Drug treatment program patients’hepatitis C virus (HCV) education needs and their use of available HCV education services. [accessed 18 June 2007];BMC Health Serv Res. 2007 7:39. Available at: [PMC free article] [PubMed]
146. World health Organization. Substitution Maintenance Therapy in the Management of Opioid Dependence and HIV/AIDS Prevention: Position Paper. Geneva: World Health Organization, United Nations Office on Drugs and Crime, UNAIDS; 2004. [accessed 1 November 2007]. Available at:
147. National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction. Effective medical treatment of opiate addiction. JAMA. 1998;280:1936–1943. [PubMed]
148. Hallinan R, Byrne A, Agho K, Dore GJ. Referral for chronic hepatitis C treatment from a drug dependency setting. Drug Alcohol Depend. 2007;88:49–53. [PubMed]
149. Moirand R, Bilodeau M, Brissette S, Bruneau J. Determinants of antiviral treatment initiation in a hepatitis C-infected population benefiting from universal health care coverage. Can J Gastroenterol. 2007;21:355–361. [PMC free article] [PubMed]
150. Sylvestre DL, Clements BJ. Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gastroenterol Hepatol. 2007;19:741–747. [PubMed]
151. Watson B, Conigrave KM, Wallace C, Whitfield JB, Wurst F, Haber PS. Hazardous alcohol consumption and other barriers to antiviral treatment among hepatitis C positive people receiving opioid maintenance treatment. Drug Alcohol Rev. 2007;26:231–239. [PubMed]
152. Sheerin IG, Green FT, Sellman JD. What is the cost-effectiveness of hepatitis C treatment for injecting drug users on methadone maintenance in New Zealand? Drug Alcohol Rev. 2004;23:261–272. [PubMed]