Hepatitis C virus (HCV) is the most common bloodborne infection in injection drug users (IDUs). Left untreated, HCV may lead to cirrhosis, liver cancer, and death. Although IDUs represent the majority of new and existing cases of HCV, they are the least likely to have access to treatment due to concerns about adherence, reinfection, psychosocial stability, and interferon -mediated neuropsychiatrie toxicity.
Hepatits C virus treatment has evolved rapidly, and studies in nonaddicted populations have shown that more than 50% of those completing therapy with newer regimens may be cured of their disease. Recent data suggest that recovering LDUs stabilized on methadone may be treated safely and with reasonable efficacy, even in the setting of preexisting psychiatric conditions or relapse to drug use.
This article provides a brief overview of the epidemiology, transmission, natural history, and clinical evaluation of the patient with HCV, and reviews the current data on treatment outcomes and candidacy issues in this population.
EPIDEMIOLOGY AND TRANSMISSION
The Centers for Disease Control and Prevention estimates that 60% of the 4 million cases of HCV and two thirds of the 35,000 new cases of HCV in the United States each year are related to injection drug use.1 Cross-sectional seroprevalence studies from different regions of the United States have documented exposure in 65% to 96% of long-term IDUs.2
Hepatits C virus is transmitted most efficiently through direct exposure to infectious blood, with sexual and other forms of contact representing far less efficient modes of transmission. Transmission is related not just to the reuse of syringes and needles, but also to sharing any part of the injection paraphernalia, including cottons, cookers, and rinsewater.3
Injection drug users acquire HCV infection soon after initiating injection drug use; most studies have shown the majority of IDUs are exposed within the first 2 years of injecting.4 Because acute infection in IDUs is rarely recognized, the length of injecting behaviors is often used to approximate the duration of infection.
Hepatitis C treatment outcomes in patients maintained on methadone (N = 76) (SVR = sustained virologie response).
The high degree of transmissibility of HCV relates to the high viral titers in infected persons; numbers in the millions of copies per milliliter are not uncommon. Education and outreach to drug users and the widespread institution of syringe exchange may be impacting positively on transmission rates, as recent studies of drug users who began injecting in the 1990s suggest the interval from initiating drug use to exposure is lengthening.5
The most important sequelae of chronic HCV infection are progressive liver fibrosis leading to cirrhosis, endstage liver disease, and hepatocellular carcinoma. Although retrospective histologic studies in non-IDUs have estimated cirrhosis to develop in approximately 20% and hepatocellular carcinoma in approximately 1% to 5% after two or more decades,6 more recent prospective studies have shown the risk of progressive HCV disease is probably lower, with cirrhosis developing in only 7% to 16% after 20 years of chronic infection.7
The rate of progression in IDUs has not been well studied. The natural history may vary in this population due to the high prevalence of comorbid conditions such as human immunodeficiency virus and chronic hepatitis B.
Alcohol abuse and dependence are also common, and there is strong evidence for a detrimental effect with consumption of 60 g/day in men and 40 g/day in women,8 Additionally, repeated exposure to multiple viral strains over the duration of an injecting career, the co-injection of drug-extending contaminants, and an impaired immune status all have the potential to variably affect disease progression.
Although careful epidemiologic studies have shown the majority of IDUs demonstrate clinically insignificant liver disease at the time of diagnosis,9 the liver-related mortality among former IDUs referred to a liver clinic was 15% over a period of 4 years.10 Although much remains to be understood, the vast prevalence of HCV in IDUs suggests a sizable number of individuals will be at risk for developing sequelae of chronic liver disease in the coming decades, requiring costly medical intervention to manage liver-related complications.
The enzyme immunoassay (EIA) is the cornerstone of screening for HCV exposure; its high sensitivity and specificity obviates the need for confirmatory testing in a high-risk population such as IDUs. Approximately 15% to 40% of those exposed to HCV will clear virus spontaneously; therefore, a positive HCV EIA does not necessarily indicate active infection.7
Liver enzymes are notoriously unreliable predictors of HCV disease activity, and since the majority of infected patients have minimal or no symptoms, a diagnosis of active infection with HCV should rely on molecular amplification techniques such as polymerase chain reaction or transcription-mediated amplification to detect the presence of viral particles in the bloodstream. Unlike human immunodeficiency virus, disease severity in HCV does not correlate with viral load and the viral titer does not help predict liver histology.
Another key molecular test is the HCV genotype. Hepatits C virus is classified into six major genotypes (1-6) on the basis of genomic sequence. In the United States, genotype 1 is predominant, comprising approximately 75% of those infected; the majority of the remainder have genotype 2 or 3." Although HCV genotype does not correlate with the extent of liver disease, it is the best predictor of response to interferon/ribavirin treatment and is a primary determinant of the appropriate length of therapy.
Liver biopsy yields additional information on HCV-related liver damage that may be unobtainable by blood testing. Although not universally recommended, it is the most accurate means of identifying patients in whom the extent of liver damage may indicate a need for treatment. In addition, it often provides a measure of reassurance for the many patients with minimal histologic damage in whom treatment is not needed.
The standard measure of HCV treatment outcome is the sustained virologie response (SVR), defined as the absence of detectable virus 24 weeks after the completion of therapy. Importantly, more than 95% of treated patients exhibiting a SVR will remain persistently free of detectable virus a decade later, probably indicative Of a virologie cure.12
Recent data suggest viral testing 12 weeks after beginning therapy provides an early milestone to identify treatment nonresponders: patients in whom the viral load is not undetectable or has not been reduced 100-fold have less than a 3% chance of SVR.13 These patients therefore may be spared the difficulties involved with a full course of therapy without sacrificing viral outcomes.
Hepatits C virus treatment has evolved rapidly over the past decade and typically consists of a combination of interferon injections and oral ribavirin. Regimens that include long-acting pegylated interferons injected weekly lead to overall SVR rates of 54% to 56%. iA Patients with genotype 1 exhibit sustained responses of approximately 40% after 48 weeks of therapy, while patients with the less common but more responsive genotypes 2 or 3 typically are treated for 24 weeks with an SVR of approximately 80%.
Unfortunately, treatment-limiting side effects are common, including flu-like symptoms, chills, and muscle and joint aches. Although often responding to increased water intake and anti-inflammatory medications, opiate addicts may liken this to a withdrawal syndrome, possibly putting them at risk for relapse to drug use. Interferon may lead to thrombocytopenia and neutropenia, potentially increasing the risk for treatment-related infections and bleeding, and ribavirin leads to hemolysis that may be severe. These cy topenias may require dose reduction, treatment discontinuation, or the administration of cytokines such as erythropoietin and G-CSF.
Impact of Substance Use and Preexisting Psychiatric Disease on Hepatitis C Treatment Outcomes in Methadone Maintenance Patients*
The neuropsychiatrie side effects of interferon can be substantial and are seen both in those with and without a history of psychiatric disease. Depression develops in 20% to 30% of patients taking interferon and may be severe, with suicide having been reported.15 The depression often is amenable to antidepressant therapy, with selective serotonin reuptake inhibitors (SSRIs) being the most effective class of medications used.
Other common neuropsychiatrie side effects include irritability, emotional lability, and impaired concentration. Despite the plethora of potential difficulties, however, aggressive side effect management and timely intervention will allow the majority of patients to successfully complete a course of therapy.
TREATMENT IN INJECTION DRUG USERS
Although minimal data exist on HCV treatment in IDUs, recent experience has demonstrated its feasibility and effectiveness, even in patients who have not been abstinent from continued drug use. A study conducted in Germany on 50 IDUs enrolled in methadone detoxification and treated either with interferon or interferon/ribavirin combination therapy demonstrated an overall sustained virologie response rate of 36%. ,6 Interestingly, there was no statistical difference in treatment outcomes in patients who remained abstinent from drugs through the treatment course compared to those who relapsed.
Another recently completed study of standard interferon/ribavirin therapy in a sample of 76 methadone maintenance patients showed an SVR of 28% and a dropout rate of 24% (Unpublished data). Although these results are modestly lower than larger treatment studies in nonopioid-dependent populations that showed response rates of approximately 40% and dropout rates of 20% (Figure), the methadone patients in the former study exhibited relatively advanced liver fibrosis and had high rates of psychiatric disease (Unpublished data).17
The impact of intervening substance use and preexisting psychiatric disease on treatment outcomes in these methadone maintenance patients is summarized the Table. Interestingly, overall response rates were not significantly different in the 34% of patients who used heroin, cocaine, or amphetamines during HCV treatment from patients who remained sober (15% versus 34%, respectively; P = .14). However, there appeared to be a trend toward a dose response, since the SVR in the intermittent drug users was 21% but none of the 8 patients who used drugs regularly showed a virologie response (P =.09) (Unpublished data).
Limited length of sobriety also had minimal predictive value, since patients who had been sober for less than 6 months had an SVR of 22% compared with 30% in tbose who had maintained sobriety for a longer period (P =.18). Patients who used marijuana demonstrated a significant improvement in SVR compared with patients who did not use marijuana (52% versus 16%, respectively; P =.006) (Unpublished data).
Surprisingly, the best predictor of reduced SVR in this study was preexisting psychiatric illness. Those who selfreported a psychiatric condition, usually depression, prior to treatment had an SVR of 22% compared with 35% in those who did not report one (P = .01). Although 46% of patients were taking psychotropics prior to therapy, by the end of therapy, 86% were taking a psychiatric medication, with SSRIs being most frequently administered. Forty-five percent of patients increased their methadone dose by a median of 15 mg (range, 3 to 180 mg) (Unpublished data).
There are limited long-term data on HCV treatment in IDUs, limiting our understanding of the potential for reinfection in those who continue to use unsafe needle practices. However, a 5year follow-up study of 27 former IDUs in Norway who had been successfully treated for HCV showed that despite frequent reinitiation of drug injection, only 1 patient who reported frequent needle sharing became virus positive.18 Although it seems clear that viral immunity is not necessarily protective, careful counseling about drug use behaviors may minimize or eliminate the risk of reinfection.
These results suggest HCV treatment in IDUs can be safe, tolerable, and effective in selected patients. Even IDUs traditionally considered ineligible for treatment, such as those who relapse to drug use and those with preexisting psychiatric disease, may benefit from treatment. This is reflected in the recent National Institutes of Health Consensus Development Conference Statement on the management of hepatitis C, which, in a reversal of its previous position, now recognizes that selected IDUs not previously considered treatment candidates due to concerns about stability and drug use may be treated for HCV on a caseby-case basis.7
BARRIERS TO TREATMENT
Despite this encouraging data, IDUs may exhibit a number of potential barriers to successful HCV treatment that should be considered prior to initiating medication therapy. The most common of these is preexisting psychiatric disease, particularly depression. However, interferon-mediated depression does not necessarily correlate with preexisting depression, and several studies have shown that patients with depression can be treated safely if their condition is stable prior to initiating HCV treatment.19,20 A more significant consideration therefore may be the lack of access to psychiatric care and medications, since approaches that incorporate timely psychiatric intervention generally lead to favorable HCV treatment outcomes.
Concerns about drug craving and relapse to substance use as a result of prescribing an injectable medication also may lead to the withholding of HCV treatment. However, no study to date has documented a causal relationship between interferon self-injection and relapse to drug use, and the use of insulin is not prescribed in PDUs with diabetes. However, this issue must be addressed with each patient individually to assess any potential risk.
Injection drug users may exhibit difficult behaviors, including poor adherence to scheduled appointments and medication regimens. However, poor medication adherence is not unique to IDUs and is problematic in many chronic medical conditions.21,22 Strategies that address these barriers are a key aspect of providing quality medical care and should be routinely examined. Weekly interferon dosing now provides a means of improving HCV treatment adherence and also may allow substance abuse treatment programs to participate more actively in the HCV treatment process.
TREATMENT CANDIDACY AND READINESS
Although carefully managed IDUs can successfully undergo HCV treatment even in the setting of relapse to drug use and psychiatric illness, the majority of DDUs do not undergo evaluation and treatment because they do not seek it and their medical providers do not advocate for it. Unfortunately, misinformatioii and negativity are much more significant treatment barriers in IDUs than are psychiatric disease and recidivism.
Although the majority of HC V-infected patients do not need treatment, tiiose with more advanced liver fibrosis and severe hepatitis-related symptoms likely will benefit from treatment. Patients undergoing the relatively arduous HCV treatment regimen must be highly motivated, attend appointments reliably, and be willing to develop an interpersonal support network to assist with the difficulties that may arise. By providing education that will motivate IDUs toward treatment readiness and by making appropriate referrals, medical caregivers who see addicted patients will be the crucial link in reducing the devastation of HCV in this population.
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Impact of Substance Use and Preexisting Psychiatric Disease on Hepatitis C Treatment Outcomes in Methadone Maintenance Patients*