Hepatitis C is a major cause of liver disease and the leading indication for liver transplantation in the United States. It is estimated that 2.7 million Americans have chronic hepatitis C virus (HCV) infection. Complications of chronic infection include progressive liver fibrosis, cirrhosis, endstage liver disease, and hepatocellular carcinoma. The actual risk of cirrhosis in chronic HCV infection is unclear, but current research estimates that 10% to 20% will develop cirrhosis 20 to 30 years after initial infection.1
Exposure to infected blood is the primary means of transmission of hepatitis C. This exposure may occur from intravenous drug use, high-risk sexual practices, blood transfusions prior to 1992, unsafe medical practices, other occupational exposures, transmission from an infected mother during childbirth, and possibly intranasal cocaine use. Hepatitis C virus does not appear to be transmitted through casual contact without blood exposure or through breastfeeding. Currently the major risk factor for acquiring hepatitis C is intravenous drug use.
It is estimated that 50% to 90% of intravenous drug users are infected with HCV. Intranasal drug users and alcohol dependent persons also appear to be at increased risk for HCV infection.1·2 Despite the high prevalence of hepatitis C infection in users of alcohol and other substances and the need for prevention of the spread of HCV in these groups, the 1997 National Institutes of Health (NIH) Consensus Development Conference on the management of hepatitis C advised against treatment of these patient cohorts until they had achieved at least 6 months of abstinence.1 Thus, to date, relatively few individuals with alcohol and other substance use disorders have received treatment for hepatitis C.
The 2002 NIH Consensus Development Conference recognized impressive advances in research and treatment of HCV. Conference recommendations included the elimination of exclusionary criteria for active users of intravenous and other drugs. A history of alcohol abuse or dependence is not a contraindication to therapy, but patients should be treated for these conditions and achieve abstinence prior to the institution of antiviral therapy,1 These patients need close monitoring and support during the course of antiviral treatment. This article focuses on the treatment of HCV infection in patients with alcohol and other substance use disorders and examines proposals for optimizing treatment in this patient population.
NATURAL HISTORY OF HEPATITIS C
The hepatitis C virus was identified in 1989 and widespread screening became available in 1992. The majority of patients previously diagnosed with nonA, non-B hepatitis appear to be infected with HCV. This virus has extensive genetic heterogeneity; to date six genotypes have been identified. Genotype 1 is the most common in the United States.
Blood-to-blood transmission of HCV, eg, sharing infected needles, appears quite efficient. The exact risk of infection with each exposure to HCV is unclear but is thought to be high. After initial infection with HCV, most individuals display no symptoms and continue to feel well.1 A small portion of infected individuals clear the virus from the bloodstream spontaneously; however, it is believed that up to 85% of HCV-infected individuals develop chronic infection.
Consequences of chronic infection include hepatic inflammation, progressive liver fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The progression of liver disease is highly variable and it is estimated that 10% to 20% of patients develop cirrhosis over a 20- to 30-year period after initial infection.1·3 Decompensated cirrhosis from HCV is estimated to account for at least 10,000 deaths per year in the United States.
Successful treatment of chronically infected individuals with interferonalpha or a combination of interferonalpha and ribavirin has been shown to reduce risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma.1 Unfortunately, the only treatment for decompensated cirrhosis is liver transplantation, an option available to few patients.1 Therefore, effective treatment of infected individuals and prevention of further spread of HCV are important public health concerns.
Alcohol Consumption and Response to Interferon Therapy
ALCOHOL AND HEPATITIS C
Alcohol use disorders appear to increase the risk for acquisition of hepatitis C. Ten percent of alcoholdependent individuals are HCV-positive, compared to 1 .8% of the general population. Thirty percent of alcohol-dependent individuals with liver disease are infected with HCV.2This increased prevalence of HCV in alcohol-dependent individuals is seen even in the absence of other identifiable risk factors for HCV.4
The nature of the interaction between alcohol and HCV is not known. It has been suggested that heavy alcohol consumption may enable initial infection by the virus and allows subsequent persistence of the virus. That impairment of immune function by alcohol may allow the survival and replication of the virus after initial infection.5 Impaired cellular immunity is associated with alcohol consumption in several studies of HCVinfected animals and humans. Impaired humoral immunity has also been postulated as a contributory factor.2·4"6
Liver Damage. Alcohol consumption accelerates liver damage associated with HCV. Alcohol and HCV appear to act synergistically in causing hepatic injury. It appears that the liver disease in the majority of patients with HCV and heavy alcohol use is related to the effects of chronic HCV infection, rather than alcoholinduced liver damage. Studies of HCVinfected patients have shown that those who consume alcohol have evidence of greater hepatic inflammatory activity. The exact mechanism by which alcohol potentiates this inflammatory reaction caused by HCV is unclear, but changes in hepatic metabolism as well as enhanced HCV replication may be contributory.2,4"13
Increased Virus Replication. Alcohol may enhance the replication of HCV, causing more serious hepatic injury than that caused by alcohol or HCV alone. Several studies have found that heavy alcohol intake was associated with higher levels of HCV-ribonucleic acid (HCVRNA).914 One study noted a clear relationship between the level of HCV-RNA and the amount of alcohol consumption and suggested that alcohol may have a direct effect on the rate of replication, clearance of HCV, or both.9 This effect was noted even with moderate alcohol consumption in two studies.9,5 Hepatitis C virus-ribonucleic acid levels appear to decrease when patients abstain from alcohol.15 However, other researchers did not find a correlation between HCVRNA levels and alcohol intake.8,12
EFFECTS OF HEAVY DRINKING
Numerous studies indicate that patients with HCV and heavy alcohol intake have increased progression of hepatic fibrosis, increased rates of cirrhosis, increased risk of hepatocellular carcinoma, and increased risk of death.2·4"17 One standard drink contains approximately 1 5 g of alcohol. Poynard et al. noted that patients who consumed greater than 50 g of alcohol (three-and-ahalf standard drinks) per day had a markedly increased rate of progression of fibrosis.13 In another study, Pessione et al. found accelerated fibrosis with moderate alcohol consumption (only one to two standard drinks per day).9
Wiley et al. studied patients with longterm heavy drinking (greater than 5 years). Heavy drinking was defined as greater than 40 g/d for women and greater than 60 g/d for men. When compared with subjects who were not heavy drinkers, these patients had a two- to three-fold greater risk of cirrhosis and decompensated liver disease. They concluded that alcohol is an independent risk factor for the histologic and clinical progression of HCV infection.8 Another study found that patients with RCV who consumed more than 80 g/d had a four-fold increased risk of cirrhosis 15 years after infection.7 Several other studies have had similar findings. Most studies have been in patients with heavy alcohol consuption; few studies have examined patients drinking less than two drinks per day.
A number of studies have also noted a relationship between HCV, heavy alcohol intake, and me development of hepatocellular carcinoma. These studies have shown a significantly increased risk of hepatocellular carcinoma in patients with HCV who were heavy drinkers.2,4-5,7,10,16'17 The role of moderate alcohol intake in the development of hepatocellular carcinoma remains unclear.
Heavy alcohol intake clearly worsens the effects of HCV infection. Patients with heavy alcohol intake have more rapid progression of fibrosis and an increased incidence of cirrhosis, hepatocellular carcinoma, and death. The limited available data indicate that moderate alcohol consumption may also have a negative impact on the effect of HCV infection. Further research is needed to clarify the effects of light to moderate alcohol consumption on the course and outcome of HCV infection.
ALCOHOL CONSUMPTION AND TREATMENT OF HEPATITIS C
Approximately 50% to 60% of patients with HCV are at risk for progression to end-stage liver disease.1 This risk is significantly increased in individuals with heavy alcohol consumption.1,2,4-17 Patients infected with HCV are strongly encouraged to abstain from the use of alcohol. Abstinence in heavy drinkers with HCV is associated with improvement in chemical markers of liver damage as well as a decrease in HCV-RNA levels.5,15
Effective treatments for hepatitis C have only recently become available. At the present time, optimal treatment of HCV consists of combination antiviral therapy with pegylated interferon and ribavirin. Successful treatment is associated with a decrease in hepatic fibrosis and cirrhosis in these patients. The best indicator of effective treatment is a susviral response, defined as the of detectable HCV-RNA in the serum. Optimal treatment is assowith sustained viral responses in to 50% of patients with genotype 1 greater than 70% of patients with 2 and 3.1
Ongoing heavy intake of alcohol is a relative contraindication to antiviral treatment of HCV. Successful antiviral treatment requires compliance with the prescribed medication regimen heavy drinkers may be less likely to Furthermore, interferon-alpha cause significant psychiatric illness alcohol further exacerbates these Most importantly, alcohol use treatment of HCV is associated poor response to antiviral therapy. appears to interfere with the antiviral actions of interferon therapy. is both an antiviral agent and modulator; the effects of alcohol on the action of interferon are poorly understood.7
There are hmited data on patients ongoing alcohol use during antiviral treatment. Loguercio et al. found an inverse correlation between rates of to interferon treatment and of alcohol intake during therapy.12 data are limited to individuals with heavy alcohol intake and there are data on patients drinking 10 g to 20 g alcohol per day. A few studies have looked at patients who abstained from for 1 to 6 months prior to antivitreatment and during interferon therapy. In these studies, patients with of infrequent and moderate use had similar response rates, those with histories of heavy alcohol consumption (greater than approximately 70 g/d to 80 g/d) had markedly responses to antiviral treatThese studies are summarized in Table 1 (page 404). Long-term abstinence may improve response to therapy. of acute alcoholic hepatitis in several individuals consuming alcohol during interferon treatment lend further support to the need for abstinence during interferon treatment,22
Hepatitis C Virus Treatment and Substance Use Disorders
The 2002 NTH Consensus Conference developed treatment recommendations based on the evidence that heavy alcohol consumption is deleterious to patients with chronic HCV and negatively impacts both the course of liver disease and response to treatment. Patients with heavy alcohol use, alcohol abuse, and alcohol dependence should be asked to be abstinent for a period of time prior to the initiation of antiviral therapy.1 These patients should be educated regarding the effects of alcohol on the course of HCV and evaluated by a chemical-ependency specialist. Individuals with alcohol abuse and alcohol dependence should be encouraged to enroll in a rehabilitation program. After an initial period öf abstinence (minimally 1 month) patients may begin antiviral therapy. Interferon therapy is associated with depression, irritability, and anxiety and these symptoms may increase risk for relapse to alcohol use in these patients.7 Because of these concerns, these patients should receive ongoing support from a chemical dependency program and close monitoring during the course of interferon therapy. Patients without alcohol abuse or dependence who consume light to moderate amounts of alcohol should be encouraged to abstain from alcohol during antiviral therapy but a pretreatment period of abstinence is not necessary in these individuals.7
The Veterans Affairs Northwest Hepatitis C Resource Center developed a coordinated plan for treatment of patients with alcohol use disorders and HCV infection. All patients with HCV infection who use alcohol are educated regarding the effects of alcohol on HCV and the course of HCV infection. Patients with light to moderate alcohol use are advised to stop using alcohol and are required to abstain from alcohol while receiving treatment for HCV. Patients with alcohol abuse or dependence are referred for chemical dependency treatment.
After successful enrollment in the program and detoxification, patients may begin interferon treatment. A minimum period of abstinence of 1 month is required, but a longer time is preferable. The hepatology clinic, the chemical dependency rehabilitation program, and the mental health clinic work together to provide needed services and support to these patients. Patients who refuse chemical dependency treatment are referred back to their primary care physician and told that they will be evaluated for antiviral treatment for HCV infection after 6 months of abstinence from alcohol or after they have enrolled in a chemical dependency program.
SUBSTANCE USE DISORDERS AND HEPATITIS C
Individuals who use illicit drugs are at extremely high risk for HCV infection. This risk is highest in users of intravenous drugs; however, individuals who do not inject drugs also are at increased risk. The etiology of the increased risk in noninjectors is unclear but intranasal drug use, which may facilitate transfer of infected blood, and high-risk sexual practices have been postulated as contributory factors. Successful treatment of HCV in this patient population may reduce transmission of the virus.' In the 1990s, the initial recommendations from the NIH and National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) were that users of illicit drugs be required to achieve 6 months (NIH) or 2 years (NIDDK) abstinence prior to initiation of interferon therapy for HCV infection. Concerns about treatment adherence in this patient population, reinfection with HCV secondary to ongoing drug use, increased interferon toxicity, and precipitation of relapse were cited as reasons for withholding treatment from active users of illicit drugs.23·24
A number of studies examined treatment adherence in illicit drug users. In some studies, drug users were less compliant with medical regimens than other individuals. However, in other studies, compliance of illicit drug users was similar to that observed in other patients. These studies have shown compliance rates of 40% to 80% depending on the treatment regimen, the study population, and the treatment setting. These rates are comparable to those described in general medical populations. Programs specifically designed to treat medical conditions in illicit drug users have excellent rates of treatment compliance.24
Opioids, cocaine, other stimulants, and marijuana have not been shown to have direct hepatic toxicity. The effect of these substances on HCV-RNA and the progression of liver disease from HCV are poorly understood at this time. These substances do not have known adverse interactions with interferon. Although data are limited, several studies have noted that HCV treatment appears safe in individuals who are not completely abstinent from drug use.23
SUBSTANCE USE AND TREATMENT OF HEPATITIS C
Interferon treatment may precipitate relapse with use of drugs and alcohol in this patient population. However, there is a paucity of data that can confirm this speculation. Side effects of interferon, including depression, anxiety, irritability, pain, and flu-like symptoms may increase the risk of relapse. The lifetime prevalence of psychiatric conditions is high among individuals with substance use disorders and these individuals may be at increased risk for interferoninduced psychiatric complications. There are reports of relapse among former drug users treated with interferon. In addition, there may be an increased rate of treatment discontinuation secondary to psychiatric complications and substance use in this patient population.25 There are little data to support these hypotheses and further research is needed in this patient population.
Concerns have also been raised about the risk of exposing former intravenous drug users to long-term therapy involving medication administration via selfinjection because this may be a trigger for relapse.26 Use of longer-acting interferon preparations with once weekly administration by a health professional may be one way of minimizing this risk.
Reinfection in intravenous drug users who continue to use drugs after successful treatment for HCV has received limited study. The existing data from two European studies suggest that such reinfection is uncommon and can be minimized by patient education regarding safe injection practices.23
There are very few published studies of interferon treatment in patients with substance use disorders. These studies are summarized in Table 2. Sylvestre has studied a cohort of patients on methadone maintenance therapy. This study showed that mterferon/ribaviriri therapy was safe, well tolerated, and effective in this group of patients. Seventy-eight percent of the patients successfully completed the course of treatment and 54% had a sustained viral response.27
Several studies examined HCV treatment in patients with ongoing drug use. In a German study, 50 patients undergoing detoxification of intravenous drugs were enrolled in HCV treatment. During the course of the study, 80% relapsed to drug use. Patients who did and did not relapse had similar rates of sustained viral responses and these rates were similar to those observed in studies of nondrug users. Treatment adherence was the strongest predictor of response to antiviral therapy in this study.28
In an ongoing study by Sylvestre, intermittent drug use and moderate alcohol use during antiviral therapy had a slight negative impact on treatment outcome that was not statistically significant. None of the patients with ongoing, regular intravenous drug use had a sustained viral response but the number of patients in this group was quite small. Interestingly, patients who smoked marijuana during antiviral treatment were more likely to show a sustained viral response. It was postulated that this was secondary to improved adherence possibly because of a positive effect of marijuana on interferon-induced side effects.29
The 2002 NIH Consensus Conference eliminated active substance use as a contraindication to treatment of HCV. Treatment of substance abusers should be considered on a case-by-case basis. These individuals may be at risk for noncompliance with treatment, psychiatric complications, and relapse of their substance use disorders. Concurrent management of these patients by hepatologists and chemical dependency specialists may improve outcome and reduce the risk of noncompliance and treatment complications.1
The Veterans Affairs Northwest Hepatitis C Resource Center developed an algorithm for the treatment of patients with substance use disorders similar to that developed for patients abusing alcohol. All individuals are educated regarding substance use and HCV. Individuals motivated to receive antiviral treatment are encouraged to abstain from the use of recreational drugs and enroll in chemical dependency treatment. They enroll in either a traditional abstinence-based treatment or a motivational harm-reduction intervention. Individuals involved in both of these treatment modalities are candidates for antiviral treatment. These individuals are not required to achieve abstinence prior to the initiation of antiviral therapy. Ideally, they receive antiviral treatment and chemical dependency treatment concurrently. Substance abusing individuals who refuse chemical dependency treatment are referred back to their primary care physicians and are eligible for antiviral treatment after 6 months of abstinence.
SMOKING AND HCV
The effect of smoking on the progression of liver disease and the success Of interferon treatment for HCV remains unclear. Experimental studies in rats have shown that nicotine can have deleterious effects on the liver. In a recent study, Hezode et al. noted that tobacco consumption in humans of greater than 15 cigarettes per day was associated with more severe hepatic inflammation.30 A study by Pessione et al. noted a relationship between smoking and hepatic fibrosis. These data, though limited, suggest that smoking may negatively impact the progression of liver disease in patients with HCV and that smoking cessation is recommended for this patient population.31 No study to date has addressed the effect of smoking on the success of antiviral treatment.
SUMMARY AND FUTURE RESEARCH NEEDS
Patients with alcohol and other substance use disorders are at high risk for chronic infection and significant longterm complications from HCV There is clear evidence of the deleterious effects of heavy alcohol use on the course and treatment of HCV. Future research is needed to assess the effects of light and moderate alcohol use on the natural history of HCV. Additional studies are also needed to assess the effects of all levels of alcohol consumption on the outcome of treatment with interferon and ribavirin.
Further research on the natural history of HCV in individuals with substance use disorders (both intravenous and nonintravenous use) is needed. The course and outcome of HCV may be different in individuals with ongoing drug use as compared to those who achieve abstinence. Furthermore, little is known about the effects of different classes of illicit drugs on the natural history of HCV. Studies are needed to develop optimal treatment approaches for the liver disease and comorbid substance use disorders and psychiatric illness commonly found in patients with HCV. In addition, the safety and effectiveness of antiviral treatment, the risk of serious side effects, and the risk of reinfection should be examined in the population of substance using patients.
Finally, comanagement strategies must be developed that address both the liver disease as well as comorbid substance use disorders in these patients to prevent the spread of HCV in the general population.
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Alcohol Consumption and Response to Interferon Therapy
Hepatitis C Virus Treatment and Substance Use Disorders