Controversies in Hepatitis C Therapy: Debating the Options for Patients with Depression, Alcoholism, or Substance Abuse

The current standard care for hepatitis C virus (HCV) is combination therapy consisting of pegylated interferon (PEG-IFN) and ribavirin. More than half of patients treated in the early stages of liver disease may expect to achieve sustained virologic responses and, in some cases, restoration of normal liver function and histology. Genotypes 2 and 3 respond better to treatment than genotype 1, so patients infected with those genotypes experience much higher rates of sustained response.

Despite the progress made in treating this disease, important controversies remain to be resolved. One concern is the high prevalence of depression prior to and/or during treatment with IFN. Should all patients entering HCV therapy be treated with antidepressant agents prophylactically? A second controversy revolves around current and recent alcohol habituation and intravenous drug use. Individuals in these categories have been excluded from clinical trials because of the prevalence of comorbid hepatic disease and because these substances are thought to decrease the efficacy of antiviral therapy. Should they or should they not be considered candidates for treatment?

This program was supported byan unrestricted educational grant from Roche Laboratories, Inc.

Overview: Psychiatric Disorders and Substance Abuse in HCV

Andrew Angelino, MD, a psychiatrist at Johns Hopkins University, opened the program with an overview of psychiatric disorders in the HCV population. “We think that the hepatitis C epidemic is fueled by psychiatric disorders,” he said. This was a reference to two categories of individuals. First, approximately half of patients seeking treatment for HCV have symptoms of depression, and 14% have histories of major depression. Depression centers on anhedonia that may adversely affect appetite, sleep, and gastrointestinal function. Second, some individuals who are infected with HCV have extraverted personalities. These individuals are intolerant to routine and boredom, they act on their feelings of the moment without regard to potential future consequences, and they engage in high-risk behaviors and impulses that may expose them to HCV.

Intravenous drug use is the main vector for HCV transmission, with prevalence studies reporting HCV antibody rates in the range of 60% to 90% in this population. Typically, exposure occurs within the first 12 months of the onset of intravenous drug use. Alcoholics who do not use intravenous drugs have an unexpectedly high rate of HCV exposure and a high infection rate. Intravenous drug users have been excluded from clinical trials in HCV therapy because of the presumption that their cravings will lead to poor adherence to protocols; and alcoholics have been excluded because of the supposition that comorbid liver disease may undermine the value of data regarding the virologic response to therapy.

To set the stage for the debate, Dr. Angelino referred to a study of 293 patients eligible for antiviral treatment for HCV, 28% of whom were accepted for therapy. Among those who were rejected, 24% had psychiatric contraindications, mostly depression, and 9% were alcoholics or intravenous drug users.

Question 1: Is there a medical or statistical basis for treating depressed patients prophylactically before admitting them to antiviral therapy for HCV to prevent progression to end-stage liver disease?

Question 2: In light of the anticipated 30% to 40% rate of new-onset depression associated with IFN therapy, is there a clinical or statistical basis for the prophylactic treatment of patients with no apparent baseline depression?

Question 3: Is there a clinical or statistical basis for rejecting current heavy users of alcohol or of intravenous drugs from treatment?

Depression: Treat Prophylacticallyor Symptomatically?

Point: All patients should receive prophylactic antidepressant treatment.
Howard P. Monsour, Jr., MD, a hepatologist from the Texas Liver Institute in Houston, advocated the affirmative side of the debate on the prophylactic treatment of depression. Anticipating that the counterpoint argument would center on trial data, Dr. Monsour sought to put those trials into a context that makes them useful for community practice. He pointed out that some of the modes of assessing depression were not validated well in HCV patients. He also noted that with PEG-IFN therapy, adverse psychiatric effects generally occur within 48 to 72 hours of initiating treatment. The registration trials are unclear as to when the depression scales were offered to patients, thus introducing a time bias.

Because of the exclusion criteria used in the registration trials, the prevalence of baseline depression in the trial populations greatly understates its prevalence in community practice. Up to 57% of patients seeking therapy may already have depression and anxiety, and many more have additional risk factors for depression including those with concomitant drug or alcohol dependency. Co-existing medical conditions and medications can also be additive for depression and irritability. Moreover, 20% of patients have two or more depressive disorders simultaneously. Dr. Monsour cited a study of 157 patients seen at hepatitis clinics. In that study, 71% of patients had active psychiatric and medical comorbidities, 95% of patients had been identified as having psychiatric disorders requiring pharmacologic intervention, and 42% of patients were under the care of psychiatrists currently (Fontana J. J Hepatol 2002;36:401). “I can assure you,” Dr. Monsour said, “that the 42% of patients under current psychiatric care would not have been admitted to the clinical trials that produced baseline depression rates of 20% to 30%.” He also cited data from the Veterans Administration indicating that in an HCV population, up to 58% of patients had been diagnosed with depression, bipolar, disthymic, or schizoaffective disorders; 27% suffered from anxiety disorders including post-traumatic stress disorder; and 89% of patients had histories of alcohol or drug dependencies. None of these patients would have been admissible to registration trials.

Turning to new-onset depression during antiviral therapy with IFN, Dr. Monsour noted that half of patients are affected with moderate or severe depression within 1 month of the initiation of therapy. The mean time to onset was approximately 2 weeks, indicating rapid psychiatric reactions to therapy. This presents two problems. First, to detect rapid-onset depression in community-dwelling individuals, frequent follow-up psychiatric reevaluation would be necessary to avoid missing depression that might affect adherence to treatment protocol. Second, data on the probability of response to antidepressants indicate that it takes 2 weeks for half of patients to respond well and 4 to 6 weeks for 30% of patients. Approximately 20% of patients do not respond at all. Thus symptomatic treatment, even if treatment-related depression is diagnosed in a timely manner, may not be efficacious before the patient has progressed to severe depression requiring reduction or discontinuation of IFN.

What, then, is the role of prophylactic treatment with antidepressants among patients entering anti-HCV therapy? Although there are few studies investigating this strategy, there are some trial data suggesting its usefulness. In one such trial, the initiation of antidepressant therapy 14 days prior to the first antiviral treatment was associated with an 11% incidence of new-onset depression compared with 45% in the placebo group. Severe depression requiring discontinuation of IFN was significantly improved. In a similar study, major depressive disorder was decreased from 50% in the placebo group to 10% in the treatment group. On the strength of these two trials, Dr. Monsour concluded that prophylactic treatment may resolve underlying comorbid psychiatric illnesses such as depression and irritability, may help to identify side effects of psychotropic drugs prior to antiviral therapy, and may allow for establishing the appropriate antidepressant dose for the patient. Most importantly, prophylactic treatment may prevent the onset or minimize the severity of major depression and anxiety disorders, thus allowing the patient to avoid IFN dose reductions or discontinuation that might hinder viral eradication.

Counterpoint: Screen carefully, monitor, and treat only as needed.
John Hoefs, MD, Director of the Liver Disease Program at the University of California at Irvine, introduced his advocacy of symptomatic treatment with this declaration: “My colleague has made an argument for prophylactic treatment of 70% of patients who would not develop depression during IFN therapy, raising the risk of side effects and greatly increasing the cost of therapy. I must say with confidence that you should reject this strategy.”

In recent years, with new treatment options, the rate of sustained virologic response in HCV has increased from 10% to over 50%. Depression, however, is a reason to reduce the dose of IFN and can potentially be a detriment to viral eradication. However, the average time to the diagnosis of depression is 12 weeks. At that point, a blood HCV RNA of greater than 1/100th of the baseline value will predict the patient who will not respond to treatment, and treatment can be discontinued. In that group, therefore, antiviral therapy is discontinued before half of depression-prone patients show clinical signs of depression. On the other hand, if treatment is effective, then depression can be treated when it appears.

Patients are qualified for prophylactic therapy if they have no indications for treatment of depression, such as patients in the signature trials of combination therapy. Only 30% of these patients develop depression during HCV therapy. Some patients should, of course, enter antiviral therapy with antidepressant treatment including those already on therapy, untreated individuals who show symptoms during screening, and any individual who experienced depression during a prior course of antiviral therapy. The important distinction (even in populations with a greater than 50% prevalence of depression), therefore, is between patients who have an indication for treatment for depression and those who do not, as well as patients who have contraindication for antidepressant treatment. There are no controlled trials of prophylactic antidepressants in treated HCV patients showing an improvement in sustained virologic response that might justify concurrent treatment in all patients. Furthermore, patients should not be exposed to the potential adverse effects of antidepressants unnecessarily. Like depression, these can necessitate IFN dose reductions or discontinuation. They include most importantly sexual dysfunction, insomnia, and irritability, all of which worsen similar IFN-induced side effects. Retinal damage leading to either temporary or permanent vision defects has been reported in association with antidepressant therapy, as has treatment-induced hepatotoxicity. In the weighing of risks against benefits before prescribing, these may be acceptable side effects for an individual who has an indication for antidepressant treatment, but they are not for the patient who has no indication.

Dr. Mansour and Dr. Hoefs agreed on the effectiveness of antidepressant treatment in patients with IFN-induced depression. In a small open-label trial in which one-third of patients experienced depression during IFN therapy, 10 of 13 patients responded to a selective serotonin reuptake inhibitor (SSRI) and an additional patient responded to an antidepressant of another class. Antidepres-sants are sufficiently effective in 90% of cases to avoid antiviral dose reduction. Despite the effectiveness of antidepressants, however, prophylactic use is not indicated. Dr. Hoefs recommended, therefore, a strategy of screening patients carefully for depression, monitoring for the occurrence of psychiatric side effects during antiviral treatment, and treating depression when it occurs. Although treatment-related depression may be of rapid onset, severe depression is not and is unlikely to be missed.

Point: Alcohol and drug abuse can be contraindications.
Gregory Everson, MD, Director of Hepatology at the University of Colorado, cited NIH guidelines of 2002 as the basis for his argument. According to those guidelines, a history of alcohol use is not a contraindication for antiviral therapy, but continued alcohol use during treatment adversely affects response. Consequently, alcohol abstinence should be practiced at least 6 months prior to and throughout treatment. The recommendation on intravenous drug use is considerably less clear. Treatment of patients with active drug use should be considered on a case-by-case basis, but use of injected drugs should not be a basis for routinely excluding patients from treatment.

It is currently estimated that between 10% and 50% of individuals with HCV infection abuse alcohol, the higher figure coming from the population of military veterans. Conversely, between 5% and 10% of alcoholics who deny histories of drug use test positive for HCV. Alcohol is a hepatotoxin and thus is a risk factor for comorbid disease, and it may inhibit the antiviral potency of standard treatments and may decrease virologic response rates to as low as 0% to 16%. Alcohol also precipitates side effects, such as depression, that may further reduce the virologic response by requiring IFN dose reduction or discontinuation. It has also been shown that alcohol is a contributing factor to an increased rate of fibrosis progression in the liver, thus increasing the risk of end-stage decompensation and death. In light of the profound effects of alcohol on the liver and on antiviral treatment, such treatment may hold little benefit for this population. Thus, Dr. Everson concluded, the NIH recommendation of alcohol abstinence before and during antiviral therapy is appropriate.

Currently, 60% to 68% of newly diagnosed cases of HCV are attributed to intravenous drug abuse and 80% to 90% of intravenous drug abusers have HCV. “I would discourage you from enrolling patients with active intravenous drug use in your treatment programs,” Dr. Everson said emphatically. In addition to the potential hepatotoxicity of injected drugs, abusers have reduced compliance with medical management and may, after successful antiviral treatment, resume old risks and experience re-infection. These patients often have comorbid psychiatric disorders, such as depression, that affect their ability to tolerate IFN and lead to dose reductions. Reasonable sustained virologic responses have been observed in only highly selective populations of active intravenous drug users treated for HCV under controlled conditions including methadone maintenance and psychiatric support. Thus, it is very difficult to transport data from these studies into community practice. Clinicians should use extreme caution when deciding to admit active intravenous drug users into antiviral therapy, as it is most often a contraindication for therapy.

Counterpoint: Alcohol and drug use should not bias admission to antiviral treatment.
In taking the opposing view, Diana L. Sylvestre, MD, of the University of California at San Francisco, said that “medical evidence is the key to treating stigmatized patients.” Approximately half of drug abusers have comorbid psychiatric disease and have been treated safely prior to being admitted to antiviral therapy for HCV. These patients should not be excluded from treatment arbitrarily. On the subject of adherence to treatment, studies show that among habitual drug users, 30% to 100% fail to meet the 80-80-80 test (i.e, receiving 80% of the dose of PEG-IFN and 80% of the dose of ribavirin 80% of the time), proportions that do not differ appreciably from adherence rates observed in populations of non-addicted patients being treated for hypertension, diabetes, or asthma. Rather than assume noncompliance, therefore, objective tests should be used. Patients who do not show up for appointments, for example, are at high risk for poor compliance and probably should not be treated.

In a study designed for intravenous drug users taking HCV treatment consisting of unmodified IFN plus ribavirin, there was no significance difference (p=0.19) in adherence between patients maintained with methadone and all patients (using drugs and not using drugs) even though a high proportion of patients relapsed to drug use. As Figure 1 indiates, there was also no significant difference (p=0.16) in virologic outcomes (Sylvestre DL, Clements BJ. Hepatol 2002;36:223A). These findings argue against the arbitrary exclusion of this population from anti-HCV treatment.

The common assumption that intravenous drug users should not be treated for HCV because of re-infection following successful eradication is unsupported by data. In fact, there is only one reported case in the literature of re-infection due to relapse to drug use following treatment. As for efficacy, Dr. Sylvestre pointed to German evidence that in a trial using unmodified IFN, patients who relapsed to drug use had a sustained virologic response rate of 24%.

Dr. Sylvestre turned to the issue of alcohol use in the selection of patients for HCV therapy. In an analysis of patients in her study population who had a 28% sustained virologic response rate, patients were divided into two groups: those who had abstained from alcohol for 6 months or more and those who had abstained for less than 6 months including those who continued to consume alcohol. There was no statistical difference between the two groups in treatment efficacy (p=0.10). With regard to histologic progression, logic suggests that if alcohol accelerates the progression of hepatic fibrosis, there is more reason rather than less to offer HCV treatment.

Dr. Sylvestre concluded that injection drug users and heavy consumers of alcohol can be treated safely for HCV by current methods, and they show good virologic outcomes in carefully designed programs even when they have psychiatric disease, active drug use, or limited sobriety. “The accelerated course of disease in these two populations and the contribution of HCV to their early mortality argue for more liberalized and aggressive HCV treatments in settings with experience with addiction management.” A support structure is essential to compliance and, therefore, to outcomes, and without it addiction may be a contraindication for treatment.