Hepatitis C virus is the most common blood-borne pathogen in the United States. An estimated 1.8% of the U.S. population is chronically infected (1). Currently, intravenous drug use is the most common route of infection; each year, 30,000 people are newly diagnosed with the hepatitis C virus (2). Chronic infection with the hepatitis C virus is associated with cirrhosis and hepatocellular carcinoma and is the most common reason for liver transplants in the United States.
The current optimal treatment for hepatitis C virus consists of pegylated interferon (IFN), given via injection once per week, and daily doses of ribavirin (3). Antiviral treatment for hepatitis C virus is either for 24 or 48 weeks, depending on the genotype of the virus. Response to treatment is measured by determining viral titers of hepatitis C viral RNA. An end-of-treatment response is defined as the absence of hepatitis C virus viral RNA immediately after the course of treatment is completed. A sustained viral response is the absence of hepatitis C viral RNA 6 months after treatment is completed. Patients with a sustained viral response have a more than 95% chance of remaining virus free indefinitely. Treatment for hepatitis C virus can pose mental health challenges because antiviral therapy can induce depressive symptoms and has occasionally been known to trigger mania or psychoses (4, 5). Antiviral therapy may also exacerbate preexisting mental health conditions, including depression, posttraumatic stress disorder, and mania. Antiviral therapy has also been associated with the relapse of substance use (6). It is generally recommended that patients with preexisting mental health or substance dependence conditions be stable at least 6 months before initiation of antiviral therapy (7).
In 2002, the National Institutes of Health Consensus Development Conference on the Management of Hepatitis C recommended that treatments for hepatitis C virus be extended to groups previously thought to be at high risk for receiving IFN treatment. These high-risk groups include those with a current or past history of substance disorder (8). It is estimated that 70%–90% of intravenous drug users are chronically infected with the hepatitis C virus but that only about 50% are ever offered treatment (9).
The Portland Veterans Affairs Medical Center Hepatitis C Resource Center includes a multidisciplinary clinic specializing in the evaluation and treatment of patients considered high risk for IFN treatment, in particular, patients with comorbid mental health and substance use disorder diagnoses. Our clinic performs mental health screening before patients receive IFN treatment and ongoing evaluation and treatment of mental health problems, including those that emerge during antiviral therapy. Our multidisciplinary team includes professionals from the areas of hepatology, mental health, and chemical dependency (10).
One high-risk group in our clinic is patients with a history of opioid dependence (11). In this report, we present the case of “Mr. O,” a particularly complex and high-risk patient with schizophrenia and a history of intravenous opioid and cocaine dependence who was receiving opioid-substitution treatment (methadone maintenance) at the time of antiviral treatment for hepatitis C virus. We describe our treatment plan for his complex clinical situation and his successful completion of antiviral therapy. We also describe an unintended consequence of successful hepatitis C virus treatment. Having been “cured” of hepatitis C virus, the patient decided to see if he was “cured” of the need for methadone and ultimately relapsed to heroin use.
Addiction psychiatrists are familiar with the phenomenon of patients receiving opioid substitution experimenting with trials of discontinuation of treatment. There may be a variety of events that trigger such experimentation. General psychiatrists and others should be aware that successful completion of treatment of hepatitis C virus may be a time of increased risk and, as in this case, may result in a relapse to heroin use. After discussing the high-intensity treatment that this patient received to successfully eradicate his hepatitis C virus, we discuss our team’s approach to the patient’s relapse to heroin use and some of the barriers that we faced in attempting to address that problem. Furthermore, the literature focuses mainly on supporting the patient through the trial of IFN treatment, a period considered high risk for the emergence of psychiatric symptoms and substance abuse relapse. The stressors that patients may experience with both successful and unsuccessful antiviral treatment are generally not addressed, and these stressors definitely contributed to our patient’s ultimate relapse to the use of heroin.
Mr. O was a 53-year-old Caucasian man with a history of chronic paranoid schizophrenia that was well controlled with olanzapine and a history of opioid and cocaine dependence who was receiving methadone maintenance treatment at the time of his pre-IFN mental health evaluation. Although considered high risk in terms of mental health and substance use disorder comorbidities, Mr. O was deemed to be a good candidate for antiviral treatment for his chronic hepatitis C virus. He received 24 weekly injections of IFN and took 24 weeks of ribavirin twice a day. Hepatitis C viral RNA levels were undetectable at the end of treatment and at 6 months posttreatment. Approximately 5 months after completing antiviral treatment, Mr. O relapsed to using intravenous heroin.
Mr. O was first seen for a pre-IFN evaluation at our multidisciplinary hepatitis C virus clinic. He was diagnosed with hepatitis C virus about 10 years earlier, when he was hospitalized with vomiting and abdominal pain. He was referred to a liver clinic by his primary care provider for consideration of antiviral therapy. He presumably contracted hepatitis C virus when he was using intravenous heroin and cocaine. Mr. O had hepatitis C virus genotype 3A. His other medical problems included constipation and erectile dysfunction.
Mr. O was diagnosed with schizoaffective disorder while he was in college. Since then, he had had at least eight psychiatric hospitalizations. He had last been hospitalized about 10 years earlier. He had a history of arrest and incarceration secondary to his behavior while he was psychotic. He also had four documented past suicide attempts: two by cutting his wrists and two by overdosing on a prescription medications. He lived independently in his own apartment and received disability payments. He attributed his success at independent living to minimizing the stress in his life and making good choices about his life and lifestyle.
Pharmacological treatment for Mr. O’s schizoaffective disorder consisted of olanzapine, 20 mg/day. He stated that this dosage effectively treated his psychotic symptoms. His only residual symptom was described as occasionally hearing “electronic beeps,” but otherwise he reported no auditory or visual hallucinations. He had no referential, paranoid, or other unusual thought content. He also has a history of treatment with sertraline for depression, but at the time of his evaluation, he reported no depression and no need for antidepressant medication. Screening for depression revealed some feelings of guilt when he thought about some of the things he has done when psychotic. He reported no other symptoms of depression, including the feeling that “life is not worth living” or active suicidal ideation. His Beck Depression Inventory score was 14.
Mr. O’s treatment plan for his chemical dependency diagnosis included methadone, 65 mg/day, prescribed by a non-VA provider. He had been paying from his own funds for this treatment. This dose had been stable for 2 years, and Mr. O was receiving six take-home doses per week. He began using heroin and cocaine approximately 20 years ago. At the time of his evaluation, his last relapse to the use of heroin was 2 years earlier, when he briefly stopped methadone maintenance treatment. He reported no use of alcohol. He admitted smoking two packs of cigarettes per day and consuming four cups of caffeinated coffee per day. He reported no known drug allergies.
Based on this information, Mr. O was deemed to be at high risk but an acceptable candidate for antiviral therapy from a mental health standpoint. After weighing the risks and benefits, he and his family agreed that he should start antiviral therapy. Because he was concerned that handling the needles used for the IFN injections might be a risk factor for relapse to opioids, it was agreed that he would receive his weekly IFN injections from his provider in the liver clinic. This protocol also allowed for weekly monitoring of his mood, psychotic symptoms, drug cravings, and self-care. He was also encouraged—but not required—to attend day treatment 2 days per week and a monthly hepatitis C treatment support group.
Course of Antiviral Treatment for Hepatitis C Virus
Mr. O then began taking antiviral therapy for his hepatitis C virus. His medications included peginterferon, 180 μg/week, administered by a liver clinic and 400 mg b.i.d. of oral ribavirin for 24 weeks. At week 12, Mr. O reported that he had received an increase in his methadone dose from 65 mg/day to 80 mg/day by his outpatient methadone provider. His methadone dose was increased because Mr. O had reported an increased need for methadone and opioid cravings. At this point, our clinic requested that he be transferred to the VA opioid treatment program for better coordination of care. Furthermore, the VA program is significantly less expensive, and it was felt that the reduced cost would enhance Mr. O’s standard of living. He was placed on the opioid treatment program’s waiting list, which was over 1 year long at the time.
At week 13, Mr. O described having some stress at his day treatment program. The specific issue was unclear, but he stated that day treatment was too stressful for him. He described the side effects from antiviral treatment, including fatigue, mild irritability, poor appetite, and a 20-lb weight loss. His Beck Depression Inventory score was 30, and he was referred to a mental health clinic for further evaluation.
He was seen in the mental health clinic during week 14, and his diagnostic differential included depression secondary to schizoaffective disorder versus IFN-induced depression. Because he had responded well to sertraline in the past, he was restarted with sertraline treatment at his previous dose of 150 mg/day. It was also suspected that the problem at day treatment was a psychotic misinterpretation of events there, but this was never confirmed, and no change in his olanzapine dose was made.
Mr. O received intensive management and completed the scheduled 24 weeks of antiviral therapy for hepatitis C virus. Hepatitis C viral RNA was undetectable at the completion of his treatment. He reported having improved mood and decreased ruminative thoughts since he started taking sertraline, although he still complained of fatigue much of the time. We decided to continue giving him sertraline until the fatigue resolved.
At a visit 3 months after completion of IFN treatment, Mr. O admitted discontinuing methadone, but he stated that he did not feel at risk for relapse to opioids at this visit. He said of methadone, “I do not need that; it is just another (street) drug.” He expressed the thought that since he was no longer infected with the hepatitis C virus, he also wanted to make a new start and be abstinent from all drugs. He had also stopped taking his antidepressant, but he continued to take olanzapine, 20 mg/day.
Mr. O received routine follow-up care in the liver clinic approximately twice per month after treatment with IFN. Approximately 5 months after antiviral therapy, he reported that he had “slipped” a couple of times and returned to using intravenous heroin. He described his use as “chipping,” occasionally using heroin obtained from neighbors in his apartment building. He was regretful about his relapse and inquired about admission to the VA methadone maintenance treatment program. He was still on the waiting list, and we estimated that he would not be admitted to the program for several months. He stated that he had stopped going to his outside methadone program and was not interested in returning to that program because of the cost.
At this point, intensive harm-reduction efforts were begun, including frequent check-in appointment contacts. Mr. O was invited to attend meetings of dual-recovery groups for those with both mental illness and substance abuse and informal lunch groups open to both actively using and abstinent clients. He was also asked to attend day treatment. At that time, it was difficult to get him to engage in any of these activities. Mr. O was reeducated with regard to safe injection practices to prevent reinfection with hepatitis C virus.
Mr. O was seen in the liver clinic 6 months after completion of antiviral treatment. At that time, he was noted to have a sustained viral response, defined as undetectable hepatitis C viral RNA. His liver enzyme levels and CBC were normal. Mr. O was informed of these results and was told that he had a greater than 95% chance of remaining virus free indefinitely. Up until this point, he had not actively participated in any of the sobriety support options provided to him, both missing group therapy sessions and not returning telephone calls. He expressed an interest in restarting methadone maintenance treatment, but he declined to return to his previous methadone provider and was still on the waiting list for the VA opioid-substitution program. He also stated that he was interested in alternative housing, preferably a situation in which the neighbors were clean and sober.
Seven months after antiviral treatment, Mr. O decided to restart methadone maintenance treatment at the outpatient treatment program. He began to regularly attend sessions of both a dual-diagnoses recovery group and another chemical dependency support group. He resumed recreational activities, such as playing the piano, which he had neglected during his relapse. He had decided not to move from his apartment but to cope with the environment by “keeping [his] world small” and staying mostly to himself.
Eight months posttreatment, he shared some of his experience on antiviral treatment with his dual-recovery group. He told them that he had never felt like relapsing when he was receiving treatment, only afterward. Eleven months after antiviral treatment, approximately 1 year after being placed on the waiting list, Mr. O was admitted to the VA opioid-substitution program. He said of the experience, “This will be a big relief.”
Fourteen months after the completion of IFN treatment, Mr. O continued to have some drug cravings that he was willing to talk about openly. He admitted that he was unable to use only small amounts of drugs and demonstrated an increased awareness about the risks and consequences of relapsing to heroin use. He said of heroin use, “It always takes all my money if I start.”
The decision to start giving antiviral therapy to a patient with a history of opioid dependence should take into account the risks and benefits for the patient. For some patients, antiviral therapy may be absolutely contraindicated, including those with acute suicidal ideation, severe personality disorders, ongoing heavy alcohol use, dementia, or other cognitive problems that might impair treatment compliance or safety. For those who have been actively using opioids, many authors recommend that the patient have 6 months of documented abstinence, although some studies have suggested that it may be possible to successfully treat patients with shorter periods of abstinence or even ongoing drug use (10).
High-risk patients benefit from an integrated treatment model that allows for input and monitoring from multiple medical and mental health providers, as was available to Mr. O. They also benefit from increased support during antiviral therapy. This support can come from a variety of sources. Family members, friends, neighbors, and employers can all be helpful. As described, clinical interventions can include more frequent visits to mental health, medical, or methadone clinics (12).
Patients receiving methadone maintenance treatment may experience increased cravings while receiving antiviral therapy because the side effects may mimic opioid withdrawal symptoms. Craving may also be secondary to mood changes caused by antiviral therapy or be cue-related to needles that are used to deliver INF. There has been research to suggest that INF does not alter the pharmacokinetics of methadone in patients with chronic hepatitis C virus who are undergoing methadone maintenance therapy (13). However, an increase in methadone dose may be necessary to decrease drug cravings during IFN treatment, as was illustrated by Mr. O. Typically, this dose increase is only 5–10 mg/day and can be tapered after antiviral therapy (14). In this case, the weekly visits for shots to the liver clinic helped to decrease the cue-related cravings and provided ongoing support and monitoring of the patient’s health status. Sertraline was eventually reinstated to treat what was either a relapse of the depression associated with schizoaffective disorder or antiviral-induced dysphoria. Several studies have shown that antidepressants can be useful in managing mood changes secondary to antiviral therapy (e.g., reference 15).
Patients who have a history of opioid dependence who are not receiving methadone maintenance treatment may also seek antiviral therapy for hepatitis C virus. In one study comparing 50 people with a history of intravenous drug use receiving methadone maintenance treatment to 50 who were not receiving such treatment (matched for genotype), it was found that the group receiving methadone maintenance treatment had a statistically better end-of-treatment response to antiviral therapy, but there was no statistical difference in the sustained viral response between the two groups. This suggests that some people with a history of intravenous drug use who are not receiving opioid-replacement therapy may also be candidates for antiviral therapy, particularly if they are expected to be highly treatment compliant. However, 12 of those who were not maintained with methadone treatment relapsed to intravenous drug use, whereas none of those taking methadone did so. This suggests that those with opioid dependence who were not receiving opioid-substitution treatment may need even closer clinical monitoring or should perhaps be considered for opioid-substitution therapy before starting antiviral therapy for hepatitis C virus (7).
If a patient relapses to the use of street drugs, appropriate harm-reduction interventions should occur until the patient is able or willing to engage more actively in treatment, as illustrated by our patient. There are several harm-reduction techniques that may be effective for heroin users, including education about safe injection practices and psychosocial interventions. Ideally the patient will be able to integrate harm-reduction skills early in treatment so that he or she will have the necessary knowledge to apply when at risk for relapse.
Mr. O relapsed after completion of antiviral treatment, so the question of whether to continue antiviral treatment after relapse to opioids was not an issue. Studies have shown that those who relapse while taking intravenous drugs and receiving treatment are likely to maintain a sustained viral response as long as they continue to keep regularly scheduled clinic appointments and take medications as prescribed. In contrast, alcohol use during antiviral therapy for hepatitis C virus may result in a decreased viral response, despite continuation of antiviral therapy (16). One 5-year follow-up study of 27 injection drug users who had cleared the hepatitis C virus showed that nine of them eventually relapsed to intravenous drug use, but only one of those became reinfected (17). Similar results have been found by other researchers (18–20). These data suggest that even if patients who have been treated for hepatitis C virus do relapse into intravenous drug use, education regarding safe injection practices can prevent reinfection with hepatitis C virus.
Although our clinic does not require a treatment contract with every person treated with antiviral therapy, some higher-risk patients are asked to sign one. Treatment contracts can include such contingencies as taking medication for mental health conditions, meeting with a therapist or mental health practitioner as appropriate, increasing the frequency of mental health or medical appointments, documenting attendance at a certain number of Alcoholics Anonymous or other sobriety meetings, and submitting to regular or random urine drug screening tests. Such requirements are not meant to be punitive but to allow the clinic to provide antiviral therapy in the safest manner possible.
Mr. O had schizoaffective disorder, and we suspected that he may have experienced increased psychotic symptoms while taking IFN. The cause of psychosis may include the physical and psychological stress of IFN treatment or complex drug interactions resulting in decreased levels of antipsychotic medication. Initially, Mr. O was taking three drugs that are metabolized by the CYP P450 1A2 system: caffeine, four cups per day; nicotine, 40 cigarettes per day; and olanzapine, 20 mg/day. Because of the caffeine and cigarettes, he likely had enzyme induction of the P450 1A2 liver isoenzyme, resulting in as much as 40% lower blood levels of olanzapine (21). Several studies have suggested that IFN may down-regulate the entire P450 system (22). This may have resulted in decreased drug metabolism in Mr. O and resulted in potentially higher levels of olanzapine. Although increased olanzapine levels might have been therapeutic, it is conceivable that the patient’s blood levels of caffeine and nicotine may have also been increased. This may have increased his irritability and potentially his paranoia.
As shown with Mr. O, completion of antiviral therapy and successful clearance of the hepatitis C virus do not mean that patients are no longer in need of close psychiatric follow-up. Mr. O felt that after antiviral therapy, he could continue toward a healthier lifestyle by no longer taking psychiatric or opioid-replacement medications. Patients should be encouraged to carefully consider major decisions about discontinuing medications or other major health-related changes after completing antiviral therapy. Patients may benefit from psychotherapeutic interventions throughout treatment to discuss what it has meant to have hepatitis C virus, their feelings about the behaviors that contributed to hepatitis C virus infection, coping with the side effects of antiviral therapy and related changes in their quality of life, and what life might be like after either clearing the virus or potentially failing to clear it.
This case also exemplifies the need for higher-intensity follow-up in those with opioid dependence. While receiving antiviral therapy, these patients are closely monitored for changes in physical and mental health and are frequently highly motivated to succeed at their goal of completing treatment and becoming negative for the hepatitis C virus. In this instance, the patient had at least weekly contact with a provider during treatment. Successful completion of antiviral therapy resulted in a reduction in the number of clinic visits. This patient and others may benefit from continued frequent clinical contacts until other life activities are substituted.
As described, patients with a history of opioid dependence and/or chronic mental illness have unique issues when they are being considered for IFN treatment (Appendix 1). Further research that examines the safety and efficacy of antiviral therapy for hepatitis C virus in those with a history of opioid dependence is warranted. Specialized treatment models for these patients may optimize treatment outcomes. Prospective controlled trials are needed to compare those receiving methadone maintenance treatment with those who are not. To date, we are aware of no studies that examine patients taking buprenorphine and compare their treatment outcomes to those taking methadone or those not taking opioid-replacement medications.
There may also be a period after antiviral therapy in which a patient is more vulnerable to relapse to opioids. It would be useful to know the typical duration of this higher-risk period and the types of continuing-care practices that would be most beneficial. Patients are supported and encouraged while receiving antiviral therapy and may miss this support after successful treatment. Higher-intensity monitoring for at least 6 months after antiviral therapy and psychotherapeutic interventions throughout treatment addressing their thoughts and feelings about hepatitis C virus and antiviral therapy may be useful.
Intravenous drug use is the most common rout of transmission of the hepatitis C virus; the majority of the patients who need treatment for hepatitis C virus have a history of intravenous drug use. These patients typically have severe comorbid psychiatric illness as well. It is no longer practical or recommended to exclude those with a history of opioid dependence from antiviral therapy. As more high-risk patients are treated for hepatitis C virus, it is increasingly important to develop multidisciplinary approaches to treating these medically and psychiatrically complex cases, and general psychiatrists will need to have a greater understanding of the complex treatment plans and dynamics that can occur. As is well known, mental health/substance abuse evaluation and management are critical to the management of hepatitis C antiviral therapy in these high-risk patients. Aggressive multidisciplinary case management is needed before and during antiviral therapy and—as made painfully clear in this case study—during the very vulnerable period after hepatitis C therapy.