Treatment for Hepatitis C in Substance Users

Although injection drug users comprise the majority of cases of infection with hepatitis, most of these individuals do not undergo treatment because of physician concerns about adherence, treatment efficacy and reinfection.

Still, based on growing evidence that injection drug users can successfully undergo treatment for chronic hepatitis C, the 2002 National Institutes of Health Consensus Statement on Hepatitis C  recommended that substance users, even those with ongoing drug use, should be considered for treatment for HCV infection on a case-by-case basis.

However, the criteria on which these treatment decisions should be based are unclear: The duration of pretreatment drug abstinence, psychiatric illness, intercurrent drug use, and the potential for injected interferon to cause relapse of drug use may all influence results of treatment for HCV infection.

Following are excerpts from an overview article by Diana Sylvestre of the UCSF Organization to Achieve Solutions in Substance Abuse (Clinical Infectious Diseases 41 Supplement 1. July 1, 2005). In it Dr. Sylvestre summarizes her group's current data about treatment for HCV infection in substance users and the effect of these potential barriers on outcomes of treatment.

Hepatitis C virus (HCV) is the most common bloodborne pathogen in injection drug users (IDUs); without treatment, it may lead to cirrhosis, liver cancer, and death. Although IDUs represent the majority of incident and prevalent cases of HCV infection, many are excluded from treatment because of concerns about adherence, reinfection, and IFN-mediated neuropsychiatric toxicity. Although studies of nonaddicted populations have shown that >50% of patients who complete therapy with newer regimens can expect to develop a sustained virological response (SVR), the short- and long-term effect of treatment for HCV infection in drug-using populations is not known.

Although few data have been published about treatment for HCV infection in IDUs, recent experience has demonstrated its feasibility even for patients with ongoing drug use. A study conducted in Germany of 50 IDUs enrolled in methadone detoxification and treated either with IFN [monotherapy] or combination therapy with IFN and ribavirin demonstrated an overall SVR rate of 36%. Interestingly, there was no statistical difference in treatment outcomes among patients who remained abstinent from drugs through the treatment course, compared with patients who relapsed.

In her article, Dr. Sylvestre summarizes the results of a study by her group of treating patients undergoing maintenance therapy with methadone with standard IFN and ribavirin, which have been reported in detail elsewhere. In addition, she reports on the preliminary results of a similar study of weekly therapy with pegylated IFN and ribavirin.

Finally, she describes the effect on treatment outcomes of characteristics typically cited as reasons to withhold treatment for HCV infection from substance users.

Dr. Sylvestre hypothesizes that maintenance therapy with opioid agonists on an outpatient basis would provide a foundation for successful treatment for HCV infection, allowing the measurement of those characteristics associated with positive and negative outcomes of treatment.

Approaching Treatment for Hepatitis C Virus Infection in Substance Users

Men and women aged 18 years were eligible if they had been undergoing maintenance therapy with methadone for 3 months and had a positive result of PCR testing for HCV. Patients who attended a minimum of 75% of our weekly clinics for 2 months were considered to be eligible for enrollment irrespective of concurrent drug use if no other contraindications were present. Patients with untreated depression were excluded until they could be stabilized by means of treatment with antidepressants.

In study 1, treatment for HCV infection consisted of IFN-2b (3 × 10⁶ IU administered sc 3 times weekly), and, in study 2, treatment consisted of pegylated IFN-2b (1.5 g/kg/week administered weekly). Ribavirin capsules were administered at standard dosages in both studies on the basis of weight.

Patients infected with HCV genotypes 2 and 3 received therapy for 24 weeks; the remainder were treated for 48 weeks. Substance use during HCV therapy was actively discouraged but did not result in discontinuation of treatment unless the patient became unreliable in attending at least 75% of scheduled appointments or the clinician thought it represented a safety risk.

The primary study end point was SVR, as measured by undetectable levels of HCV RNA 6 months after the completion of therapy. Patients were considered to have achieved SVR if they had no detectable virus at this time point or as having a nonresponse if results of PCR were positive. All analyses were done on an intent-to-treat basis.

Results

Study 1: standard IFN-2b plus ribavirin.     A total of 76 patients were enrolled at 2 sites. The average age was 50 years; 46 patients (61%) were men, 54 (71%) were white, 10 (13%) were African American, and 12 (16%) were Latino. The mean (±SD) estimated duration of HCV exposure was 28 ± 9 years. The mean duration of lifetime heroin use was 21 years, and 44 (64%) of 69 patients reported a history of heavy alcohol use.

The median duration of abstinence from illicit drug use was 1 year (range, 018 years), and 23 patients (30%) had been abstinent for <6 months. Forty-five patients (59%) reported a previous psychiatric diagnosis.

Forty-five patients (59%) were infected with HCV genotype 1, 10 (13%) were infected with HCV genotype 2, and 19 (25%) were infected with HCV genotype 3. One patient was infected with HCV genotype 8a, and 1 was infected with untypeable HCV. Twenty-three (30%) of the 76 study patients had cirrhosis, as measured directly by a biopsy exhibiting stage 4 fibrosis or indirectly by a platelet count of <75,000 cells/mm³.

During treatment for HCV infection, 15 patients (20%) ingested alcohol, but only 1 reported heavy (>50 g/day) ingestion. A total of 45 patients (59%) used illicit drugs during treatment. Of these, 18 patients (24%) used only marijuana, and 27 (36%) used heroin, cocaine, or methamphetamine of some quantity.

A total of 8 patients (11%) were classified as regular users, as determined by the use of illicit substances every day or every other day for 1 month.

Overall, 58 (76%) of the 76 patients completed therapy for HCV infection, and 18 patients (24%) discontinued treatment early. Thirty-seven patients (49%) had an end-of-treatment response (ETR), and 21 (28%) had an SVR [emphasis added--Ed]

Fifty-six patients (74%) exhibited at least 1 of the characteristics generally considered to be associated with reduced treatment outcomes: comorbid mental illness, <6 months of pretreatment abstinence, or intervening drug use during treatment for HCV infection.

Patients lacking these negative predictors showed response rates similar to those published in large-scale registration trials, including a discontinuation rate of 15%, an ETR rate of 55%, and an SVR rate of 40%. The difference in rates of SVR between the group exhibiting barriers, compared with patients without barriers, was statistically significant on multivariate logistic regression analysis (P = .035).

Thirty-five percent of patients without a prior psychiatric condition had an SVR, compared with 10 (22%) of the 45 patients who reported a prior psychiatric condition (P = .01). There was no difference in dropout rates between the 2 groups; 11 (24%) of the 45 patients with a prior psychiatric condition discontinued therapy, compared with 7 (23%) of the 31 patients without a prior psychiatric condition.

Sixteen (30%) of the 53 patients who had been abstinent for 6 months before initiating treatment for HCV infection had an SVR, compared with 5 (22%) of the 23 patients who had a shorter duration of sobriety. This difference was not statistically significant (P = .18).

Of  the 57 patients queried retrospectively about treatment-related drug craving, 9 (16%) reported that IFN injections led to some amount of drug craving, and 3 (5%) said that they contributed to relapse. Although 15 patients (26%) reported that treatment for HCV infection contributed to drug use, 11 of those patients (19%) reported only marijuana use. However, 4 patients (7%) said that treatment for HCV infection contributed to the use of heroin, cocaine, or methamphetamine, and, for 2 of these patients (4%), the drug use became regular.

Study 2: pegylated IFN alf-2b plus ribavirinpreliminary results. To date, 28 patients have been enrolled. The average age is 48 years; 11 patients (39%) are women, 22 (79%) are white, 5 (18%) are African American, and 1 (4%) is Latino. Seventeen patients (61%) are infected with HCV genotype 1, and 19 (68%) have reported a preexisting psychiatric diagnosis. Thirteen patients (46%) were treated with an antidepressant before initiating therapy, and 22 (79%) were taking an antidepressant before completion of treatment for HCV infection.

The rate of ETR to date is 78% (n = 21) and the rate of SVR is 52% (n = 28). Three patients (11%) have discontinued therapy.

Discussion

These results show that patients undergoing maintenance therapy with methadone can successfully undergo treatment for HCV infection in an outpatient setting that can address their special needs, even in the presence of comorbid mental illness, intervening drug use, and short duration of pretreatment drug abstinence.

Although the rates of virological response may be modestly lower than those reported in large studies of combination therapy with IFN and ribavirin in nonaddicted patients, these results should be considered in the context of the many potential treatment barriers in our study population. With this perspective, it appears that the overall effect of such barriers as mental illness, limited duration of pretreatment abstinence, and drug use in patients undergoing methadone maintenance was relatively modest. In addition, regimens of longer-acting pegylated IFNs may simplify administration of medication and lead to further improvements in treatment outcomes.

Interestingly, a preexisting psychiatric diagnosis was the barrier that was most clearly associated with reduced outcomes of treatment for HCV infection. The etiology of this phenomenon remains unclear.

The findings of the UCSF investigators that neither limited duration of pretreatment abstinence from drug use nor intervening drug use during treatment for HCV infection significantly reduced treatment outcomes offers further support for making treatment decisions on a case-by-case basis and have a number of additional implications for HCV-infected substance users.

First, they suggest that the optimal duration of pretreatment abstinence should not be arbitrarily determined. Motivated patients who need treatment for HCV infection may start therapy prior to achieving 6 months of sobriety if clinically indicated.

Second, the results also suggest a strategy for intervening if relapse to drug use occurs during treatment for HCV infection. Although treatment is often discontinued in such circumstances, our results suggest that a strategy that incorporates early intervention to prevent drug relapse from becoming regular should help preserve continuity of treatment and response rates.

Finally, although relapse to drug use is not a common sequela of treatment for HCV infection, it may occur in a minority of treated patients and, therefore, should be discussed with at-risk patients before therapy is initiated.

Conclusions

In conclusion, Dr. Sylvestre writes, “Providing integrated treatment for HCV infection in settings closely associated with substance abuse treatment services may minimize the effect of drug use on outcomes of treatment for HCV.”

“These results and the results of others suggest that IDUs can tolerate and benefit from treatment for HCV infection.”

“Further improvements in outcomes of treatment for HCV infection among addicted patients may be expected as strategies for addressing IFN-mediated neuropsychiatric toxicity are refined and as optimal models to deliver integrated services to these challenging patients become more readily available.”

Department of Clinical Medicine, University of California, San Francisco, Organization to Achieve Solutions in Substance Abuse, Oakland, California.

07/06/05

Reference
D L Sylvestre. Approaching Treatment for Hepatitis C Virus in Substance Users. Clinical Infectious Diseases 41(Supp 1): S79-S82. July 1, 2005.

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