Moderate Cannabis Use Associated with Improved Treatment Response in Hepatitis C Patients on Methadone

By Liz Highleyman

Interferon-based therapy for chronic hepatitis C virus (HCV) infection is often limited by side effects including flu-like symptoms, fatigue, insomnia, loss of appetite, nausea, muscle and joint pain, and depression, which can lead to poor adherence, dose reduction, or treatment discontinuation.

Medicinal cannabis may relieve such side effects and help patients stay on treatment, according to a study published in the October 2006 European Journal of Gastroenterology and Hepatology.

Several studies - as well as ample anecdotal evidence - have demonstrated that medical marijuana can reduce nausea, increase appetite, and improve wasting in people with HIV.

Diana Sylvestre, MD, of the University of California at San Francisco and colleagues conducted a study to define the impact of cannabis use during HCV treatment. The prospective observational study included 71 patients at OASIS (Organization to Achieve Solutions in Substance Abuse), a community-based clinic providing medical and psychiatric treatment to substance users in Oakland, California.

Patient Demographics

Eligible participants were recovering substance users with HCV who had been on methadone maintenance therapy for at least 3 months. Patients with non-HCV-related liver disease or decompensated cirrhosis were excluded. Among the 30 patients with liver biopsy results, the mean Metavir inflammation grade was 2.4 and the mean fibrosis stage was 2.6. Subjects with untreated depression were first stabilized on antidepressants.

Use of cannabis during the study was "neither endorsed nor prohibited." About one-third of participants used marijuana during hepatitis C treatment. "Regular" marijuana use was defined as every day or every other day for at least 4 weeks. Drug and alcohol use were assessed by self-report and random monthly urine testing.

22 patients (31%) reported cannabis use during ant-HCV treatment, while 49 (69%) did not.

Baseline characteristics were generally similar between marijuana users and non-users.

The median age was about 50 years in both groups.

Compared with non-users, cannabis users were somewhat more likely to be male (68% vs 57%) and Caucasian (86% vs 69%), but less likely to have genotype 1 HCV (48% vs 61%).

About 60% of participants reported a previous psychiatric diagnosis (usually depression); cannabis users and non-users had similar rates of psychiatric diagnosis and antidepressant use.

32% of cannabis users and 37% of non-users reported use of other illicit substances during HCV treatment (including heroin, cocaine, and methamphetamine), while 14% and 24%, respectively, reported alcohol consumption; these differences were not statistically significant.

Participants were treated with conventional interferon alfa-2b (3 million units 3 times weekly) plus 1000-1200 mg daily ribavirin. Patients were initially treated for 48 weeks regardless of genotype, but the protocol was later amended to allow 24-week therapy for those with genotypes 2 or 3.

Adherence to therapy was assessed by self-report, ribavirin pill counts, and returned empty interferon vials. Participants were considered adherent if they took 80% or more of prescribed interferon and ribavirin for at least 80% of the projected treatment course.

Results

In an intent-to-treat analysis, 37 patients (52%) achieved an end-of-treatment response (undetectable HCV RNA at the end of 24 or 48 weeks of therapy):

- 14 cannabis users (64%);
- 23 non-users (47%) (P = 0.21).

Overall, 21 out of 71 participants (30%) achieved sustained virological response (SVR), or continued undetectable HCV RNA 6 months after the end of therapy:

- 12 of 22 cannabis users (54%);
- 9 of 49 non-users (18%) (P = 0.009).

Post-treatment virological relapse rates were 14% for cannabis users and 61% for non-users (P = 0.009).

End-of-treatment response rates were similar among occasional cannabis users (10 of 16; 62%) and regular users (4 of 6; 67%).

10 of 16 occasional users (62%) went on to achieve SVR, compared with 2 of 6 regular users (33%), but the difference was not statistically significant.

Most patients (93%) reported at least one treatment-related side-effect, with similar rates among cannabis users and non-users.

Overall, 17 of 71 patients (24%) discontinued therapy early:

- 1 cannabis user (5%);
- 16 cannabis non-users (33%) (P = 0.01).

Overall, 48 patients were adherent (68%):

- 19 cannabis users (86%);
- 29 non-users (59%) (P = 0.03).

There was no significant difference in adherence between occasional and regular cannabis users (87% vs 83%)

91% of cannabis users took at least 80% of prescribed interferon, compared with 76% of non-users. For ribavirin, the corresponding rates were 91% and 84%; these differences were not statistically significant.

However, cannabis users were significantly more likely than non-users to remain on therapy for at least 80% of the projected treatment duration (95% vs 67%; P = 0.01).

The average duration of HCV treatment was 38 weeks for cannabis users, compared with 33 weeks for non-users.

Conclusion

In conclusion, the authors wrote, "Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them maintain adherence to the challenging medication regimen."

Discussion

In their discussion, the authors wrote that their results "suggest that the use of cannabis during HCV treatment can improve adherence by increasing the duration of time that patients remain on therapy; this translates to reduced rates of post-treatment virological relapse and improved SVR."

"Although other potential mechanisms may contribute to its enhancement of treatment outcomes, such as altered immunological function and improved nutritional status," they added, "it appears that the moderate use of cannabis during HCV treatment does not lead to deleterious consequences."

In this study, it appears that the treatment response benefit was primarily due to improved ability to stay on adequate doses of interferon and/or ribavirin. Sylvestre told HIV and Hepatitis.com that the researchers could not judge whether there was a direct antiviral effect. "It was probably more of a side-effect management effect than an antiviral effect, but we can't rule out the latter," she said.

There remain concerns about the safety of marijuana use by individuals with chronic hepatitis C. Cannabinoid receptors are present on immune cells, and use of the drug may suppress immune function. In addition, there is some evidence that frequent marijuana use may contribute to liver fibrosis. As reported in the July 2005 issue of Hepatology, French researchers found that HCV positive individuals who smoked cannabis daily were more likely to have severe fibrosis and were at higher risk for rapid fibrosis progression than those who used marijuana only occasionally or not at all. However, the participants in that study were not receiving treatment for hepatitis C.

Notably, in the current study, there was no direct dose-response relationship between the amount of cannabis consumed and the likelihood of sustained virological response. In fact, the patients who used the largest amounts of cannabis did not show as much benefit from hepatitis C therapy. The researchers did not perform pre- and post-treatment histological assessments using paired liver biopsies, and did not measure immune parameters.

"The lack of dose response in our study argues against specific receptor or metabolism-related effects, and suggests instead that cannabis exerted its benefit by non-specific improvements in symptom management," the authors stated. "Interestingly, because the benefits of heavy cannabis use were less apparent, we cannot rule out the possibility that detrimental biological or immunological mechanisms may be relevant at higher levels of consumption. Obviously, further study is needed."

Unfortunately, because cannabis is strictly controlled in the U.S. and the federal government considers the drug illegal even in states with medical marijuana laws, it is difficult to conduct randomized, controlled trials.

Editorial

In an accompanying editorial, a group of hepatitis C experts from Canada and Germany noted that people who use illicit drugs are the main risk group for new hepatitis C infections, and "will form the largest HCV treatment population for years to come."

While past treatment guidelines advised against hepatitis C treatment for active substance users and those with a recent history of active use, this categorical recommendation is no longer in effect in the U.S. and Europe, since recent studies have shown that such patients can achieve good treatment outcomes as long as they are able to maintain adequate adherence. Treatment remains a challenge for this population, however, in part because substance users have a higher prevalence of depression and other psychiatric conditions, which are associated with an increased likelihood of neuropsychological side effects during interferon therapy.

Sylvestre's study, the editorial authors wrote, "suggests that cannabis use may benefit treatment retention and outcomes in illicit drug users undergoing HCV treatment" and that "there is substantial evidence that cannabis use may help address key challenges faced by drug users in HCV treatment." Several recent studies have demonstrated the benefits of combining anti-HCV therapy with methadone maintenance, in effect offering "one-stop shopping."

The authors suggested that the therapeutic effects of cannabis "may be of principal importance and benefit for the distinct needs of illicit drug users" on methadone maintenance, because methadone itself is associated with some of the same side effects as interferon (bone aches, loss of energy, depression).

"Overall, cannabis use may thus even offer dual benefits, in facilitating adherence to both methadone maintenance therapy and HCV treatment in the HCV-infected drug user, and thus contribute to public health benefits related to both these interventions," they noted.

"While further research is required on the biological and clinical aspects of the benefits of cannabis use for HCV treatment, and the effectiveness of cannabis use for HCV treatment needs to be explored in larger study populations," they concluded, "we advocate that in the interim existing barriers to cannabis use are removed for drug users undergoing HCV treatment until the conclusive empirical basis for evidence-based guidance is available."

In particular, they suggested that medical marijuana laws and programs that specify its use for patients with specific conditions such as AIDS and cancer should also include people with hepatitis C.

9/15/06

References

D L Sylvestre, B J Clements, Y Malibu. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. European Journal of Gastroenterology and Hepatology 18(10): 1057-1063. October 2006.

B Fischer, J Reimer, M Firestone, and others. Treatment for hepatitis C virus and cannabis use in illicit drug user patients: implications and questions. European Journal of Gastroenterology and Hepatology 18(10): 1039-1042. October 2006.

C Hezode, F Roudot-Thoraval, S Nguyen, and others. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 42(1): 63-71. July 2005.