Cannabis use improves retention and virological outcomesin patients treated for hepatitis CDiana L. Sylvestrea,b, Barry J. Clementsb and Yvonne Malibub Objectives Despite the widespread use of polypharmacy, likely than non-users to take at least 80% of the prescribed the management of hepatitis C virus (HCV) interferon or ribavirin, they were significantly more likely to treatment-related side-effects is often incomplete, and remain on HCV treatment for at least 80% of the projected many patients turn to cannabis for symptom relief.
treatment duration, 95 versus 67% (P = 0.01).
Unfortunately, there are few data about cannabis use ontreatment outcomes, leaving clinicians without the data Conclusions Our results suggest that modest cannabis use may offer symptomatic and virological benefit to some patients undergoing HCV treatment by helping them Methods To define the impact of cannabis use during HCV maintain adherence to the challenging medication treatment, we conducted a prospective observational study regimen. Eur J Gastroenterol Hepatol 18:1057–1063 of standard interferon and ribavirin treatment in 71 2006 Lippincott Williams & Wilkins.
recovering substance users, of whom 22 (31%) usedcannabis and 49 (69%) did not.
European Journal of Gastroenterology & Hepatology 2006, 18:1057–1063 Keywords: cannabis, compliance, hepatitis C, interferon Results Seventeen of the 71 study patients (24%)discontinued therapy early, one cannabis user (5%) and aDepartment of Medicine, University of California, San Francisco, California, USA 16 non-users (33%) (P = 0.01). Overall, 37 patients (52%) and bOrganization to Achieve Solutions in Substance-Abuse (OASIS), Oakland,California, USA were end-of-treatment responders, 14 (64%) cannabisusers and 23 (47%) non-users (P = 0.21). A total of 21 out of Correspondence to Diana L. Sylvestre, MD, Department of Medicine, 71 (30%) had a sustained virological response: 12 of the University of California, San Francisco, CA, USATel: + 1 510 834 5442; fax: + 1 510 834 0196; 22 cannabis users (54%) and nine of the 49 non-users (18%) (P = 0.009), corresponding to a post-treatmentvirological relapse rate of 14% in the cannabis users and Sponsorship: This study was supported in part by unrestricted educational grants 61% in the non-users (P = 0.009). Overall, 48 (68%) were from Schering Oncology Biotech and The San Francisco Foundation.
adherent, 29 (59%) non-users and 19 (86%) cannabis Received 27 September 2005 Accepted 27 January 2006 users (P = 0.03). Although cannabis users were no more so affected may compensate by reducing their inter- Although hepatitis C virus (HCV) treatment outcomes feron or ribavirin doses or by discontinuing treatment have improved dramatically over the past decade, the altogether. Maximizing HCV treatment outcomes thus intolerability of interferon/ribavirin combination therapy requires a thorough familiarity with an array of successful remains a barrier to treatment success. The majority of side-effect management strategies [5,9,10].
patients develop significant treatment-related side ef-fects [1–5], with almost 80% experiencing an initial ’flu- Faced with intolerable treatment-related side-effects that like syndrome that includes fevers, chills, and muscle and respond inadequately to conventional medications, some joint aches. Although the acute effects of treatment tend patients turn to Cannabis sativa (marijuana) for symptom to modulate over time, many will experience debilitating relief. Cannabis sativa contains over 400 chemical entities fatigue (70–72%), headaches (66–67%), nausea (35–46%), [11,12], but delta-9-tetrahydrocannabinol (THC) is the anorexia (19–27%), depression (21–44%), and insomnia major psychoactive component. Although the majority of studies of cannabis are observational in nature, thereis anecdotal evidence that it may have benefits in Many patients require the use of adjunctive pharmaco- modulating some of the common side-effects associated logical agents for side-effect management [5,8]. These with HCV treatment, including nausea [13,14], anorexia include a spectrum of medications including antiemetics, [15,16], weight loss [17], musculoskeletal pain [18–21], anti-inflammatory agents, antihistamines, sleeping pills, insomnia [22], anxiety [23], and mood instability [24].
antidepressants, anxiolytics, stimulants, and antipsycho-tics. Unfortunately, symptom relief is often incomplete However, the benefits of cannabis during HCV treatment despite the widespread use of polypharmacy, and patients remain unconfirmed and concerns about its safety remain Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
European Journal of Gastroenterology & Hepatology [25–27]. Cannabinoid receptors appear to be upregulated in hepatic myofibroblasts of human cirrhotic liver samples HCV treatment consisted of IFN-a 2b, 3 Â 106 units [28], and smoking daily cannabis has been reported to administered subcutaneously three times a week and accelerate the progression of hepatic fibrosis in patients ribavirin capsules, 1000 mg taken orally daily in two with chronic HCV [29]. Cannabinoid receptors are also divided doses for patients weighing less than 165 lb, or present on immune cells [30], and cannabis use may 1200 mg daily for those weighing 165 lb or more. Patients suppress a variety of immune functions, including anti- were initially treated for 48 weeks regardless of genotype; body production [31], cell proliferation [32], natural however, subsequent data supporting the efficacy of 24 killer cell activity [33], and macrophage function [34,35], weeks of treatment for genotypes 2 and 3 led to a and also alter the production of such cytokines as protocol amendment that shortened the treatment course interferon gamma and tumor necrosis factor [36]. In for patients with these genotypes. Medications were self- addition, there is a potential drug–drug interaction between ribavirin and marijuana, as both are metabolized by the cytochrome P450 system [37]. Obviously, theoverall benefit of cannabis in terms of side-effect management may be outweighed by worsening histology The use of cannabis during study was neither endorsed and impairments in virological outcomes; therefore, its nor prohibited by study staff, and all patients obtained use as a potential therapeutic agent must be more clearly their cannabis outside the construct of the study protocol.
defined in the setting of HCV treatment.
However, because marijuana use was legalized for medicaluse in the state of California, it was often obtained with Although widespread restrictions limit the ease with outside medical approval through local ‘cannabis clubs’.
which these questions can be formally studied, the Cannabis use was quantified by self-report, with ‘regular’ pervasive use of cannabis during HCV treatment provides use defined as the use of cannabis every day or every a means for an observational study of its potential risks other day for a minimum duration of 4 weeks; ‘occasional’ and benefits. In the context of a prospective study of reflected the use of less than daily quantities.
HCV treatment in recovering heroin users maintained onmethadone we have conducted such a study, by measur- ing the impact of intercurrent cannabis use on treatment After providing informed consent, participants completed adherence, retention rates, and virological outcomes.
a questionnaire that elicited baseline demographic,psychosocial, psychiatric, and substance use character-istics. The duration of HCV infection was estimated as one less than the number of years since injection drug use was initiated. Liver biopsy was suggested but not Recruitment and treatment took place at OASIS required, and was scored on the METAVIR scale of 0–4, (Organization to Achieve Solutions in Substance-Abuse), with 0, none; 1, minimal–mild; 2, mild–moderate; 3, a community-based non-profit clinic providing medical moderate–severe; and 4, cirrhosis.
and psychiatric treatment to substance users in Oakland,CA. Although the clinic does not provide methadone Patients were monitored for treatment-related neutro- treatment, comprehensive primary medical and psychia- penia, thrombocytopenia, and hemolytic anemia using tric care services are provided on-site. All experimental standard published algorithms, and medication doses procedures were followed in accordance with the were adjusted accordingly [38]. Drug and alcohol Helsinki Declaration of 1975, as revised in 1983, and consumption were assessed by monthly self-report were approved by the Ethical Review Committee (Kansas questionnaires, and monthly random urine drug test results were obtained from the subject’s methadonetreatment program. An HCV-RNA PCR was performed at Men and women aged 18 years and older were considered baseline, at 6 months, at the end of treatment, and 6 eligible if they had been maintained on methadone for a months after the completion of therapy. Substance use period of 3 months or more and had a positive HCV during HCV therapy was actively discouraged, but did not polymerase chain reaction (PCR). Patients with non- result in treatment discontinuation unless the patient HCV-related liver disease or decompensated liver disease became unreliable in attending appointments or the were excluded. Those with untreated depression were clinician felt it represented a safety risk. HCV treatment excluded until stabilized on antidepressant treatment.
was discontinued if requested by the patient, or forsevere cytopenias, uncontrolled or worsening psychiatric Drug use was assessed by self-report as well as by random conditions, or decompensating liver disease. The protocol monthly urine toxicology testing, as per standard protocol was evaluated and approved by the Ethical Review Committee, Kansas City, Missouri, USA.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cannabis and hepatitis C virus treatment Sylvestre et al.
Demographic characteristics of study patients The primary study endpoint was sustained virological response (SVR), as determined by undetectable levels of HCV RNA on analysis 6 months after the completion of therapy using the Bayer HCV-RNA branched DNA 3.0 assay, with a lower limit of detection of 550 IU/ml.
Patients were classified as sustained virological respon- ders at this time point if they had no detectable virus, or as non-responders if the PCR was positive. End-of- treatment response was defined as undetectable levels of HCV RNA at the completion of therapy. All analyses were performed on an intent-to-treat basis.
AdherenceAdherence to interferon was assessed by the timing ofreturned empty interferon vials and by a monthly (P = 0.31). Thirty patients underwent liver biopsy.
questionnaire that detailed the number of missed doses Among these, the mean METAVIR inflammation grade of medication. Adherence to ribavirin therapy was was 2.4 (1.5–3.5) and the mean fibrosis stage was 2.6 assessed by pill counting and by query during a monthly (0–4). There was no significant difference in liver fibrosis questionnaire. Using adherence criteria developed by between the two groups; the mean fibrosis stage was others, patients were considered adherent to the HCV 2.5 ± 0.4 for the cannabis users and 2.7 ± 0.2 for the non- treatment regimen if they took 80% or more of the users (P = 0.36). The 20 patients (28%) who had platelet prescribed interferon and 80% or more of the prescribed counts of less than 100 000 cells/ml were also equally ribavirin for at least 80% of the projected treatment divided between the groups, comprising 29% (n = 14) of the non-users and 27% (n = 6) of the group that usedcannabis.
Statistical analysisAll data were compiled in and analysed using SPSS Forty-two patients (59%) reported a previous psychiatric version 11.5.0 for Windows (SPSS Inc., Chicago, Illinois, diagnosis; the majority had depression (n = 33) or USA). Associations between outcome measures and depression/anxiety (n = 6). Cannabis users were no more cannabis use were determined using the Student’s t or likely to report a psychiatric diagnosis than non-users Wilcoxon signed rank test for categorical variables.
(P > 0.5), and there were no differences in the rates of Bivariate analysis of categorical data was performed using antidepressant use between users and non-users during the chi-square and Fisher’s exact tests. P values less than HCV treatment (P > 0.5). Similarly, a total of 25 (35%) 0.05 in two-tailed comparisons were considered statisti- used other illicit substances during HCV treatment, cally significant. Logistic regression was used to assess for including heroin, cocaine, and methamphetamine, but statistical independence among variables that showed a this did not differ between the two groups (37% in the univariate association with a P value of 0.20 or less.
cannabis non-users and 32% in the users; P > 0.5), norwere there differences in rates of alcohol consumption (24% in the non-users and 14% in the users; P = 0.36).
Baseline characteristicsSeventy-one patients were enrolled; 22 (31%) smoked cannabis while undergoing HCV treatment and 49 (69%) The majority of patients, 93% (n = 66), reported at least did not. The demographic characteristics of the study one treatment-related side-effect, most commonly ’flu- patients are shown in Table 1. The median age was 50 like symptoms, nausea, or headache, but there was no years, and 43 (61%) were male, 53 (75%) Caucasian, 10 difference in reported symptoms between the cannabis (14%) African-American, and eight (11%) Latino; there users and non-users (P > 0.5). The association of were no differences in the demographic characteristics cannabis use with HCV treatment outcomes is shown between the cannabis users and non-users. The median in Fig. 1. Seventeen of the 71 study patients (24%) estimated duration of HCV exposure was 30 ± 9 years.
discontinued therapy before completing the full course.
Of these, 16 did not use cannabis and one was a cannabis Forty patients (56%) had genotype 1, 29 (41%) had user. The discontinuation rate of the 49 cannabis non- genotypes 2 or 3, one patient had genotype 8a, and one users was 33%; it was 5% in the cannabis users (P = 0.01).
patient’s genotype was untypable. There was no differ- Of the 16 non-users who terminated treatment early, ence in the frequencies of genotypes between the eight discontinued as a result of intolerable side-effects cannabis users and non-users; 30 of the non-users (61%) and four discontinued because of depression. Three of and 10 of the cannabis users (48%) had genotype 1 the 16 were terminated at the discretion of the medical Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
European Journal of Gastroenterology & Hepatology provider: one because of excessive alcohol intake, one because of worsening liver disease, and one because ofintractable anemia. The remaining patient in this cohort relocated and was unable to obtain medications. Thesingle cannabis user who discontinued treatment devel- oped worsening liver disease and was unable to continue.
Overall, 37 of the 71 patients (52%) were end-of-treatment responders and 21 (30%) had an SVR. The association of cannabis use with response rates is shownin Fig. 1. Fourteen of the cannabis users (64%) and 23 of the non-users (47%) were end-of-treatment responders(P = 0.21). Twelve of the 22 cannabis users (54%) and nine of the 49 non-users (18%) had an SVR, correspond- ing to a post-treatment relapse rate of 14% (n = 2) with the cannabis users and 61% (n = 14) with the non-users.
Multivariate logistic regression analysis taking sex, race, genotype, and the use of other illicit substances intoaccount, revealed that this finding was statistically Quantity of cannabis versus hepatitis C virus treatment outcomes The association of the estimated quantity of cannabis (P = NS). ETR, End-of-treatment response; SVR, sustained virological used with virological outcomes is shown in Fig. 2. Ten of regular (n = 16); & occasional (n = 6).
the 16 occasional cannabis users (62%) had an end-of-treatment virological response compared with four of thesix regular users (67%, P > 0.5). SVR were also not 71 study patients (68%) took at least 80% of the prescribed statistically different between the occasional and regular interferon and ribavirin for at least 80% of the projected users of cannabis, seen in two of six of the regular users duration of treatment, and were therefore considered (33%) and 10 of the 16 (62%) occasional users (P = 0.35).
adherent. Of those, 29 did not use cannabis and 19 werecannabis users. The corresponding adherence rates were59% in the non-cannabis group and 86% in the cannabis AdherenceThe association of cannabis use with the components of group (P = 0.03); there was no difference in adherence treatment adherence is shown in Fig. 3. Overall, 48 of the between occasional users (87%) and regular users (83%)(P > 0.5).
As shown in Fig. 3, cannabis users were no more likely than non-users to take at least 80% of the prescribedinterferon, 91 versus 76% (P = 0.2), nor were they more likely to take at least 80% of the prescribed ribavirin, 91 versus 84% (P > 0.5). However, cannabis users were significantly more likely than non-users to remain onHCV treatment for at least 80% of the projected treatment course, 95 versus 67% (P = 0.01). The average duration of HCV treatment in cannabis users was 38 weeks compared with 33 weeks for the non-users.
The results of this observational study 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 Hepatitis C treatment outcomes versus cannabis use. ETR, End-of- rates of post-treatment virological relapse and improved treatment response; SVR, sustained virological response. & All SVR. Although other potential mechanisms may con- tribute to its enhancement of treatment outcomes, such P = 0.009 for SVR difference, 0.01 for treatment discontinuation.
*Difference is statistically significant.
as altered immunological function and improved nutri-tional status, it appears that the moderate use of cannabis Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cannabis and hepatitis C virus treatment Sylvestre et al.
ganglia, cerebellum, and hippocampus, accounting for itseffects on motor coordination and short-term memory [46]. It is also expressed at high concentrations onprimary afferent nociceptors of the dorsal spinal cord, which are responsible for the ability of cannabinoids to Although CB1 cannabinoid receptors mediate the central nervous system effects of cannabinoids [46], an additionalsubset of cannabinoid receptors, the CB2 receptors, is present on immune cells [30]. The presence of these receptors on B lymphocytes and natural killer cellssuggests that cannabinoids may impact upon the immune response. Some studies have shown that THC can be immunosuppressive and can impair cell-mediated im-munity [32,47,48], humoral immunity [49], and cellular defences against a variety of infectious agents in experimental animals [35,47,50]. There is an increased recurrence of herpes simplex viral lesions in marijuanasmokers [51] and an altered responsiveness of human Cannabis use versus treatment adherence. & Cannabis non-users(n = 49); cannabis users (n = 22). Adherence, percentage that took papilloma virus to IFN-a 2a treatment [52]. Although at least 80% of both interferon and ribavirin for at least 80% of the uncontrolled studies suggested an association between projected duration of treatment. P = 0.01 for difference in treatment marijuana use and the progression of HIV disease, a duration, 0.03 for overall adherence. *Difference is statisticallysignificant.
recent prospective study demonstrated no evidence ofdetrimental effects of cannabinoids on immune para-meters in patients with HIV [53]. The majority of studies during HCV treatment does not lead to deleterious on the effects of cannabis have been conducted in cell culture or on animal models with supraphysiological dosesof the compound, and their clinical relevance is unclear.
Although its availability in the United States has been Although their potential contribution to liver disease is not restricted since 1937 and its benefit unconfirmed, understood, both the CB1 and CB2 receptors have also cannabis is frequently obtained illicitly for self-medication.
been reported to be expressed on hepatic myofibroblasts in It has been used recreationally for millennia, and is the cirrhotic livers [28]. Activation of these receptors can lead third most commonly used drug after tobacco and alcohol to cellular apoptosis, and a recent study demonstrated that [39]. In the United States, 6.2% of individuals aged 12 the use of cannabis on a daily basis may enhance the years or older have used cannabis in the past month, with progression of hepatitis fibrosis in patients with HCV [29].
4.8 million individuals using it on 20 or more days [39].
By implicating these receptors as mediators of the fibroticprocess, these results raise concerns about the safety of THC can produce alterations in mood, perception, cognition, and memory [14], and studies have shownthat THC has anticonvulsive, analgesic, anti-anxiety, and In spite of this, our results suggest that moderate anti-emetic properties [13,14]. Clinical trials have cannabis use during HCV treatment may offer significant demonstrated that cannabinoids reduce nausea and benefit to certain patients. Although the lack of a direct improve appetite in humans [15,16], and cannabis has dose response suggests that its principal contribution is shown benefit in modulating the nausea of cancer related to a non-specific improvement in the tolerability chemotherapy [40–43], multiple sclerosis-related spasti- of the challenging medication regimen, we cannot rule city [44], and the wasting syndrome of HIV [17].
out additional biological effects. We did not measurerelevant immune parameters in our patients, nor did we Progress has been made in understanding the pharmacol- assess potential differences in nutritional status. P450- ogy of cannabinoids in humans. Of the two known mediated drug–drug interactions between cannabinoids cannabinoid receptors, CB1 is responsible for the and ribavirin may have led to additional benefit, but these neurological and behavioral effects of marijuana. CB1 were not assessed. However, the lack of dose response in was the first cannabinoid receptor identified [45], and is our study argues against specific receptor or metabolism- the most abundant G-protein-coupled receptor in the related effects, and suggests instead that cannabis central nervous system [13]. It is also expressed on exerted its benefit by non-specific improvements in peripheral neurons and is found abundantly in the basal symptom management. Interestingly, because the bene- Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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