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, 0
18 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 ribavirin
preliminary 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.
Third, although comorbid psychiatric
conditions may be associated with reduced rates of response to
treatment for HCV infection, addicted patients with a history of depression
or other mental illness may be successfully treated as long as
their condition is stabilized before treatment for HCV infection is initiated.
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.
D L Sylvestre. Approaching Treatment for
Hepatitis C Virus in Substance Users. Clinical Infectious Diseases
41(Supp 1): S79-S82. July 1, 2005.
