Treatment of Chronic Hepatitis C in Active Drug Users

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Treatment of Chronic Hepatitis C in Active Drug Users
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Article

Gary L. Davis, M.D., and James R. Rodrigue, Ph.D.

N Engl J Med 2001; 345:215-217July 19, 2001

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It is
currently estimated that between 2.7 million and 4.0 million persons in
the United States have chronic hepatitis C virus (HCV) infection.1
Many of these persons have potentially progressive disease. Studies
suggest that mortality and health care costs from complications of
chronic hepatitis C and cirrhosis, such as hepatocellular carcinoma and
liver failure, will increase dramatically over the next 10 to 20 years.2,3 Several reports indicate that this increase has already begun to occur.4,5
Thus, the development of more effective interferon-based treatments is
particularly encouraging. A standard regimen of interferon and ribavirin
results in sustained eradication of HCV in 40 percent of patients,
whereas the combination of pegylated interferon and ribavirin results in
a sustained response in 54 to 56 percent.6-8
Injection-drug
use has been the greatest risk factor for HCV infection since the early
1980s. Drug use currently accounts for 60 percent of newly acquired
cases and 20 to 50 percent of cases of chronic infection.9,10
Among injection-drug users who share needles or other equipment, the
risk of infection is phenomenally high; 50 to 80 percent of such persons
become infected after one year of drug use, and nearly all become
infected after eight years of use.11-13 The high risk is due, in part, to limited knowledge among drug users about infectivity and the routes of transmission of HCV.14
Furthermore, among patients with chronic hepatitis C, cirrhosis and
associated complications are two to three times as likely to develop in
those with chronic alcohol use, which is common among injection-drug
users, as in those who do not drink.15 Thus, persons with current or past substance abuse should be informed about HCV infection and screened for it.
Most physicians who care for HCV-infected drug users withhold antiviral treatment until drug use has stopped.16
This practice is supported by the recommendations of three consensus
conferences on the management of hepatitis C, held in the United States,
Canada, and Europe.17-19
Specifically, it was recommended that such patients be referred for
treatment of their addiction before they receive antiviral therapy.17
The justifications for this approach were that drug use poses a greater
short-term threat to health than does hepatitis C, that it increases
the risk of adverse events associated with antiviral treatment, and that
it is likely to be a reason for poor compliance with treatment. The
argument against this recommendation, made by patients and some
clinicians, particularly those who specialize in the treatment of
addiction, is that it denies active drug users access to potentially
lifesaving treatment of HCV infection.16
Are the current recommendations justified by the data? Should antiviral
treatment continue to be discouraged for patients who are drug users?
The National Institutes of Health (NIH) consensus conference did not establish strict treatment rules.17
Rather, it sought to standardize nomenclature, make data-based
management and treatment recommendations, and identify areas in need of
further research. Thus, the NIH recommendations are only guidelines and
should not be used as the basis for withholding antiviral treatment if
the physician believes that it is in the patient's best interest to
provide it. Indeed, treatment options and the standard of care have
changed substantially since 1997, when the NIH recommendations were
issued, because therapies have improved. Nonetheless, these
recommendations were carefully considered and continue to be justified
by the available data.
Interferon-based therapy has serious side
effects and is especially problematic in patients with psychiatric
disorders such as depression.6,20
In fact, a history of severe depression or other psychiatric conditions
is considered to be a relatively strong contraindication to
interferon-based therapy, since dose-dependent and reversible
neuropsychiatric effects occur in 30 to 40 percent of patients during
treatment, may be severe or may limit treatment in 10 to 20 percent, and
are more common among persons with a history of a psychiatric disorder
than among those without such a history.6,20,21
A survey has shown that up to 36 percent of HCV-infected patients do
not receive antiviral treatment because they have psychiatric diagnoses
other than substance-abuse disorders.22
The
lifetime prevalence rates for major depression, bipolar disorder, and
anxiety disorders among adults with substance-abuse disorders are high
and may be even higher among those who are also infected with HCV.21,23,24
Failure to treat these psychiatric conditions adequately may increase
the risk that a patient will resume substance abuse and that antiviral
treatment will fail.24
In addition, the availability of needles and syringes for the
administration of interferon may pose a problem for patients who have
previously been addicted to intravenous drugs. Indeed, there are
anecdotal reports of relapses among former drug users, as well as
overdoses, some of which have been fatal.16
Ho and colleagues reported that 68 percent of patients with a prior
psychiatric diagnosis (68 percent of whom had a history of alcohol or
drug dependence) had major psychiatric problems during monotherapy with
interferon, as compared with 28 percent of those with no prior
psychiatric diagnosis.21
In addition, the patients with a history of substance abuse were three
times as likely to be lost to follow-up during the treatment period (20
percent vs. 7 percent).21
A
sustained virologic response to interferon-based therapy is less likely
in HCV-infected patients with substance abuse than in other
HCV-infected patients for several reasons. First, treatment must be
modified or discontinued in a large portion of such patients.16,20
Second, approximately one fifth of patients do not comply with
monitoring and are lost to follow-up before completing an adequate
course of treatment.21 Third, both injection-drug use and chronic alcohol use have been reported to suppress cellular immunity.25
This effect may prevent a sustained response to treatment, since
interferon-based therapy is thought to act, at least in part, by
augmenting the response of type 1 helper T cells to the virus.26 Alcohol also decreases the cellular effects of interferon.27 Finally, regular alcohol intake increases HCV levels and reduces the virologic response to treatment.28,29 Taken together, these factors make a sustained response to treatment unlikely in patients with active substance abuse.
One
concern about treating HCV infection in active injection-drug users is
that those in whom the virus is cleared may become reinfected. HCV
infection, even when it is cleared spontaneously or with antiviral
treatment, does not confer protective immunity, and cases of reinfection
have been reported.30,31
Therefore, persons who continue to be exposed to the virus are at risk
for reinfection, and the risk is probably the same as that for drug
users who have never been infected.12
In at least half of patients with active injection-drug use, clearance
of HCV after treatment with interferon-based therapy is likely to be
followed by reinfection within one year.
The costs associated with HCV infection in injection-drug users are considerable.32
Since injection-drug use is the most common cause of chronic hepatitis
C, it accounts for most of the costs of antiviral treatment and
management of liver failure and associated complications. A typical
12-month regimen of interferon-based therapy costs about $16,000 for
medications, plus the cost of office visits and laboratory tests to
monitor for side effects. Antiviral treatment may have a limited benefit
in drug users, given the likelihood that only a small proportion of
such patients will be able to complete treatment and that more than half
will die at a younger age than they would have if they had not used
drugs.33,34
The death rate among active drug users is 3 to 14 times as high as that
in the general population, and most of these deaths are related to drug
use.34
Indeed, studies of the cost effectiveness of identifying and treating
HCV-infected drug users have been difficult to design and the results
inconclusive because of the uncertainty of assumptions about treatment
efficacy and survival.35
Despite
the many valid arguments against the treatment of HCV infection in
active drug users, an individualized approach is best. Most such
patients will not be appropriate candidates for interferon-based therapy
because of psychological contraindications, coexisting conditions, or
problems with compliance. However, antiviral treatment should be
considered for patients with ongoing drug use who are likely to comply
with the treatment regimen and who do not have psychological or other
contraindications. It has been suggested that among HCV-infected drug
users, those enrolled in a methadone-maintenance program are the best
candidates for antiviral treatment, because participation in such a
program increases the likelihood of compliance with the antiviral
regimen. However, a substantial number of such patients continue to use
drugs while receiving methadone, and their risk of exposure to HCV is
therefore not necessarily reduced.36
All
potential candidates for antiviral treatment should undergo a
comprehensive psychological assessment. Careful monitoring is important
for all patients receiving treatment for HCV infection, but it is
critical for those who are drug users. There should be close
collaboration between a physician who is experienced in treating HCV
infection and an expert in the assessment and treatment of substance
abuse. Together, they can provide services that will promote adherence
to the antiviral regimen, treat coexisting conditions, and implement
strategies to prevent relapse. With such a collaborative approach, at
least some HCV-infected drug users can be successfully treated.

Gary L. Davis, M.D.
University of Florida College of Medicine, Gainesville, FL 32610-0214

James R. Rodrigue, Ph.D.
University of Florida College of Health Professions, Gainesville, FL 32610-0165


Dr.
Davis has received grant support from Schering Plough Research
Institute, Roche Pharmaceuticals, and other pharmaceutical
manufacturers.
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