FORMER ADDICTS FACE BARRIERS TO TREATMENT FOR HCV

Most injection drug users, including those who succeed in kicking the
habit, are left with a worrisome legacy: infection with hepatitis C virus
(HCV). But for a variety of reasons, some former addicts who develop
HCV-related liver disease -- notably those receiving methadone maintenance
therapy (MMT) -- are confronted with barriers to getting much-needed
treatment for their illness, barriers that sometimes force them to choose
between dying of liver disease and risking relapse and a return to abusing
drugs.

The problem is not a trivial one. More than any other group of individuals
in the United States, injection drug users are likely to acquire the
infection. According to the National Center for Infectious Diseases, half
or more of all HCV infections are associated with illegal drug use and
injection drug users typically become infected with stunning swiftness.

Despite the HCV burden in this group, physicians say that patients
receiving MMT including individuals who haven't injected drugs for many
years are all too frequently turned away for medical treatment for HCV or
liver transplantation for HCV-related end-stage liver disease, excluded
solely because of their medically approved use of methadone.

There are some legitimate concerns about the potential adverse effects of
drugs used to treat hepatitis C for patients receiving MMT including a
possible risk of relapse to active drug abuse. But experts agree that these
concerns do not mean that patients taking the opioid agonist should be
denied access to potentially life-saving HCV treatment.

ACCESS DENIED

J. Thomas Payte, MD, a San Antonio, Tex, physician in private practice who
has treated people with opioid addiction since the early 1960s, noted that
many of his MMT patients who have turned their lives around -- evidenced by
years of psychosocial stability, steady employment, and complete abstinence
from illegal drugs or alcohol -- are discriminated against when they seek
drug treatment for HCV or a liver transplant.

He described the plight of one of his patients, a 46-year-old Arizona man
with HCV who, after becoming a heroin addict at 17, had been stably
maintained with methadone for more than 25 years. This man was on a waiting
list for a liver transplant by 1996, but when a move to Texas forced him to
seek placement on a transplant list in the San Antonio area, he was told he
would not be considered until he had withdrawn from methadone. He died the
following year.

Even though methadone treatment had served as a safe and effective
long-term treatment for his opioid addiction, "he was expected to suffer
and destabilize the addictive disorder to qualify for treatment of another
disorder," Payte testified at a forum held by the United Network for Organ
Sharing last September.

Payte noted that some of his patients have "made very difficult attempts"
to withdraw from methadone when they were already ill with their liver
disease. "Going through this protracted withdrawal process they almost
decide they'd rather die of the disease than have to go through that in
order to get treatment," Payte said.

Catherine Baca, MD, a physician at the University of New Mexico Health
Sciences Center in Albuquerque who treats patients with substance abuse
problems, has seen similar resistance by transplant centers with respect to
accepting people receiving methadone therapy.

"I had to call a half-dozen centers for a patient who was denied care
before I found one that was willing to accept him," she said.

A number of studies have shown that advising patients to stop methadone
therapy puts them at high risk for relapse, said Baca. "Yet that's exactly
what some people are requiring."

One barrier to gaining access to treatment is the stigma associated with
addiction and with MMT, said Payte. The cost of the drugs is another
obstacle. Many patients receiving methadone therapy don't have private
health insurance or the financial resources to pay for costly HCV regimens,
which include alfa interferon monotherapy, combination therapy with alfa
interferon and ribavirin, or pegylated interferon (alfa interferon linked
to a polyethylene glycol molecule, approved last month by the US Food and
Drug Administration [FDA] for treatment of HCV).

Yet another avenue for gaining access to treatmentclinical trialsis often
barred to patients taking the opioid agonist, Baca noted. The reason: the
pharmaceutical companies sponsoring the trials list methadone as an
exclusionary criterion.

MISCONSTRUED GUIDELINES

It's not just stigma and financial constraints that are hindering
methadone-taking patients' access to treatment, but a too-broad
interpretation of hepatitis C treatment guidelines that arose from a 1997
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
consensus conference. Among other things, the guidelines originally
recommended a 2-year period of abstinence by heavy alcohol users and users
of illicit drugs before they could be considered for HCV treatment, said
Allan Rosenfield, MD, dean of Columbia University's Mailman School of
Public Health.

Some clinicians apparently perceived the guidelines "to also exclude those
individuals who are receiving methadone maintenance," said Steffanie
Strathdee, PhD, an epidemiologist at Johns Hopkins School of Public Health,
who has studied a group of injection drug users with HCV. In other cases,
physicians who had participated in clinical trials that cited methadone use
as an exclusion may have carried that thinking forward without any formal
justification when the drugs were approved and being used in the clinic.

Rosenfield, who also heads the New York State AIDS Advisory Council, was
among those who worked to persuade the NIDDK to revise these
recommendations. "This Council concluded that the objections to treating
active or recently active users of illicit substances are not supported by
the medical literature," he said in a letter to the National Institutes of
Health.

The now-revised NIDDK guidelines
(http://www.niddk.nih.gov/health/digest/pubs/chrnhepc/chrnhepc.htm) state
that current substance abuse or alcohol abuse is a contraindication to alfa
interferon therapy. Continued alcohol consumption can increase liver
damage, and there is concern that people who continue to inject drugs risk
reinfection with multiple genotypes of HCV, which hepatologists worry may
make treatment more difficult. The document also recommends a 6-month
abstinence period before starting treatment, noting that interferon can be
associated with relapse in individuals with a history of drug or alcohol abuse.

Now, however, the modified guidelines also explicitly note that "patients
can be successfully treated while on methadone."

UNRESOLVED CONCERNS

But there remain some important unresolved concerns about the safety of
hepatitis C therapy for former injection drug users, including those
receiving MMT, cautions William D. Schwieterman, MD, of the FDA's Center
for Biologics.

"There are reasons why the agency has some concerns about the safety of
interferon in this population," explained Schwieterman, drawing attention
to a warning on the label of newly approved pegylated interferon. This
product requires only one weekly injection, compared with thrice-weekly
injections for other interferons. It also appears to be as effective as the
interferon-ribavirin combination which until now had been the most
successful HCV treatment and is expected to see wide use.

The label warns of the drug's potential for causing adverse
neuropsychiatric events, including the possibility that patients with a
history of drug abuse will relapse after starting the interferon regimen.
During clinical trials, investigators observed relapses, drug overdoses,
and deaths in such patients, including individuals who were receiving MMT.

All of the interferons warn about the potential for neuropsychiatric
adverse events, including depression and suicide. But there's some
suggestion that former drug users receiving pegylated interferon may be
more prone to such events, as well as a return to injection drug use.

"But it's just too soon to tell with any certainty whether the pegylated
interferons are going to prove more toxic in this regard," said
Schwieterman. Nor is it known what the mechanism might be for this kind of
toxicity.

The FDA has asked the drug's manufacturerKenilworth, NJ-based
Schering-Plough Corpto conduct a phase 4 postmarketing study to examine the
catabolism of methadone in patients receiving the drug, he noted. "We think
it's an important enough question that it ought to be addressed directly."

Some people have also raised concerns about risks related to exposing
former injection drug users to a long-term therapy that requires
subcutaneous needle exposure, Schwieterman said. The possibility that such
behavioral associations may play a role in fostering relapse "is something
that needs to be considered," he said. "It's a very complicated issue."

Thus, while MMT is not a contraindication for patients seeking drug
treatment for HCV, it's very important that clinicians be aware of the
particular concerns about the drugs' safety for this group of patients,
said Schwieterman. "For each patient, the physician has to consider the
anticipated potential benefits versus the anticipated potential risks," he
said.

Whether unforeseen problems will indeed emerge when greater numbers of
patients on methadone undergo drug treatment for HCV remains to be seen,
said Leonard B. Seeff, MD, a hepatitis C researcher with the NIDDK. "The
proof is in the pudding we're going to have to find out as we go along
whether this course has problems."

Since limiting such risks will require careful monitoring of patients
receiving hepatitis C regimens, MMT with its requirement for daily visits
to a clinic may provide the means to help keep patients on track and to
reach a population with an enormous HCV burden, said Strathdee. The
epidemiologist, with David L. Thomas, MD, and other Hopkins colleagues, has
been examining the natural history of HIV, HCV, and other infections in a
group of people with a history of injection drug use.

"We found that if HIV-positive drug users were enrolled in treatment for
their drug abusewhich is most often methadone maintenance they were more
likely to be receiving HIV therapy," said Strathdee. "The two go hand in
hand when they start to get their drug use under control, they start to
feel they can take charge of their lives and make other healthy choices."