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Liz Highleyman
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In This Issue:
Hepatitis C
Long-Term HCV Persistence
Post-Transplant HCV Therapy
Interferon and Liver Rejection
Long-Term
HCV Persistence
Sustained virological response (SVR), the
gold standard for judging the effectiveness of hepatitis C
therapy, means that HCV RNA is still undetectable in the serum
six months after the end of treatment. But achieving SVR does
not necessarily mean HCV is completely and permanently eradicated
from the body. In the June 2004 issue of the Journal of
Virology, T.N. Pham and colleagues reported that HCV
genetic material persists in certain immune system white blood
cells. Using a highly sensitive PCR assay, the researchers
detected HCV RNA in the peripheral blood mononuclear cells
(PBMCs) of all 16 tested patients up to five years after spontaneous
or treatment-induced HCV clearance. The virus was also detected
in monocyte-derived dendritic cells in 6 out of 7 patients
tested. “These results imply that HCV RNA can persist
at very low levels in the serum and peripheral lymphoid cells
and that an intermediate replicative form of the HCV genome
can persist in PBMC for many years after apparently complete
spontaneous or antiviral therapy-induced resolution of chronic
hepatitis C,” the authors concluded.
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Post-Transplant HCV Therapy
This long-term persistence helps explain why HCV almost always
reinfects the new liver after patients with chronic hepatitis
C receive transplants. In the July 2004 issue of the Journal
of Hepatology, Montserrat Garcia-Retortillo and Xavier
Forno reviewed the current state of knowledge about HCV prevention
and treatment in liver transplant recipients. HCV replication
in the new liver typically occurs within a few weeks after
transplantation, following a sharp decrease in viral load.
Unlike hepatitis B, therapeutic immunoglobulins (antibodies)
do not appear to prevent infection of the new liver, although
studies are underway with new types of antibody preparations.
Although anti-HCV therapy can be risky
in people with decompensated cirrhosis, interferon plus ribavirin
are increasingly used in HCV patients awaiting a liver transplant.
While adverse events are common and these patients often must
discontinue therapy or decrease their dosage, some do achieve
SVR—although the rates are lower than those seen in
HCV patients with less advanced liver disease. Other researchers
have tried treating patients with interferon-based therapy
soon after liver transplantation, while their HCV viral load
is still low. Although adverse events and treatment discontinuation
are again common, studies show that a small number of patients
can benefit from therapy started within the weeks following
transplant. More commonly, however, HCV treatment may be started
months or years after liver transplantation. Because liver
damage tends to progress more rapidly in people with compromised
immune systems—and transplant recipients must take immunosuppressive
drugs to prevent organ rejection—frequent biopsies of
the new liver are indicated to monitor disease progression.
In the July 2004 issue of Liver Transplantation,
Todd Stravitz and colleagues reported on a retrospective evaluation
of interferon therapy in 23 post-transplant patients with
recurrent hepatitis C and histological evidence of fibrosis
progression. The patients completed at least six months of
interferon therapy (83% with pegylated-interferon), but only
four were able to tolerate ribavirin. After six months of
treatment, 11 patients (48%) had undetectable HCV RNA; of
these, eight (35% of the total) achieved SVR. Liver biopsies
performed two years after HCV became undetectable showed decreased
necroinflammatory activity, and 6 of 11 patients showed histological
improvement on follow-up liver biopsies. Eight (35%) of the
23 patients treated with interferon showed evidence of liver
rejection and two required retransplantation. These results
are consistent with those of other studies showning that post-transplant
SVR rates are lower than those seen in non-transplant HCV
patients, but that patients who do respond often show improved
necroinflammatory activity and decreased fibrosis progression.
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Interferon and Liver Rejection
Because of its immunomodulatory activity, interferon may increase
the risk of organ rejection. This is known to occur in kidney
transplant recipients, but data regarding liver recipients
has been inconsistent. In the same issue of Liver Transplantation,
Sammy Saab and colleagues examined acute rejection in 44 new
liver recipients treated with interferon for recurrent HCV.
Five (11.4%) developed acute liver rejection during interferon
therapy, a rate higher than that seen in liver transplant
patients not receiving interferon. These five started interferon
an average of 42 months (and up to 83 months) after transplantation,
and were treated an average of three months before rejection
set in. Rejection was successfully treated with steroids and
increased immunosuppressive drugs in three patients, although
two of these rapidly developed cirrhosis. One other patient
required a second liver transplant, and the final patient
died due to sepsis. “Interferon-based therapy may lead
to acute rejection and subsequent graft loss and should therefore
be used with caution,” the authors concluded. Because
it stays in the body longer, pegylated interferon may be more
likely to cause rejection than standard interferon. (In this
study, four of the five patients who experienced rejection
were receiving pegylated interferon.) Conversely, ribavirin
may reduce the risk of rejection, but many post-transplant
patients cannot tolerate the drug.
Interferon-induced organ rejection may
be related to increased HLA mismatches between the recipient
and the donor liver. HLA antigens are cell markers that allow
the immune system to distinguish “self” from “non-self.”
Interferon may enhance the expression of HLA antigens in the
donor liver and bile ducts, triggering an attack by the recipient’s
immune system. Some laboratory studies have shown HLA expression
is enhanced in response to interferon.
However, in the August 2004 issue of the
American Journal of Transplantation, Francesca Cardarelli
and colleagues reported that among 44 liver transplant recipients
tested, anti-HLA antibodies were detected in about 8% of HCV
patients receiving interferon, 20% HCV patients not on interferon,
and 10% of HCV-negative patient—not a statistically
significant difference. Among this group of patients, none
experienced acute rejection after starting interferon.
In an editorial in the July Liver Transplantation
Didier Samuel noted that, “[A]nti- viral treatment is
now fully part of the overall therapeutic strategy post-transplantation.”
But caution is warranted, and more research is needed.
“[F]rom these [Stravitz’s and Saab’s] reports,
we can conclude that while there is a risk of rejection during
interferon-based treatment for hepatitis C recurrence after
liver transplantation, the prevalence and the severity of
rejection remains matters for debate.”
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