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Treatment considerations in patients with hepatitis C and cirrhosis
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J Clin Gastroenterol. 2003 Nov-Dec;37(5):395-8.
E Jenny Heathcote
University Health Network, Toronto Western Hospital, Toronto,
Patients with cirrhosis due to hepatitis C have a high chance of
dying from progressive liver disease and thus have much to gain from
successful antiviral therapy.
The highest sustained virologic responses in patients with cirrhosis
have been achieved using pegylated interferon alfa plus Ribavirin;
43% or more remain with undetectable virus 6 months after the
cessation of 48 weeks of treatment.
In those who achieve a sustained virologic response, the degree of
fibrosis is less as judged on post-treatment liver biopsy; cirrhosis
may even regress. In those individuals with cirrhosis who achieve a
sustained virologic response, the risk of developing hepatocellular
carcinoma is significantly reduced and it is likely that their chance
of developing liver failure is less.
Patients who do not achieve sustained virologic response can still
show histologic improvement as demonstrated on liver biopsy
post-therapy as compared to baseline.
Patients with compensated cirrhosis can benefit from therapy while
those who are decompensated are prone to more safety issues. Thus,
individuals with any evidence of hepatic decompensation should
generally not be given interferon-based antiviral therapy, but
treatment should be encouraged for those whose status is Child Class
Successful antiviral therapy in patients with cirrhosis due to
hepatitis C is potentially lifesaving, but those with cirrhosis are
unfortunately a "difficult to treat" patient population. They are
difficult to treat because not infrequently they have
contraindications to current anti viral therapies, have a high side
effect profile, and a lower rate of sustained virologic response to
interferon (IFN)-based treatment compared with those without
cirrhosis. Liver biopsy plays a vital role in the pre treatment
assessment of liver disease severity. Without liver biopsy, the
presence of underlying cirrhosis will often go unrecognized.
CONTRAINDICATIONS TO ANTI-VIRAL THERAPY IN CIRRHOSIS CAUSED BY
Peripheral Blood Count
Cirrhosis gives rise to portal hypertension that is frequently
complicated by features of hypersplenism, specifically
thrombocytopenia with or without leukopenia. Although
thrombocytopenia may on occasion be immune-mediated in individuals
with hepatitis C, it is most often a manifestation of hypersplenism.
It is, however, extremely unusual for the platelet count to fall
(with or without antiviral therapy) to such an extent that it
promotes a bleeding disorder, although easy bruising and gum bleeding
(often promoted by periodontal gum disease) complications may occur.
Spontaneous episodes of septicemia are well-recognized in patients
with cirrhosis. Such events are thought most often to be secondary to
intra- and extrahepatic shunting of bacteria delivered to the liver
via the portal vein. Although the precise role of leucopenia in
promoting episodes of spontaneous sepsis in patients with cirrhosis
remains undefined, IFN has a known bone marrow-suppressive effect and
could produce a severe enough neutropenia to put the patient in
danger. It is for these reasons that guidelines with regards to
minimal acceptable numbers of circulating absolute neutrophils and
platelets have been proposed. Most industry-initiated studies have
prohibited the start of anti viral therapy in patients with cirrhosis
with a platelet count of less than 70 x 106/mL or an absolute
neutrophil count of less than 1.5 x 106/mL. In addition, guidelines
recommending dose reduction and possible treatment discontinuation if
the platelet count falls below 50 x 106/mL or the absolute neutrophil
count falls to less than 0.5 x 106/mL. These guidelines have not been
Although the data are scant, there is good evidence that IFN-based
therapy is inadvisable in individuals with decompensated cirrhosis
due to hepatitis C.1 Early complications, mostly due to sepsis have
been described and such individuals generally tolerate the treatment
poorly. In addition, treatment may promote hepatic decompensation.
Tolerance of Antiviral Therapy in Patients With Cirrhosis
Intolerance, particularly due to neuropsychiatric side effect of IFN
therapy, has been best described in individuals with cirrhosis due to
hepatitis B.2 All forms of IFN therapy may be associated with a wide
array of neuropsychiatric side effects. Although never formally
examined, it is possible that anti viral therapy in cirrhotics could
accentuate subclinical hepatic encephalopathy. The latter, depending
on the method of assessment has been reported to be common in
otherwise asymptomatic individuals with cirrhosis.3 Recent
information suggests that individuals infected with hepatitis C virus
(HCV), even in the absence of underlying cirrhosis, have significant
neuropsychiatric deficiencies, particularly in the field of
cognition.4, 5 It possible that this may in part explain the poor
tolerance of IFN by individuals with hepatitis C.
Efficacy of Anti Viral Efficacy in Cirrhosis caused by Hepatitis C
Sustained Virologic Response
The early studies using standard IFN monotherapy showed disappointing
results in patients with cirrhosis.6 When the data from 6 European
trials were pooled, the likelihood of a sustained virologic response
(undetectable HCV RNA 6 months after completing therapy) was
negligible in treatment-naive individuals with cirrhosis infected
with HCV genotype 1. The response rates were somewhat improved once
the combination of IFN alfa 2b plus ribavirin was introduced.
Sustained virologic responses were reported in as many as 20% of
patients with cirrhosis infected with HCV genotype 2 or 3.7
Early studies with peginterferon alfa-2a (40KD) (PEGASYS) indicated
that this long-acting form of IFN, even when given as monotherapy,
markedly enhanced the sustained virologic response in individuals
with cirrhosis or bridging fibrosis. In one study that recruited only
patients with cirrhosis or bridging fibrosis, the overall sustained
virologic response was 30% when peginterferon alfa-2a 180 [million
units]g was given once weekly for 48 weeks. This represented a marked
improvement over the 8% rate achieved with unpegylated IFN alfa-2a.8
Efficacy was poorest in those infected with HCV genotype 1 (sustained
virologic response of 12%), whereas in those with HCV genotype non-1
infections, the sustained virologic response was 51%.
In a large, randomized study, Pegylated IFN alfa-2b 1.5 [million
units]/kg weekly (PEGINTRON) plus Ribavirin 800 mg per day for 48
weeks produced a sustained virologic response of 44% in the subset of
individuals with bridging fibrosis or cirrhosis: a similar rate of
41% was seen in those treated with IFN alfa-2b plus Ribavirin.9
Treatment with peginterferon alfa-2a (40 KD) (PEGASYS) in combination
with Ribavirin improves sustained virologic response, relative to
standard IFN plus Ribavirin, in patients with cirrhosis. In a recent
study, once-once weekly peginterferon alfa-2a 180 [mu]g plus
Ribavirin 1000 to 1200 mg per day, administered for 48 weeks,
produced a sustained virologic response of 43%; inanother study using
the IFN alfa-2b plus Ribavirin the SVR was 33% (Fig. 1).10 Another
study using the same peginterferon alfa-2a plus Ribavirin regimen
showed a sustained virologic response in 50% of patients with
bridging fibrosis or cirrhosis (See Fig. 1).11
[Unable to display image]
Comparison of posttreatment with pretreatment liver biopsies in
individuals who have undergone a course of IFN-based therapy shows
animprovement in total histologic activity index (HAI) scores, both
in patients with a sustained virologic response and in some who do
not clear virus but who experience a fall in viral titer and
improvement in liver biochemistry during treatment. Improvements in
the necroinflammatory component of this score have generally been
greater than the degree of improvement in fibrosis.
In a trial in patients with advanced fibrosis or cirrhosis, 54% of
those treated with peginterferon alfa-2a (40KD) (PEGASYS) monotherapy
(180 [mu]g once weekly) had an improvement of 2 points or more in
their total HAI scores, which was a significant improvement over the
31% histologic response rate seen in patients treated with standard
IFN alfa-2a (P = 0.02).8 In addition, the degree of improvement in
HAI score was significantly greater (P = 0.02) with peginterferon
alfa-2a (40KD) (-2.6 points) than with standard IFN alfa-2a (-0.8).12
A recent study specifically assessed changes in liver fibrosis
observed in 153 patients with cirrhosis at baseline who were
subsequently treated with either standard IFN alfa-2b plus ribavirin
or pegylated IFN alfa-2b plus Ribavirin.13 Regression of fibrosis,
assessed by the 5-point METAVIR scoring system, where 0 = no fibrosis
and 4 = cirrhosis, was observed in 75 patients. In 23 patients, the
METAVIR stage fell by 1 point; in 26 patients, by 2 points; in 23
patients by 3 points; and in 3 patients, no fibrosis was seen on the
posttreatment biopsy. Whereas one may question the reliability of a
change from 4 to 3, there is little difficulty distinguishing stage 2
from stage 4 using the METAVIR scale. In only 1/3 of patients was
this improvement associated with a sustained virologic response.
These changes were noted shortly after the cessation of therapy and
it is reasonable to assume that further improvement in the degree of
fibrosis is likely over longer follow-up periods in patients with a
sustained virologic response, as was reported by Shiratori et al.14
Long Term Survival
Early reports suggested that IFN-based antiviral therapy, when given
to individuals with cirrhosis, did not result in any long-term
benefit, as the rate of hepatic decompensation and the incidence of
hepatocellular carcinoma were not affected. However, sustained
virologic response was rarely achieved in these early studies.6
Subsequently, long-term follow-up of large numbers of treated
patients indicated that a significant reduction in the rate of
hepatocellular carcinoma was achieved in those individuals with
cirrhosis who achieved a sustained virologic response (Table 1).15
Benefit in terms of a reduction in rates of hepatocellular carcinoma
may also be seen in patients who have a sustained biochemical
response to therapy even though viremia may persist. Unfortunately,
these data were not obtained from long-term follow-up of randomized
controlled trials. Data in support of reduced rates of hepatic
decompensation in patients with cirrhosis patients treated with
IFN-based therapy is hard to interpret for the same reason, (ie,lack
of randomization). As IFN therapy for chronic hepatitis C has now
been licensed for a decade, randomization of patients to an untreated
control arm in a prospective trial would be considered unethical.
Thus, in many long-term follow-up studies, which suggest that death
from liver failure is reduced in patients with hepatitis C treated
with IFN-based therapy, the comparison group has always been those,
who, for whatever reason, did not receive treatment as the result of
some circumstance other than randomization. Such patients may have
had contraindications to therapy due to the severity of their liver
disease or were denied treatment because of serious comorbidities,
(eg, psychiatric conditions). In the study by Fattovich et al,16
individuals treated with IFN had an apparent survival benefit, but
when the untreated patients were matched for baseline signs of liver
function (eg, bilirubin) no apparent difference in survival was
observed between treated and untreated individuals. In another study
by Serfaty et al,17 668 patients with compensated cirrhosis due to
hepatitis C were followed for a mean of 40 months. Using multivariate
analysis, nontreatment with IFN was the only independent risk factor
for both hepatocellular carcinoma and hepatic decompensation.
Table 1. Annual Incidence of Hepatocellular Carcinoma (liver cancer)
[Unable to display image]
In terms of progression to hepatocellular carcinoma and survival, no
long-term data are available following treatment with IFN plus
ribavirin. As this therapy results in a markedly enhanced rate of
sustained virologic response compared with standard IFN monotherapy,
and as follow-up studies beyond 2 years suggest that the relapse of
viral infection does not occur, it is highly likely that the
combination therapy will demonstrate a long-term survival benefit,
particularly in individuals who already had developed cirrhosis prior
to the onset of antiviral therapy. Therapy based on Pegylated IFNs
could be expected to further improve the outcome; however,
information is needed regarding the long-term benefits of treatment
with Pegylated IFNs on liver disease progression and survival. The
hepatitis C antiviral long-term treatment against cirrhosis trial
(HALT-C), an ongoing NIH-sponsored study, is assessing the effect of
long-term treatment with peginterferon alfa-2a (40KD) on progression
to cirrhosis, hepatocellular carcinoma, and liver transplantation in
patients with fibrosis at the start of treatment.18 In the trial,
patients with significant hepatic fibrosis who did not respond to
previous therapy (IFN with or without ribavirin) are administered
peginterferon alfa-2a (40KD) plus ribavirin for 20 weeks. Those with
persistent HCV viremia are subsequently randomized to continue
therapy with peginterferon alfa-2a (40KD) alone for an additional 42
months, or to stop treatment. Preliminary data from this trial show
that 59 of 138 patients (43%) treated for up to 20 weeks with
peginterferon alfa-2a (40KD)plus ribavirin achieved a virologic
response, and there was no significant difference between responders
and nonresponders in terms of cirrhosis on liver biopsy (32% and 43%,
respectively) but we have yet to know whether there will be a
difference in the sustained virologic response rates.19
Despite the fact that individuals with cirrhosis may be more at risk
for developing troublesome neuropsychiatric complications and
laboratory events such as leukopenia or thrombocytopenia, these
patients have the most to gain from successful antiviral therapy.
There are good recent data to suggest that the rate of hepatocellular
carcinoma is reduced by effective antiviral therapy. It remains
unproven but likely that survival free of liver failure is improved
in this particular patient population treated successfully for
hepatitis C. Even though antiviral therapy in individuals with
cirrhosis due to hepatitis C seems to have a marked benefit, regular
surveillance for liver cancer, portal hypertension and liver failure
should probably be maintained lifelong
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