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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, Ontario,
Canada.
ABSTRACT
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 A.
BACKGROUND
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 HEPATITIS
C
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 formally
validated.
Hepatic Decompensation
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%; in another 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
figure 1.
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Histologic Response
Comparison of posttreatment with pretreatment liver biopsies in
individuals who have undergone a course of IFN-based therapy shows an
improvement 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)
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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
SUMMARY
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
REFERENCES
- Crippin JS, McCashland T, Terrault N, et al. A pilot study of the
tolerability and efficacy of antiviral therapy in hepatitis C
virus-infected patients awaiting liver transplantation. Liver Transpl.
2002; 8:350-355.
- Renault PF, Hofnagle JH, Park Y, et al. Psychiatric Complications
of long-term Interferon alfa therapy. Arch Int Med. 1987;
147:1577-1580.
- Groeneweg M, Moerland W, Quero JC, et al. Screening of subclinical
hepatic encepherlopathy. J Hepatol. 2000; 32:748-753.
- Forton DM, Thomas HC, Murphy CA, et al. Hepatitis C and cognitive
impairment in a cohort of patients with mild liver disease. Hepatology.
2002; 35:433-439.
- Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment
in patients with chronic hepatitis C. Hepatology. 2002; 35:440-446.
- Valla DC, Chevallier M, Marcellin P, et al. Treatment of hepatitis
C virus-related cirrhosis: a randomized, controlled trial of
interferon alfa-2b versus no treatment. Hepatology. 1999;
29:1870-1875.
- Schalm SW, Weiland O, Hansen BE, et al. Interferon-ribavirin for
chronic hepatitis C with and without cirrhosis: analysis of individual
patient data of six controlled trials. Eurohep Study Group for Viral
Hepatitis. Gastroenterology. 1999; 117:408-413.
- Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon
alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J
Med. 2000; 343:1673-1680.
- Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b
+ ribavirin compared with interferon alfa-2b + ribavirin for initial
treatment of chronic hepatitis C: a randomised trial. The Lancet.
2001; 358:958-965.
- Fried MW, Shiffman ML, Reddy KR, et al. Pegylated interferon
alfa-2a (Pegasys) in combination with ribavirin: efficacy and safety
results from a phase III, randomized, actively controlled, multicenter
study [abstract]. Gastroenterology. 2001; 120:A55.
- Hadziyannis SJ, Cheinquer H, Morgan T, et al. Peginterferon alfa
2a (40KD)(PEGASYS) in combination with ribavirin (RBV); efficacy and
safety results from a phase III randomized, double-blind, multicentre
study examining effect of duration of treatment adn RBV dose [abstract
1]. J Hepatol. 2002; 36( 1): 3.
- Balart LA, Lee SS, Schiffman M, et al. Histologic improvement
following treatment with once weekly Pegylated interferon alfa-2A
(PEGASYS TM) and thrice weekly interferon alfa-2A (Roferon) in
patients with chronic hepatitis C and compensated cirrhosis [plus oral
presentation]. Gastroenterology. 2000; 118 (Suppl 2): 961.
- Poynard T, McHutchinson J, Manns M, et al. Impact of Pegylated
Interferon alfa-2b and Ribavirin on liver fibrosis in patients with
chronic hepatitis C. Gastroenterology. 2002; 122:1303-1313.
- Shiratori Y, Imazeki F, Mariyania M, et al. Histologic improvement
of fibrosis in patients with hepatitis C who have a sustained response
to Interferon therapy. Ann Int Med. 2000; 132:517.
- Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy
reduces the risk of hepatocellular carcinoma: national surveillance
program of cirrhotic and non-cirrhotic patients with chronic hepatitis
C in Japan. Ann Int Med. 1999; 131:174-181.
- Fattovich G, Giustina G, Degos F, et al. Effectiveness of
interferon alfa on incidence of hepatocellular carcinoma and
decompensation in cirrhosis type C. European Concerted Action on Viral
Hepatitis (EUROHEP). J Hepatol. 1997; 27:201-205.
- Serfaty L, Aumaitre H, Chazouilleres O. et al. Determinants of
outcome of compensated hepatitis C virus-related cirrhosis. Hepatology.
1998; 27:1435-1440.
- Di Bisceglie AM. BOnkovsky HL, Deinstag JL, et al. Design of
HALT-C trial (hepatitis C antiviral long-term treatment to prevent
cirrhosis) [abstract]. Gastroenterology. 2000; 118 (Suppl. 2): 1435.
- Shiffman ML. Retreatment of interferon and interferon-ribavirin
non-responders with peginterferon alpha-2a and ribavirin: Initial
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The Second Time Around: Retransplantation for
Recurrent Hepatitis C
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Roayaie et al. present a sobering view of the outcome of
re-transplantation for re-current HCV. Of 116 patients relisted more
than 90 days after initial transplantation, 32% died while waiting, 24%
still are waiting, and 44% (51 patients)received a second
transplant.Forty-two of these 51 lost their first transplant because of
HCV-induced cirrhosis and are the focus of the study.Of the 42,only 13
(31%)are alive,at a median of 41 months follow-up; 20 patients (48%)died
after <6 months, 65%of these 20 due to sepsis; 9 (21%) died >6 months
after transplantation, 66%of these 9 due to recurrent HCV.
Overall, 70% of patients receiving second transplants died after <3
years due to early sepsis or late complications of HCV. The median
survival time was 12.9±6.7 months. Of the 13 living patients, only 4 are
faring well.Seven patients underwent a third transplantation; five of
these seven died.Patients who underwent retrans- plantation for HCV
fared significantly worse (P=0.002)than did those who received
transplants for other conditions. The most significant predictors of
poor outcome in a multivariate analysis were PT (Prothrombin Time) >16
and donor age >60 years. The pretransplantation MELD score was not
correlated with survival after the second transplantation.
Thus, if hepatitis C is severe the first time around, it will be more
severe the second time around, and still more severe the third time
around. This raises the eternal dilemma of the seed versus the soil.Is
this process selecting bad hosts or virulent agents? Are there
more-virulent strains of HCV that initially result in cirrhosis and then
cause increasingly rapid cirrhosis as they reinfect each new liver,or
are there hosts who, by virtue of genetic make-up and/or impaired
immunity, constitute the 20%--30% who develop cirrhosis from the primary
infection and then again each time they receive an HCV-naive liver? This
issue cannot be resolved at present,but it is fundamental to our
understanding of the pathogenesis of hepatitis C.
This study also raises difficult ethical issues. Given these poor
outcomes in a subset of patients, are we justified in using the limited
number of available livers for retransplantation rather than primary
transplantation in patients who might fare better? Are we under
obligation to provide a second liver, if necessary, once committed to a
patient for the primary transplantation? These will remain incredibly
difficult questions as long as the supply of organs remains limited.
Overall, we need better seed, better soil,and more livers (or liver
equivalents).(See Hepatology 2003;38:1428 --1436.)
Pilot Study of Pegylated
Interferon Alfa-2b and Ribavirin for Recurrent Hepatitis C After Liver
Transplantation
Recurrent hepatitis C is often treated with an interferon and ribavirin
combination therapy, but the results have been disappointing. Given the
promising results reported with pegylated interferon and ribavirin for
hepatitis C, researchers at the University of Nebraska were interested
in evaluating the effectiveness of this treatment in liver transplant
recipients with recurrent hepatitis C (HCV).
Between November 2001
and September 2002, patients with recurrent HCV were screened to
determine if they were eligible for treatment. Liver function tests, HCV-RNA,
and liver biopsies were performed on all patients prior to treatment.
HCV-RNA was repeated
at 3 months, the end of treatment (EOT), and 6 months after EOT for
patients who were HCV-RNA negative at EOT.
Patients were
prospectively followed after starting weekly
pegylated interferon alfa-2b 1.5 mcg/kg
per week and ribavirin 800 mg per day (Schering-Plough, Kenilworth, NJ,
USA) with folic acid 1 mg per day. Thirty-nine patients eligible for
treatment displayed a median age of 50.4 years. Eighteen patients
completed treatment, 4 remain on treatment, and 17 were intolerant.
Sustained HCV-RNA
eradication occurred in 66.7% of patients who completed treatment. Side
effects led to treatment withdrawal in 17 patients (43.6%) In an
intention-to treat analysis, sustained HCV-RNA eradication occurred in
30.8% of patients.
Side effects are an
important limiting factor in the treatment of recurrent HCV with
pegylated interferon and ribavirin. However, these results are
encouraging as sustained HCV eradication occurred in at least 66.7% of
patients who completed treatment.
The authors recommend
implementation of prospective randomized trials to evaluate the
effectiveness of the peginterferon/ribavirin combination and its impact
on quality of life and histology among this group of patients.
Section of Gastroenterology and Hepatology,
University of Nebraska Medical Center.
01/14/04
Reference
S Mukherjee and others. Pilot study of pegylated interferon alfa-2b and
ribavirin for recurrent hepatitis C after liver transplantation.
Transplantation
Proceedings
35(8): 3042-3044. December 2003.
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