Response to Standard of Care Antiviral Treatment in Patients with HCV Liver Cirrhosis – a Systematic Review

Response to Standard of Care Antiviral Treatment in Patients with HCV Liver Cirrhosis – a Systematic Review

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J Gastrointestin Liver Dis. 2011 Sep;20(3):293-8.

Simona Bota¹, Ioan Sporea¹, Alina Popescu¹, Roxana Sirli¹, Adriana Maria Neghina², Mirela Danila¹, Mihnea Strain¹

1) Department of Gastroenterology and Hepatology;
2) Department of Biochemistry, Victor Babes University of Medicine and Pharmacy, Timişoara, Romania

Abstract

Background:Patients with HCV liver cirrhosis are a category difficult to treat. The aim of this study was to establish the sustained virological response (SVR) rates in HCV patients with liver cirrhosis treated with standard of care therapy (Pegylated Interferon and Ribavirin for 48 weeks in genotypes 1 and 4 and 24 weeks in genotypes 2 and 3).

Methods:Searching the PubMed, Medline, Lilacs, Scopus, Ovid and Medscape databases we identified all the articles published until February 2011 that included only HCV cirrhotic patients. These studies evaluated the SVR after standard of care treatment: Pegylated Interferon alpha 2a (doses ranging between 135-180 ľg/week) or Pegylated Interferon alpha 2b (1 or 1.5 ľg/kg/week) and Ribavirin (doses ranging between 800-1200 mg/day). We used the following key words: HCV, liver cirrhosis, sustained virological response (SVR).

Results:The overall SVR rate was 33.3% (95%CI-confidence interval=30.6-36.2%). SVR was significantly higher in patients with genotypes 2 and 3 (422 patients) as compared to those with genotypes 1 and 4 (692 patients): 55.4% (95%CI=50.7-60.1) versus 21.7% (95%CI=18.7-25), p<0.0001.

Conclusion:The overall SVR rate in cirrhotic patients treated with standard of care therapy is 33.3%, but lower in cases affected by genotypes 1 and 4 (21.6%) which makes them a priority regarding the development of more potent drugs for effective treatment.

Key words
Hepatitis C - HCV - liver cirrhosis - sustained virological response - systematic review - pegylated interferon - ribavirin.

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Discussion
This systematic review summarizes and analyzes the
available data on SVR in HCV liver cirrhosis managed with
SOC therapy and finally shows an overall value of 33.3%,
with better results in genotypes 2 and 3 as compared to
genotypes 1 and 4 ( p<0.0001).

A recent meta-analysis [25], that included 5,008 cases
from 12 randomized controlled clinical trials, compared
the SVR rates in patients treated with Pegylated Interferon
alpha 2a plus Ribavirin versus Pegylated Interferon alfa
2b plus Ribavirin. Overall, Pegylated Interferon alpha 2a
significantly increased the number of patients who achieved
SVR versus Pegylated Interferon alpha 2b (47% versus 41%;
risk ratio=1.11, 95%CI=1.04-1.19; p=0.004). Pegylated
Interferon alpha 2a was associated with higher SVR than
Pegylated Interferon alpha 2b in those affected by genotype
1 (risk ratio=1.25, 95%CI=1.03-1.42) as well as genotypes
2 and 3 (risk ratio=1.11, 95%CI=1.02-1.22).

Our systematic analysis in cirrhotic patients shows similar
SVR rates regardless of the type of Pegylated Interferon used
in SOC therapy (Pegylated Interferon alpha 2a -35.6% vs.
Pegylated Interferon alpha 2b – 34.8%, p=0.9).

Also the SVR rates did not differ significantly in patients
with or without esophageal varices (p=1), and in patients
with Child-Pugh class A or Child-Pugh class B cirrhosis
(p=0.9). The results of the latter subgroup may have been
biased by the low number of patients with Child-Pugh class
B as compared to those with Child-Pugh class A cirrhosis
(99 patients vs. 854 patients).

As expected, the SVR rate was significantly lower in
patients treated with standard IFN as compared to naïve
patients ( p=0.003).

The limitations of this systematic review are that not all
the studies were randomized, and that the SVR rate according
to the treatment status, the Child-Pugh class or the presence
of esophageal varices were not analyzed in all the studies.
Regarding the antiviral treatment in cirrhotic patients,
Saab et al [26] published a study that tried to determine the
most cost-effective timing for Pegylated Interferon plus
Ribavirin treatment (48 weeks) in patients with advanced
liver disease related to genotype 1 HCV infection. The
study included about 4,000 participants followed over
17 years. A Markov model was constructed to compare
treatment strategies: no treatment, antiviral therapy in
patients with compensated cirrhosis, antiviral therapy in
patients with decompensated cirrhosis, and antiviral therapy
in patients with progressive fibrosis due to recurrent HCV
post-transplantation. Outcomes of interest included the
total cost per patient, number of quality-adjusted life years
(QALYs) saved, cost per QALY saved, number of deaths
and hepatocellular carcinomas and number of transplants
required. Compared to the no-antiviral treatment strategy,
treatment during compensated cirrhosis increased QALYs
by 0.950 and saved 55.314 dollars, treatment during
decompensated cirrhosis increased QALYs by 0.044 and
saved 5511 dollars and treatment during posttransplant
advanced recurrence increased QALYs by 0.061 and saved
3223 dollars. Treatment of patients with compensated
cirrhosis resulted in 119 fewer deaths, 54 fewer hepatocellular
carcinomas and 66 fewer transplantations with respect to the
no-treatment strategy.

So, even if the SVR rate in HCV cirrhotic patients with
genotype 1+4 is very low (21.6% in our current review),
with lots of adverse events (especially hematological:
anemia, neutropenia, thrombocytopenia) which determined
the discontinuation of therapy, according to the previous
presented study [26], it is cost-effective to treat cirrhotic
patients with antiviral therapy.
The low SVR rate in genotypes 1 and 4 urges also the
need for new therapies and new predictors of SVR even in
cirrhotic patients treated previously with IFN standard.
In recent years, several studies reported that genetic
polymorphism in the IL28B gene, encoding interferonlambda-
3, is associated with an approximately twofold
change in response to treatment [27-30].

IL28B genotypes are significantly related to the SVR
rates following SOC treatment (Pegylated Interferon plusRibavirin). In patients of European ancestry, CC genotype
is associated with a twofold (95%CI=1.8-2.3) higher rate of
SVR than the TT genotype [27]. It has been also shown that
SVR rate was 69% in CC genotype as compared to 33% in
TC genotype and 27% in TT genotype (p<0.0001) [31].
No studies that analyzed the relationship between IL28B
genotype and SVR matched the inclusion criteria used in
this systematic review.

In the latter years, several studies have used triple
therapy (SOC therapy + direct antiviral agents) in patients
with HCV genotype 1 infection [32-34]. The most studied
direct antiviral agents were Boceprevir (SPRINT 2 trial) and
Telaprevir (ADVANCE and ILLUMINATE trials) [34, 35].
These trials included naïve patients and the proportion of
patients with bridging fibrosis/cirrhosis was 20-23% in the
ADVANCE trial, and 7-11% in the SPRINT 2 trial.

In the trial with Telaprevir, the SVR rate in patients with
F0-F2 (n=290) was higher than in patients with F3-F4 (n=73)
(78% vs. 62%, p=0.007) [36, 37]. Also, in the trial that used
Boceprevir [35], the SVR rate was significantly higher
in non-cirrhotic versus cirrhotic patients (odd ratio=2.5,
95%IC=1.4-4.6, p=0.003).

The REALIZE trial used Telaprevir and Pegylated
Interferon alpha 2a plus Ribavirin in patients with HCV
genotype 1 infection who had no response or a partial
response to previous therapy or who had a relapse after
an initial response. A total of 663 patients were assigned
to one of three groups: two which included Telaprevir and
the control group with SOC therapy [38]. In cirrhotics,
the SVR rates with SOC therapy as well as for the pooled
12 weeks Telaprevir + 48 weeks Pegylated Interferon and
Ribavirin therapy were as follows: prior relapsers - 13% and
84%, respectively; prior partial responders - 20% and 34%,
respectively; null-responders - 10% and 14%, respectively
[38, 39].

The RESPOND-2 trial, that used Boceprevir in patients
previously treated, included prior relapsers and prior partial
responders, but excluded the null responders. There were
also three arms in this study: SOC therapy and two arms
with Boceprevir (for 32 weeks and 44 weeks, respectively,
in association with SOC therapy).The SVR rates for the
three arms in patients with F3-F4 were 13%, 44% and 68%,
respectively [40].

A recent study [41] used both Pegylated Interferon alpha
2a and Pegylated Interferon alpha 2b in combination with
Ribavirin and Telaprevir with similar rates of SVR.
IL28B genotyping in the ADVANCE trial showed a
higher SVR rate in CC genotype (90%) as compared to
CT and TT genotypes (71% and 73%, respectively) [42].
Similarly, in the trial that used Boceprevir, the SVR rate was
significantly higher in the CC genotype as compared with
the CT and TT genotypes [43].

This data shows that triple therapy had good results
for the treatment of naïve patients affected by genotype 1
HCV with advanced fibrosis and cirrhosis – F3-F4 (62%)
as compared to SOC therapy (SVR rate of 21.6% reported
by this review in cirrhotic patients with genotype 1 and 4).Both SOC therapy and triple therapy are influenced by the
IL28B genotype.

In cirrhotic patients formerly treated with standard IFN,
the SVR rate with SOC therapy in this review was 25.9%.
Therefore, patients with genotype 1 HCV who do not achieve
SVR need to be treated with triple therapy. The results of
the studies presented above are very encouraging for prior
relapser patients (84% in REALIZE trial) and satisfying for
the partial responder patients (34% in REALIZE trial), but of
important concern remain the non-responder patients (14% in
REALIZE trail). The SVR rate obtained with triple therapy
in cirrhotic non-responder patients is comparable with the
value reported in those who underwent SOC therapy (10%).
Thus, new drugs should be developed and made available
to the former as soon as possible.

Conclusion
The overall SVR rate in cirrhotic patients treated with
standard of care therapy is 33.3%, but lower in cases affected
by genotypes 1 and 4 which makes them a priority with
regard to the development of more potent drugs for effective
treatment.

Reference