HCV-Related Advanced Fibrosis/Cirrhosis

[Guest guest]

HCV-Related Advanced Fibrosis/Cirrhosis

Discussion

This is the first prospective PEG-IFN/RBV trial focusing specifically

on patients with HCV-related advanced fibrosis/cirrhosis. It shows

that SVR is achievable with the STD combination in some 70% of

genotype 2/3 and some 30% of genotype 1/4 infected patients,

respectively. Side effects and drug intolerance were frequent and

required dose reductions in roughly two thirds and early termination

in one third of patients.

With the STD RBV combination (48 weeks), Hadziyannis. et al found in

a retrospective subgroup analysis of the limited number of cirrhotics

an SVR in 73% of genotype 2/3 and 41% of genotype 1 infections,

respectively.[7] This compares favourably with our observations, but

SVR in patients with advanced fibrosis/cirrhosis are 10-20% lower

than those in HCV patients with less advanced disease.[6,7,]

With the LOW RBV combination (48 weeks), we observed SVR in 45% of

genotype 2/3 and 32% of genotype 1/4 patients; the former, but not

the latter, is clearly lower than that in Hadziyannis et al.s'

analysis (73% and 28%, respectively).[7] While the dose of PEG-IFN

was the same in both studies, we dosed RBV at a lower level (600-800

mg vs 800 mg po daily).[7] Thus, the daily RBV dose effectively

administered in our LOW RBV group averaged 9.1 mg/kg (5.7-12.9). This

is lower than the daily RBV dose ( & #8805;10.6 mg/kg) suggested to be

optimal after our study was started - albeit in combination with PEG-

INF & #945;-2b[5] - and may explain, at least in part, the aforementioned

efficacy difference to Hadziyannis et al.'s study.[7] The reason for

this apparently pertaining to genotype 2/3 infection only remains

unclear.

Conversely, our observation of the RBV dose affecting SVR in genotype

2/3, but not 1/4 infections, is at variance with previous data.[7] It

is tempting to speculate that this may, at least in part, be

attributable to the frequent dose reductions necessary; only one

third of patients received a full dose regimen as per protocol.

Unfortunately, our study was not powered for such subgroup analyses

and numbers become too small to allow meaningful comparison of the

two RBV dose groups according to both, genotype and the 80/80/80 rule.

When this study was planned, STD PEG-IFN was known to be tolerated by

patients with HCV-related advanced fibrosis/cirrhosis,[8] but the

optimal RBV dose was unclear. RBV is excreted mainly in urine[17-19]

and its elimination depends on the glomerular filtration rate.

[20,21,] In cirrhotics, kidney function was impaired in 1/3,[22] and

may be impaired despite a normal serum creatinine,[23] and mild

anaemia is common.[24] Thus, cirrhotics are at risk of RBV

accumulation and vulnerable to haemolytic anaemia, a common dose-

dependent side effect of RBV.[25] It was therefore felt appropriate

to compare a lower (800/600 mg) with STD RBV (1200/1000 mg).

While 24 weeks of antiviral treatment suffice in genotype 2/3

infection with minimal/moderate fibrosis,[7] antiviral therapy is

generally less effective in more advanced fibrosis.[7,26,27] We

therefore chose to treat also genotype 2/3 patients for 48 weeks.

Based on the retrospective subgroup analysis of cirrhotics in

Hadziyannis et al.'s trial,[7] 24 weeks of treatment may have

sufficed. Shortening therapy is anticipated to improve

tolerability/acceptance and cost-effectiveness but would again

require formal prospective testing.

Patients failing to respond to a viraemia decline of & #8805;2 log or to

nondetectable levels after 12 weeks of treatment had a <7% chance of

reaching SVR. In these patients, the risk of side effects outweighs

the small potential benefit of continuing therapy. Thus, as in

patients with less advanced fibrosis,[6] cessation of treatment seems

appropriate.

Apart from genotype 2/3, a normal baseline platelet count was the

sole parameter significantly associated with SVR by multivariate

analysis. Patients with normal platelet counts are likely to have

less advanced liver disease and, therefore, to respond better to

antiviral treatment [7,26,27]. Moreover, they are more likely to

tolerate full dose therapy. This favours treatment before portal

hypertension has lead to thrombocytopenia, but should not lead to

exclusion of patients with decreased baseline platelet counts, as a

reasonable chance of cure remains. Thus, overall, 41% of patients

with platelet counts of <150 000/ & #956;L still reached an SVR with the STD

RBV combination in our study.

In summary, the less than ideal tolerability of a STD combination of

PEG-IFN and RBV in patients with HCV-related advanced

fibrosis/cirrhosis seems to be balanced by its reasonable efficacy

and these patients' high medical need for therapy.

CLICK HERE for subscription information about this journal.

Acknowledgements

The authors like to thank Pfitzenmaier (Dr M. Köhler GMBH,

Pharma Biometrie Consulting, Freiburg i Br, Germany) for statistical

counselling and analysis. The meticulous help of Karin Riederer,

andra Grau and Germann (Division of Gastroenterology and

Hepatology, University Hospital, Zurich, Switzerland) in co-

ordinating and monitoring the study is gratefully acknowledged. We

thank Prof. Grob and Dr Helen Joller (Division of Clinical

Immunology, University Hospital Zurich, Switzerland) for their

support in determining HCV genotypes and viraemia levels. We express

our special thanks for contributing patients to the study to the

following investigators of the Swiss Association for the Study of the

Liver (SASL) (alphabetical order): Bertschinger Ph., Stadtspital

Waid, Zurich; Criblez D., Kantonsspital Luzern; Jost R.,

Kantonsspital Winterthur; Koelz H.R., Stadtspital Triemli, Zurich;

Malinverni R., Hopital Cadolles Neuchatel; Pirovino M.,

Kantonsspital, Olten; Wirth H.P. Regionalspital Männedorf. Finally,

we would like to thank Dr A. Zehnder, Dr Ch. Hirt and Ms C. Kundert,

Roche Pharma (Schweiz) AG for their continuing support.