EASL  Sunday April 30-- European Association for the Study of the Liver - Report 3

Rotterdam, April 27-May 3, 2000

Today, Sunday, the streets are clear, Everyone must be sleeping off the effects of carousing. But EASL is going forth. Hepatologists don't drink. At Saturday's afternoon's pre-conference afternoon session, a research group presented a meta-analysis of interferon/ribavirin vs. interferon alone studies. This is described below. In Sunday's sessions there was a nice talk on the possible explanations for the mechanism of action of ribavarin including an explanation of the benefits of combination therapy versus IFN montherapy. Since I'm going out to jog now the description of that talk will have to wait. Later this afternoon is the Glaxo wellcome 3TC hepatitis B symposium, and tomorrow and the following days are the official EASL presentations of the Schering and Roche data for their respective PEG IFNs. In addition, each company is having a symposium.

The 1999 EASL Consensus Statement recommended interferon+ribavirin for treating interferon naÔve patients with chronic hepatitis C. The statement also recommended relapsers use either ribavirin+interferon or high dose IFN. But for treatment of non-responders to prior treatment, no consensus was reached. The objective of the meta-analysis was to evaluate the safety and efficacy of treating chronic hepatitis C with RBV/IFN or ribavirin or RBV monotherapy in IFN-naÔve patients, relapsers, and non-responders (probably only treated previously with IFN monotherapy). Apparently, there are different types of non-responders. Some see a viral load reduction while on treatment, and the amount of reduction can vary. But viral load rebounds while on therapy (this is called breakthrough). But some patients don not see any viral load reduction at all. They are called refractory to interferon. Breakthroughs and relapsers can respond to subsequent therapy but I don't think there is data on re-treatment of individuals refractory or completely non-responsive to IFN. This is an area of concern. A pilot human study of IL-10 was published suggesting this may be a treatment for such individuals. It improved fibrosis but did not reduce HCV viral load. The first human study in HCV negative individuals started recently for hammerhead ribozymes, an antiviral for HCV.

Studies included in meta-analysis were only randomized clinical trials (RCTs), and they compared RBV/IFN to no intervention, placebo, or IFN plus no intervention or placebo. As well they included studies comparing RBV monotherapy to no intervention, placebo, or RBV/IFN. Patients included were those with chronic HCV > 6 months or HCV RNA with elevated ALT> 6 months and/or biopsy findings compatible with chronic hepatitis. Patients were excluded who were coinfected with HBV or HIV, and/or clinical evidence and/or biochemical evidence of hepatic decompensation. Primary outcome measures were virologic responses (loss of detectable HCV-RNA, liver related morbidity (HCC - cancer- and biochemical or clinical evidence of decompensated liver disease), and mortality. Histology response (improvement of histology scores), biochemical response (normalization of AST and/or ALT), quality of life, and adverse events were secondary outcome measures.

So far included in meta-analysis are 11 RCTs looking at 2411 IFN naÔve patients, 12 RCTs looking at 1398 relapsers, 16 RCTs looking at 1519 non-responders, and 2 RCTs with 82 non-responders and relapsers. All of these trials have been published since 1991. When comparing IFN/RBV to IFN studies and looking at the IFN-naÔve patients, there were 164/1175 (14%) discontinuations in the IFN/RBV arm compared to 106/896 (11.8%) in the IFN alone arm. This was not statistically significant. In the relapser group 19/360 (5%) discontinued in the IFN/RBV group, and 13/343 (3.7%) in the IFN group, not significant. In the non-responder group it was almost significant: IFN/RBV group 28/398 discontinued (7%), vs, 12/352 (3.4%) in the IFN alone group.

There is a treatment effect by treating patients with RBV+IFN but only on surrogate markers. They have no data on mortality or morbidity due to the short time of follow-up.

Perhaps, the most important data they reported was seeing about a 20% virologic response in treating non-responders with IFN/RBV. This study defines a virologic response as an undetectable HCV-RNA so you could assume that more than 20% reduced their HCV viral load but did not reach undetectable. It is generally considered and some data has been reported supporting the theory that reducing viral load improves fibrosis. Although it is uncertain that improved fibrosis affects long-term outcome, because there is no long-term data supporting this idea. But, a number of researchers have said they expect that short-term improvement of fibrosis should translate generally into longer term clinical improvement. At the end of this conference or shortly afterwards the EASL Consensus Statement will be issued, and we'll see if this new data is reflected in the 2000 Statement.