Report from EASL; The European Association for the Study of the Liver Conference, Rotterdam, April 28-May 3, 2000 - Report 5

Viral Kinetics; Hard To Treat Populations

In the early morning of this final day of the EASL conference there was a Clinical Basic Science Session on Viral Kinetics. Here Neumann and Pawlotsky talked about their findings that viral load decline during phase 2 (days 2-28) after initiating therapy are very predictive of achieving a sustained response. If a person does not see a considerable decline during phases 1 & 2 Neumann says their data and the data of others show the person is highly unlikely to achieve a sustained response. Therefore, they believe induction therapy with 10 MIU daily is recommended to maximize the viral decline during the first few weeks or month of therapy. Thereafter, they suggest a maintenance dose that must be daily is acceptable.  They said the three times weekly dosing is inadequate because 24 hours after interferon dosing the blood levels of interferon are gone and viral replication starts up. However, there is some controversy about this. It appears widely agreed that daily dosing is important and that 3 times per week dosing is inadequate. Of course pegylation addresses this. But, one researcher I spoke with about this disagreed and feels the response to interferon is more complex, that induction therapy is not necessary. But, Neumann's data and theories on viral kinetics and induction therapy are highlighted at key hepatitis and liver meetings. There have been several studies using induction therapy which showed there was not much improvement in sustained response compared to 3 times weekly, but Neumann contends that is because the maintenance dosing was not daily. An ongoing study is exploring high dose daily induction followed by daily mantenance and results should be available relatively soon. Study of induction dosing with pegylated should be conducted. Other developing therapies should be explored in combination with pegylated interferon to improve overall virologic treatment response.

Cirrhotics and Viral Response. At yesterday's Roche symposium, they presented data that 45% of cirrhotics had a sustained viral response in the Pegasys study. Previously in a larger study of cirrhotics, Heathcote reported 30% of cirrhotics achieved a sustained response with monotherapy Pegasys. But in the Heathcote study only 10% of genotype 1 had a sustained response, and the data on genotype 1 from the new study presented at EASL was not available yet.

Why are genotypes 1 not as responsive to interferon? It is unknown. It could be cellular, virologic, immunologic, or genetic. Maybe their cells or their virus have become unable to respond to interferon as well.

The Need To Study Cirrhotics and Genotype 1.  The reduced response of difficult to treat populations--genotype 1 and cirrhotics is a great concern. I discussed with Neumann and Pawlotski the need to conduct kinetics studies of why cirrhotics are not as responsive in the hopes that better understanding of this problem turning into a treatment approach that could improve response. The concern about genotype 1 and cirrhotics is paramount because most HCV infected people in the USA are genotype 1. Most African-Americans are genotype 1. And the demographics of HCV/HIV co-infection in the USA is very much driven by IVDUs who are likely to be mostly genotype 1. Researchers and clinicians should key into this need and someone or some group needs to consider conducting such a study. And of course cirrhotics with genotype 1 are the least responsive to therapy.

Genotype 1 is also a hard population to treat and research needs to find out why and figure a way to improve response. For some reason it appears that these individuals' immune system and/or virus are unable to respond to interferon.