## Hepatitis C

I once previously wrote something about hepatitis C in this blog which was directed to the mathematical modelling aspects. Here I want to write about the disease itself. This has been stimulated by talks I heard at a meeting of the Mainzer Medizinische Gesellschaft. The speakers were Ralf Bartenschlager from Heidelberg and and Stefan Zeuzem from Frankfurt. The first speaker is a molecular biologist who has made important contributions to the understanding of the structure and life cycle of the virus. For this work he got the 2015 Robert Koch prize together with Charles Rice from the Rockefeller University. The second speaker is a clinician.

Hepatitis C is transmitted by blood to blood contact. According to Zeuzem the main cause of the spread of this disease in developed countries is intravenous drug use. Before there was a test for the disease it was also spread via blood transfusions. (At one time the risk of infection with hepatitis due to a blood transfusion was 30%. This was mainly hepatitis B and by the time of discovery of hepatitis C, when the risk from hepatitis B had essentially been eliminated, it had dropped to 5%.) He also mentioned that there is a very high rate of infection in certain parts of Egypt due to the use of unsterilized needles in the treatment of other diseases. Someone asked how the disease could have survived before there were injections. He did not give a definitive answer but he did mention that while heterosexual contacts generally carry little risk of infection with this virus homosexual contacts between men do carry a significant risk. The disease typically becomes chronic and has few if any symptoms for many years. It does have dramatic long-term effects, namely cirrhosis and cancer of the liver. He showed statistics illustrating how public health policies have influenced the spread of the disease in different countries. The development in France has been much more favourable (with less cases) than in Germany, apparently due to a publicity campaign as a result of political motives with no direct relevance to the disease. The development in the UK has been much less favourable than it has even in Germany due an almost complete lack of publicity on the theme for a long time. The estimated number of people infected in Germany is 500000. The global number is estimated as 170 million.

There has been a dramatic improvement in the treatment of hepatitis C in the past couple of years and this was the central theme of the talks. A few years ago the situation was as follows. Drugs (a combination of ribavirin and interferon $\alpha$) could be used to eliminate the virus in a significant percentage of patients, particularly for some of the sub-types of the virus. The treatment lasted about a year and was accompanied by side effects that were so severe that there was a serious risk of patients breaking it off. Now the treatment only lasts a few weeks, it cures at least 95% of the patients and in many situations 99% of them. The side effects of the new treatments are moderate. There is just one problem remaining: the drugs for the best available treatment are sold for extremely high prices. The order of magnitude is 100000 euros for a treatment. Zeuzem explained various aspects of the dynamics which has led to these prices and the circumstances under which they might be reduced in the future. In general this gave a rather depressing picture of the politics of health care relating to the approval and prescription of new drugs.

Let me get back to the scientific aspects of the theme, as explained by Bartenschlager. A obvious question to ask is: if hepatitis C can essentially be cured why does HIV remain essentially incurable despite the huge amount of effort and money spent on trying to find a treatment? The simple answer seems to be that HIV can hide while HCV cannot. Both these viruses have an RNA genome. Since the copying of RNA is relatively imprecise they both have a high mutation rate. This leads to a high potential for the development of drug resistance. This problem has nevertheless been overcome for HCV. Virus particles are continually being destroyed by the immune system and for the population to survive new virus particles must be produced in huge numbers. This is done by the liver cells. This heavy burden kills the liver cells after a while but the liver is capable of regenerating, i.e, replacing these cells. The liver has an impressive capability to survive this attack but every system has its limits and eventually, after twenty or thirty years, the long-term effects already mentioned develop. An essential difference between HIV and HCV is that the RNA of HCV can be directly read by ribosomes to produce viral proteins. By contrast, the RNA of HIV is used as a template to produce DNA by the enzyme reverse transcriptase and this DNA is integrated into the DNA of the cell. This integrated DNA (known as the provirus) may remain inactive, not leading to production of protein. As long as this is the case the virus is invisible to the immune system. This is one way the virus can hide. Moreover the cell can divide producing new cells also containing the provirus. There is also another problem. The main target of HIV are the T-helper cells. However the virus can also infect other cells such as macrophages or dendritic cells and the behaviour of the virus in these other cells is different from that in T-helper cells. It is natural that a treatment should be optimized for what happens in the typical host cell and this may be much less effective in the other cell types. This means that the other cells may serve as a reservoir for the virus in situations where the population is under heavy pressure from the immune system or drug treatment. This is a second sense in which the virus can hide.

Some of the recent drugs used to treat HCV are based on ideas developed for the treatment of HIV. For instance a drug of this kind may inhibit certain of the enzymes required for the reproduction of the virus. There is one highly effective drug in the case of HCV which works in a different way. The hepatitis C virus produces one protein which has no enzymatic activity and it is at first sight hard to see what use this could be for the virus. What it in fact does is to act as a kind of docking station which organizes proteins belonging to the cell into a factory for virus production.

The hepatitis C virus is a valuable example which illustrates the relations between various aspects of medical progress: improvement in scientific understanding, exploitation of that information for drug design, political problems encountered in getting an effective drug to the patients who need it. Despite the negative features which have been mentioned it is the subject of a remarkable success story.