The Treatment of Hepatitis C

An Introduction to the Use of New Medicines

An editorial accompanying the article “Treatment Options in Hepatitis C — The Current State of the Art,” by Stefan Zeuzem in this issue of Deutsches Ärzteblatt International

When Deutsches Ärzteblatt International invited me to write an editorial on the treatment of hepatitis C, I hesitated. The topic is evidently relevant not only to gastroenterology, but also to my own specialty, hematology/oncology; it is, however, currently surrounded by emotionally charged debate, sparked by the many new drugs against hepatitis C and their high prices. For both specialties, the availability of new treatment options coincides with major progress in our understanding of the disease. Yet discussions of how patients with hepatitis C should be treated are often narrowly centered on the question of drug costs, and the views expressed on the matter are often rigid and partisan. We can learn much from the way the new drugs for hepatitis C have been dealt with up to now.

Pharmaceutical firms set the prices of the new drugs that they introduce

The treatment of hepatitis C with long-term, lasting benefit through sustained virus eradication is one of the most recent medical success stories. In his review article, Professor Stefan Zeuzem summarizes the current state of development of effective drugs, and the treatment recommendations that are now in effect (1). The morbidity of hepatitis C lies mainly in its late sequelae: it takes a chronic course in 50–70% of infected persons, hepatic cirrhosis develops within 30 years in 20–30%, and hepatocellular carcinoma develops in 3–6% of the patients in the latter group per year. Viral eradication can be achieved in 90–100% of patients by combination therapy with two specific inhibitors. 12 weeks of treatment are indicated in most stages of the disease.

Ever since the first of the new drugs was introduced, Germany has made them accessible to all patients with chronic hepatitis C, being the only country other than the USA to do so. The alternative approach would have been a long-term plan such as that developed by the World Health Organization for the elimination of hepatitis C by the year 2030 (2), which has been adopted by a number of countries, including the United Kingdom. Conceptually, a plan of this type takes account of the fact that the disease often takes a chronic and clinically asymptomatic course, gives priority to advanced stages of disease, and spreads the cost of treatment over a period of up to two decades.

Sofosbuvir, the first highly effective drug against hepatitis C, is very expensive (3). When it was introduced in Germany, the price of treatment added up to more than €100 000 per patient; since then, the monthly costs have remained essentially the same, but a reduction of the required duration of treatment has lowered the overall price per patient to €40 000—50 000. The high price is due to systemic features of new drug introduction in Germany. The initial price can be set by the manufacturers themselves. They are liable to their shareholders, who expect a return on their investment; often, as in the case of sofosbivir, this investment involves a financial gamble in the form of patent purchases or corporate acquisitions (4).

From an economic perspective, the market for breakthrough drugs is not really free and competitive. Although similarly effective drugs may come out within a few years, like for the interferon-free treatment of hepatitis C, for kinase and immune checkpoint inhibitors in oncology, and for combination therapy for HIV, these drugs generally cost no less than their predecessors. The situation seems about to change in the case of hepatitis C, as the combined preparation of grazoprevir with elbasvir is indeed lower-priced.

In Germany, the the mandatory early risk-benefit assessment of new drugs, as specified by the the Pharmaceutical Market Reorganization Act (Arzneimittelmarktneuordnungsgesetz, AMNOG) of 2010, has had an unfavorable effect on the initial drug prices. The decisions of the Joint Federal Committee (Gemeinsamer Bundesausschuss, G-BA) according to this law provide the basis for subsequent rebate negotiations between health-insurance carriers and drug companies; thus, the price at market entry has a large influence on the final price (5). Moreover, early ratings of drug benefits have become so rapid and efficient, with more than 200 of them carried out to date, that the German prices are used as reference values in many other countries.

Rebate contracts with health-insurance carriers are not transparent for physicians

All new drugs for hepatitis C have had to undergo an early risk-benefit assessment as per the AMNOG. The beginning was rocky; the methods of reporting health technology assessment institute, IQWIG (Institute for Quality and Efficiency in Health Care), and the decisions of the G-BA were at first heavily focused on overall survival as the main endpoint, and the approval trials yielded no relevant information because of their short follow-up periods. In view of the slow, chronic course of hepatitis B, significant differences with respect to, for example, morbidity and mortality due to hepatocellular carcinoma can be expected to manifest only after a long interval, sometimes decades. It was only after intense discussions with medical scientists that the surrogate parameter “sustained virologic response” was recognized as a valid endpoint for the early risk-benefit assessment (6).

The contracts that some health insurance carriers made with the drug manufacturer before the early risk–benefit assessment turned out to be financially disadvantageous for them: these contracts were based on an assumed 24-week duration of treatment, but more recent data show that 12 weeks actually suffice. Communication between the insurance carriers and medical scientists was inadequate to prevent this situation. The lower prices that were negotiated after the early rating of benefit lessened the overall cost of treatment, but a new rise of about 20% is expected because combination therapy is now recommended. Unfortunately, the rebate contracts are not transparent for physicians, who nonetheless bear the responsibility for economically as well as medically optimal prescribing. Final price negotiations, including some involving new combined preparations, are now in progress.

Patients are inadequately informed about added value

The most important question in the discussion of drug prices has yet to be answered: how should the value of a new drug be measured? In Germany, hardly any health-economic data are available for a reliable price calculation. Intuitively, the successful eradication of a virus that one was infected with in an earlier phase of life, and that can cause hepatic cirrhosis or cancer, ought to have a high value: one thing less to worry about for the remaining years of one’s life. Can this be measured? The scientific basis for determining the benefit of a new drug is rather thin. Nearly all large-scale trials of new drugs are still oriented towards the key variables for drug approval, i.e., efficacy and safety. Instruments for the assessment of patient-oriented benefit (patient-reported outcome, quality of life) have been increasingly used in many studies in the past few years, but their influence on final decisions in early ratings of drug benefit has been only slowly increasing.

While we go on actively debating about the costs of new drugs, we still have homework to do with regard to the scientific determination of their added benefit.

Conflict of interest statement
The author states that he has no conflict of interest.

Translated from the original German by Ethan Taub, M.D.

Corresponding author:
Prof. Dr. med. Bernhard Wörmann
Deutsche Gesellschaft für Hämatologie und
Medizinische Onkologie
Alexanderplatz 1
D-10178 Berlin, Germany
E-Mail: [e-mail]

Cite this as:
Wörmann B: The treatment of hepatitis C—an introduction
to the use of new medicines. Dtsch Arztebl Int 2017; 114: 9–10.
DOI: 10.3238/arztebl.2017.0009

References

1. Zeuzem S: Treatment options in hepatitis C—the current state of the art. Dtsch Arztebl Int 2017; 114: 11–21

2. World Health Organization. Combating hepatitis B and C to reach elimination by 2030. Advocacy Brief. May 2016. Available from: http://apps.who.int/iris/handle/10665/206453 (last accessed on 19 December 2016).

3. Korzilius H: Arzneimittel. Fragwürdige Preispolitik der Industrie. Dtsch Arztebl 2014; 111(47): 2056–8

4. Roy V, King L: Betting on hepatitis C: how financial speculation in drug development influences access to medicines. BMJ 2016; 354: i3718

5. Busse R, Panteli D: Arzneimittelpreise im europäischen Vergleich: methodische Überlegungen und aktuelle Ergebnisse. http://www.mig.tu-berlin.de/fileadmin/a38331600/2016.lectures/Berlin_2016.12.02.rb_AMPreise-Vergleich-web.pdf (last accessed on 19 December 2016).

6. Wörmann B, et al.: Frühe Nutzenbewertung neuer Arzneimittel in Deutschland 201 –2014. https://www.dgho.de/informationen/gesundheitspolitische-schriftenreihe/band-6 (last accessed on 19 December 2016).