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Telaprevir, boceprevir and interferon lambda are new promising drugs for the treatment of hepatitis C (hepatitis C). Entecavir and tenofovir have been used successfully in the treatment of hepatitis B. Research is underway on other molecules that are expected to expand the arsenal of antiviral drugs that will increase the effectiveness of the treatment of chronic liver infections.
The number of people infected with hepatitis B (HBV) and C (HCV) viruses, which are responsible for 80% of The number of cases of primary liver cancer (also called hepatocellular carcinoma), the third cause of death, is on the rise. According to estimates, about 350-400 million people live with HBV in the world, and about 170 million with HCV.
Three drugs instead of two
The standard treatment of hepatitis C is currently the so-called a combination therapy that combines the effects of two drugs: pegylated interferon alfa 2a or 2b, given to the patient once a week by injection, and ribavirin, an oral drug that must be taken once a day. It works by enhancing the body’s natural immune response to the virus. However, in people infected with the C virus of genotype 1, which is characteristic of the white race and dominates in Poland, the effectiveness of such treatment is only about 30-50%. Remaining patients are unable to achieve a sustained virological response.
Two new oral drugs called HCV protease inhibitors – telaprevir and boceprevir – are a chance to increase the effectiveness of treatment in such patients. The mechanism of their action is to interfere with the replication (multiplication) of the hepatitis C virus by inhibiting the activity of its key enzyme – NS3 / 4A serine protease. When these drugs are added to standard therapy, the sustained response rate in previously untreated patients increases to around 60-70%.
Boceprevir stayed in July this year. approved by the European Commission for the treatment of chronic hepatitis C caused by genotype 1 infection. It is to be used in combination with pegylated interferon alfa and ribavirin in adult patients with compensated liver disease who have not received treatment before or whose previous treatment has failed. The decision of the European Commission means that the drug has been authorized in 27 Member States of the European Union and in the countries belonging to the European Economic Area. The marketing authorization was based on the results of two phase III clinical trials (HCV SPRINT-2 and VCV RESPOND-2) in which a total of approximately 1500 patients participated.
The efficacy and safety of telaprevir therapy was the subject of the REALIZE study, the results of which were presented at this year’s ILC (International Liver Congress) – the 46th annual meeting of the European Liver Research Society (EASL) in Berlin. The study included 662 patients infected with the C virus genotype 1. The results showed that telaprevir is also effective in patients who did not respond to standard therapy. After adding this drug to it, the percentage of durable response to treatment was 29-33%, while in the control group only 5%.
– Thanks to such advances in the treatment of hepatitis C, it will be possible to significantly reduce the dangerous effects of this disease – emphasized Prof. Stefan Zeuz from the JW Goethe University Hospital in Frankfurt, who participated in the REALIZE study.
In the opinion of experts, the nearest future in the treatment of hepatitis C will belong to the three-drug therapy. – There is no doubt that the combination of interferon and ribavirin will be required in the coming years. But adding one of the latest drugs to them will significantly increase the effects of therapy – emphasized in an interview with PAP Prof. Robert Flisiak, head of the Department of Infectious Diseases and Hepatology at the Medical University of Bialystok.
New molecules, high hopes
The drug that will enhance the efficacy of standard combination therapy is not necessarily a protease inhibitor. It turns out that other drugs from the same class of preparations acting directly on the virus are also tested: inhibitors of NS3 polymerase – an enzyme that controls the replication of HCV genetic material and an inhibitor of the NS5A replication complex that plays a similar role.
The first representative of the group of inhibitors of the NS5A complex is the drug designated BMS-790052. Studies of this molecule to date have shown that when added to standard therapy (interferon + ribavirin) in previously untreated HCV genotype 1 patients, treatment efficacy increases from 25% to 92%.
– The advantage of inhibitors of the NS5A complex is also the fact that they also affect other genotypes of the C virus – emphasizes Dr. Stanislas Pol, hepatologist and gastroenterologist at the University of Paris. Descartes V, head of the Department of Hepatology at the Cochin Hospital in Paris.
The NS3 polymerase inhibitor is the drug with the symbol BMS-650032. Its effectiveness is tested, among others in patients infected with C virus genotype 1 who did not respond to standard therapy. After using the four-drug therapy, consisting of pegylated interferon alpha, ribavirin, an inhibitor of the NS5A replication complex (BMS-790052) and an inhibitor of NS3 polymerase (BMS-650032), 100% of patients were obtained. persistent virologic responses. The results of this study are very promising, but it is at a too early stage for any specific conclusions to be drawn from it. It is also worth adding that only 21 patients participated in it.
The second class of antiviral drugs that scientists have high hopes for are the so-called host targeting antivirals (HTA). They do not act directly on the virus, like NS3 polymerase inhibitors and NS5A virus replication complex (DAA) inhibitors (directly acting agents), but inhibit proteins in the human body that play a key role in its replication. The HTA class includes cyclophilin inhibitors with their first representative alisporivir, also known as DEB025. The results of the second phase of the study of this drug, also taking place in Poland, indicate a very high, 76% sustained virological response rate obtained after adding DEB025 to standard therapy (pegylated interferon alpha 2a and ribavirin) versus 55 percent. in the control group. According to the researchers participating in this study, it is the only drug that shows activity against both the C virus genotype 1 as well as the virus 2, 3 and 4, against which protease inhibitors (boceprevir and telaprevir) are helpless.
Efficiency and safety
In addition to testing drugs to improve treatment effectiveness, research is underway to find a safer alternative to pegylated inerferon alpha, pegylated interferon lambda. The difference between them is that receptors for interferon lambda – a mediator of antiviral activity – are mainly found in the liver, which allows for more precise administration of the drug and limitation of its side effects. In the case of interferon alpha, the receptors are present in various organs and tissues, incl. in the brain and blood cells, which increases the risk of side effects such as depression, fatigue, flu-like symptoms, muscle and bone pain, haematological disorders. Because of them, about 20 percent. treatment must be interrupted or the dose of interferon reduced.
The results of the Phase II EMERGE study, which enrolled 526 treatment-naïve chronic hepatitis C patients with different viral genotypes, showed that patients treated for 12 weeks with pegylated lambda interferon in combination with ribavirin had a higher response rate and They have fewer side effects than patients receiving standard combination therapy (pegylated interferon alpha and ribavirin), and the incidence of serious side effects was similar in both groups. However, comparing the safety and efficacy of both interferons requires further clinical trials and observations.
A modern weapon in the fight against WZW B
In the case of hepatitis B, the standard of treatment is two groups of drugs: interferons and nucleoside and nucleotide analogues, mainly entecavir and tenofovir. Poland is the only European country in which the outdated lamivudine is used – cheap, but causing drug resistance, which, according to experts, irritates and seriously hinders further treatment of patients.
Treatment for viral hepatitis is generally life-long. Newer drugs reduce the level of viral load faster and give a chance for an earlier treatment termination – emphasize the doctors, adding that after four years of therapy, they only cause 1,2 percent. resistance, while lamivudine as much as 60-80%.
– It should start with a drug that is potent and does not generate resistance, because ineffective treatment is not only a waste of time, but above all a greater risk of severe complications from HBV infection, e.g. liver cancer. If entecavir is administered to patients with lamivudine resistance, the patient’s chance of recovery is significantly reduced, they argue.
As recommended by the European Society for the Study of the Liver, pegylated interferon alfa or entecavir / tenofovir should be used first. However, specialists emphasize that the long-term use of tenofovir may have side effects on the kidneys and bones. For this reason, therapy with this drug is associated with the need for systematic (once a month in the first year, then quarterly in subsequent years) assessment of kidney function, which affects the patient’s comfort and the overall cost of treatment.
The most recent data, presented to journalists by Dr. Ashley Brown from Imperial College Healthcare in London during the international congress of liver diseases in Berlin, shows that in clinical practice 95,7% of patients responded to entecavir treatment after four years of treatment. previously untreated patients.
February 28 this year. The European Commission has approved a new indication for this drug – for the treatment of adult patients with the so-called hepatic decompensation, i.e. clinical symptoms of liver cirrhosis. When administered at the stage of cirrhosis, its symptoms disappear and it improves the histology of the liver tissue.
Text: Mariola Marklowska-Dzierżak