February 24, 2012

Prospect of ‘personalised’ anti-viral therapy

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February 24, 2012 By Gary Culliton

In his latest Clinical Update, Gary Culliton looks at recent developments in the treatment of the hepatitis C virus and advances made possible by new protease inhibitor therapies.

Hepatitis C virus infection is a disease that will be “cracked” in the long term, believes Dr Stephen Stewart, Consultant Hepatologist at the Centre for Liver Disease at Dublin’s Mater Hospital. “It’s perfectly reasonable to expect that hepatitis C will be eradicated in 10 years’ time,” Dr Stewart said.

Though hard-to-treat patients continue to pose a challenge, a new era of personalised anti-viral therapy is coming. Non-interferon based drugs are now having very high sustained virological responses. Among the questions that will be asked are whether the patient has symptoms from hepatitis C, is it causing harm (will the patient die of something else before the virus ever causes harm) and what is the likely response to treatment.

The difficult-to-treat genotype has been genotype 1 HCV. With pegylated interferon and ribavirin, ‘cure’ rates of 50 per cent were being achieved. Guidelines can predict a likelihood of response to standard therapy and indicate when triple therapy might be used.

Certain things will determine likelihood of response to pegylated interferon. These include the height of the viral load, the degree of scarring in the liver, the age of the patient and the virus genotype. The Liver Centre in the Mater seeks to identify a polymorphism in the IL 28b gene, which very strongly determines response to interferon.

There are a variety of different tests.

Pegylated interferon and ribavirin have been the standard of care until very recently. This therapy stimulates the immune system to help clear hepatitis C. Interferon stimulates a variety of different genes to produce antiviral compounds and to boost the host immune response against the virus. The aim is to prompt the body to produce its own compounds. There are approximately 500 genes that are switched on by interferon. Not all of them are fully understood. These would help the patient to fight hepatitis C. People with very advanced disease cannot easily be treated as there is conflict in the liver in patients on interferon, between the host and the virus.

Sustained virologic response (SVR) is the target. SVR has been dramatically improved in treatment-naïve and re-treated patients, Dr Stewart said.

Up to now, genotype 1 HCV patients who failed on pegylated interferon and ribavirin would not have continued with the therapy. Trials have been conducted on boceprevir and telaprevir.

Four particularly difficult-to-treat patients at the Mater have received telaprevir under a named patient programme. In two Phase III studies, the addition of boceprevir to peginterferon alfa-2b and ribavirin (PR) significantly improved sustained virologic response (SVR). A recent study (Bruce R Bacon et al, NEJM 2011) found that the addition of boceprevir to peginterferon–ribavirin resulted in significantly higher rates of sustained virologic response in previously-treated patients with chronic HCV genotype 1 infection, as compared with peginterferon–ribavirin alone.

The HCV RESPOND-2 and HCV SPRINT-2 studies each evaluated two treatment strategies to potentially shorten overall treatment duration compared to the use of PR alone for 48 weeks, which is the current standard duration of therapy. These protease inhibitors are directly-acting antiviral agents.

The virus is prevented from breaking into its components and reorganising into the complete viral article. These agents act on the virus, rather than the host. Triple therapy — including these agents with pegylated interferon and ribavirin — increases average response from about 50 per cent to around 80 per cent in treatment-naïve patients. These are also effective agents in people who have been treated with pegylated interferon and ribavirin and who have failed therapy. Given a choice between a year on interferon involving a likely response of 50 per cent or six months on interferon with boceprevir or telaprevir involving an 80 per cent chance of cure, few hepatologists would argue against triple therapy on clinical grounds, Dr Stewart said.

There will be a debate about the cost and to whom the therapy should be given, however. Patients will go through the full course of treatment if the end result is that they are hepatitis C negative, Dr Stewart said. The “number one aim” is to increase the percentage of patients who are cured, he said. Secondary aims would include reducing the period of treatment.

The body produces interferon when faced with viral infections. Treatment with it can be accompanied by flu-like symptoms, which can be severe in some cases. Interferon treatment can cost €50,000 per year.

Guidance on when and whether there will be reimbursement is awaited. Some hepatitis C cases are mild: these patients may never die of hepatitis C and it may be judged more cost-effective not to treat it.

Internationally, researchers are trying to develop algorithms that help to determine the likelihood of a good response with standard therapy.

Efforts to prevent the HCV from ‘subverting the immune system’

One of the problems with treatment of hepatitis C is that some of the viral genotypes are easier to treat than others. “Patients with genotype 1 HCV are generally less receptive to interferon treatment than genotype 2 or 3 HCV,” said Dr Aideen Long of the Institute of Molecular Medicine at St James’s Hospital in Dublin.

Hepatitis C therapy is principally confined to ribavirin and interferon. The virus is able to block the body’s own mechanism for making interferon itself. The virus has a protease that can interfere with the pathway that leads to the production of endogenous interferon. Protease inhibitors are emerging that target the virus’s protease.

There are a number of ways in which the virus can nullify the immune system. Dr Long’s group found that the hepatitis C virus has a way of targeting the adaptive or T cell part of the immune system. “We’ve found the virus stops T cells from the IL2 cytokine — effectively the T cell growth factor,” said Dr Long. This is important in driving proliferation of T cells. The ‘envelope protein’ of the virus binds to the T cell, causing an enzyme called protein kinase C beta to be sequestered in a part of the cell where it cannot work. It is thus not able to regulate the secretion of IL2 — for which it is required. The secretory pathway is blocked.

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Dr Long’s group is attempting to indentify the signal that is delivered into the cell when the virus binds CD 81, a putative receptor for the hepatitis C virus

Dr Long’s group is attempting to indentify the signal that is delivered into the cell when the virus binds CD 81, a putative receptor for the hepatitis C virus. The key will be to discover how the signal the virus is delivering is getting into the cell — making the protein kinase C beta.

If this mechanism can be worked out, it can be blocked. Methods to block the interaction of the virus with CD81 are also being considered.

The hepatitis C virus is subverting the body’s own immune system. If this mechanism can be blocked, the body’s immune system can work.

Studying pathogen mechanisms for new therapies

By establishing the mechanisms that allow pathogens to evade the immune system, new targets for therapy can be devised, said Prof Cliona O’Farrelly, Professor of Comparative Immunology in the School of Biochemistry and Immunology at TCD.

Initial hepatitis C infection is asymptomatic or mild in over 90 per cent of cases. Most studies have shown that 60-85 per cent of hepatitis C-infected people develop chronic infection. A proportion of people with chronic infection develop progressive liver fibrosis, which may lead to cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC).

Hepatitis C is transmitted primarily through exposure to contaminated blood or blood products, most commonly through contaminated needles and syringes. With the advent of routine blood screening for hepatitis C antibodies, transfusion-related hepatitis C has almost disappeared. At present, injecting drug use is the most common risk factor.

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Recent research suggests that between 20,000 and 50,000 people in the country have the hepatitis C virus — a hidden iceberg of eventual liver disease and health problems

Recent research suggests that between 20,000 and 50,000 people in the country have the hepatitis C virus — a hidden iceberg of eventual liver disease and health problems. Even if only a proportion of these develop malignancy, liver failure and need transplantation, it will still be a significant number and have a major impact on the health service. However progress is being made across the research world, including at the Trinity Biomedical Sciences building, where research centres on immunology and pathogen evasion of the immune response.

The protease inhibitors telaprevir and boceprevir work best when given with ribavirin and alpha interferon, as a triple therapy. There have been five big studies. The protease inhibitors increase the response to ribavirin and alpha interferon up to perhaps 80 per cent. “There is huge excitement in the whole hepatology and HCV world,” Dr O’Farrelly said. “It’s the first really serious breakthrough since the virus was described back in 1987.”

Some 20 per cent of people still do not respond to therapy. A proportion of patients with chronic HCV infection will go on to develop severe liver disease. A small number develop malignancies and some will require transplantation.

Putting a patient on treatment, if their disease is going to be mild, is not ideal. A significant proportion of patients have relatively mild symptoms. The IL 28 SNP does identify chronicity; it does not identify the subgroup of chronic patients who will progress quickly.

Interferon stimulates the immune system and activates immune genes. It used to be thought that ribavirin worked by blocking HCV replication. This is not the case. It is in fact a nucleotide analogue. Dr O’Farrelly’s group at St James’s has recently produced a paper showing that ribavirin amplifies the alpha interferon response and increases its effect.

There are problems with combined ribavirin and interferon therapy. It is expensive and is associated with significant side-effects. Not everybody gets the same side-effects and there is no way of predicting which people will get the side-effects.

There are six different genotypes of HCV. Genotype 1 HCV is among the most common in Ireland. About 50 per cent of people with this genotype do not respond. This is probably because of the mechanism by which the virus evades the alpha interferon response.

There are additional side-effects with telaprevir. Treatment for anaemia might have to be considered.

Quite a few people die with hepatitis C, rather than of it. They might not need the triple therapy. “It must be really awful to go for treatment, fail the treatment and then find you didn’t need it,” said Dr O’Farrelly.

Her group is looking for predictive biomarkers and algorithms for patients who will respond. Collaborations are in progress with a number of hepatologists. A large study is now being assembled of patients who have been treated and who are going on treatment in Ireland.
Publication within 12 months is expected.

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