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Ribavirin
/ Interferon Recent media reports about new treatments for chronic hepatitis C have sparked a lot of interest in the results of clinical trials on ribavirin/interferon combination therapy. This treatment involves differing doses of the drug interferon or long acting Pegylated interferon along with another drug ribavirin for a more powerful effect on the hepatitis C virus. While this new therapy is of great interest to people with chronic hepatitis C who have never had treatment, it also offers possibilities for those who relapse after interferon therapy. What is ribavirin? Ribavirin is a drug that has activity against some viruses. This type of drug is known as a synthetic guanosine nucleoside analogue. The way it works in hepatitis C is not completely understood. However, research studies show that ribavirin treatment causes liver function tests (blood tests showing liver inflammation and activity) to return to normal in some people. Laboratory examination of liver biopsies also shows improvement in some people’s liver tissue. Taking ribavirin alone is not effective against hepatitis C virus infection in the long term. When ribavirin is used in combination with the drug interferon, researchers have found that about twice as many people as those using interferon alone show a long term clearance of detectable hepatitis C virus from the blood. Some researchers suspect that ribavirin may partially block the virus from reinfecting new cells. What
is interferon? Interferons are a group of small proteins made by the human body in response to viral infections, eg colds, hepatitis. Your body produces different types and amounts of interferon to fight different types of infections. The type of interferon used to treat hepatitis C has been copied from some of the human interferons to produce a chemically synthesised interferon. Interferon therapy is thought to work by stimulating processes within cells which help to slow down the reproduction and growth of the virus. These processes can increase the body's immune response to the virus so that you can fight the infection more effectively. What
is Pegylated interferon? Pegylated Interferon is produced when chemical substances called polyethylene glycol (PEG) are attached to interferon. The PEG attachment to interferon helps the interferon to act in a number of ways. It shields the interferon from the body, so that it slows the rate at which the immune system attacks and breaks down the interferon. In addition, the PEG-interferon molecule is larger. This means it is able to stay in the circulation for longer as it is less likely to leak out into other tissues and it is also filtered and removed by the kidneys at a slower rate. Because of this, Pegylated interferon only needs to be given once a week as a subcutaneous injection (under the skin). This dose provides a consistent concentration of interferon in the blood that is enough to achieve a beneficial result. What
does the current research show?
For those interested in the technical detail, read on... Standard
combination therapy In November 1998 the International Hepatitis Interventional Therapy Group released long-term results from several studies on ribavirin and interferon alfa-2b combination therapy in humans. These studies were particularly important as they were large studies across several centres, some of them international, well designed and conducted in line with current international clinical trial methods. Combination therapy
in people who have relapsed The researchers noted that good sustained responses to the treatment were more likely in people who started the treatment with a lower level of virus in the blood and people with a genotype (strain of the virus) other than genotype 1. 73% of this group achieved a good long-term response. (For more information on genotypes, see the section on Implications for Australians.)
Combination therapy
in people who have never had treatment This study found that 6 months after completing the 12 months of treatment, there was no detectable virus in the blood of 38% of those who had taken interferon and ribavirin. Those people with a genotype other than 1 were just as likely to respond well long term with 6 months’ treatment (69%) as those with 12 months (66%). However, those with genotype 1 were better off with the 12 month course: 28% of these had no detectable virus compared to 16% of those on the 6 month course. Table 1: Rates of treatment response according to treatment group and genotype
Another large international trial studied 832 people with chronic Hepatitis C in Europe, Canada and the US. None of the people in the trial had been treated with interferon or ribavirin before. Overall, this study found that the people most likely to experience an improvement in liver inflammation and to find no detectable virus in their blood 6 months after the end of treatment were those who had taken interferon and ribavirin for 12 months (41%). Five factors were also associated with better results:
Pegylated
interferon In December 2000 researchers published results from a large multi-centre trial where some people were treated with:
More than 60% of the people treated had hepatitis C virus genotype 1. The two groups had quite different results. Table 2 summarises the results six months after treatment finished: Table 2: Rates of Treatment response according to treatment doses
Cirrhosis Table 3 summarises this study's results, showing the percentage of people with cirrhosis who had no detectable Hepatitis C virus in their blood and normal ALT levels six months after completing treatment. Table 3: Rates of Treatment response according to treatment doses
The results of this trial are encouraging for people who have cirrhosis, as until now their treatment options have been limited. The result for the Interferon group is comparable to previous trials. However, the Pegylated Interferon group had a response that was more than three times better than the standard Interferon group.
Ribavirin/Pegylated
interferon combination therapy Roche and Schering Plough, the two pharmaceutical companies producing Pegylated interferon, released preliminary results from small clinical trials at a major conference in November 2000. The results look promising - the overall number of people with undetectable levels of hepatitis C virus at the end of treatment with ribavirin and Pegylated interferon was 60 - 70%. When the larger international studies are completed towards the end of 2001, their results will provide more concrete findings. Implications
for Australians Many of the clinical trials have linked their results to genotypes (strains) of hepatitis C virus. What do these results mean for Australians? The Victorian Infectious Diseases Reference Laboratory studied blood samples from more than 500 different people living in Australia who have hepatitis C and found that the genotype spread was
Genotype 3 was more common in younger people.
Generally, these studies have confirmed that long-term benefits from treatment are more than twice as likely with combination therapy as with interferon alone. The studies have also pointed out that particular treatment strategies might work better for some people with different genotypes (refer to Table 1). For example, the duration of treatment may affect results:
However, with all genotypes, it is important to remember that other factors need to be taken into account. Other studies have shown that factors which may also play a part in the progression of disease and response to treatment are:
One research group has suggested that several factors could be used to determine whether a person continues treatment at week 24:
Currently there is no standard treatment in Victoria. Researchers are still debating how best to treat people using available therapy. There may some differences between the treatment options offered by liver clinics across the state. What
about the side-effects? Ribavirin/interferon combination therapy has been associated with some side-effects. Side-effects vary considerably from person to person and while one person may experience several side-effects intensely, another may have few or only mild reactions. Decisions about treating side-effects are made in consultation with your doctor. Interferon
A few people also experience lowering of blood counts, especially white blood cells and platelets, and thyroid abnormalities. Most of these side-effects are not serious and are reversible once treatment is stopped. Interferon treatment, including Pegylated interferon, is not recommended for people currently experiencing major depression or psychiatric illness as the treatment can make their illness worse. People who have experienced depression in the past will usually be reviewed by a psychiatrist before being considered for treatment. Some people have found that by taking interferon at night, they sleep through the flu-like symptoms. Using paracetamol can also reduce the side-effects. However, some people with liver damage may not be able tolerate paracetamol, so you should always consult your doctor before taking it. Pegylated interferon However, people treated with Pegylated interferon seem to experience less negative effects on their quality of life than people treated with standard interferon. Pegylated interferon is given as an injection once a week. It is also released into the body more slowly than standard interferon. It stays at a relatively steady concentration level throughout the treatment instead of fluctuating in peaks and troughs like standard interferon treatment. This may explain why standard interferon has more of a negative effect on quality of life than Pegylated interferon. When Pegylated interferon concentration levels in the body stay constant, your body has a better chance to adapt to the side effects. The psychological impact of having the injection once a week instead of 3 times a week may also be reduced. Ribavirin
Lifestyle
issues If you are interested in this treatment, you would need to be prepared for its impact on your lifestyle and relationships. Although ribavirin is taken in tablet or capsule form, the combination therapy would also involve giving yourself a small interferon injection into the fat layer of your body (often the abdomen) up to three times per week. This can be painful and cause bruising. You would also need to have built it into your weekly routine. You may need to take time off work to deal with side-effects or to have arranged a more flexible workload with your employer. With the mood altering effects of the therapy, personal relationships may also come under pressure, so it would be valuable to have talked this over with the important people in your life. Are you thinking about having children? Taking ribavirin means that both men and women cannot start a pregnancy during therapy or for six months after therapy. You will need to consider this issue with your partner when you are deciding whether to have the treatment. You may choose to delay the therapy. Talk to your doctor about your options. Thinking through these issues and discussing them with your doctor is an important process when considering treatment. You may also wish to discuss this with a counsellor. Hepatitis
C/HIV co-infection Antiretroviral therapies to treat HIV infection have increased the life expectancy of many people with HIV. They have also highlighted the issues relating to hepatitis C/HIV co-infection.
Co-infected people are now encouraged to discuss their treatment options for hepatitis C with their doctor. Ribavirin/interferon combination therapy for people co-infected with HIV and hepatitis C This is currently under investigation. There are only a few small studies looking at using interferon alone to treat co-infected people. Overall, the likelihood of the co-infected person with a good immune system responding well to treatment seems to be similar to a person infected with hepatitis C only. However, the likelihood of a good response decreases for people with more advanced immune damage due to HIV. Standard ribavirin/interferon
combination therapy Preliminary results have been released from some small European studies on standard ribavirin/interferon combination therapy for co-infected individuals. The studies found that:
Long-term results are not yet available.
Pegylated interferon/ribavirin
combination therapy Drug interactions Viral load Other issues Availability
& Cost Availability and cost of this therapy varies. To be eligible for treatment you need to have had a liver biopsy (except for people with bleeding or clotting disorders) and to have had at least 6 months of abnormal liver function tests (ALT levels). This treatment is now available to people with cirrhosis.
If you still have detectable signs of the virus ('HCV PCR positive; abnormal ALT') after 24 weeks of treatment, your treatment will be stopped as these are signs that the treatment is not working. Contact the Liver Clinic at your hospital to see whether trials are being conducted there or whether this treatment is available there. People under 18 are excluded from trials and special access schemes using ribavirin. There are other factors that may exclude you from treatment, so speak to your liver specialist to see if you are eligible. Most costs of trial medications are covered in clinical trials. Normal pharmacy dispensing fees will still apply. Pegylated interferon For
the future? Combination therapy with interferon and ribavirin is likely to make a significant impact on outcomes of treatment in people with chronic hepatitis C who have not had drug therapy or have relapsed after drug therapy. More than twice as many people as those taking interferon alone are experiencing good responses in the long-term. Moreover, the length of treatment is shortened by half in some cases. Other developments are also likely to shape the future. The results with Pegylated interferon look very encouraging and provide a viable alternative for people who for various reasons may not be able to take ribavirin in combination with interferon. Several large scale studies are also well underway examining the effectiveness of combining ribavirin with Pegylated interferon. Preliminary results appear encouraging. Other areas under investigation include ways to slow or inhibit the development of scarring in the liver, and drugs to slow the reproduction of hepatitis C virus in the liver.The community living and working with hepatitis C is waiting for their final results with anticipation. Prepared by: Jo Mitchell,
Clinical Services Co-ordinator, Suzanne O’Callaghan,
Co-ordinator, Dr Stuart
Roberts, Deputy Director, Review panel: Prof Frank
Dudley, Director of Gastroenterology
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