Hepatitis C, part three
 Illustration: John Clarkson |
Henry Grahame-Smith surveys the latest treatments
The hepatitis C virus (HCV) is one of the viruses, like HIV, that have the ability to evade the body's defences. This does not always happen; about one in five people clear the virus within six months of infection. But the rest will remain chronically infected.
However, unlike HIV it is possible to treat HCV and achieve what is called a 'sustained response'. This means a normalisation of the liver enzyme ALT - which indicates that the liver is no longer inflamed - and an undetectable viral load that persists for at least six months after stopping treatment.
Doctors are cautious about using this word 'cure'. But essentially, in the vast majority of cases, this is what 'sustained response' means.
However, while cure is possible, it isn't easy. The basis of hepatitis C treatment is a naturally-occurring body chemical called interferon-alfa. The interferons are cytokines 'messenger' chemicals that regulate and stimulate the immune system and can reduce viral replication.
Synthetic forms of interferon-alfa rapidly became established as the cornerstone in the treatment of non-A, non-B hepatitis, as it was known before the hepatitis C virus was discovered in 1989. If you were to take interferon-alfa orally the digestion process would break it down. You need to inject it into the layer of fat under your skin (subcutaneous injection). Interferon-alfa should be injected three times a week, and initially the course of treatment was set at six months.
Hepatitis
C combination therapyDuring this time a drug called ribavirin, which had been shown in 1972 to possess broad antiviral activity against certain other viruses, was also being investigated. It does not need to be injected and comes as capsules to be taken twice a day. However, early studies using ribavirin, taken on its own, to treat HCV failed to demonstrate any direct antiviral effect or a reduction in HCV viral load.
Earlier optimism about the success of HCV treatment was further tempered as it became apparent that the sustained response rates achieved, when using interferon-alfa monotherapy, were modest at best. Some clinical trials were reporting sustained response of up to 20 per cent but in some large trials it was as low as 10 per cent.
The hepatitis C virus replicates very rapidly, doubling in number every 2-3 hours. Interferon-alfa is cleared from the body very quickly, within 6-7 hours. Injecting interferon-alfa three times a week results in long periods when there is not enough of the drug circulating in the blood to maintain the antiviral pressure on the hepatitis C virus. This gives the virus time to recover, a chance to make more of itself and lets the infection persist.
Various strategies were explored to improve the sustained response rate. Doubling the dose of earlier trials, but only taking it for six months, produced no significant improvements in the sustained response rate. Doubling the duration of treatment, however, to twelve months did see significant improvements in the sustained response rate to nearly 40 per cent. Taking the double dose for 12 months provided further sustained response rate improvements.
However, it was generally felt this was not worth the increase in the incidence and the severity of side-effects that resulted. This brought about recommendations that interferon-alfa monotherapy should be continued for 12 months unless there was evidence that the treatment was no longer working.
Since
1995, several clinical trials have investigated other tactics including taking
interferon-alfa and ribavirin as a combination treatment. The ribavirin seems
to somehow help maintain the antiviral effect during the times of low level interferon-alfa
leading to an increase in the overall sustained response rate up to 40 per cent.
Although a larger proportion of people taking the combination treatment, compared
to those taking interferon-alfa monotherapy, were unable to complete the course
of treatment, due to unwanted side-effects, this combination soon became the "gold
standard".
Several factors are now known to affect the likelihood of combination therapy, containing interferon-alfa and ribavirin, successfully achieving a sustained response. Some of these factors relate to the individual who is taking the treatment with the treatment tending to be more effective:
However, the single most useful factor in predicting the effectiveness of combination therapy concerns the characteristics of the HCV in your body.
It is very easy to think and talk about the hepatitis C virus as if only one type exists. However, it is in fact a range of viruses, all similar enough to be called HCV, yet with slight variations in their genetic make-up. The classification scheme most often used divides HCV into six major genotypes, designated by the numbers 1 to 6. Most people with HCV in the UK, Europe and the USA will have genotypes 1, 2 or 3.
The rate of disease progression is roughly the same for all genotypes, but some genotypes respond considerably better to treatment than others. Results from two trials involving 1,744 people show that six months of combination therapy, in those with genotypes 2 and 3, achieved a sustained success rate of 67 per cent. This rate does not increase by extending the duration of treatment by a further six months.
Six months of combination treatment is only able to produce a sustained response rate for 17 per cent of those infected with genotype 1, though after a year of treatment this increases to 28 per cent.
Since infection with other genotypes is relatively rare in the UK, Europe and the US, clinical trial data about their response treatment is limited. And there are conflicting data regarding genotype 4, with some trials suggesting that it is similar to genotype 1 in how it responds to treatment and two others indicating that it is similar to genotypes 2 and 3.
Having a low HCV viral load at the time you start treatment has also been shown to predict a better treatment outcome, particularly in people with genotype 1. The 2001 clinical guidelines on the management of hepatitis C, compiled on behalf of the Royal College of Physicians of London and the British Society of Gastroenterology, suggests 12 months of treatment if you have genotype 1 and a high viral load (over 2 million copies). Only six months of treatment may be needed for those with genotype 2 or 3, irrespective of viral load, and those with genotype 1 and a low viral load.
Your specialist clinician should consider your case individually taking all these factors into consideration along with others issues such as any other health concerns you may have and the nature of any support networks that could help while you are on treatment.
These response rates are still too low. Research continues to develop new strategies and approaches.
It was already known that attaching a long chain of sugar molecules (called a peg) to interferon slows its absorption and decreases its breakdown and clearance from the body. Two pharmaceutical companies have been developing and testing different versions of pegylated interferon alfa, Schering-Plough with PegIntron and Roche with Pegasys.
Three large trials have examined the efficacy of combination therapy containing pegylated interferon and ribavirin in people who had not previously taken any treatment for HCV infection. Overall, the new combination is more effective than the standard interferon-ribavirin combination or 'pegylated' interferon alone. The two new pegylated interferons have not gone head to head in a clinical trial but similar sustained response rates were reported when they were used in combination with ribavirin.
The biggest improvements were seen in the sustained treatment response rates in people with HCV of genotype 1, with all three trials achieving a rate around 45 per cent. Over 75 per cent of people with genotypes 2 and 3 responded. Both versions seem to be just as well tolerated as the standard interferon; between around one in ten patients stopped therapy.
However, it's worth noting that these trials excluded people with very severe liver damage and any other additional conditions.
The two versions of pegylated interferon-alfa have been approved for use in this country and, in October 2003, the National Institute for Clinical Excellence will publish guidance on their best use.
There are many drugs under investigation as possible treatments for chronic hepatitis and at least 30 in clinical trials. Some target the disease in similar ways to interferon-alfa but hope to be more effective or easier to take, including one, in phase 1 trials, that can be taken orally. A couple work in a similar way to ribavirin but seem to potentially cause anaemia (low levels of red blood cells) less often than ribavirin.
Thymosin alfa-1 (trade name Zadaxane), which boosts the immune system, has shown little toxicity and preliminary efficacy against HCV in combination with interferon. A phase three study is evaluating combination therapy for HCV positive people for whom prior treatment failed.
Histamine, which also boosts the immune system, may have a benefit in combination with other HCV drugs and is in a phase three trial combined with pegylated interferon.
There are a number of novel treatment strategies in development, with Boehringer Ingelheim's drug BILN 2061 probably one of the most eagerly anticipated. It is a protease inhibitor, different from those used in HIV, which has shown great therapeutic potential against HCV and has been selected for in-depth clinical evaluation.
Others, such as interleukin-10, IP-501 or interferon gamma-1b, are being investigated as drugs that may potentially slow, prevent or reverse liver damage caused by the virus.
Over the next few years, it could become standard practice to use HCV viral load tests, during the first few weeks of treatment, as predictors of sustained treatments response. This would mean that people unlikely to benefit from treatment would not need to suffer the potential side-effects of treatment for the full six or twelve months.
As clinicians become more experienced in using these therapies it will become easier for people with HCV to make informed treatment choices and their quality of life should improve.
One of the most crucial pieces of learning both doctors and patients have to take on is how to manage the side effects of current treatment. Interferon produces side effects which can vary from unpleasant to unbearable. These include aches, pains, fevers, chills, diarrhoea and, of most significance to many patients, severe depression. A course of therapy may make a major dent in your quality of life for six months or a year.
The trials which have shown the best response rates tend to be ones where the side effects were proactively managed in the shape of concurrent prescriptions for painkillers and/or antidepressants, and significant counselling and social support. As with HIV adherence, support to take treatment is as important as getting information about it.
