There is a growing group of people who have failed to clear the virus after one or more rounds of interferon based treatment. Someone who relapses after treatment (a relapser) is defined as having achieved a sustained virologic response (SVR) during the course of treatment but in whom the virus was again detectable during the three month follow up period. For people who relapse after treatment the variations in dosage and length of interferon based treatments below offer some chance of clearing the virus.
Amongst those people who do not achieve SVR there are two categories and it is important to differentiate between them.
- The first group are nil responders. Those who do not show an appreciable decline in HCV RNA during treatment. These people can be recognised within 12 weeks of starting peg-interferon/ribavirin therapy as they do not achieve a 2 log reduction from the level at the start of treatment after 12 weeks. Continued treatment of these nil responders will not result in further decline in viral load and there is no point in continuing the treatment. It is not clear that any current alterations to dosage or classes of interferon will be helpful to this group.
- The second group are partial responders. These are people who have an early virologic response. Their HCV RNA drops more than 2 logs from the level at the start of treatment within the first 12 weeks, but then slows down or evens out. This group of partial responders have a much better chance of responding and achieving SVR during retreatment.
Many trials do not make this vital distinction between partial and nil responders so the conclusions can be misleading. It is now known that there are a number of factors involved with a decreased chance of clearing the virus.
- A high viral load.
- Older age
- Cirrhosis
- Obesity
- Genotype 1
- Failure to respond to treatment by week 12
- Failure or inability to stick to a prescribed regimen
- HIV co-infection
- Immunosuppressant treatment following liver transplantation
Certainly for people who have not responded to standard interferon therapy there is about a 30% chance of a SVR when they are treated with pegylated interferon and ribavirin. However, for those people who have failed to respond to standard interferon plus ribavirin the rate of SVR is only 10-20%. For people who have not responded to pegylated interferon and ribavirin the options are much more limited.
As pegylated interferon and ribavirin is likely to be the basis for treatment for some years there are numerous trials in progress that are looking at variations in dose, length of treatment, different classes of interferon and alternatives to ribavirin. There is also a trial in progress comparing the different brands of peg-interferon currently available. All the trials are predominantly targeted at non-responders and those who have relapsed. As yet there is no indication of significant increases in efficacy, but many trials are still in progress.
An apparently obvious approach would be to increase the dose of interferon or ribavirin to try to produce a better response. Two factors would appear to support this: 1. the fact that it is not that easy to find the optimal dosing regimen and 2. that the two peginterferons currently licensed use different dosing schemes: weight-based vs a fixed-dose approach. Consequently a number of trials have sought to assess the value of retreatment using higher doses. There have also been trials of extending treatment duration up to 72 weeks. The evidence so far is by no means clear cut, but some of the early results do show higher SVR rates and drop in virus load in some of the trials.
a. Pegylated Inteferon
There are a whole range of trials currently underway in the USA looking at higher doses and longer treatment time for peginterferon/ribavirin. In a trial called the REPEAT trial, patients who had previously failed to respond to peginterferon alfa-2b and ribavirin were retreated with varying doses of peginterferon alfa-2a. Peginterferon was administered at 180mg/week or at 360mg/week along with ribavirin 1000-1200 mg/day. Some people were treated for 48 weeks, some for 72 weeks. In the high dose group, 42% of patients were HCV RNA undetectable at week 12 compared with 25% of patients treated with the standard dose. It remains to be seen whether or not these patients will go on and eventually achieve SVR with 48 or 72 weeks of treatment as the study continues.
In an extensive high dose treatment trial across 100 academic and community sites throughout the USA called the RENEW trial results showed increases in SVR but the rates were only 17% for those on 3.0 kg dose of peg-interferon compared to 12% with those on standard 1.5 kg dose.
Prolonging therapy past the standard 48 weeks is another strategy for treating non-responders. One study from Spain has examined the use of measuring viral loads at 4 weeks of treatment to determine whether prolonged therapy might improve the sustained virologic response. In this study, all patients in whom the virus was still detectable after four weeks were split into two random groups to receive either 48 or 72 weeks of treatment, since they were shown not to be early responders. The results showed that 46% of the 72-week group and 32% of the 48-week group attained an SVR. This was considered a significant difference.
b. Ribavirin with Erythropoietin (Epoetin)
Anaemia is the most problematic side effect of ribavirin. It can often lead to the need to reduce the dose or abandon treatment with ribavirin altogether. The use of the drug epoetin in conjunction with peg-interferon and high doses of ribavirin has been shown to reduce anaemia and the need for ribavirin dose reductions, which in turn leads to higher SVRs. In a study evaluating high dose ribavirin with epoetin it was found that patients who received high dose ribavirin had a significant increase in SVR over those receiving the standard dose, from 34% to 49%. This increase in SVR was the result of a marked reduction in the incidence of relapse, dropping from about 36% to 9%.
Recent studies have also indicated that high doses of ribavirin with epoetin increases SVR in people with genotype 1.
