Pegylated Interferon (Pegasys) Non-Responders Still Appear to Improve Histology (liver condition) 50% of the Time

Robert Reindollar, from the Carolinas Center for Liver Diseases (Charlotte, NC) reported on a comparison of PEGylated Interferon (40kDa: 40 kilodalton weight) (Pegasys) to Roferon (regular interferon). Data from multiple studies was assembled to examine the relationship between virologic and histologic responses following treatment with either Peg IFN a-2a or regular IFN a-2a in IFN-naÔve  (patients never before treated with interferon) patients. Data from two large Pegasys clinical trials were gathered to examine baseline predictors of histologic improvement in patients without a virologic response. The two trials were multi-national pivotol studies including one study in people with chronic HCV and another in patients with compensated cirrhosis.   

Only patients with paired liver biopsies were included in the study. That is, patients who had biopsies before and after treatment. The total number of patients were 599, and 430 had paired biopsies. Patients were randomized to receive either IFN a-2a 3 MIU three times weekly (n=202) or PEGasys IFN a-2a 180 ug once weekly (n=228). They received 48 weeks of treatment and 24 weeks follow-up after treatment ended. A baseline liver biopsy within 12 months of starting this study, and a biopsy at the end of 24 weeks of follow-up were obtained.

Patients who were excluded because they did not have paired biopsies had an equal amount (41% vs 43%) of cirrhosis or bridging fibrosis as the group with paired biopsies. This was established to show that the study analysis did not leave out sicker patients. Reindollar also said this data shows the high number of patients in this analysis who are difficult to treat because they have advanced fibrosis.

An equal amount of patients with cirrhosis or bridging fibrosis were in both treatment arms, IFN & PEG IFN (39% vs 43%, respectively; non-cirrhotics, 61% vs 57%).

The demographics between the two treatment groups were also the same with regards to: sex, race, age (45 yrs), genotype, baseline HCV-RNA (7.4 million copies/ml), baseline HAI score, and baseline ALT (93 vs 103).

SUSTAINED VIROLOGIC RESPONSE

In non-cirrhotics: 35% (Pegasys) vs 15% (regular interferon)

In cirrhotics or bridging fibrosis: 30% (Pegasys vs 8% (regular interferon)

HISTOLOGIC RESPONSES (improved condition of the liver)

57% (130/228) receivng Pegasys achieved a histologic response

41% (83/202) receiving regular interferon achieved a histologic response

(p=0.001)

In those individuals who achieved a sustained virologic response, the percent achieving a histologic response was about the same regardless of which treatment a person received (79% [19/24] IFN, 83% [62/75] PEG IFN; p=0.76).

Partial Virologic Responders (decrease of 2-log in viral load)

In this group, as well, the percent achieving a histologic response was the same regardless of which treatment group a person was in-- 43% (36/84, IFN), 44% (47/108) PEG IFN; p=1.00.

NON-RESPONDERS

This is the interesting and perhaps most important data. The patients receiving PEG IFN-- 47% (21/45) had a histologic improvement. In the group receiving regular interferon, 30% (28/94) had a histologic improvement; p=0.06.

This suggests that PEG IFN improves histology or the condition of the liver more than regular interferon for persons who do not achieve a good virologic response. It is uncertain if this improved histology will translate into a long-term real clinical benefit and studies are ongoing to examine this. But many doctors believe that this benefit is real and very important for individuals particularly with advanced fibrosis who are in danger of progressing to cirrhosis. For those individuals, maintenance therapy may be crucial in preventing progression of HCV. Although, this is not proven either, studies are ongoing to examine this. Again, doctors use maintenance therapy and believe that it may be helpful for individuals with advanced fibrosis who are at risk of progressing to cirrhosis.

In summary Reindollar said:

About 80% of patients who achieve a sustained virologic response have a histologic response. Perhaps, most importantly, patients without a virologic response (non-responders) more individuals receiving PEG IFN gain a histologic improvement than those receiving regular IFN (47% vs 30%).

You may be asking why individuals receiving PEG IFN achieve a better histologic improvement than individuals receiving regular interferon. It may be because of the additional amount of interferon a person is exposed to with PEG IFN and the fact that interferon levels in the blood are constantly maintained at a high level. When taking regular interferon the blood levels go up and down every time you take a dose. It is thought that interferon has two effects--an antiviral effect and immune-modulatory effect. That is, it reduces viral load and improves the immune response to HCV. It is believed you can improve the immune response to HCV even if you don't improve the viral load. This has not been established but the ongoing studies are examining this. If it is true that an immune response improvement occurs and is beneficial, this can be crucial for individuals who cannot achieve a virologic response, particularly for those with advanced fibrosis who are in danger of progressing to cirrhosis.

Analysis is still ongoing to discover the predictors of a histologic response and Reindollar said results should be available soon.