Measuring treatment response
 

Robert Brown MD: The first test that we use in the serum is the liver function panel. Many of these tests are not tests of liver function. We define them as the tests of hepatic inflammation, predominantly the AST and the ALT, and tests of the actual functioning of the liver-the bilirubin, the albumen and the prothrombin time. We monitor those during treatment, but they have not a lot of significance in terms of the efficacy.

To monitor the efficacy of therapy you need direct viral assays. These are either a polymerase chain reaction or PCR, or a branch chain DNA or bDNA technology. These vary based on their performance characteristics, but the distinction is not terribly important.

Rajender Reddy MD: Sustained virologic response is defined as a negative HCV RNA by the most sensitive qualitative HCV RNA assay six months off of therapy. If someone achieves a sustained virologic response, it has been determined and demonstrated that over time these patients are likely to have that sustained virologic response.

Robert Brown MD: The rate of relapse four to five years later, which is the length of follow up we have for most of these studies, seems to be less than 5%. You can also measure response based on normalization of liver enzymes, a so-called biochemical response.

Rajender Reddy MD: Biochemical response is defined as normalization of ALT, or alanine aminotransferase. If it normalizes on treatment, it is called an on-treatment biochemical response. If it is normal at the end of six months of followup, it is defined as a sustained biochemical response. However, I want to emphasize that it is the HCV RNA response that is much more important than a biochemical response.

David Bernstein MD: The sustained viral response rates in patients treated with combination pegylated interferon plus ribavirin in genotype 1 disease have been reported to be 52 to 56%. In those patients infected with genotypes 2 and 3 disease, the sustained viral response rates to pegylated interferon plus ribavirin therapies have been reported to be 76 to 82%.

Rajender Reddy MD: The factors that have been associated with a positive treatment outcome include genotypes other than 1, which is primarily genotype 2 or genotype 3, young individuals do better.

David Bernstein MD: There are some other factors, as well. Patients who have an initial low level of virus are more likely to respond than those who have a high level of virus. Patients that do not have cirrhosis are more likely to respond than those who do have cirrhosis. Men are less likely to respond than women. And those patients that are heavier are less likely to respond to therapy than those that are thinner.

Robert Brown MD: We currently don't know the long-terms effects of having a sustained virologic response. We know that on liver biopsies six months, a year after treatment, liver disease tends to improve or at least stabilize. What we really want to know in the long run is do we have a lower rate of cirrhosis, complications of cirrhosis and hepatocellular carcinoma? There is some anecdotal evidence that this is true but we do not yet have conclusive evidence that we are going to see stabilization of the liver disease for a long time.

When the viral load should be measured is currently controversial. Patients at six months of therapy who still have detectable virus are not going to respond. And a treatment decision needs to be made on whether therapy should be continued.

Recently there's been more interest in viral load measurements earlier than six months. This is the so-called early viral load testing or EVL.

Rajender Reddy MD: Early virologic response is defined as the virologic response seen at week 12 of therapy. The viral load would have to drop by at least two logs or become HCV RNA negative for one to say that the patient has achieved an early virologic response.

Robert Brown MD: Viral load testing at three months which does not show a reduction in the level of virus has been predictive of a lower response rate. Though variability in labs outside of clinical trials, has made some of us question the clinical utility of applying early viral load testing.

I think until we get standardization of laboratories, it is difficult to use early viral load testing as a pure stopping rule. We use early viral load testing in our center to help guide our decision making. So, for example, a patient who is tolerating therapy very poorly and has an early viral load test which is completely flat, we may use that information to make informed decisions with the patient. However, I don't think we're at a point where early viral load testing can become the standard of care for stopping treatment until we have complete standardization of laboratory testing.