Arrival of Protease Inhibitors Offers Hepatitis C Patients New Options, New Questions

With the arrival of protease inhibitors for hepatitis C, patients now have more treatment options than ever before. How should physicians advise them on the risks and benefits of these new treatments? Andrew Muir, MD, of Duke University Medical Center in Durham, NC, reviewed the state of the field and offered his own guidelines in a “Hepatology Update” session at The Liver Meeting, the 63^rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

The combination of treatments available now means that “we can cure most of the patients we see,” Muir said. A critical question in planning treatment is whether, and when, to begin with one of the protease inhibitors. According to Muir, the question now is, “Do we treat now or do we wait?”

There are multiple factors that influence the likely response to the two new protease inhibitors, boceprevir and telaprevir. A patient’s race is a principle factor affecting treatment, with African-Americans less likely to respond to treatment with these medications than whites. Nonetheless, Muir noted, the average benefit is still expected to be better in these patients than for no treatment.

Other factors shown in trials to reduce response are presence of fibrosis or cirrhosis, and viral genotype, with genotype 1a being more difficult to treat than 1b.

IL28B genotype is also an important factor. Patients with the CC genotype respond the best, while those with either CT or TT do less well. Patients with the CC genotype are much more likely to be eligible for short-duration therapy, and that often influences their decision to move forward with treatment.

“If you have that early response, you have an excellent chance of being cured. It just doesn't happen to everybody,” said Muir.

For patients who are treatment-experienced, a major predictor of benefit is response to prior therapy. Patients who originally did well but then relapsed are likely to do best, while those with only a partial or null response do worse. Patients who relapse “have a great chance of being cured, even in patients with cirrhosis. This is not true for cirrhotic patients who are partial- or non-responders. In these patients, response to protease inhibitor treatment is very low,” Muir said. “We have to accept the fact that these patients have a very low likelihood of being cured. Patients need to understand that in making decisions.”

The adverse effects of the protease inhibitors must also be considered. Among them, the potential for anemia is significant. “This is one of the key things we have learned in the last few months. We have to think about this as we advise patients,” Muir said.

The clinician should anticipate a 4 to 6 gram per deciliter drop in hemoglobin from baseline, he said. In other words, physicians should “plan for anemia.”

Treatment strategies include a reduction in the ribavirin dose, and adding erythropoietin. From the results of a randomized comparison trial, their efficacy appears to be identical. “They are both reasonable options,” Muir said, but noted that erythropoietin is not approved by the FDA for this indication.

Omitting ribavirin altogether is usually not a good idea, because “you don't want to put them in a position that you have to stop ribavirin,” said Muir. “My first reduction is down to 600 milligrams” of ribavirin, he said, with weekly monitoring until the hemoglobin is stable. “Embrace dose reduction and you can have great response rates.”

Reduction of peginterferon-alpha is also reasonable if the patient is anemic.

Finally, Muir noted that protease inhibitors may have a higher rate of serious adverse events (AEs) outside of clinical trials, according to recent studies, which showed that serious AEs occurred in almost half the patients on telaprevir, and almost 40% of patients on boceprevir, leading to premature discontinuations in about a quarter of patients.

He also pointed out that the patient must be able to take the medications scrupulously every seven to nine hours, and attend regular follow-up visits for monitoring.

For his own patients who do not fit the criteria used in the trials, Muir said that he is more likely to recommend transplantation if they are not responding well to first-line treatment.

“Peginterferon and ribavirin remain the backbone of treatment.” But with the new treatment options, “our conversations with patients are getting longer,” he said.