Four-Drug Therapy Wiped Out Hepatitis C Virus in Most Cases

January 19, 2012

By Gene Emery

NEW YORK (Reuters Health) Jan 18 - Combining the experimental oral drugs asunaprevir and daclatasvir with the established treatment of peginterferon alfa-2a and ribavirin eliminated all traces of hepatitis C virus (HCV) in the blood of every volunteer, even after ribavirin-peginterferon alfa-2a treatment had already failed, in small phase II study released online today by the New England Journal of Medicine.

The ten patients treated with all four drugs all had undetectable viral levels 12 weeks after treatment stopped, and nine still had undetectable levels after 24 and 48 weeks.

Another 11 patients received only asunaprevir and daclatasvir, and four of them had a sustained virologic response at 12 and 24 weeks after treatment.

"This is a watershed moment in the annals of HCV therapy because it shows that a sustained virologic response can be achieved without interferon," Dr. Raymond T. Chung of Massachusetts General Hospital wrote in an editorial in the January 19 issue.

Dr. Anna Lok of the University of Michigan and chief author of the study told Reuters Health that the cure rate for the peginterferon/ribavirin regime is low. "It's only 36%. But considering that these are difficult patients to treat, 36% is not too bad," she said.

All 21 patients in the current study had genotype 1 HCV, the most common in the U.S., and all had failed to respond to peginterferon plus ribavirin (i.e., they had not had at least a 2 log10 decline in HCV RNA after at least 12 weeks of treatment).

The response was far better when the four drugs were used. By the end of treatment, at week 24, all 10 patients in that group had undetectable levels of HVC RNA. Forty-eight weeks after the end of therapy, only one had any trace of the virus, and the amount was too small to quantify, according to the researchers.

About 4.1 million people in the United States and 180 million worldwide are infected by hepatitis C, with its associated risk of cirrhosis and liver cancer.

In the randomized phase II study, where patients knew what treatment they were getting, everyone received 600 mg of asunaprevir twice daily and 60 mg of daclatasvir once daily for 24 weeks. Both are made by Bristol-Myers Squibb, which paid for the trial.

Ten of the 21 also got 180 mcg of Pegasys brand peginterferon alfa-2a each week and Copegus brand ribavirin, where the daily dose was 1,000 mg for those weighing less than 75kg and 1,200 mg for those weighing more. Both are Roche products.

After 24 weeks of therapy, all 10 patients getting the four-drug regimen and five of the 11 patients receiving the non-interferon regimen had no trace of virus in their blood.

The six patients in the non-interferon group who had viral breakthrough during the treatment period all had HCV genotype 1a. Another patient in that group had viral recurrence after treatment ended.

By 24 weeks after treatment ended, the virus had returned in one of the 10 getting all four drugs. But that one person was retested 13 days after recurrence and levels of HCV RNA were undetectable, a phenomenon that was seen in other patients, said Dr. Lok. "Because it was not persistent, we believe 100% actually maintained virus clearance all the way to week 48."

"To be able to get to 90% or 100% is very remarkable," she said. "On the other hand, we all know that a lot of patients can't handle interferon and ribavirin because of the side effects. What we hear from the patients is that they hate interferon. They prefer not to get treatment. Everyone is looking for when can we have an interferon-free regimen."

In the new study, the side effects were similar in the two experimental groups. The three most common were diarrhea, fatigue and headache, reported by 45% to 73% of patients. Six patients had transient elevations of alanine aminotransferase to more than 3 times the upper limit of normal. Side effect rates were complicated by the fact six of the 11 volunteers randomized to receive only daclatasvir and asunaprevir received rescue therapy with interferon and ribavirin after a viral breakthrough.

None of the 21 dropped out because of the side effects.

Dr. Lok said 48 weeks of peginterferon and ribavirin usually costs about $40,000. Adding a protease inhibitor as a third drug costs another $50,000, and new biologicals often go for a comparable amount.

The eventual price of the experimental drugs is not known, assuming they are approved.

Thus, a four-drug regimen would add to the cost, Dr. Lok said, but "if this pans out, it's only 24 weeks of treatment. And if you get a cure once and for all, you don't have to worry about managing the complications of cirrhosis, liver transplant, liver cancer down the road."


N Engl J Med 2012; 366:216-224.


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