From Medscape Medical News
New Antivirals Show Poor Safety in HCV With Cirrhosis
Daniel M. Keller, PhD
May 2, 2012 (Barcelona, Spain) — Two relatively new direct-acting antiviral drugs have poor safety profiles in patients with hepatitis C virus (HCV) and cirrhosis, including a high rate of serious adverse events leading to study discontinuation. However, the efficacy of the drugs is good, as evidenced by high rates of on-treatment virologic responses, Christophe Hézode, MD, from Hôpital Henri Mondor in Créteil, France, reported here at the International Liver Congress 2012.
In phase 3 trials of the 2 drugs — telaprevir and boceprevir — rash, pruritus, and anemia were reported with telaprevir, and anemia and dysgeusia were reported with boceprevir. However, those trials included a relatively small number of patients with cirrhosis. A French compassionate-use program allowed the early use of these 2 protease inhibitors before they were approved for patients with cirrhosis, who were entered into a national multicenter registry to prospectively collect clinical data and biological specimens.
An interim analysis evaluated the safety and efficacy of the drugs in these patients who received at least 16 weeks of antiviral treatment (n = 455). The patients had compensated cirrhosis and had relapsed after previous treatment or were partial responders (defined as having had a decrease in HCV RNA of at least 2 log10 IU/mL at week 12 of therapy).
Telaprevir patients (n = 296) received 12 weeks of telaprevir with pegylated interferon (pegIFN) plus ribavirin and then continued only the pegIFN/ribavirin out to week 48. Boceprevir patients (n = 159) received pgIFN/ribavirin for 48 weeks, during which they also received boceprevir for weeks 4 to 48. Both groups were followed for virologic response after week 48.
The telaprevir and boceprevir groups were similar at baseline; mean age was 57 years, HCV RNA level was 6.5 log10 IU/mL, mean hemoglobin was 14.4 to 14.8 g/dL, mean neutrophil count was 3.2 to 3.3 × 109/mm3, and mean platelet count was 150,000/mm3.
High Serious Adverse Event Rate
"The rate of serious adverse events was high, around 50%, with early discontinuation due to severe adverse events observed in 14% of the patients," Dr. Hézode said.
"The second message is that 6 patients died — 2% of the cohort. The main reasons for these deaths were sepsis and hepatic decompensation" that was probably related to interferon, not telaprevir.
A third safety signal was the "difficult management of anemia," requiring the use of recombinant erythropoietin or transfusions, he explained.
Dr. Hézode said that in the boceprevir group, "the serious adverse event rate was high, around 40%, and early discontinuation due to serious adverse events was observed in 7% of patients." Two patients died from sepsis. Hepatic decompensation occurred in 4.4% of patients. Significant anemia occurred in one third of patients, two thirds required recombinant erythropoietin, and 10.7% received transfusions.
Dr. Hézode presented efficacy data on boceprevir, which was fairly good; 37% achieved undetectable HCV RNA levels at week 8 in an intention-to-treat analysis, rising to 58% at week 12 and 61% at week 16.
He concluded that the safety profile of these 2 direct-acting antiviral drugs in compensated cirrhotic patients is poor, but virologic responses are good. The high rate of serious adverse events (38.4% to 48.6%) was much higher than in phase 3 trials (9% to 14%).
Dr. Hézode recommended that patients with cirrhosis be treated cautiously with telaprevir or boceprevir and that they be monitored carefully, especially in light of the high incidence of anemia and its poor response to erythropoietin administration.
Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University, staff member at Hippokration General Hospital in Athens, Greece, and member of the European Association for the Study of the Liver Governing Board Scientific Committee, told Medscape Medical News that "we were surprised by that high rate of so many serious adverse events, and even deaths, but I believe...they had included many patients with, in fact, contraindications to treatment."
He cited, for example, a low platelet count as a contraindication to interferon. "They went beyond the official indications, beyond the inclusion and exclusion criteria that were present in the phase 3 trials. I believe this is why they had such high rates of serious adverse events," Dr. Papatheodoridis said.
He noted that the number of platelets or neutrophils is a laboratory marker that reflects the severity of liver disease. "These were patients with very advanced liver disease who...should not have been treated with interferons," he said. "If you add the [protease inhibitor], which has more side effects, of course the safety profile will be worse."
Dr. Papatheodoridis said the investigators should do "the easy subanalysis" of patients with and without contraindications or who met or failed to meet prespecified criteria for entry into the trial, which Dr. Hézode said he plans to do.
Although there were no deaths in the telaprevir or boceprevir phase 3 trials, it is now obvious that it is very dangerous to use these drugs in such advanced patients.
"The usual indications are the indications for interferon — the inclusion criteria," Dr. Papatheodoridis said.
"For the new drugs, the only new contraindication might be other drugs that the patients take for other diseases because they might have drug–drug interactions."
Dr. Hézode and Dr. Papatheodoridis have disclosed no relevant financial relationships.
The International Liver Congress 2012: Abstract 8. Presented April 19, 2012.
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