BY ED SUSMAN
WASHINGTON, DC – More than 10,000 doctors and allied health care professionals gathered here to learn about new advances – especially in the treatment of Hepatitis C Virus — at the 64th meeting of the American Association for the Study of Liver Diseases.
An investigational three drug oral combination that avoids the use of both interferon and ribavirin – two treatments associated with intolerable side effects in many people – appears to allow a high percentage of hepatitis C virus infected patients to achieve a sustained virologic response.
The 12-week sustained virologic response – akin to remission from the infection – was reached by 92.2 percent of patients treated with daclatasvir plus asunaprevir and a 75 mg twice daily dose of BMS-791325, a new nonnucleoside agent, said Gregory Everson, MD, professor of medicine at the University of Colorado Anschutz Medical Campus, Aurora.
He also said that a 12-week sustained virologic response was achieved by 91.7 percent of patients on the regimen that used a 150 mg twice daily dose of BMS- 791325.
In his late-breaker oral presentation, Dr. Everson said the efficacy of the treatment was observed in cirrhotic patients and in non-cirrhotic patients; in patients with Genotype 1a and in Genotype 1b and in patients with favorable and unfavorable genetics.
“This was a well-tolerated regimen with low rates of adverse events and treatment discontinuation, regardless of the dose of BMS-791325,” he said. There were three serious adverse events – one among the 80 patients on the low dose regimen; two among the 86 patients on the high dose, he said.
The treatment course was 12 weeks, followed by a 12 week observation period to determine if a sustained virologic response had been achieved.
In the Phase 2b trial, researchers enrolled treatment naïve patients, stratified by genotype 1a of genotype 1b and by presence of biopsy confirmed cirrhosis. About10 percent of cirrhotics were assigned to each group. The primary endpoint was sustained virologic response at 12 weeks by achieving the lower limit of assay quantification.
“The results in this trial look promising,” said Michael Fried, MD, director of the University of North Carolina Liver Center, Chapel Hill. “But this was a Phase 2b trial. We have to see what happens in the Phase 3 studies.”
In the study, researchers enrolled a predominantly male cohort (67 percent) who had a median age of 54 years. About 83 percent of the cohort was white; black or African Americans accounted for 16 percent of the group. About 82 percent of the patients were infected with hepatitis C virus genotype 1a. About 9 percent of the patients – 15 individuals – were diagnosed with cirrhosis.
In another study, researchers said that combination therapy to treat patients co-infected with HIV and Hepatitis C Virus can achieve a high percentage of virological end-of-treatment response to the hepatitis infection without aff ecting control of the HIV, the virus that causes AIDS.
At 48 weeks, 83 percent of patients had a sustained response to hepatitis infection with the combination of telaprevir plus pegylated interferon and ribavirin, and maintained suppression of HIV to less than 50 copies/ml, said Laurent Cotte, MD, coordinator of the study for the French National Agency for Research (ANRS), and a physician at Centre Hospitalier Universitaire de Lyon.
Dr. Cotte said more than half the patients with HIV in France are co-infected with Hepatitis C Virus making this population of patients difficult to treat.
“Despite a high discontinuation rate related to toxicity (20.3 percent), a very high virological response rate was achieved at Week 48 with the combination therapy in patients who were already experienced with pegylatedribavirin HIV co-infected patients,” Dr. Cotte said at his poster presentation.
The researchers began dosing a cohort of 69 patients. He said 8 patients discontinued treatment before 16 weeks due to adverse events; 10 patients discontinued between 16 weeks and the end of the study. At Week 16, 88 percent of the patients in the intention-to-treat analysis had achieved a virologic response to the telaprevir-based combination. By the end of the study, 83 percent of the intention-to-treat population had maintained that virological response, he said. Dr. Cotte noted that the patients are being followed to determine if they can sustain that response and, in effect, cure the patient of the hepatitis C infection.
All the patients were treated with highly active anti-retroviral therapy and had controlled their HIV to undetectable levels using the 50-copies/ml assay.
Dr. Cotta acknowledged the sweeping advances being made in treatment for Hepatitis C Virus, noting that pegylated interferon and ribavirin may soon be obsolete drugs. “When we started this study, this was the standard of care treatment,” he said. “But even with these newer regimens, this study will be the set point that shows what we will need for this population. It shows that these patients can be treated effectively.”
“We had a very good sustained virological response – 83 percent of the patients achieving that by week 48. We also had significant adverse events, notable anemia, the need for erythropoietin, the need for blood transfusion and reduction in ribavirin dosing. Over the course of 48 weeks, about 70 percent of patients experienced those Grade 3 or Grade 4 events.
Babies fine with tenofovir
Pregnant women being treated for Hepatitis B Virus infections with the nucleotide inhibitor tenofovir appear to avoid mother-to-child transmission of the pathogen to their children. Of the 14 pregnancies followed through to delivery, no birth defects were observed even among the 12 women who took tenofovir throughout the pregnancy – including the first trimester, said Christiane Stern, MD, senior medical scientist for Gilead Sciences, Boulogne, France, who presented the poster on behalf of a consortium of French doctors and hospitals who participated in the VIREAL study.
“In a Hepatitis B Virus real-life cohort, tenofovir treatment during pregnancy was well tolerated, including in patients treated from the first trimester,” Dr. Stern said. “No safety issues were reported for breast-feeding while on tenofovir up to 1 year.” She said five women reported breast-feeding, including three women taking tenofovir.
The researchers from three dozen hospitals in France recruited 441 chronic hepatitis B patients who were treated with tenofovir from June 2008 to April 2010. There were 16 pregnancies in the study cohort, 14 of which there was enough follow-up data for analysis. In 11 of the 14 cases women were on tenofovir throughout the pregnancy; in one case treatment with tenofovir was commenced at four weeks of gestation. The other two cases involved women whose high level of hepatitis B status was discovered late in pregnancy were given tenofovir after 20 weeks and 30 weeks to prevent mother-to-child transmission.
“As clinicians, this is information that we need to tell our patients,” Alexander Lalos, MD, a private practice gastroenterologist and a member of the adjunct faculty of Commonwealth Medical College, Scranton, Penn. “Many women want to know if it is safe to take certain medications while they are pregnant. Now we can say that there is a study which shows that it is safe.”
Dr. Lalos said that preventing mother-to-child transmission of Hepatitis B Virus is crucial in breaking the cycle in which women pass on infection to their children, creating chronic infection which can then be passed on to others. “About 10 percent of mothers with hepatitis B virus infection transmit the virus to their newborns if they are not treated,” he said.
Dr. Stern noted that the all but two of the babies were full term – 37 weeks of greater; One child was born at 34 weeks and one at 35 weeks. There were two Caesarean deliveries. In 11 cases where Apgar scores were recorded, all received scores of 10 at 10 minutes.
“Mother-to-child transmission is one of the main routes of Hepatitis B Virus transmission and the risk of transmission increases if the pregnant women has virus DNA greater than 6-7 log IU/ml at delivery,” she said. “Antiviral therapy given during the last trimester of pregnancy, in association with serovaccination of the newborn, can reduce the risk of mother-to-child transmission. However, tenofovir use from the first trimester had not been well-documented in patients with hepatitis B virus monoinfection.”