Monday, March 31, 2014

Advances in the Treatment of Hepatitis C

Advances in the Treatment of Hepatitis C as seen at CROI 2014

March 28, 2014
By Mariel Selbovitz

The opening day of the 21st Conference on Rtroviruses and Opportuistic Infections (CROI 2014) featured a press conference on advances in the treatment of hepatitis C, with a focus on how new drugs may be used in the real world, given barriers such as high cost and a shortage of experienced medical providers.

As new Hepatitis C drugs are approved, more clinical trial options become available and interferon-free regimens near FDA approval, Hepatitis C treatment is changing rapidly. Several presentations at CROI 2014 focused on what has become the ever-evolving face of Hepatitis C treatment.

Anita Kohli presented data from the first three arms of the eight arm SYNERGY study1. The objective of the SYNERGY study is to use multiple drugs to target various stages of the HCV life cycle with the goal of shortening the duration of therapy.

Twenty treatment-naive patients were enrolled in each of the study arms for a total of 60 study participants. Four different drugs were used (2 as a co-formulated fixed dose tablet) to target different stages of the Hepatitis C life cycle.

Sofosbuvir is a nucleotide NS5B polymerase inhibitor and Ledipasvir is an NS5A inhibitor, both of which were used in all three arms as a fixed dose tablet. In the first arm, this regimen was given for 12 weeks. In the second arm, GS-9669, a non-nucleoside NS5B polymerase inhibitor (which works at a different site in the NS5B region than Sofosbuvir), was added. The third arm consisted of Sofosbuvir/Ledipasvir and GS-9451. GS-9451 is a protease NS3/4 inhibitor.

The study population reflected what researchers felt was an accurate representation of the HCV patient population in the U.S. and was a difficult to treat cohort. Across the three arms of the trial the average age of participants were 54- 57; 65- 80% were male, 80-95% were black, 55- 85% had Genotype 1a and 15-45% had genotype 1b. 75-90% maintained an unfavorable Il-28B genotype of CC or TT, 65- 75% had a viral load of greater than 800, 000 IU/mL and 25-40% had stage 3 or 4 liver disease.

Study results showed that 59 of the 60 patients across all 3 arms achieved SVR 12, and that 39 of the 40 patients in the two 6 week arms achieved SVR 12 after 6 weeks of therapy.

In the Sofosbuvir/Ledipasvir group all patients were virally suppressed below the level of quantification by week 4 and remained suppressed at SVR12. In the Sofosbuvir/Ledipasvir and GS-9669 group all patients were virally suppressed by week 4 and remained suppressed at end of treatment. One African American male with stage 3 liver disease, a high viral load and genotype 1a relapsed at week 4. All other patients achieved SVR12 in this arm. In the Sofosbuvir/Ledipasvir and GS-9451 arm, all patients were virally suppressed at week 4 and remained suppressed at SVR12.

Blood draws were taken over the initial 36 hours following the first medication dose on a subset of patients (n=29). Viral kinetic analysis was performed to determine if the addition of a third agent could enhance viral clearance of HCV and to develop a future model of treatment with combination regimens that could possibly shorten therapy even further.

Researchers found the 3 drug regimen of Sofosbuvir/Ledipasvir and GS-9451 led to a significantly faster decline of virus than the other 2 regimens, at day 7, day 14 and day 21.

Rapid normalization was seen of ALT and AST across all arms with 90-100% normalization by day 14.

No deaths or discontinuations occurred. All regimens were well tolerated. The highest percentages of adverse events were headache, which was seen in 25% of the Sofosbuvir/Ledipasvir group and 25% of the Sofosbuvir/Ledipasvir and GS-9669 group, and diarrhea at 5% in the Sofosbuvir/Ledipasvir group, 25% in the Sofosbuvir/Ledipasvir and GS-9669 group and 15% in the Sofosbuvir/Ledipasvir and GS-9451 group. Two grade 3 adverse events occurred but were not related to study drugs. One was site pain from a liver biopsy and the second was vertigo in a patient with a history of severe vertigo reported at baseline.

There were 11 grade 3 laboratory abnormalities in 9 patients:
In the Sofosbuvir/Ledipasvir arm there was one case each of elevated ALT, elevated AST, elevated LDL, hyperglycemia and hypoglycemia
In the Sofosbuvir/Ledipasvir and GS-9669 arm, 2 patients experienced a-symptomatic Hypophosphatemia
In the Sofosbuvir/Ledipasvir and GS-9451 one patient who had a history of anemia experienced decreased hemoglobin and three patients experienced elevated serum creatine but 2 had been elevated at baseline and the third developed renal insufficience after initiating 1600 mg/daily ibuprofen; all three returned to normal.

While most clinical trials of next-generation hepatitis C drugs are sponsored by pharmaceutical companies, the National Institutes of Allergy and Infectious Diseases (NIAID) is conducting parallel studies in underserved populations, looking for simple, well-tolerated treatments for people prone to difficulties with poor adherence and side effects. In the NIAID SYNERGY study, Anita Kohlifrom the National Institutes of Health and colleagues evaluated brief interferon- and ribavirin-free oral DAA regimens using a fixed-dose coformulation of Gilead Science’s recently approved HCV polymerase inhibitor sofosbuvir (Sovaldi, formerly GS-7977) and NS5A inhibitor ledipasvir (formerly GS-5885).

The SYNERGY studied found overall that 6 weeks of treatment with 3 Hepatitis C drugs that targeted different steps of the Hepatitis C viral life cycle was safe and efficacious, had a very high rate of viral clearance and offered a shorter course of treatment with fewer side effects then the currently available treatment.

Several new drugs and drug combinations are proving to be safe and efficacious for use in HCV patients. Trevor Hawkins of Southwest CARE Center in Sante Fe, New Mexico presented data on all-oral combination Daclatasvir, Asunaprevir and BMS-791325 for the treatment of HCV Genotype 12.

Daclatasvir (DCV) is a once- daily NS5A replication complex inhibitor that has been studied in over 5,500 patients and has been found to have a potent pan-genotypic activity in vitro. Asunaprevir (ASV) is a twice-daily, NS3 protease inhibitor that has been studied in over 2,000 patients and is active against genotypes 1,4,5, and 6 in vitro. BMS-791325 is a twice-daily, non-nucleoside NS5B polymerase inhibitor that is active against genotypes 1,3,4,5 and 6 in vitro. Various dose and drug-to-drug interactions have been seen with all three drugs.

A1443-014 is a randomized, phase IIb, 2 arm, 166 patient, open label study where patients received study drug for 12 weeks with follow-up to SVR 48. Patients were stratified by genotype 1a or 1b and whether or not they had biopsy-confirmed cirrhosis, receiving either DCV 30 mg BID +ASV 200 mg BID + BMS-791325 75 mg BID or DCV 30 mg BID+ ASV 200 mg BID+ BMS-791325 150 mg BID.

Researchers felt the study participant demographics were common for HCV clinical trials with an average 67% of the two arms being male; average age was 54, 83% were white and 16% African American. 82% had genotype 1a and 18% had genotype 1b and 38% had either FIB-3 or FIB-4 as determined by FibroSure/FibroTest. Those with FIB-4 received biopsies and an average 9% of the two arms had cirrhosis. Two/thirds were non-CC.

Study results found 92% of study participants achieved SVR. All treatment failures occurred in Genotype 1a. There were no predictors of failure other than Genotype.

In the DCV+ASV+BMS-791325 75 mg arm, 71/77 achieved SVR-12. The most frequent adverse events in this group were headache at 21.3%, diarrhea at 15%, fatigue at 15% and nausea at 12.5%. Grade 3/4 lab abnormalities included high AST in 1 patient and high glucose fasting serum in 1 patient.

In the DCV+ASV+ BMS-791325 150mg., 77/84 patients achieved SVR-12. In this arm the most frequent adverse events were headache in 27.9%, diarrhea in 15.1% and fatigue and nausea in 8.7% each. Grade 3/4 lab abnormalities included high glucose fasting serum in 1 patient and high bilirubin in 1 patient. There was 1 discontinuation due to adverse events and one patient discontinued BMS-791325 only and added peg/IFNa/RBV for 12 weeks.

Both regimens were found to be safe and effective and researchers recommend the continuation of clinical trials into Phase III trials.

Vincent LoRe from the University of Pennsylvania reported on a multi-site Veterans Administration (VA) study3, which analyzed predicting risk of end-stage liver disease (ESLD) in HIV/HCV co-infected patients for individualized HCV therapy decisions. The study evaluated the efficacy of utilizing laboratory and clinical variables to predict end-stage liver disease in HIV/HCV patients.

Researchers utilized data from the Veterans Aging Cohort Study (VACS) to identify 4,280 co-infected patients in the VA, all of who had been on HIV antiretroviral therapy for at least one year. Data was gathered of baseline predictors that included diabetes, Hepatitis B, race, obesity, a viral load greater than 400 c/mL, CD4 count below 200 cells/mm3 and a class 4 Fibrosis rating, from the initial year on therapy.

Study participants were followed for a total of 6.8 years where researchers found 8% of patients had developed ESLD as defined by hepatic liver decomposition, hepatocellular carcinoma or liver-related death.

Researchers discovered that utilizing Fibrosis 4 rating may be an effective means of means of predicting ESLD over time and could help to inform HCV treatment decisions. Additional predictors that were measured with FIB-4 were insufficient in adding greater predictability. Ongoing analysis continues for additional predictors.

Combination Oral, Hepatitis C Antiviral Therapy for 6 or 12 Weeks: Results from the SYNERGY Trial A Kohil et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection GT Everson et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014
Predicting Risk of ESLD in HIV/HCV Patients for Individualized HCV Therapy Decisions V Lo Re et al. Conference on Retroviruses and Opportunistic Infection, Boston, MA , March 3-6, 2014

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