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New Hepatitis C Treatments Highlighted at Digestive Disease Week

Direct-acting antiviral agents for hepatitis C were a key theme of Digestive Disease Week 2014, taking place this week in Chicago. While the conference covers all aspects of gastroenterology and hepatology, new treatments that can cure more than 90% of chronic hepatitis C patients with few side effects in as little as 8 to 12 weeks are bringing about a revolution in the field.

Meeting attendees also heard other liver disease news, including the latest data on potential complications of hepatitis B and C such as advanced cirrhosis, liver cancer, and liver transplantation. Beyond the liver realm, popular topics this year included irritable bowel disease, celiac disease and gluten intolerance, the influence of gut microbes on overall health, and how gut flora can be altered by diet, drugs, pre- and pro-biotics, and fecal transplants.

Sofosbuvir/Ledipasvir

Many of the oral presentations on new direct-acting antivirals, or DAAs, were reprised from the European Association for the Study of the Liver (EASL) International Liver Congress held last month in London, most of which were already covered by HIVandHepatitis.com.

Here again, Gilead Science's recently FDA-approved nucleotide HCV polymerase inhibitor sofosbuvir (Sovaldi) and AbbVie's forthcoming "3D" combo received the most attention.

Results were presented from Gilead's ION Phase 3 clinical trial program, evaluating sofosbuvir plus the HCV NS5A replication complex inhibitor ledipasvir, which are being developed as a coformulation.

As described in a late-beaker poster presented on Tuesday, ION-1 showed that once-daily sofosbuvir/ledipasvir was highly effective, curing 97% to 99% of previously untreated patients with HCV genotype 1 (including about two-thirds with hard-to-treat subtype 1a). Adding ribavirin or extending treatment did not significantly increase sustained response rates, as there was no room for improvement.

Paul Kwo from Indiana University School of Medicine presented findings from ION-2 in a Sunday morning session entitled "Hepatitis C Treatment: On the Horizon." This study, which tested sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-experienced genotype 1 patients, saw 12-week post-treatment sustained virological response (SVR12) rates of 94% to 99%, again with no added benefit from ribavirin or longer treatment duration. Patients with cirrhosis, however, did seem to do better with 24 rather than 12 weeks (100% vs 82%-86%).

During a plenary session on Monday, Kris Kowdley from Virginia Mason Medical Center presented results from ION-3, which reduced treatment duration to 8 weeks for treatment-naive genotype 1 patients without liver cirrhosis. The cure rate was 94% for sofosbuvir/ledipasvir without ribavirin for 8 weeks -- about equal to the rates for sofosbuvir/ledipasvir dual therapy for 12 weeks or triple therapy for 8 weeks.

Edward Gane from Auckland City Hospital in New Zealand presented findings from ELECTRON-2, which evaluated the sofosbuvir/ledipasvir coformulation in hard-to-treat populations.

Among people with HCV genotype 3, the SVR12 rate was only 65% with sofosbuvir/ledipasvir alone for 12 weeks, but rose to 100% for those who added ribavirin. Among genotype 1 patients previously treated with sofosbuvir-containing regimens (including sofosbuvir/ribavirin dual therapy), retreatment with sofosbuvir/ledipasvir plus ribavirin gave a cure rate of 100%. Finally, for genotype 1 patients with decompensated cirrhosis, the SVR12 rate was just 65% due to a several post-treatment relapses -- but this represents an improvement for a patient population that currently has no good treatment options.

In all these trials sofosbuvir/ledipasvir was generally safe and well-tolerated. Serious adverse events and treatment discontinuations for this reason were rare. The most common side effects were headache, fatigue, insomnia, and nausea, with anemia occurring more often among people who used ribavirin.

AbbVie 3D

Kowdley also presented findings from the Phase 3 SAPPHIRE I trial, which evaluated AbbVie's HCV protease inhibitor ABT-450 boosted with ritonavir, the NS5A inhibitor ombitasvir (ABT-267), the non-nucleoside NS5B polymerase inhibitor dasabuvir (ABT-333), and ribavirin taken for 12 weeks. This study included more than 600 previously untreated people with HCV genotype 1 who did not have liver cirrhosis. Here the overall SVR12 rate was 96%, with similar high rates for those with HCV subtype 1a (95%) and 1b (98%).

Ira Jacobson from Weill Cornell Medical College presented data from SAPPHIRE-II, which looked at the same regimen, again for 12 weeks, for genotype 1 prior non-responders without cirrhosis. Here too, the overall SVR12 rate was 96%. Cure rates were similar for HCV subtypes 1a and 1b, and reached 95% even for prior interferon null responders -- traditionally one of the most difficult groups to treat.

Another late-breaking poster described findings from TURQUOISE-II, which looked at another challenging group, people with compensated cirrhosis, both treatment-naive and prior non-responders. In this largest study to date of a cirrhotic population, nearly 400 participants were treated with the 3D regimen plus ribavirin for either 12 or 24 weeks. SVR12 rates were remarkably consistent with those seen in non-cirrhotics in the SAPPHIRE studies: 92% in the 12-week arm and 96% in the 24-week arm. Cirrhotic prior null responders with HCV subtype 1a treated for 12 weeks had the lowest response rate, at 80%, but this improved to 93% with 24 weeks.

This regimen, too, was generally safe and well-tolerated with few serious adverse events or discontinuations due to adverse events, even among cirrhotic patients. The most frequently reported side effects were fatigue, headache, weakness, insomnia, nausea, and itching.

New results from AbbVie's PEARL-II and PEARL-IV trials -- not presented at the EASL Congress -- are scheduled for the final day of the DDW meeting.

Taken together, these findings indicate that nearly all people with chronic hepatitis C will be able to be successfully treated, even traditionally hard-to-treat groups like people with advanced liver disease and prior null responders. Given such effective and well-tolerated therapies, experts say that many more people should be considered eligible for treatment, but the high cost of the new drugs presents a barrier to widespread access.

5/6/14

References

IM Jacobson, P Marcellin, A Mangia, et al. All Oral Fixed-Dose Combination Sofosbuvir/Ledipasvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Naive Genotype 1 HCV-Infected Patients: the Phase 3 ION-1 Study. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Tu2038.

P Kwo, KR Reddy, PJ Pockros, et al. All Oral Fixed-Dose Combination Sofosbuvir/Ledipasvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCV-Infected Patients: the Phase 3 ION-2 Study. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 236.

K Kowdley, SC Gordon, KR Reddy, et al. Sofosbuvir/Ledipasvir With and Without Ribavirin for 8 Weeks Compared to Sofosbuvir/Ledipasvir for 12 Weeks in Treatment-Naive Non-Cirrhotic Genotype-1 HCV-Infected Patients: the Phase 3 ION-3 Study. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 764.

E Gane, RH Hyland, P Pang, et al. Sofosbuvir/Ledipasvir Fixed Dose Combination Is Safe and Effective in HCV Infected Populations Including Decompensated Patients and Patients With Prior Sofosbuvir Treatment Experience. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 238.

K Kowdley, JJ Feld, E Coakley, et al. SAPPHIRE I: Phase 3 Placebo-Controlled Study of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333, and Ribavirin in 631 Treatment-Naive Adults With Hepatitis C Virus Genotype 1. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 475.

IM Jacobson, S Zeuzem, T Baykal, et al. SAPPHIRE II: Phase 3 Placebo-Controlled Study of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333, and Ribavirin in 394 Treatment-Experienced Adults With Hepatitis C Virus Genotype 1. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 235.

K Kowdley, F Poordad, R Trinh, et al. TURQUOISE-II: SVR12 Rates of 92%-96% in 380 Hepatitis C Virus Genotype 1-Infected Adults With Compensated Cirrhosis Treated With ABT-450/r/ABT-267 and ABT-333 Plus Ribavirin (3D+RBV). Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Tu2039.