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AASLD 2014: AbbVie 3D Cures Recurrent HCV in Most Liver Transplant Recipients Without Cirrhosis

AbbVie's 3D regimen (newly named Viekirax + Exviera) demonstrated a sustained virological response rate of 97% for people with HCV genotype 1 recurrence after liver transplantation who had not yet developed advanced liver fibrosis or cirrhosis, according to results from the CORAL-I study presented at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting this month in Boston and published in the November 11 advance edition of the New England Journal of Medicine.

Hepatitis C virus (HCV) almost always re-infects the new liver after transplantation, often resulting in rapid progression to severe fibrosis or cirrhosis and potential graft loss. Liver transplant recipients have historically been difficult to treat because they do not respond as well to interferon-based therapy and many cannot tolerate its side effects or effects on immunosuppressant drugs used to prevent organ rejection. But now, new direct-acting antiviral agents (DAAs) can be combined in interferon-free regimens that produce high cure rates and are very well-tolerated.

Parvez Mantry from the Liver Institute at Methodist Dallas presented findings from CORAL-I (M12-999), an ongoing Phase 2 trial evaluating AbbVie's all-oral 3D regimen in liver transplant recipients with recurrent HCV genotype 1 infection and mild-to-moderate liver fibrosis.

The 3D regimen consists of the HCV protease inhibitor paritaprevir (ABT-450), NS5A inhibitor ombitasvir (ABT-267) and a ritonavir booster in a once-daily coformulation, taken with the twice-daily non-nucleoside HCV polymerase inhibitor dasabuvir (ABT-333).

This study included 34 participants. About 80% were men and the mean age was 60 years. Most (85%) had harder to treat HCV subtype 1a, the rest 1b. Three-quarters had unfavorable IL28B gene variants. Liver biopsies showed that 18% had no fibrosis (Metavir stage F0), 38% had mild fibrosis (stage F1), and 44% had moderate fibrosis (stage F2). The median time between transplantation and treatment was 40 months. None had received treatment since transplantation, but some had previously been treated with pegylated interferon/ribavirin.

All patients in this open-label study received the 3D regimen plus ribavirin for 24 weeks. Ribavirin dosing was managed by study investigator based on tolerability. A prior drug-drug interaction study showed that combining the 3D regimen with immunosuppressants led to increased levels of tacrolimus (by 7-fold) and cyclosporine (by 3-fold), so their doses were adjusted accordingly.

Results

• At 12 and 24 weeks post-treatment, 97% of participants achieved sustained virological response (SVR12 and SVR24), or continued undetectable HCV viral load.
• The 1 patient without SVR experienced early viral relapse 3 days after finishing treatment; testing at that time revealed emergent resistance-associated variants not present at baseline.
• Treatment was generally safe and well-tolerated.
• 2 patients had serious adverse events and 1 person discontinued early due to adverse events but still went on to achieve SVR12.
• The most frequently reported side-effects were fatigue (50%), headache (44%), cough (32%), anemia (29%), diarrhea (27%), insomnia (27%), weakness (24%), and nausea (24%).
• Most anemia was mild to moderate and no one stopped treatment for this reason, though 5 patients received erythropoietin; everyone who reduced their ribavirin doses went on to achieve SVR.
• 2 people had grade 3/4 bilirubin elevations, consistent with paritaprevir's known effect on bilirubin transporter proteins.
• There were no episodes of acute or chronic rejection, no graft loss, and no deaths.
• Tacrolimus and cyclosporine concentrations remained generally stable while taking the 3D regimen.

"This multi-targeted, interferon-free regimen of ABT-450/ritonavir/ombitasvir, dasabuvir, and ribavirin achieved high response rates in immunosuppressed liver transplant recipients with recurrent HCV genotype 1 infection," the investigators concluded. "This phase 2 study in liver transplant recipients with mild to moderate liver disease shows that antiviral therapy may offer clinical benefit before the acceleration of fibrosis to advanced liver disease and its associated complications in this patient population."

Session moderator Anna Lok said that these results are "very impressive," but raise the question of whether the addition of ribavirin and such a long treatment duration are needed for patients with early fibrosis, given that the 3D regimen taken for 12 weeks has shown similar high SVR12 rates in non-transplant studies.

Mantry noted that the study protocol is now being amended to include patients with more advanced fibrosis and cirrhosis, and will also test the 3D regimen without ribavirin for transplant recipients with early HCV recurrence.

"Recurrence of HCV infection in the new graft post-liver transplantation is universal in those that have the virus prior to transplantation, and can be associated with an aggressive disease course," explained Dr. Paul Kwo, medical director of liver transplantation and professor of medicine, Indiana University School of Medicine in an AbbVie press release. "The high SVR rates seen in CORAL-I are promising and offer valuable information as we continue to assess this regimen within this specific patient population."

"Recurrent hepatitis C post liver transplantation has historically been difficult to treat, and we have considered post-liver-transplant patients a special population in need of new treatment strategies," stated co-investigator Paul Kwo in an Indiana University press release announcing the findings. "What this study showed is that this special population is no longer special. We can treat them as successfully as if they haven’t had a liver transplant with drugs that are well tolerated and without risk of rejection."

11/25/14

References

PS Mantry, PY Kwo, E Coakley, et al. High Sustained Virologic Response Rates in Liver Transplant Recipients With Recurrent HCV Genotype 1 Infection Receiving ABT-450/r/Ombitasvir+Dasabuvir Plus Ribavirin. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract198.

PY Kwo, PS Mantry, E Coakley, et al An Interferon-free Antiviral Regimen for HCV after Liver Transplantation. New England Journal of Medicine. November 11, 2014 (Epub ahead of print).

Other Sources

AbbVie. AbbVie to Present Results from Studies in Chronic Hepatitis C patients with HIV-1 Co-infection (TURQUOISE-I) and Liver Transplant Recipients (CORAL-I) at The Liver Meeting 2014. Press release. November 11, 2014.

Indiana University. IU Researcher Publishes 'Landmark' Results for Curing Hepatitis C in Liver Transplant patients. Press release. November 11, 2014.