- Category: Experimental HCV Drugs
- Published on Friday, 08 November 2013 00:00
- Written by Liz Highleyman
An interferon-free combination of sofosbuvir plus ribavirin administered before liver transplantation prevented hepatitis C recurrence in nearly two-thirds of patients, while the same regimen led to early viral clearance in three-quarters of those treated after transplantation, according to studies presented this week at the 64thAASLD Liver Meeting in Washington, DC.
Over years or decades, chronic hepatitis C virus (HCV) infection can cause advanced liver disease including cirrhosis and liver cancer, and hepatitis C is a leading indication for liver transplantation. Hepatitis C patients awaiting liver transplants are in dire need of treatment, but often cannot tolerate interferon-based therapy. Left untreated, HCV almost always infects the new donor liver soon after transplantation, which can lead to cirrhosis, graft failure, and death.
Sofosbuvir + Ribavirin Pre-transplant
Michael Curry of Beth Israel Deaconess Medical Center in Boston presented findings from a study of sofosbuvir and ribavirin to prevent HCV recurrence following orthotopic liver transplantation. Sofosbuvir (formerly GS-7977) is a once-daily oral nucleotide polymerase inhibitor with a high barrier to resistance.
The open-label Phase 2 Study 2025 enrolled 61 patients at 16 sites, representing 8 United Network for Organ Sharing regions in the U.S. and 2 international sites. Most participants (80%) were men, 90% were white, and the median age was 59 years. A majority (73%) had HCV genotype 1 -- including 39% with harder-to-treat subtype 1a -- 13% had genotype 2, 12% had genotype 3, and 1 person had genotype 1. Three-quarters had previously been treated for hepatitis C and 22% had the favorable IL28B CC gene variant associated with interferon responsiveness.
Participants had well-compensated liver disease and were listed for transplantation due to hepatocellular carcinoma, a type of primary liver cancer. The median MELD score was 8 and most had Child-Pugh scores of 5 (43%), 6 (30%), or 7 (23%). People with hepatitis B or HIV coinfection, decompensated cirrhosis, or kidney impairment were excluded.
Participants received 400 mg once-daily sofosbuvir plus 1000-1200 mg/day weight-based ribavirin while awaiting transplants. The original protocol called for treatment lasting 24 weeks but this was later extended to 48 weeks. The last dose was taken on the day of transplantation. They received standard immunosuppressive therapy (tacrolimus, mycophenolate mofetil, or prednisone) to prevent rejection of the new liver.
The primary study endpoint was post-transplant virological response, or continued undetectable HCV RNA among patients who received sofosbuvir/ribavirin for more than 12 weeks and had undetectable viral load at the time of transplantation.
A total of 41 of participants underwent transplantation with undetectable HCV RNA while 3 people did so while viral load was still detectable. 10 discontinued treatment, 4 finished treatment but were still awaiting transplants, and 1 was still on therapy while waiting.
- HCV viral load declined rapidly after starting sofosbuvir/ribavirin.
- Most patients who received treatment for any duration (93%) or for at least 12 weeks (91%) had HCV RNA below the lower limit of quantitation (LLOQ) at the time of transplantation.
- Among those with undetectable HCV at transplantation, 64% maintained viral suppression at 12 weeks post-transplant.
- People who did not experience HCV recurrence had undetectable viral load for a median of 95 days before transplantation compared with just 5.5 days for those who did have a recurrence; only 1 patient had a recurrence after having undetectable HCV for 30 days or more.
- In a multivariate analysis, longer duration of undetectable HCV RNA prior to transplantation was the only factor that significantly predicted HCV non-recurrence; HCV genotype 1b and IL28B CC status were of borderline significance in a univariate analysis but not the multivariate analysis.
- Sofosbuvir/ribavirin was generally safe and well-tolerated in this difficult-to-treat population.
- There were 11 serious adverse events -- none of which were considered related to sofosbuvir -- and 2 discontinuations due to adverse events (3%), as well as 7 cases of grade 4 laboratory abnormalities.
- 3 people died before transplantation and 5 afterwards.
- The most common side effects were fatigue (38%), anemia (23%), headache (23), nausea (16%), and rash (15%).
"Sofosbuvir + ribavirin treatment prior to transplantation prevented HCV recurrence in the majority (64%) of patients who were HCV RNA <LLOQ at transplant," the researchers concluded. "The number of consecutive days with HCV RNA [undetectable] prior to transplant appears to be the strongest predictor of post-transplant virological response."
These results, Curry said, are a "vast improvement" over current treatment. But it is not yet possible to answer an audience question about whether it might be advisable to delay transplantation in order to take sofosbuvir longer.
Sofosbuvir + Ribavirin Post-transplant
The second study, by Michael Charlton of the Mayo Clinic and colleagues, looked at sofosbuvir plus ribavirin for treatment of established HCV recurrence after liver transplantation.
The open-label Phase 2 Study 0126 included 40 participants in France, Germany, New Zealand, Spain, and the U.S. Again, about 80% were men, most were white, and the median age was 59 years. More than 80% had HCV genotype 1 (including 55% with 1a), 15% had genotype 3, 1 had genotype 4, and none had genotype 2. Most (88%) were treatment-experienced and one-third had the IL28B CC variant.
Participants had undergone liver or combined liver and kidney transplantation between 6 months and 12 years (median 4 years) prior and did not experience organ rejection or have signs of decompensation. 40% had cirrhosis in the engrafted liver while 23% had bridging fibrosis (Metavir stage F3) and 35% had mild-to-moderate fibrosis (stage F1-F2).
Participants were treated with 400 mg once-daily sofosbuvir for 24 weeks. They also started with a low 400 mg dose of ribavirin, which was gradually increased based on tolerability (determined by hemoglobin levels).
- HCV again declined rapidly after starting therapy.
- At week 4 and at the end of treatment all participants had undetectable viral load.
- 4 weeks after completing treatment, 77% had early sustained virological response (SVR4); this is a promising result, but too early to determine a cure as relapse has been seen after this point in other sofosbuvir studies.
- No baseline factors were found to predict which patients would relapse, including HCV genotype, IL28B status, prior treatment, or extent of fibrosis; Charlton noted that the average ribavirin dose was "almost identical" for responders and non-responders
- There were 6 serious adverse events (15%) and 2 (5%) that led to treatment discontinuation.
- There were no deaths, cases of graft loss, or episodes of rejection.
- The most common side effects were fatigue (28%), headache (25%), joint pain (23%), and diarrhea (23%).
- There were 11 grade 4 laboratory abnormalities (28%); 15% developed anemia and several required erythropoietin, blood transfusions or ribavirin dose reduction.
- No interactions were reported between sofosbuvir and any immunosuppressant agents including tacrolimus (used by 70%), mycophenolate mofetil (35%), prednisone (28%), or cyclosporin (25%), though 4 people did increase their tacrolimus does while on sofosbuvir.
Based on these findings, the investigators concluded, "Sofosbuvir + ribavirin is a potential all-oral therapy for treatment of HCV infection following liver transplantation."
MP Curry, X Forns, RT Chung, et al. Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation.64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract213.
MR Charlton, EJ Gane, MP Manns, et al. Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation: Preliminary Results of a Prospective, Multicenter Study.64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. AbstractLB-2.
AASLD. First Study of its Kind Shows that All-oral Treatment Regimen Prevents Hepatitis C Recurrence in Liver Transplant Recipients Who Received Allografts. Press release. November 5, 2013.
Gilead Sciences. Gilead Announces Phase 2 Results for Sofosbuvir-Based Regimens in Hepatitis C Patients Before and After Liver Transplantation. Press release. November 2, 2013.