Sofosbuvir a ‘Potentially Lifesaving Therapy’ for Liver Transplant Patients With Hepatitis C
by Kate O'Rourke
The outlook for patients with hepatitis C undergoing liver transplantation got a lot sunnier with the results of two studies presented at The Liver Meeting 2013. In one study, researchers showed the combination of sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin used in this patient population pre-transplantation prevented recurrence of the hepatitis C virus (HCV) infection in 64% of patients. Used after transplantation, the regimen achieved a sustained virologic response (SVR) rate of 77% four weeks after treatment completion. “These studies are both very dramatic,” said Adrian Di Bisceglie, MD, president elect of the American Association for the Study of Liver Diseases, who was not involved with the studies. “They signal a potential dramatic change in our practice of medicine related to hepatitis C and liver transplant.”
Reinfection of a transplanted liver is inevitable in patients who have HCV RNA-positive serum at the time of transplantation. Recurrence of HCV infection is the most common cause of mortality and graft loss after liver transplantation. Between 10% and 50% of transplant patients with recurrent HCV infection progress to cirrhosis within five years, and once cirrhosis is established, 42% of patients have graft failure within 12 months. Current therapies to treat HCV infection before and after liver transplantation have limited efficacy and are poorly tolerated, causing severe adverse reactions and significant interactions with immunosuppression medications.
Michael Charlton, MD, professor of medicine at Mayo Clinic, Rochester, Minn., presented a late-breaking abstract on the topic at The Liver Meeting. In this study, Dr. Charlton and his colleagues enrolled 40 patients with HCV infection who underwent liver transplantation between six and 150 months before study enrollment. Patients were given 24 weeks of treatment with ribavirin plus sofosbuvir, a nucleotide polymerase inhibitor with potent antiviral activity against HCV genotypes 1 to 6.
Both treatment-naive and treatment-experienced patients were included in the study; individuals with decompensated liver disease were excluded. The majority of patients had HCV genotype 1 (55%, 1a and 28%, 1b); the remainder had HCV genotype 3 (15%) or 4 (3%).
At the time of study analysis, 77% of patients had achieved SVR at four weeks after treatment completion, and 12 of 13 patients for whom data were available at week 12 still had SVR. Dr. Charlton reported that there were no interactions reported between sofosbuvir and any immunosuppressive agents, including cyclosporine and tacrolimus, and no deaths, graft losses or episodes of liver rejection.
Adverse events (AEs) included fatigue (28%), headache (25%), arthralgia (23%), diarrhea (23%), cough (18%), nausea (18%) and anemia (15%). Grade 3/4 laboratory abnormalities occurred in 53% of patients and included decreased levels of lymphocytes (33%) and hemoglobin (20%), and hyperglycemia (10%).
“In this difficult-to-treat population—enriched with a high prevalence of genotype 1, prior treatment experience, advanced fibrosis and receiving immunosuppression—77% of patients treated with 24 weeks of sofosbuvir plus ribavirin achieved SVR at week 4,” said Dr. Charlton.
Michael Curry, MD, medical director for liver transplantation at Beth Israel Deaconess Medical Center, Boston, presented an abstract on pre-transplantation treatment with sofosbuvir. In this study, 61 patients with HCV infection were enrolled to receive sofosbuvir plus ribavirin until the time of liver transplantation, or up to 48 weeks. The patient population included those infected HCV genotypes 1a (39%), 1b (34%), 2 (13%), 3a (12%) and 4 (2%).
At the time of analysis, 44 patients were scheduled to receive a liver transplant; of these, 41 were negative for HCV infection and three were positive. The remaining 17 patients stayed on treatment, were post-treatment and awaiting a transplant, had discontinued treatment or had liver cancer progression.
Of the 33 patients who received at least 12 weeks of treatment with sofosbuvir, 91% had HCV RNA levels below the lower limit of quantitation at the time of transplantation. Moreover, of the 44 patients who received any duration of treatment, 93% had undetectable HCV RNA at transplantation. Post-transplant virologic response (pTVR) rate at 12 weeks was 64%. The number of consecutive days with undetectable HCV RNA before transplantation was the strongest predictor of pTVR (P<0.0001). On-treatment HCV RNA suppression was rapid.
Dr. Curry characterized the treatment as safe and well tolerated. Although 18% of patients experienced a serious AE, none of the AEs were deemed related to sofosbuvir: Laboratory abnormalities and AEs observed pre-transplantation were similar to those seen in the post-treatment study. Only 3% of patients discontinued treatment because of side effects.
‘Potentially Lifesaving’ Implications
According to Dr. Di Bisceglie, the studies will have an immediate effect on clinical practice.
“Sofosbuvir has been available on a compassionate use basis after transplantation for a little while, so probably a couple dozen patients around the country have already seen some benefit,” he said.
Sofosbuvir was approved for the treatment of HCV infection in December 2013, including patients with hepatocellular carcinoma awaiting liver transplantation to prevent HCV recurrence.
“Its availability, combined with these data, will probably mean we are going to start treating patients after liver transplantation very quickly. This is a potentially lifesaving therapy, and I’m sure physicians will not want to wait until it is approved for this indication,” Dr. Di Bisceglie said.
He called the pre-transplant data “dramatic,” but thinks clinicians will be more likely to use the medications after transplantation at first.
Until sofosbuvir’s label includes a transplant indication, he noted, clinicians “might meet resistance from third-party payors.”
Dr. Curry disclosed having a financial relationship with Gilead Sciences. Drs. Charlton and Di Bisceglie have received support from and have served as consultants for Gilead.
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