Gilead Sciences, a biopharmaceutical company that discovers, develops and commercialises innovative therapeutics in areas of unmet medical need, has announced results from several phase 2 clinical studies evaluating investigational uses of Harvoni (ledipasvir 90 mg/sofosbuvir 400 mg) and other Sovaldi (sofosbuvir 400 mg)-based regimens for the treatment of chronic hepatitis C virus (HCV) infection in patients with advanced liver disease, including patients with decompensated cirrhosis, patients with fibrosing cholestatic hepatitis C (a rare and severe form of the disease following liver transplantation) and patients with portal hypertension.

These data will be presented this week at the 50th Annual Meeting of the International Liver Congress 2015 in Vienna, Austria.

"The patients included in these analyses are among the most difficult to both treat and cure and, until now, have had limited or no treatment options," said Michael P Manns, MD, professor and chairman, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

"These data demonstrate that, even among these difficult-to-treat patient groups, sofosbuvir-based oral therapy offers the potential of high cure rates, improves outcomes and is generally well tolerated with a favorable safety profile."

Harvoni and Sovaldi are each approved in the United States for the treatment of chronic HCV infection. Harvoni is indicated for patients with genotype 1; Sovaldi is used in combination with other agents and its efficacy has been established in patients with genotypes 1-4.

In SOLAR-2 (Study GS-US-337-0124, Oral #G02), 328 genotype 1 or 4 HCV patients with decompensated liver disease before liver transplantation or recurrent HCV infection following liver transplantation were randomized to receive either 12 or 24 weeks of Harvoni plus ribavirin (RBV). Ten patients were excluded from the analysis because of transplantation (n=7) or because they were pre-transplantation, but not decompensated (n=3); an additional 27 of these patients have not yet reached post-treatment week 12.

Of the 32 genotype 4 patients, 27 (84 percent) achieved SVR12. Additionally, among patients with compensated and decompensated cirrhosis before and after liver transplantation, virologic response was associated with improvements in Model for End-Stage Liver Disease (MELD) and CPT scores used to stage end-stage liver disease.

The most common adverse events were fatigue, anemia, nausea and headache. Overall, six patients discontinued treatment due to adverse events, five of whom had decompensated cirrhosis.

Further supporting the safety profile of Harvoni plus RBV among this patient population was data from a pooled safety analysis of 659 patients treated in the SOLAR-1 and SOLAR-2 studies (ePoster #P0774). Both studies evaluated Harvoni plus RBV for 12 or 24 weeks in genotype 1 or 4 HCV patients with decompensated liver disease or recurrent HCV infection following liver transplantation.

SOLAR-1 was conducted in the United States, with data presented in November at The Liver Meeting 2014 and SOLAR-2 was conducted in Australia, Canada, Europe and New Zealand. Overall, adverse events were similar to those seen in previous studies, including the phase 3 ION studies. Fewer than three percent (n=19/659) of patients discontinued due to an adverse event, none of which were attributed to Harvoni treatment.

There were a total of 20 deaths in these two studies, none of which was assessed by the investigator as related to study treatment.

A further subset of the SOLAR-1 and SOLAR-2 studies (ePoster #P0779) demonstrated 100 percent SVR12 rates among 11 patients who were confirmed to have fibrosing cholestatic hepatitis (FCH), following 12 or 24 weeks of Harvoni plus RBV. FCH is a rare and severe form of recurrent hepatitis that occurs after liver transplantation. It is associated with high morbidity and mortality rates and there are no currently approved treatment options.

Study GS-US-334-0125 (ePoster LB #4283) evaluated 50 genotype 1-4 HCV-infected patients with cirrhosis and portal hypertension.

Patients were randomized to receive either 48 weeks of Sovaldi plus RBV initially (n=25) or at the conclusion of a 24-week observation period (n=21). Four patients in the observation arm discontinued the study prior to receiving treatment. Of the patients who received treatment with Sovaldi plus RBV, 72 percent (n=33/46) achieved SVR12.

A subset of 37 patients had paired hepatic venous pressure gradient (HVPG) measurements at baseline and end of treatment. Of these, 38 percent (14/37) of patients experienced a =10 percent reduction and 24 percent (9/37) of patients experienced a =20 percent decrease in HVPG from baseline to end of treatment. A baseline total bilirubin of <1.5 mg/dL was associated with a =20 percent decrease in HVPG (p=0.03). This study is the first to demonstrate the effect of direct acting antivirals like Sovaldi on HVPG, and additional assessments will be undertaken in these patients one-year post treatment.

The safety and efficacy of these investigational uses of Harvoni and Sovaldi have not been established.

Amiodarone is not recommended for use with Harvoni due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease.

Rifampin and St. John's wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations. Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Most common (=10 per cent, all grades) adverse reactions were fatigue and headache.


In addition to rifampin and St. John's wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.