Regulatory Decision Summary for HARVONI

Health Canada considers that the benefit of treating chronic HCV infection with Harvoni outweighs the known risks associated with the proposed regimen in the following patient populations: 1) patients with HCV/HIV-1 co-infection; 2) patients with HCV infection with decompensated cirrhosis; and 3) patients with HCV recurrence after liver transplantation.

Harvoni is a fixed dose tablet of 90 mg/400mg ledipasvir/sofosbuvir. The recommended dose and treatment duration is based on the patient population.

The clinical safety and efficacy of Harvoni in patients with HCV genotype 1 infection and HIV-1 co-infection were assessed in one multicentre, open label, Phase III study with Harvoni treatment for 12 weeks. The efficacy of Harvoni was assessed by measuring the sustained virologic response rates at follow-up Week 12 (SVR12). The benefits of Harvoni in HIV-1 co-infected patients include the achievement of high SVR12 rates (95.8%) in a regimen that does not include ribavirin (RBV) and/or PEG-interferon and is therefore free of the associated toxicities. The harm associated with Harvoni is an increased risk of renal toxicity in patients taking tenofovir disoproxil fumarate(TDF)-containing regimens, especially those who have pre-existing renal disease. There is uncertainty about the effect of race and interleukin 28B (IL28B) genotype status in this patient population; all 10 relapses in the clinical trial were reported in Black patients with non CC IL28B alleles.

The clinical safety and efficacy of Harvoni in pre- and post-transplantation patients with compensated or decompensated cirrhosis and HCV genotype 1 infection were assessed in two identically designed, multicentre, open label, Phase II studies with Harvoni plus RBV treatment for 12 or 24 weeks (n=614). The data were limited in transplantation patients with Child-Turcotte-Pugh (CTP) Score C cirrhosis who received treatment for 12 weeks or 24 weeks (n=8 and n=9, respectively). The benefits of Harvoni in combination with RBV in this subpopulation include high SVR12 rates in HCV treatment-naïve and HCV treatment-experienced patients with decompensated cirrhosis who had not undergone liver transplantation and in post-transplantation HCV treatment-naïve and HCV treatment-experienced patients without cirrhosis, with compensated cirrhosis and with decompensated CTP B cirrhosis. Most of the patients who achieved SVR showed an improvement in CTP and Model of End-stage Liver Disease (MELD) scores which suggests that the treatment is beneficial in reversing hepatic impairment. The SVR12 rates were substantially lower in post-transplantation subjects with decompensated CTP C cirrhosis, however the number of subjects studied was small (n=17).

The harm associated with Harvoni in combination with RBV is an increased risk of anemia which is associated with the use of RBV. There is also a risk of developing treatment-emergent, non-structural protein 5A (NS5A) resistance associated variants in patients who relapse and there are currently limited treatment options for patients who have failed direct-acting antiviral (DAA) therapy. Another harm associated with the use of Harvoni in combination with RBV is risk of drug-induced liver injury.

Uncertainties with the use of DAAs such as Harvoni include the risk of recurrence of hepatocellular carcinoma (HCC) and the potential for reactivation of Hepatitis B Virus. Harvoni is not approved for treatment of HCV/HBV co-infected patients and further analysis of safety data is required to properly assess the effect of DAAs on the recurrence of HCC. Although the efficacy and safety data in post-transplantation patients with decompensated CTP C cirrhosis are limited, additional efficacy and safety information is available in pre-transplantation patients with decompensated CTP C cirrhosis. Moreover, there are currently very few treatments available to post-transplantation patients with decompensated CTP C cirrhosis. The regimen of Harvoni with RBV provides an option in this difficult-to-treat subpopulation.

The risks and uncertainties associated with the use of Harvoni with or without RBV are manageable through the inclusion of appropriate warnings and cautionary statements in the Harvoni Product Monograph. Based on the evidence provided, the anticipated benefits of Harvoni are considered to outweigh the possible risks under the conditions of use recommended in the Harvoni Product Monograph at this time.