The FDA has approved Mavyret (Abbvie) and Vosevi (Gilead), two new fixed-dose combinations of direct-acting antiviral (DAA) drugs, for treatment of chronic hepatitis C virus (HCV) infection caused by any of the six major HCV genotypes in patients without cirrhosis or with compensated cirrhosis. Both are approved for use in treatment-experienced patients. Mavyret is also approved for treatment-naive patients.

Per capita spending on prescription drugs in the US is higher than in other industrialized nations, including Canada.

The FDA recently announced that it will require the labeling of all direct-acting antiviral drugs used for treatment of hepatitis C virus (HCV) infection to include a boxed warning about a risk of hepatitis B virus (HBV) reactivation associated with their use.1

Twenty-four cases of HBV reactivation occurring during treatment with direct-acting antiviral drugs for HCV were identified from the FDA Adverse Event Reporting System and the medical literature.2-5 Before starting direct-acting antiviral treatment for HCV, some of these patients were hepatitis B surface antigen (HbsAG) positive and others showed evidence of resolved HBV infection. HBV reactivation generally occurred within 4-8 weeks of starting treatment. Reactivation of HBV can cause increases in bilirubin and aminotransferase levels, fulminant hepatitis, hepatic failure, and death. Of the 24 patients, two died and one required a liver transplant.

HBV reactivation was not identified before FDA approval of these drugs because the clinical trials used to support their approval excluded patients with HBV co-infection. The mechanism by which HBV reactivation occurs during treatment with direct-acting antiviral drugs for HCV is unknown. Patients should be screened for current or past HBV infection before starting treatment with a direct-acting antiviral and monitored for HBV reactivation during and following treatment with these drugs.

1. FDA Drug Safety Communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. Available at: www.fda.gov. Accessed October 13, 2016.
2. JM Collins et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir. Clin Infect Dis 2015; 61:1304.
3. A De Monte et al. Direct-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol 2016; 78:27.
4. AR Ende et al. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep 2015; 9:164.
5. C Wang et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol 2016 July 5 (epub).

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The FDA has approved Epclusa (Gilead), a fixed-dose combination of sofosbuvir (Sovaldi) and velpatasvir, a new direct-acting antiviral agent, for oral treatment of chronic hepatitis C virus (HCV) infection. Epclusa is the first oral combination to be approved for treatment of all six major HCV genotypes.

The FDA has approved Zepatier (Merck), a fixed-dose combination of two direct-acting antiviral agents — elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A protease inhibitor — for oral treatment of chronic hepatitis C virus (HCV) genotype 1 or 4 infection.

Harvoni, a once-daily fixed-dose combination of the direct-acting antiviral agents ledipasvir and sofosbuvir approved by the FDA in 2014 for treatment of hepatitis C virus (HCV) genotype 1 infection,1 has now been approved for use in patients infected with HCV genotype 4, 5, or 6, and in patients co-infected with HCV and HIV-1. A 12-week course of treatment with Harvoni plus ribavirin has also been approved as an alternative to 24 weeks of Harvoni alone for treatment-experienced, cirrhotic patients with HCV genotype 1 infection.

HCV genotypes 4, 5, and 6 are responsible for <2% of HCV cases in the US and Canada. They are more prevalent in the Middle East, North Africa, and Central sub-Saharan Africa (genotype 4), Southern sub-Saharan Africa (genotype 5), and Southeast Asia (genotype 6).2

In two open-label trials (both summarized in the package insert), 44 patients infected with HCV genotype 4, 41 patients with genotype 5, and 25 patients with genotype 6 received 12 weeks of treatment with ledipasvir/sofosbuvir.3 The rates of sustained virologic response 12 weeks after stopping treatment (SVR12) were 93%, 93%, and 96% in patients infected with HCV genotypes 4, 5, and 6, respectively.

In a single-arm trial (ION-4), 335 patients co-infected with HIV-1 and HCV genotype 1 (98%) or 4 (2%) received 12 weeks of treatment with ledipasvir/sofosbuvir. An SVR12 was achieved in 322 patients (96%), including 94% of 67 cirrhotic patients and 97% of 185 treatment-experienced patients.4

In a randomized, double-blind trial (SIRIUS), 154 treatment-experienced patients with HCV genotype 1 infection and cirrhosis who had not responded to peginterferon plus ribavirin with and without a protease inhibitor received either ledipasvir/sofosbuvir plus ribavirin 1000-1200 mg daily for 12 weeks or ledipasvir/sofosbuvir without ribavirin for 24 weeks. An SVR12 was achieved in 74 of 77 patients (96%) in the 12-week arm and in 75 of 77 patients (97%) in the 24-week arm.5

1. A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C. Med Lett Drugs Ther 2014; 56:111.
2. JP Messina et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015; 61:77.
3. EJ Gane et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015; 149:1454.
4. S Naggie et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373:705.
5. M Bourlière et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015; 15:397.

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The FDA has approved Technivie (Abbvie), a fixed-dose combination of the direct-acting antiviral agents ombitasvir and paritaprevir and the pharmacokinetic enhancer ritonavir, for oral treatment of chronic hepatitis C virus (HCV) genotype 4 infection in patients without cirrhosis. It is indicated for use in combination with ribavirin. Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir, an HCV RNA polymerase inhibitor that has little activity against HCV genotype 4, is approved as Viekira Pak for treatment of HCV genotype 1 infection.1

HCV genotype 4 is uncommon in the US and Canada. It is the most prevalent strain of HCV in Central sub-Saharan Africa, North Africa, and the Middle East.2 Technivie plus ribavirin was the first all-oral treatment approved for treatment of HCV genotype 4. Ledipasvir/sofosbuvir (Harvoni)3 was also recently approved for this indication; it does not require coadministration with ribavirin and can be used in patients with or without cirrhosis. Its use for this and other new indications will be reviewed in a future issue.

FDA approval of Technivie was based on an open-label trial (PEARL-I) in 86 treatment-naive and 49 treatment-experienced non-cirrhotic patients with HCV genotype 4 infection. Treatment-naive patients were randomized to receive Technivie with or without ribavirin for 12 weeks; all treatment-experienced patients received the combination plus ribavirin for 12 weeks. The rate of sustained virologic response 12 weeks after stopping treatment (SVR12), the primary endpoint, was 91% (40/44) in treatment-naive patients not receiving ribavirin and was 100% in both treatment-naive (42/42) and treatment-experienced (49/49) patients receiving the combination plus ribavirin.4

Adverse effects observed with Technivie in the clinical trial included asthenia, fatigue, nausea, insomnia, pruritus, and skin reactions. Like Viekira Pak, Technivie has been associated with serious, sometimes fatal cases of hepatic decompensation and is contraindicated in patients with moderate to severe (Child-Pugh B/C) hepatic impairment.5 It is also contraindicated in patients taking ethinyl estradiol (because of a risk of ALT elevation), CYP3A4 inducers such as rifampin, or certain sensitive CYP3A4 substrates such as midazolam or simvastatin.6

Each Technivie tablet contains 12.5 mg of ombitasvir, 75 mg of paritaprevir, and 50 mg of ritonavir. The recommended dosage is two tablets taken once daily in the morning with a meal for 12 weeks. Ribavirin should be coadministered with Technivie at a daily dose of 1000 mg in patients weighing <75 kg or 1200 mg in those weighing ≥75 kg. Use of Technivie alone may be considered in treatment-naive patients who cannot take or tolerate ribavirin. A 12-week supply of Technivie costs $76,653.7

1. A 4-drug combination (Viekira Pak) for hepatitis C. Med Lett Drugs Ther 2015; 57:15.
2. JP Messina et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015; 61:77.
3. A combination of ledipasvir plus sofosbuvir (Harvoni) for hepatitis C. Med Lett Drugs Ther 2014; 56:11.
4. C Hézode et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; 385:2502.
5. In brief: hepatic injury with hepatitis C drugs. Med Lett Drugs Ther 2015; 57:156.
6. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2013; 55:e44.
7. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. November 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015 www.fdbhealth.com/policies/drug-pricing-policy.

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The FDA recently announced labeling changes for the combination antiviral products Viekira Pak (ombitasvir/paritaprevir/ritonavir with dasabuvir)1 and Technivie (ombitasvir/paritaprevir/ritonavir)2 warning of a risk of serious, potentially fatal liver injury.3 Viekira Pak, approved in December 2014 for treatment of hepatitis C virus (HCV) genotype 1 infection, including patients with compensated cirrhosis, and Technivie, approved in July 2015 for treatment of HCV genotype 4 infection without cirrhosis, have been identified as "possible" or "probable" causes in 26 postmarketing cases of hepatic decompensation, including 10 cases (mostly in patients with preexisting advanced cirrhosis) that resulted in death or liver transplant. Hepatic injury generally occurred within 1-4 weeks of treatment initiation.

All therapies for chronic HCV infection have been associated with cases of hepatic decompensation in patients with advanced fibrosis or cirrhosis, but cause and effect are difficult to determine. Viekira Pak and Technivie are now contraindicated in patients with moderate to severe (Child-Pugh B/C) hepatic impairment. Ledipasvir/sofosbuvir (Harvoni), another recently approved treatment for HCV genotype 1 infection,4 is still indicated for treatment of patients with any degree of compensated hepatic impairment (Child-Pugh A/B/C). The efficacy and safety of all three combinations in patients with decompensated cirrhosis have not been established.

1. A 4-drug combination (Viekira Pak) for hepatitis C. Med Lett Drugs Ther 2015; 57:15.
2. In brief: Technivie for HCV genotype 4 infection. Med Lett Drugs Ther 2015; in press.
3. FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. Available at: www.fda.gov. Accessed October 29, 2015.
4. A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C. Med Lett Drugs Ther 2014; 56:111.

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The FDA recently announced changes in the labeling of the hepatitis C drugs Sovaldi (sofosbuvir) and Harvoni (sofosbuvir/ledipasvir) to warn about a risk of serious and potentially fatal bradycardia when either drug is taken with the antiarrhythmic drug amiodarone (Cordarone, and others).1 Symptomatic bradycardia was reported following initiation of treatment with Harvoni or with Sovaldi plus simeprevir (Olysio) or the investigational antiviral drug daclatasvir in 9 patients already taking amiodarone; it occurred within 24 hours of starting hepatitis C therapy in 6 patients and within 2-12 days in 3 others. One patient died of cardiac arrest and 3 required pacemaker implantation. In 3 patients who continued taking amiodarone, rechallenge with Harvoni or Sovaldi resulted in recurrence of symptomatic bradycardia. In another patient, rechallenge 8 weeks after stopping amiodarone did not result in bradycardia.

The mechanism of this effect is unknown. Factors possibly contributing to the cardiac events include concomitant beta blocker therapy (in 7 patients) and preexisting cardiac and hepatic disease. Hepatic impairment increases the risk of cardiac conduction abnormalities and could increase adverse effects of amiodarone, which is metabolized by the liver.2 Use of sofosbuvir without amiodarone has not been associated with significant bradycardia.

The new labels warn that sofosbuvir and amiodarone should not be taken concurrently. If concomitant use is necessary, cardiac monitoring in an inpatient setting is recommended for the first 48 hours. Daily monitoring of heart rate, either at home or in an outpatient setting, should continue for at least the first 2 weeks of treatment. Amiodarone has a very long half-life, and its effects may persist for weeks to months after discontinuation.

1. FDA. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir Harvoni or Sovaldi in combination with another direct acting antiviral drug. Available at http://www.fda.gov. Accessed April 2, 2015.
2. U Klotz. Antiarrhythmics: elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet 2007; 46:985.

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The FDA has approved Viekira Pak (Abbvie), a fixed-dose combination of two new direct-acting antiviral agents (ombitasvir, paritaprevir) with the pharmacologic enhancer ritonavir in one tablet, co-packaged with a third new direct-acting antiviral agent (dasabuvir) in a second tablet, for oral treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Genotype 1 is responsible for 70-80% of HCV infections in the US.

The FDA has approved a fixed-dose combination (Harvoni [har voe' nee] – Gilead) of sofosbuvir and ledipasvir (led' i pas' vir), two oral direct-acting antiviral agents, for treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Genotype 1 is responsible for 70-80% of HCV infections in the US. Sofosbuvir (Sovaldi) was approved earlier for use in combination with other antiviral drugs for treatment of HCV infection. Ledipasvir is a new drug.