Interferon was a component of all treatment for hepatitis C virus (HCV) for more than 20 years. It was also a major cause of limited treatment success because it results in numerous adverse events, requires injection, and has variable activity against different HCV genotypes and in patients with different genetic backgrounds. 

Adding ribavirin to interferon improved response but has contributed additional adverse events and has increased pill burden. The first directly-acting antivirals for HCV, the protease inhibitors telaprevir and boceprevir, could only be used with interferon and ribavirin and added considerable complexity as well as adverse effects. 

The current HCV treatment landscape has now been completely transformed by multiple directly-acting antiviral  combinations that have been approved in the past 18 months or are likely to be approved in the next year.


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Sofosbuvir (Sovaldi®), a nucleotide polymerase inhibitor, has pangenotypic activity, a high genetic barrier to resistance and a safety profile superior to numerous other candidate drugs in the same class that failed during clinical development.1 

Combining sofosbuvir with ribavirin for HCV genotype 2 or 3 infection2 or with the second generation protease inhibitor simeprevir for genotype 13 yields high sustained virologic response  rates from interferon-free regimens.

A new phase of HCV treatment began in the last quarter of 2014 with approval of agents in the very potent NS5a inhibitor class.

Ledipasvir is marketed in a fixed-dose combination with sofosbuvir. A second NS5a inhibitor, ombitasvir, is marketed in combination with the HCV protease inhibitor paritaprevir, the pharmacokinetic enhancer ritonavir and the non-nucleoside polymerase inhibitor dasabuvir.(Viekira Pak, Abbvie). 

Daclatasvir  is the third NS5a inhibitor already approved in Europe and likely to receive FDA approval in the near future. Daclatasvir has clinically important activity against all HCV genotypes 4 and therefore is a very attractive partner for sofosbuvir. Daclatasvir will likely be approved for use in combination with sofosbuvir, but because of the anticipated extreme cost of two drugs developed by different pharmaceutical companies, access may be limited to difficult-to-treat patients such as those with genotype 3 infection 5 or genotype 1 infection that previously failed protease inhibitor-containing therapy.6 

Daclatasvir is also being developed for treatment of genotype 1 in combination with two other directly-acting antivirals  made by Bristol-Myers Squibb: asunaprevir, a protease inhibitor, and beclabuvir, a non-nucleoside polymerase inhibitor. A fourth regimen of the NS5a inhibitor elbasvir and the next-generation protease inhibitor grazoprevir is also in late-stage clinical development. 

These new regimens given for 8 to 24 weeks produce sustained virologic response  rates in the 85% to 100% range with few serious adverse events. Cirrhosis, genotype, and prior treatment experience are the main factors that dictate duration of therapy, and for some regimens and patient types, addition of ribavirin is still necessary to maximize response.7-13 

These treatment outcomes represent a remarkable improvement in efficacy, tolerability, and safety when compared with older interferon-based treatments. Yet access to treatment has been restricted purely in response to unprecedented cost. 

Because liver damage from HCV progresses slowly, many infected individuals will never develop end-stage liver disease. Therefore, most third-party payers have restricted access to treatment to those with evidence of advanced fibrosis, even though most studies have identified advanced fibrosis as a risk factor for treatment failure. 

However, estimates of the proportion of individuals with HCV who will develop end-stage liver disease are imprecise,14 and untreated chronic HCV has been linked to numerous other complications including, renal disease, vasculitis, hepatocellular carcinoma, lymphoma, certain other cancers, insulin resistance and diabetes, cardiovascular disease, and neurocognitive and immune dysfunction.15 

There is no scientific basis for restricting HCV treatment to those with advanced fibrosis. New studies suggest the incidence of new HCV infections in the United States may be badly underestimated.16 

Treatment restrictions also prevent these powerful new drugs from being used to affect HCV transmission. Both the pharmaceutical and health insurance industries bear the responsibility for these  short-sighted and unscientific restrictions. 

There is an urgent need for HCV drug manufacturers, health insurance providers, and public health policy makers to work together to significantly reduce the cost of medication, allowing the number of treated people with HCV to increase dramatically. 

This would permit the developers of these innovative new treatments to protect deserved profits without losing the opportunity for a major public health benefit from expanded indications to treat HCV. 

References

1.   Keating GM. Sofosbuvir: a review of its use in patients with chronic hepatitis C. Drugs. 2014;74:1127-1146. doi:10.1007/s40265-014-0247-z.

2.   Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and rivavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370:1993-2001. doi:10.1056/NEJMoa1316145..

3.   Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384:1756–1765.

4.   Belda, O, Targett-Adams P. Small molecule inhibitors of the hepatitis C virus-encoded NS5A protein. Virus Research. 2012;170:1-14.

5.   Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61:1127-1135.

6.   Sulkowski MS, Gardiner DF, Rodriquez-Torres M. et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-221. doi:10.1056/NEJMoa1306218.

7.   Kowdley KV, Gordon GC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-1888. doi:10.1056/NEJMoa1402355.

8.   Bourliere M, Bronowicki JP, de Ledinghen V, 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;15:397-404. doi:10.1016/S1473-3099(15)70050-2.

9.   Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r–ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-1992. doi:10.1056/NEJMoa1402338.

10.  Poordad F, Hezode C, Trinh R, et al. ABT-450/r–ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973-1982. doi:10.1056/NEJMoa1402869.

11.  Poordad F, Sievert W, Mollison L, et al. Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 Infection. JAMA. 2015;313:1728-1735. doi:10.1001/jama.2015.3860.

12.  Muir AJ, Poordad F, Lalezari J,et al. Daclatasvir in combination with asunaprevir and beclabuvir for hepatitis C virus genotype 1 infection with compensated cirrhosis. JAMA. 2015;313:1736-1744. doi:10.1001/jama.2015.3868.

13.  Zeuzem S, Ghalib R, Reddy KR, et al.  Grazoprevir–elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med. 2015;doi:10.7326/M15-0785.

14.  Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis. 2012;206:469-477. doi:10.1093/infdis/jis385.

15.  Seeff LB.  Natural history of chronic hepatitis C. Hepatology. 2002;36:S35-S46.

16.  Onofrey S, Aneja J, Haney GA, et al. Underascertainment of acute hepatitis C virus infections in the US Surveillance System: a case series and chart review. Ann Intern Med. 2015;doi:10.7326/M14-2939.