December 12, 2013

HCV Treatment: Where We're At, Where We're Going

Medscape Gastroenterology

Rowen K. Zetterman, MD

December 11, 2013

Hepatitis C Today

Worldwide, 170-200 million people, including 3.2-5 million Americans, are infected with hepatitis C virus (HCV). Clinical outcomes of chronic HCV infection include chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and complications of cirrhosis or HCC that result in the need for orthotopic liver transplantation. After liver transplantation, recurrence of HCV infection in the new graft is virtually uniform and can result once again in end-stage liver disease in need of transplantation.

There are 6 major genotypes of HCV, with genotype 1 accounting for 70%-75% of HCV infections in the United States. Genotype 1a is responsible for two thirds and genotype 1b for one third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a. Response to treatment is also influenced by the patient's interleukin 28B (IL28B) polymorphism, which results in a greater response in patients with the IL28B CC genotype than in those with IL28B TT genotype.[1]

Where We're At With Treatment

Interferon alpha has been used for 20 years to treat patients with HCV. The mechanism of viral efficacy for interferon has yet to be clearly established. Ribavirin was coupled to interferon therapy in 1998 and has resulted in a doubling of HCV treatment response.[2] Pegylated interferon alpha plus ribavirin has been used since 2001,[3] producing an overall 40% response for treated patients with HCV genotype 1.

Four classes of direct-acting antiviral (DAA) drugs have been developed, including NS3/4A protease inhibitors, NS5B nucleoside inhibitors, NS5B nonnucleoside inhibitors, and NS5A inhibitors.

In 2011, boceprevir and telaprevir, which are NS3/4A protease inhibitors, were approved for the treatment of patients infected with HCV genotype 1.[4,5] Pegylated interferon with ribavirin and either boceprevir or telaprevir is the current standard of care for HCV genotype 1, but this combination is less effective for genotypes 2 and 3. Boceprevir and telaprevir must be administered every 8 hours, and the rapid development of viral resistance prevents them from being used without pegylated interferon and ribavirin.[6,7] The combination of a protease inhibitor plus pegylated interferon and ribavirin results in more anemia and drug interactions than pegylated interferon and ribavirin alone.

The US Food and Drug Administration (FDA) recently approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3.

Boceprevir and Telaprevir

The current standard of care for HCV genotype 1 is either boceprevir or telaprevir with pegylated interferon and ribavirin. Therapy is 24-48 weeks in duration and results in a sustained viral response (SVR) in 67%-75% of patients. Patients with extended rapid viral response (eRVR) associated with a marked reduction in viral titer by 4 weeks of therapy and HCV absence at 12 weeks may require only 24 weeks of total treatment. Side effects, such as anemia, are frequent, as are drug interactions and medication intolerance.

Some have questioned whether the results of protease inhibitor therapy plus pegylated interferon and ribavirin are actually as good in general use as they were in early trials. A recent evaluation of Veterans Affairs treatment groups found that in similar patients who received either boceprevir or telaprevir, only 50% developed SVR.[8] With current therapy, treatment response is better in previously untreated patients, those with HCV genotype 1b, patients with IL28B CC genotype, and patients without advanced fibrosis or cirrhosis of the liver.

Where We're Going With Treatment


Simeprevir, a new oral NS3/4A protease inhibitor, was recently approved by the FDA for the treatment of patients with HCV genotype 1 when administered with pegylated interferon and ribavirin.

Two studies (QUEST-1 and QUEST-2) evaluated oral simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin, compared with pegylated interferon and ribavirin alone.[9] In the simeprevir group, 80% of patients had an eRVR at 12 weeks (compared with only 12% eRVR for pegylated interferon and ribavirin alone) and went on to receive 12 additional weeks of pegylated interferon and ribavirin. This resulted in a 91% SVR in the eRVR simeprevir group compared with 21% in other patients, including those treated as long as 48 weeks (QUEST-1). In the second trial (QUEST-2), simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin for 24 weeks resulted in an SVR of 81%, compared with only 50% for interferon and ribavirin alone. No difference in response rates in patients with genotype 1a or 1b were found in this study.

In a third study (PROMISE) of patients in whom previous HCV treatment had failed, patients were treated with 12 weeks of simeprevir and 24 or 48 weeks of pegylated interferon and ribavirin. This study found that those with eRVR who had been treated for a total of 24 weeks had a 79% SVR, compared with 37% in those receiving placebo.[10] Patients with IL28B genotype CC had a 90% SVR, and those with advanced fibrosis had a 77% SVR, but SVR was only 45% in patients infected with HCV containing an NS3 Q80K mutation.


Sofosbuvir, a nucleoside polymerase inhibitor, has been approved by the FDA for treatment of genotypes 1 through 6.

The open-label NEUTRINO trial[11] included patients with genotypes 1, 4, 5, or 6 who were treated with oral sofosbuvir (400 mg daily) and pegylated interferon with weight-based ribavirin for 12 weeks. This resulted in a 92% SVR for genotype 1a, 82% SVR for genotype 1b, 96% SVR for genotype 4, and 100% SVR for the few patients with genotype 5 or 6. Black patients had an SVR of 87%, compared with 91% in Hispanics and Latinos. The treatment response was better in patients with IL28B CC genotype and in those without cirrhosis.

The POSITRON and FUSION trials[12] evaluated sofosbuvir plus ribavirin in patients with genotype 2 and 3 HCV infections compared with placebo plus ribavirin. SVR was observed at 12 weeks of therapy in 78% of patients with previous treatment failure or patients who were previously unable to take pegylated interferon and ribavirin (POSITRON), and at 16 weeks in 73% of patients with previous treatment failure (FUSION). Both studies observed lower response in patients with genotype 3 and in those with cirrhosis.

Sofosbuvir with weight-based ribavirin oral therapy alone has been evaluated in small numbers of patients with HCV genotype 1. In a phase 2 trial of 25 previously untreated patients with all degrees of fibrosis, 68% achieved an SVR when treated with sofosbuvir 400 mg/day plus weight-based ribavirin compared with a 48% SVR in 25 patients treated with sofosbuvir 400 mg plus ribavirin 600 mg daily.[13]The study group included 83% black patients, 23% with advanced liver disease, 70% with HCV genotype 1a, and 48% with a body mass index > 30 kg/m2.

Drugs Under Development

Nearly 40 other drugs are currently under development and evaluation for the treatment of patients with HCV disease. These drugs include faldaprevir,[14,15] ledipasvir,[16] daclatasvir,[17] asunaprevir,[18]danoprevir,[19] alisporivir, and mericitabine, to name a few.

Why Wait to Treat?

Many studies have identified that viral clearance improves overall clinical outcomes of infected patients. In the Veterans Affairs Registry,[20] patients who developed undetectable HCV RNA levels had a 27% reduction in morbidity and a 45% reduction in overall mortality. Thus, it seems evident that we need to develop treatments that are able to clear HCV from all infected patients. Unfortunately, as many as 50% of infected patients do not respond to or cannot tolerate the current standard of care treatment with pegylated interferon, ribavirin, and boceprevir or telaprevir.

Are gastroenterologists and hepatologists currently recommending treating patients with current therapies, or waiting until new drugs become available? A survey of 337 physicians in 2012 found that one half recommended that previously untreated patients with early or minimal fibrosis should be treated with current therapy, whereas 49% recommended waiting for new therapies.[21] For patients who had not responded to previous therapy with pegylated interferon and ribavirin, 74% recommended retreating with the available DAA drugs boceprevir or telaprevir plus interferon and ribavirin, and only 26% suggested waiting for new therapies. Because this survey was completed in March 2012, would those same figures hold today?

Should we treat HCV genotype 1-infected patients who have little hepatic fibrosis with current drugs, such as boceprevir or telaprevir, coupled with ribavirin and pegylated interferon? Arguments in favor of treating now include reasonable success in previously untreated patients, especially those with IL28B CC genotype,[22] recognizing that the response will be reduced in black patients, those with IL28B TT genotype, and those with underlying cirrhosis or high viral loads. On the other hand, waiting means waiting for recently approved medications that appear to have similar efficacy and are associated with less anemia, reduced daily pill numbers, and fewer drug interactions.

Even though response is also reduced with the new drugs in patients with IL28B genotype, overall treatment response with the new drugs seems better than it is with currently available protease inhibitors. Response to simeprevir is affected by the presence of viral Q80K, and it appears that FDA approval will come with a recommendation to consider other treatments for patients infected with the viral Q80K mutation.

What about patients with HCV genotype 1 who have advanced hepatic fibrosis or cirrhosis? Should we be treating them with current protease inhibitors, or should we wait for better therapies? Better side-effect profiles, similar or improved response to treatment with new drugs, the near availability of simeprevir and sofosbuvir for commercial use, and the better response to initial therapy in treatment-naive patients compared with those who have been previously treated suggest that treatment of these patients should be delayed until new drugs are available.[23]

For patients with HCV genotypes 2 or 3, waiting for sofosbuvir seems reasonable. Boceprevir and telaprevir-based treatments have less effectiveness in treating these HCV genotypes. Although we need more data on the treatment of HCV genotypes 4, 5, and 6, preliminary studies to date suggest that the treatment efficacy of simeprevir and sofosbuvir for these genotypes is similar to that of current therapies.

Pursuit of All-Oral Therapy

Will we ever have effective and completely oral therapies for HCV treatment?

For genotypes 2 and 3, that could happen by early 2014, with sofosbuvir plus ribavirin treatment being approved for HCV genotypes 2 and 3. Although patients with genotype 3 are less likely to achieve SVR than those with genotype 2, additional new drugs and studies of combinations of DAAs may further improve SVR for both genotypes.

The meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2013 included several presentations about oral therapy for HCV treatment. A fixed combination of oral sofosbuvir 400 mg and the NS5A inhibitor ledipasvir 60 mg with ribavirin for 12 weeks achieved a 100% SVR in previously treated patients with HCV genotype 1 infection and advanced fibrosis of the liver.[24] Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/µL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.[25] A combination of sofosbuvir and simeprevir plus ribavirin for 12 weeks (COSMOS trial) resulted in a 96% SVR in previously treated patients with genotype 1 and a 93% SVR when sofosbuvir and simeprevir were given alone.[26]

These studies suggest that new DAAs and future combinations of DAAs will identify new treatments for FDA approval that will lead to all oral therapies for HCV infection.

Cost Considerations

What of the cost of new DAAs?

Although the pricing of simeprevir or sofosbuvir has not been established, some have suggested that approximately $80,000 per treated patient will be the likely cost for each of these new drugs. How does that compare with the cost of current standard-of-care treatment with pegylated interferon, ribavirin, and boceprevir or telaprevir?

A presentation at the AASLD meeting suggested that the cost of the current standard of care is $189,000 per SVR achieved.[27] In a study of 147 patients, of whom 44% achieved SVR, the direct per-patient costs of telaprevir ($55,273), pegylated interferon ($30,418), and ribavirin ($4926) were supplemented by the additional costs for erythropoietin, transfusions, granulocyte colony-stimulating factor, emergency department visits, and hospitalizations, resulting in a median cost of $83,509 per treated patient. Because SVR was achieved in only 44% of those who were treated, the cost of treatment per successful SVR ($83,509 per treated patient × 2.27, because only 44% of treated patients achieved SVR) was approximately $189,000.

A Future of Improved Treatments

The large number of clinical trials of new DAA drugs to treat HCV infection is encouraging. Simeprevir and sofosbuvir should be available sometime in early 2014, to be coupled with pegylated interferon and ribavirin for the treatment of genotype 1, and sofosbuvir plus ribavirin (but without interferon) for genotypes 2 and 3.

The reduced pill burden, shortened treatment time even with pegylated interferon and ribavirin, similar or improved response rates compared with current protease inhibitor/pegylated interferon and ribavirin therapy, apparent reduction of drug interactions with these newer agents, and somewhat diminished effect of genetic response factors (such as IL28B) all suggest a future of improved treatments for the HCV-infected patient. It seems reasonable that many HCV-infected patients can wait for new drugs to become available.


  1. Ge D, Fellay, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment induced viral clearance. Nature. 2009;461:399-401. Abstract

  2. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492.Abstract

  3. Manns MP, McHutchison JG, Gordon SC, et al, and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. Abstract

  4. Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206. Abstract

  5. Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. Abstract

  6. Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir and hepatitis C virus-infected patients. Hepatology. 2009;50:1709-1718. Abstract

  7. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA and hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131:997-1002. Abstract

  8. Backus LI, Belperio PS, Shahoumaian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large US cohort. Aliment Pharmacol Ther. 2014;39:93-103.Abstract

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  10. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir (TMD435) with peg-interferon-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMIS phase III trial. Hepatology. 2013;58 Suppl:737A-738A.

  11. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887. Abstract

  12. Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877. Abstract

  13. Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310:804-811. Abstract

  14. Sulkowski MS, Bourliere M, Bronowicki JP, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology. 2013;57:2155-2163. Abstract

  15. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369:630-639. Abstract

  16. Lawitz E, Poordad F, Hyland RJ, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin resulted in 95% sustained virologic response in patients with HCV genotype 1, including patients with cirrhosis: the LONESTAR trial. Hepatology. 2013;58 Suppl:315A-316A.

  17. Lok AS. HCV NS5A inhibitors in development. Clin Liver Dis. 2013;17:111-121. Abstract

  18. Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol. 2013;58:655-662. Abstract

  19. Marcellin P, Cooper C, Balart L, et al. Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection. Gastroenterology. 2013;145:790.e.8-800.e.8.

  20. McCombs J, Matsuda T, Tonnu-Mihara I, et al. The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs clinical registry. JAMA Intern Med. 2013 Nov 5. [Epub ahead of print]

  21. Chen EY, Lee WM, Hynan LS, Singal AG. A survey of hepatitis C treatment clinical practice patterns using the newly approved protease inhibitors. J Clin Gastroenterol. 2013;47:800-806. Abstract

  22. Shiffman ML, Benhamou Y. Patients with HCV and F1 and F2 fibrosis stage: treat now or wait? Liver Int. 2013;33:105-110. Abstract

  23. Ferenci P. Commentary: triple therapy for patients with chronic hepatitis C and advanced fibrosis? Aliment Pharmacol Ther. 2013;38:1407-1408.

  24. Gane EJ, Stedman CA, Hyland RH, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON study. Hepatology. 2013;58 Suppl:243A-244A.

  25. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology. 2013;58 Suppl:313A-314A.

  26. Jacobson IM. SVR results of a once-daily regimen of simeprevir (TMC-438) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. Program and abstracts of American Association for the Study of Liver Diseases The Liver Meeting® 2013; November 1-5, 2013. Abstract LB-3.

  27. Bichoupan K, Martel-Laferriere V, Ng M, et al. Real world costs of telaprevir-based triple therapy, including costs of managing adverse events, at the Mount Sinai Medical Center, NY: $195,000 per SVR12. Hepatology. 2013;58 Suppl:329A-330A.



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