Its June and time for me to take a short sabbatical with the family, we shall be traveling by boat, plane and train!
the renowned Mitchell L. Shiffman, MD., and colleagues. The article offers a summary of the good doctors treatment strategies for HCV genotypes 1-6;
Upon my return both the blog and website will be updated, see you all in a few weeks.
Mitchell L. Shiffman, MD, April G. Long, NP, Amy James, FNP, Phillip Alexander, NP
DOI:
http://dx.doi.org/10.1016/j.mayocp.2014.04.013
Source:
Mayo
Abstract
The treatment of chronic hepatitis C virus (HCV) is evolving rapidly. In 2014, the standard of care and new backbone of HCV treatment is the polymerase inhibitor sofosbuvir (SOF). Our treatment approach in patients with HCV genotype 1 is 12 weeks of SOF, peginterferon (PEGINF), and ribavirin (RBV). In patients with cirrhosis or extrahepatic manifestations of HCV who cannot tolerate PEGINF, we use 12 weeks of SOF and simeprevir. The latter is less costly and more effective than SOF and RBV for 24 weeks. Our treatment approach in all patients with genotype 2 is SOF and RBV for 12 weeks. Hepatitis C virus genotype 3 is now the most costly and difficult to cure. Our approach to treatment-naive patients with genotype 3 is SOF and RBV for 24 weeks. In patients who have previously undergone PEGINF and RBV treatment, we use PEGINF, SOF, and RBV for 12 weeks, which is equally if not more effective and less costly than SOF and RBV for 24 weeks. Patients with cirrhosis who cannot tolerate PEGINF should be treated for 24 weeks with SOF and RBV, although the sustained virologic response is suboptimal.
Chronic hepatitis C virus (HCV) affects an estimated 4 million persons in the United States and 300 million persons
worldwide.1x1Armstrong, G.L., Wasley, A., Simard, E.P., McQuillan, G.M., Kuhnert, W.L., and Alter, M.J. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006; 144: 705–714
CrossRef | PubMedSee all References1 In the 1960s through the 1980s, most US patients were infected with HCV through the transfusion of blood products and injection drug use. These patients have been infected for 30 to 50 years, and this is the primary driver for the increasing rates of cirrhosis and hepatocellular carcinoma (HCC) in the United States
today.2x2Davis, G.L., Alter, M.J., El-Serag, H., Poynard, T., and Jennings, L.W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010; 138: 513–521
Abstract | Full Text | Full Text PDF | PubMed | Scopus (253)See all References2 Many of these patients are asymptomatic, and the disease remains undiagnosed. The need to identify these patients is why the US Preventive Services Task Force and the Centers for Disease Control and Prevention have recommended that all persons born between 1945 and 1965 be screened for HCV.
3x3Moyer, V.A. and US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013; 159: 349–357
CrossRef | PubMed | Scopus (22)See all References, 4
Long-term studies conducted over the past 2 decades have found that a sustained virologic response (SVR) is long-lasting and that HCV can be “cured.”
5x5Swain, M.G., Lai, M.Y., Shiffman, M.L. et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010; 139: 1593–1601
Abstract | Full Text | Full Text PDF | PubMed | Scopus (81)See all References, 6x6Manns, M.P., Pockros, P.J., Norkrans, G. et al. Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin. J Viral Hepat. 2013; 20: 524–529
CrossRef | PubMed | Scopus (5)See all References Patients who achieve an SVR have improvement in liver histologic features and regression of fibrosis.
7x7George, S.L., Bacon, B.R., Brunt, E.M., Mihindukulasuriya, K.L., Hoffmann, J., and Di Bisceglie, A.M. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009; 49: 729–738
CrossRef | PubMed | Scopus (116)See all References, 8x8Shiffman, M.L., Hubbard, S., Long, A. et al. Five year prospective evaluation of liver histology in patients with chronic hepatitis C virus following treatment with interferon/peginterferon and ribavirin. J Hepatol. 2009; 50: S52
Abstract | Full Text PDFSee all References Patients with cirrhosis who achieve an SVR rarely experience hepatic decompensation and have a 10-fold decrease in the risk of HCC and a significant reduction in mortality.
9x9van der Meer, A.J., Veldt, B.J., Feld, J.J. et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012; 308: 2584–2593
CrossRef | PubMed | Scopus (67)See all References, 10x10Backus, L.I., Boothroyd, D.B., Phillips, B.R., Belperio, P., Halloran, J., and Mole, L.A. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol. 2011; 9: 509–516.e1
Abstract | Full Text | Full Text PDF | PubMed | Scopus (98)See all References, 11
For the past 15 years, interferon and then peginterferon (PEGINF) have been the backbone of HCV treatment on which ribavirin (RBV) and more recently HCV protease inhibitors have been
added.12x12Ferenci, P. Treatment of chronic hepatitis C—are interferons really necessary?. Liver Int. 2012; 32: 108–112
CrossRef | PubMed | Scopus (8)See all References12 In late 2013, the treatment of chronic HCV entered a new era when 2 new oral antiviral agents, simeprevir (SMV) and sofosbuvir (SOF), were approved by the US Food and Drug Administration (FDA). Simeprevir is a protease inhibitor, and its approval by the FDA was based on studies in which it was used with PEGINF and RBV in patients with HCV genotype
1.13x13You, D.M. and Pockros, P.J. Simeprevir for the treatment of chronic hepatitis C. Expert Opin Pharmacother. 2013; 14: 2581–2589
CrossRef | PubMed | Scopus (1)See all References13 Although SMV inhibits the NS3/4A protease like telaprevir (TPV) and boceprevir (BOC), it is taken only once daily, has fewer adverse effects and drug-drug interactions, and appears to have a somewhat higher SVR rate.
14
Sofosbuvir is a polymerase inhibitor that is highly effective in suppressing replication in all HCV
genotypes.15x15Koff, R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014; 39: 478–487
CrossRef | PubMed | Scopus (1)See all References15 It is also taken once daily and has few drug-drug interactions and minimal adverse effects. Resistance is extremely rare, and SVR rates of over 90% are achieved in most patients with HCV. In 2014, SOF has become the new backbone of HCV treatment.
The treatment of HCV continues to evolve rapidly. Several pharmaceutical companies have developed and are currently testing combinations of oral antiviral agents for HCV
(Table 1Table 1).16x16Kowdley, K.V., Lawitz, E., Poordad, F. et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014; 370: 222–232
CrossRef | PubMed | Scopus (7)See all References, 17x17Lawitz, E., Poordad, F.F., Pang, P.S. et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. () Lancet. 2014; 383: 515–523
Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References, 18x18Everson, G.T., Sims, K.D., Rodriguez-Torres, M. et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014; 146: 420–429
Abstract | Full Text | Full Text PDF | PubMed | Scopus (7)See all References, 19x19Lawitz, E, Hezode, C, Gane, E et al. Efficacy and safety of MK-5172 and MK-8742 ± ribavirin in hepatitis C genotype 1 infected patients with cirrhosis or previous null-response: the C-WORTHY Study. J Hepatol. 2014; 60: S25–26
Abstract | Full Text PDFSee all References, 20x20Zeuzem, S., Soriano, V., Asselah, T. et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013; 369: 630–639
CrossRef | PubMed | Scopus (46)See all References
Two of these treatments have already completed phase 3 clinical trials, and an all-oral antiviral treatment for HCV genotype 1 is expected to be available before the end of 2014. The current dilemma for physicians wanting to treat HCV and patients who want to be cured of this virus is not whether HCV should be treated but rather what agents should be used and when treatment should be initiated. This article summarizes the data that led to the FDA approval of SMV and SOF and describes our treatment approach to patients with chronic HCV in 2014. Given the rapid proliferation of new oral antiviral agent combinations for treatment of HCV, this approach will need to be modified in 2015.
Sofosbuvir is the first polymerase inhibitor to be approved by the FDA for the treatment of chronic
HCV.15x15Koff, R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014; 39: 478–487
CrossRef | PubMed | Scopus (1)See all References15 It is a nucleotide analogue that inhibits the NS5B polymerase and is effective in all HCV genotypes. Sofosbuvir is incorporated into the growing RNA sequence during replication and acts as a chain terminator. A specific sequence variation in the polymerase, S282T, is resistant to SOF by preventing incorporation of the nucleotide analogue into the growing polypeptide chain. However, this sequence variation also impacts the ability of HCV RNA to elongate with normal nucleotides and is therefore a nonviable sequence variation that cannot persist long-term. Resistance to SOF is therefore extremely uncommon and was not observed in any patient treated in the phase 3 clinical trials.
28x28Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887
CrossRef | PubMed | Scopus (119)See all References, 29x29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and 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
CrossRef | PubMed | Scopus (93)See all References, 30x30Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. () Hepatology. 2013; 58: 733ASee all References Virtually all patients treated with SOF have undetectable HCV RNA within 2 to 4 weeks of initiating treatment, and all patients are treated for a fixed duration (12 or 24 weeks) on the basis of their genotype.
Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5, and
6.28x28Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887
CrossRef | PubMed | Scopus (119)See all References28 This was a single-arm study with no comparison with PEGINF and RBV. More than 90% of patients treated with SOF triple therapy had undetectable HCV RNA within 2 weeks, and virtually all patients achieved an RVR. The overall SVR rate was 90%; the SVR rate was 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All 7 patients with HCV genotypes 5 and 6 achieved an SVR. Sofosbuvir triple therapy has not been evaluated in patients in whom either PEGINF and RBV or triple therapy with a protease inhibitor failed. However, because protease inhibitors and SOF have a completely different site of action, there is no virologic reason why SOF should not be equally effective in patients in whom treatment with a protease inhibitor failed. In treatment-naive patients with HCV genotype 1 who have the least favorable treatment response characteristics—Metavir fibrosis score of F3 or F4, high viral load,
IL28B non-CC genotype—the SVR rate with SOF, PEGINF, and RBV was 71%. In contrast, the SVR rate for patients with these characteristics treated with PEGINF and RBV with or without a protease inhibitor is only 3% to 50%. On the basis of these data, the FDA recommended that all patients with chronic HCV genotypes 1 and 4, regardless of treatment history, could be treated with SOF, PEGINF, and RBV for 12 weeks.
The combination of SOF and RBV represents the first interferon-free regimen approved by the FDA to treat patients with chronic HCV. Sofosbuvir and RBV were studied in 4 clinical trials in patients with genotypes 2 and
3.
28x28Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887
CrossRef | PubMed | Scopus (119)See all References, 29x29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and 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
CrossRef | PubMed | Scopus (93)See all References, 30x30Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. () Hepatology. 2013; 58: 733ASee all References In patients with HCV genotype 2, SOF and RBV for only 12 weeks yielded superior SVR rates compared with PEGINF and RBV for 24 weeks. In patients without cirrhosis, SOF and RBV achieved SVR rates of 90% to 97%. In patients with cirrhosis, the SVR ranged from 60% to 94%. The lowest SVR in patients with genotype 2 was observed in a single study that included only 10 patients in whom previous treatment with PEGINF and RBV had
failed.29x29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and 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
CrossRef | PubMed | Scopus (93)See all References29 Extending the duration of SOF and RBV from 12 to 16 weeks in this study yielded an SVR of 78%. Excluding this one study, the SVR in patients with cirrhosis was 90%. The overall SVR rate for all patients with cirrhosis included in all 4 registration studies was 84%; in patients with cirrhosis and previous PEGINF and RBV treatment, the SVR was 82%. On the basis of these data, the FDA recommended that all patients with genotype 2 could be treated with SOF and RBV for 12 weeks.
In patients with genotype 3, treatment with SOF and RBV for 12 weeks yielded an SVR rate of only 61% to 68% in treatment-naive patients without cirrhosis and 21% to 34% in patients with
cirrhosis.
28x28Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887
CrossRef | PubMed | Scopus (119)See all References, 29x29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and 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
CrossRef | PubMed | Scopus (93)See all References, 30x30Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. () Hepatology. 2013; 58: 733ASee all References These SVR rates are somewhat lower, or at best similar, to that observed with 24 weeks of PEGINF and RBV. In patients in whom previous PEGINF and RBV therapy failed, 12 weeks of SOF and RBV yielded SVR rates of only 19% and 37% in patients with and without cirrhosis, respectively. Extending the duration of SOF and RBV to 16 weeks in patients with previous PEGINF and RBV failure did not significantly change the SVR in patients without cirrhosis but increased the SVR in patients with cirrhosis to 61%. The highest SVR rates in patients with genotype 3 were observed when the duration of SOF and RBV was extended to 24 weeks.
In the treatment-naive population, the SVR rate was 92% to 93% in patients with or without cirrhosis. In patients in whom previous treatment with PEGINF and RBV failed, 24 weeks of SOF and RBV achieved an SVR rate of 85% in patient without cirrhosis but only 60% in patients with
cirrhosis.30x30Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. () Hepatology. 2013; 58: 733ASee all References30 On the basis of these data, the FDA recommended that all patients with HCV genotype 3 could be treated with SOF and RBV for 24 weeks.
Sofosbuvir and RBV were also studied in patients with genotypes 1, 2, and 3 who had coinfection with human immunodeficiency virus
(HIV).31x31Sulkowski, M.S., Rodriguez-Torres, M., Lalezari, J.P. 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: 313ASee all References31 The duration of treatment was 24 weeks for patients with genotypes 1 and 3 and 12 weeks for patients with HCV genotype 2. Sustained virologic response rates of 76%, 88%, and 92% were observed for patients with genotypes 1, 2, and 3, respectively. This study led the FDA to approve SOF and RBV for the treatment of HCV in patients coinfected with HIV. This represents the first antiviral agent to be approved for treatment of HCV-HIV coinfection. The results of this study supported the FDA recommendation to use SOF and RBV for 24 weeks in patients with HCV genotype 1 who had intolerance or contraindications to the use of PEGINF.
Sofosbuvir and RBV have also been studied without PEGINF in patients with HCV and HCC awaiting liver transplant and in patients with post–liver transplant HCV recurrence. The pretransplant HCC study patients who met criteria for the MELD exception were treated with SOF and RBV up until the time they underwent liver
transplant.32x32Curry, M.P., Forns, X., Chung, R.T. et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. () Hepatology. 2013; 58: 314A
PubMedSee all References32
Treatment was stopped at the time of the transplant. Overall, 64% of patients did not have HCV recurrence after the transplant. In patients with undetectable HCV RNA for at least 30 days before undergoing transplant, 95% did not experience HCV recurrence. These data led the FDA to approve SOF and RBV for use in patients with HCC awaiting liver transplant.
Two studies have been conducted in the post–liver transplant
population.
33x33See all References, 34x34Forns, X., Fontana, R.J., Moonka, D. et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. () Hepatology. 2013; 58: 732ASee all References One study included patients with stable normal graft function at least 6 months after
transplant.33x33See all References33 These patients were treated with SOF and RBV for 24 weeks. Of the 40 patients in this study, 83% had genotype 1. All patients had undetectable HCV RNA within 4 weeks of initiating SOF and RBV. Only data on HCV RNA undetectable 4 weeks after stopping treatment (SVR-4) are available to date, but this level was achieved in 77% of the patients. The other posttransplant study was a compassionate use program for patients with severe HCV recurrence after
transplant.34x34Forns, X., Fontana, R.J., Moonka, D. et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation. () Hepatology. 2013; 58: 732ASee all References34 Most of these patients had either fibrosing cholestatic hepatitis within the first year or had development of decompensated recurrent cirrhosis 2 or more years after their transplant. Of the 20 patients treated with SOF and RBV for 24 weeks, all had undetectable HCV RNA, 64% had clinical improvement, and 60% achieved an SVR; 30% of patients died of complications of their advanced liver disease despite achieving a virologic response.
Sofosbuvir is an extremely safe antiviral agent with minimal adverse
effects.15x15Koff, R.S. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014; 39: 478–487
CrossRef | PubMed | Scopus (1)See all References15 In a study in which SOF and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only adverse effects occurring more frequently with SOF and RBV than with placebo were anemia and pruritus, both of which were attributed to
RBV.29x29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and 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
CrossRef | PubMed | Scopus (93)See all References29 In the 5 phase 3 clinical trials, the drop-out rate due to adverse events was greatest in the placebo-treated group (4%); the drop-out rate was only 2% in patients treated with PEGINF, SOF, and RBV for 12 weeks and less than 1% in all SOF and RBV treatment groups.
Combining SOF and SMV in Patients With Genotype 1
The combination of SOF and SMV for either 12 or 24 weeks with or without RBV has been evaluated in 167 patients with HCV genotype
1.35x35See all References35 No single arm of this 2-cohort, 4-arm study had more than 54 patients, and only SVR-4 data are currently available for half the patients. However, the results are extremely noteworthy. Sustained virologic response rates of 93% to 100% were observed in all but one of the groups regardless of whether patients were treated for 12 or 24 weeks and whether they received RBV or not. The lowest SVR (79%) was observed in the group treated with SOF, SMV, and RBV for 24 weeks in which 4 patients had nonvirologic failure. All 14 patients with cirrhosis achieved SVR-4 within just 12 weeks of initiating SOF and SMV. Of the 7 patients with cirrhosis and previous nonresponse, all achieved SVR. In patients with genotype 1a and the Q80K sequence variation, the SVR rate was 90%. In patients without this sequence variation, the SVR rate was 100%.
Adding PEGINF to SOF and RBV in Patients With Genotype 3
Of all patients with HCV, those with genotype 3 have the most difficulty achieving a cure. Many believe this is difficulty is related to the much higher hepatic content of micovesicular steatosis that is unique to patients with HCV genotype
3.36x36Restivo, L., Zampino, R., Guerrera, B., Ruggiero, L., and Adinolfi, L.E. Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-α-2a plus ribavirin and RVR. J Viral Hepat. 2012; 19: 346–352
CrossRef | PubMed | Scopus (6)See all References36 Sustained virologic response in patients with genotype 3 is also negatively impacted by previous nonresponse to PEGINF and RBV. In patients without cirrhosis, a previous nonresponse to PEGINF and RBV is associated with a reduction in SVR from 93% to 85%, and in those with cirrhosis, the SVR is reduced from 92% to 60%.
28x28Lawitz, E., Mangia, A., Wyles, D. et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368: 1878–1887
CrossRef | PubMed | Scopus (119)See all References, 29x29Jacobson, I.M., Gordon, S.C., Kowdley, K.V...., and 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
CrossRef | PubMed | Scopus (93)See all References, 30x30Zeuzem, S., Dusheiko, G.M., Salupere, R. et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. () Hepatology. 2013; 58: 733ASee all References This negative impact of previous PEGINF and RBV treatment is also observed in patients with genotype 2 but to a far lesser extent. In patients with genotype 2 who have previously undergone PEGINF and RBV treatment, the SVR in response to SOF and RBV is reduced from 97% to 91% in those without cirrhosis and from 100% to 88% in those with cirrhosis.
The SVR in patients with HCV genotype 3, especially patients previously treated with PEGINF and RBV, appears to be enhanced by adding PEGINF to SOF and
RBV.37x37See all References37 In a small study of only 24 patients with genotype 3 and previous nonresponse to PEGINF and RBV (half of whom had cirrhosis), 12 weeks of treatment with PEGINF, SOF, and RBV yielded an SVR of 83% in patients with and without cirrhosis. In the same study, 14 patients with HCV genotype 2, cirrhosis, and previous nonresponse to PEGINF and RBV achieved an SVR of 93% when re-treated with PEGINF, SOF, and RBV.
Our Treatment Approach
In January 2014, a joint guideline for treating HCV was issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of
America.38x38See all References38 These recommendations and the FDA recommendations for use of
SOF39x39See all References39 are summarized in
Table 2Table 2. Our treatment approach to chronic HCV at the Liver Institute of Virginia in 2014 is based on the available data and focuses on maximizing SVR while also respecting the cost of treatment
(Table 2Table 2). In several situations, we believe the American Association for the Study of Liver Diseases/Infectious Diseases Society of America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.
Table 22014 Treatment Recommendations for Patients With HCV
Variable | AASLD/IDSA | FDA | LIV |
Genotype 1: Treatment naive and prior PEGINF and RBV relapse |
INF tolerant, no cirrhosis or compensated cirrhosis | PEGINF, SOF, and RBV for 12 wk |
INF intolerant, no cirrhosis | SOF and SMV ± RBV for 12 wk | SOF and RBV for 24 wk | Defer treatment |
INF intolerant, cirrhosis |
|
| SOF and SMV for 12 wk |
Genotype 1: Prior PEGINF and RBV nonresponse |
INF tolerant, no cirrhosis or compensated cirrhosis | SOF and SMV ± RBV for 12 wk | PEGINF, SOF, and RBV for 12 wk |
INF intolerant, no cirrhosis | SOF and SMV ± RBV for 12 wk | SOF and RBV for 24 wk | Defer treatment |
INF intolerant, cirrhosis |
|
| SOF and SMV for 12 wk |
Genotype 1: Prior treatment with PEGINF, RBV, and TPV or BOC |
INF tolerant, no cirrhosis or compensated cirrhosis | SOF for 12 wk, PEGINF and RBV for 12-24 wk | PEGINF, SOF, and RBV for 12 wk |
INF intolerant, no cirrhosis | NR | SOF and RBV for 24 wk | Defer treatment |
INF intolerant, cirrhosis |
|
| SOF and SMV for 12 wk |
Genotype 2 |
Treatment naive or PEGINF-RBV relapse, no cirrhosis or compensated cirrhosis | SOF and RBV for 12 wk | SOF and RBV for 12 wk | SOF and RBV for 12 wk |
Prior PEGINF-RBV nonresponse, no cirrhosis | SOF and RBV for 12 wk |
|
|
Prior PEGINF-RBV nonresponse, cirrhosis | SOF and RBV for 12-16 wk |
|
|
Genotype 3 |
Treatment naive | SOF and RBV for 24 wk | SOF and RBV for 24 wk | SOF and RBV for 24 wk |
Prior PEGINF-RBV, INF tolerant, no cirrhosis or compensated cirrhosis |
|
| PEGINF, SOF, and RBV for 12 wk |
Prior PEGINF-RBV, INF intolerant, no cirrhosis |
|
| Defer treatment |
Prior PEGINF-RBV, INF intolerant, cirrhosis |
|
| SOF and RBV for 24 wk |
Genotype 4 |
INF tolerant | PEGINF, SOF, and RBV for 12 wk |
INF intolerant | SOF and RBV for 24 wk | SOF and SMV for 12 wk |
Genotypes 5 and 6 |
INF tolerant | PEGINF, SOF, and RBV for 12 wk | NA | PEGINF, SOF, and RBV for 12 wk |
INF intolerant | NR | NA | SOF and RBV for 24 wk |
Genotypes 1, 4, 5, and 6
Genotype 1 is the most common form of HCV worldwide. Genotype 4 is the dominant genotype in Egypt and the Middle East, genotype 5 is frequent in South Africa, and genotype 6 is common in Vietnam and
Cambodia.40x40Nguyen, M.H. and Keeffe, E.B. Chronic hepatitis C: genotypes 4 to 9. Clin Liver Dis. 2005; 9: 411–426
Abstract | Full Text | Full Text PDF | PubMed | Scopus (29)See all References40 In the United States, genotypes 4 through 6 are uncommon and rarely seen except in immigrants from the aforementioned regions of the world.
In patients with genotypes 1, 4, 5, or 6 without cirrhosis, our treatment approach is PEGINF, SOF, and RBV for 12 weeks. The SVR rate is 92% or greater, and less than 2% of these patients will be unable to tolerate this regimen. For patients who have not achieved an SVR during previous treatment with PEGINF and RBV or PEGINF, RBV, and either TPV or BOC, our approach is the same. Patients without cirrhosis who prefer not to be treated with PEGINF or have intolerance or contraindications to PEGINF can defer treatment and wait for an FDA-approved all-oral antiviral combination. Two such regimens are expected to be available before 2015. We do not promote either SOF and RBV for 24 weeks or SOF and SMV for 12 weeks in patients without cirrhosis.
In patients with cirrhosis and genotypes 1, 4, 5, or 6, our approach is still PEGINF, SOF, and RBV for 12 weeks as long as the platelet count and serum albumin level are normal and there is no history of hepatic decompensation or evidence of esophageal varices or subclinical hepatic encephalopathy. In contrast, we would not treat patients with cirrhosis and any of these laboratory or clinical abnormalities with a PEGINF-containing regimen. In a previous study in which patients with these characteristics were treated with PEGINF, RBV, and either TPV or BOC, more than half experienced severe anemia, 25% discontinued treatment, and 1% to 2% died as a result of hepatic
decompensation.41x41Hézode, C., Fontaine, H., Dorival, C...., and CUPIC Study Group. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013; 59: 434–441
Abstract | Full Text | Full Text PDF | PubMed | Scopus (65)See all References41 In our opinion, the risk that this poor outcome could also occur with a 12-week PEGINF and RBV–containing regimen is considerable. In addition, the SVR that could be achieved with PEGINF, SOF, and RBV is reduced to 80% or less in such patients.
In patients with genotype 1 or 4 and cirrhosis who have intolerance or contraindications to PEGINF, our treatment approach is SOF and SMV for 12 weeks. In patients with HCV-induced extrahepatic manifestations such as symptomatic cryoglobulinemia, glomerulonephritis, or B-cell lymphoma, regardless of fibrosis stage, we also use SOF and SMV. We do not believe that testing for the Q80K sequence variation is necessary when treating patients who have genotype 1a with SOF and SMV. The SVR when this sequence variation is present is still 90%, and there is no suggestion from the data that adding RBV or extending the duration of therapy to 24 weeks enhances SVR. We do not recommend 24 weeks of SOF and RBV in these patients; the cost of this regimen is prohibitive, and the SVR rate is estimated to be only in the 70% to 75% range, approximately 20% lower than that observed with SOF and SMV. We also do not recommend deferring treatment in this population, and payers should recognize their need for treatment. These patients have cirrhosis, are at risk for development of severe and life-threatening complications of cirrhosis, and should not have to wait for an alternative all-oral regimen.
In patient with genotypes 5 or 6, cirrhosis, and intolerance or contraindications to PEGINF, we use SOF and RBV for 24 weeks. Although this regimen is costly, this group represents only a limited number of patients with HCV, and no alternative treatment is on the horizon. Simeprevir has activity against HCV genotypes 5 and 6 in vitro, but without any clinical data to support its use, it is difficult to recommend this treatment.
Our treatment approach to patients with HCV genotype 1 does not include TPV, BOC, or SMV in combination with PEGINF and RBV. All of these antiviral agents have a lower SVR rate and require a longer duration of PEGINF and RBV compared with an SOF-containing
regimen.
Genotype 2
Our treatment approach for all patients with genotype 2, regardless of fibrosis stage, is SOF and RBV for 12 weeks. This group includes patients with cirrhosis in whom PEGINF and RBV failed previously. The SVR rate in this nonresponse subpopulation with cirrhosis is 88% but exceeds 90% in all other subpopulations. A more effective, less costly regimen is unlikely to be developed for patients with HCV genotype 2 in the foreseeable future.
Genotype 3
Patients with genotype 3 are now the most difficult and costly to treat and the most controversial regarding recommendations for treatment. Treatment-naive patients, regardless of the degree of fibrosis, require twice the duration of SOF and RBV (24 weeks) and twice the cost to achieve an SVR of at least 90%. We believe that SOF, RBV, and PEGINF for 12 weeks would yield an SVR of at least 90% and be more cost-effective, but with no data in the treatment-naive population, this approach is difficult to adopt. Therefore, our approach to treatment-naive patients with genotype 3 with or without cirrhosis is SOF and RBV for 24 weeks.
In patients with genotype 3 who have previously undergone PEGINF and RBV treatment and do not have cirrhosis, 24 weeks of SOF and RBV is nearly twice as costly yet offers an SVR similar to 12 weeks of PEGINF, SOF, and RBV (85% vs 83%, respectively). Because only 12 weeks of PEGINF is generally tolerated, we use the cheaper regimen (PEGINF, SOF, and RBV for 12 weeks). Patients with genotype 3 who do not have cirrhosis and are intolerant of PEGINF can defer treatment until a more cost-effective therapy is available. In patients with cirrhosis who do not have contraindications to PEGINF, our approach is to also use PEGINF, SOF, and RBV. The SVR with this treatment is also 83% compared with only 60% for 24 weeks of SOF and RBV. In patients with cirrhosis that is too advanced for PEGINF (see criteria outlined in the “Genotypes 1, 4, 5, and 6” section) and patients with PEGINF intolerance for other reasons, we have no choice but to use the inferior and more costly treatment (SOF and RBV for 24 weeks).
Recommendations
For 2014, SOF has replaced PEGINF as the backbone of HCV therapy. Sofosbuvir is superior to all other currently available antiviral agents with respect to efficacy, adverse effects, drug-drug interactions, viral resistance, and duration of therapy. Peginterferon should still be used in many patients with genotype 1 and in selected patients with genotype 3 because it offers higher efficacy and is less costly than 24 weeks of SOF and RBV. In 2015, another era of HCV treatment will begin, and our need for PEGINF and possibly RBV will no longer exist. Patients with genotype 1 and no cirrhosis may choose to defer treatment until then.
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