- Email: [email protected]
My Treatment Approach to Chronic Hepatitis C Virus
DIAGNOSIS & TREATMENT GUIDELINES My Treatment Approach
My Treatment Approach to Chronic Hepatitis C Virus Mitchell L. Shiffman, MD; April G. Long, NP; Amy James, FNP; and Phillip Alexander, NP 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. ª 2014 Mayo Foundation for Medical Education and Research
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hronic hepatitis C virus (HCV) affects an estimated 4 million persons in the United States and 300 million persons worldwide.1 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.2 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.3,4 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.”5,6 Patients who achieve an SVR have improvement in liver histologic features and regression of fibrosis.7,8 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.9-11 For the past 15 years, interferon and then peginterferon (PEGINF) have been the backbone
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of HCV treatment on which ribavirin (RBV) and more recently HCV protease inhibitors have been added.12 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 1.13 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.15 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 1).16-20 Two of these treatments have
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From the Liver Institute of Virginia, Bon Secours Health System, Richmond, and Newport News, VA.
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TABLE 1. Interferon-Free All-Oral Combination Therapies for Patients With HCV Genotype 1 That Are Anticipated to Be Available During 2015 Company
Protease inhibitor
Polymerase inhibitor
NS5A replication complex inhibitor
AbbVie Inc Gilead Sciences Boehringer-Ingelheim Bristol-Myers-Squibb Merck & Co, Inc
ABT-245/r . Faldaprevir Asunaprevir MK-5172
. Sofosbuvir . . .
ABT-267 Ledipasvir Deleobuvir Daclatasvir MK-8742
Non-nucleotide polymerase inhibitor
Anticipated approval
ABT-333 . . 791325 .
4th quarter, 2014 3rd quarter, 2014 2nd quarter, 2015 3rd quarter, 2015 4th quarter, 2015
Ellipses indicate not applicable.
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. SIMEPREVIR Simeprevir is a pangenotypic NS3/4A protease inhibitor that is effective in vitro against HCV genotypes 1 through 6.21 To date, clinical trials have been completed only in patients with genotype 1. A study in patients with HCV genotype 4 is currently under way. Preliminary data from this study suggest that PEGINF, SOF, and RBV could achieve SVR rates approaching 80%.22 Simeprevir is highly effective and has been approved by the FDA for treatment of patients with chronic HCV genotype 1. Simeprevir binds to the same site as TPV and BOC. It has not been studied in patients in whom TPV or BOC treatment failed or resistance to TPV or BOC developed. Given its mechanism of action, it is unlikely to be effective and should not be used in these patients.13 Simeprevir is used as triple therapy with PEGINF and RBV for 12 weeks, followed by an additional 12 weeks of PEGINF and RBV (total duration of therapy, 24 weeks) in all patients who are treatment naive or who have had a relapse while taking PEGINF and RBV, including those with cirrhosis. Approximately 2
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80% of patients achieve a rapid virologic response (RVR), and HCV RNA is undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately 90%.23-25 As opposed to TPV and BOC, for which the duration of therapy is adjusted on the basis of whether an RVR is achieved, response-guided therapy is not necessary with SMV. In patients who have no response to PEGINF and RBV, 12 weeks of SMV, PEGINF, and RBV is followed by 36 weeks of PEGINF and RBV (total duration of therapy, 48 weeks). The SVR rate in these patients is 53% to 65%.26 All patients with HCV RNA levels greater than 25 IU/mL at weeks 4, 12, or 24 should stop treatment. Although controlled clinical trials comparing the SVR rates of the 3 protease inhibitors have not been conducted, each has been evaluated against a placebo control with PEGINF and RBV. Comparison of the improvement in SVR over control for the 3 protease inhibitors suggests that RVR and SVR rates are somewhat higher with SMV compared with TPV or BOC.13 Simeprevir offers considerable advantages over TPV and BOC, the most important of which is that SMV does not cause additional anemia compared with PEGINF and RBV.23-26 In phase 2 and 3 clinical trials, patients treated with SMV, PEGINF, and RBV did not have any adverse events with greater frequency than those taking PEGINF and RBV. Simeprevir is taken as a single once-daily tablet, no special diet is required, and far fewer drug-drug interactions have been observed. The success in patients treated with SMV, like other protease inhibitors, is dependent on an effective interferon response, which is modulated by IL28B genotype.27 In treatmentnaive patients, the SVR approaches 90% in patients with IL28B CC genotype and declines in
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patients with the CT and TT genotypes.23,24 In patients with a previous nonresponse to PEGINF and RBV, the SVR rates during retreatment with SMV triple therapy follow a similar trend of interferon responsiveness: higher rates of SVR with a previous partial response and lower SVR rates in previous nonresponders.26 The primary limitation of SMV is that a sequence variation at the Q80K loci of HCV significantly limits the antiviral efficacy of this protease inhibitor and reduces SVR to values that are similar to that achieved with PEGINF and RBV.23-26 This sequence variation is present in about 40% of patients with HCV genotype 1a. It is not present in HCV genotype 1b. The FDA has suggested that all patients with genotype 1a undergo resistance testing for the presence of the Q80K sequence variation in HCV and that the physician strongly consider using a treatment other than SMV if this sequence variation is present. The Q80K sequence variation has the greatest impact and considerably lowers SVR in patients who are genetically less sensitive to PEGINF. In contrast, patients with IL28B CC genotype, who are highly sensitive to interferon, have similar SVR rates regardless of the presence or absence of the Q80K sequence variation.23-26 We therefore disagree with the FDA recommendations somewhat and strongly believe that patients with HCV genotype 1a and Q80K who have IL28B CC genotype could be treated successfully with SMV, PEGINF, and RBV. We do not recommend and we do not treat our patients who have HCV genotype 1 with SMV, PEGINF, and RBV. However, if a physician or payer chooses this regimen, our recommendation would be to test those patients with genotype 1a for IL28B genotype. If the patient has IL28B CC genotype, then no viral resistance testing is necessary. If the patient has IL28B CC or TT genotype, the patient would then need to be tested for Q80K, and if absent, they could also be treated with SMV, PEGINF, and RBV. In contrast, if the patient has IL28B CT or TT genotype and Q80K sequence variation, we would not recommend SMV. SOFOSBUVIR Sofosbuvir is the first polymerase inhibitor to be approved by the FDA for the treatment of chronic HCV.15 It is a nucleotide analogue Mayo Clin Proc. n XXX 2014;nn(n):1-9 www.mayoclinicproceedings.org
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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.28-30 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 6.28 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 characteristicsdMetavir fibrosis score of F3 or F4, high viral load, IL28B non-CC genotypedthe 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
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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 3.28-30 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.29 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 treatmentnaive patients without cirrhosis and 21% to 34% in patients with cirrhosis.28-30 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 4
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rate of 85% in patient without cirrhosis but only 60% in patients with cirrhosis.30 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).31 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 posteliver 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.32 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 posteliver transplant population.33,34 One study included patients with stable normal graft function at least 6 months after transplant.33 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
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patients with severe HCV recurrence after transplant.34 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.15 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.29 In the 5 phase 3 clinical trials, the drop-out rate due to adverse events was greatest in the placebo-treated group (4%); the dropout 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 1.35 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%. Mayo Clin Proc. n XXX 2014;nn(n):1-9 www.mayoclinicproceedings.org
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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 3.36 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%.28-30 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.37 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.38 These recommendations and the FDA recommendations for use of SOF39 are summarized in Table 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 2). In several situations, we believe the American Association for the Study of Liver Diseases/Infectious Diseases Society of
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TABLE 2. 2014 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 PEGINF, SOF, and RBV for 12 wk cirrhosis INF intolerant, no cirrhosis SOF and SMV RBV for 12 wk SOF and RBV for 24 wk INF intolerant, cirrhosis Genotype 1: Prior PEGINF and RBV nonresponse INF tolerant, no cirrhosis or compensated SOF and SMV RBV for 12 wk PEGINF, SOF, and cirrhosis INF intolerant, no cirrhosis SOF and SMV RBV for 12 wk SOF and RBV for 24 wk INF intolerant, cirrhosis Genotype 1: Prior treatment with PEGINF, RBV, and TPV or BOC INF tolerant, no cirrhosis or compensated SOF for 12 wk, PEGINF and RBV PEGINF, SOF, and cirrhosis for 12-24 wk INF intolerant, no cirrhosis NR SOF and RBV for 24 wk INF intolerant, cirrhosis Genotype 2 Treatment naive or PEGINF-RBV relapse, SOF and RBV for 12 wk SOF and RBV for 12 wk no cirrhosis or compensated cirrhosis Prior PEGINF-RBV nonresponse, no SOF and RBV for 12 wk cirrhosis 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 Prior PEGINF-RBV, INF tolerant, no cirrhosis or compensated cirrhosis Prior PEGINF-RBV, INF intolerant, no cirrhosis Prior PEGINF-RBV, INF intolerant, cirrhosis Genotype 4 INF tolerant PEGINF, SOF, and RBV for 12 wk INF intolerant SOF and RBV for 24 wk Genotypes 5 and 6 INF tolerant PEGINF, SOF, and RBV NA for 12 wk INF intolerant NR NA
Defer treatment SOF and SMV for 12 wk RBV for 12 wk Defer treatment SOF and SMV for 12 wk RBV for 12 wk Defer treatment SOF and SMV for 12 wk SOF and RBV for 12 wk
SOF and RBV for 24 wk PEGINF, SOF, and RBV for 12 wk Defer treatment SOF and RBV for 24 wk
SOF and SMV for 12 wk PEGINF, SOF, and RBV for 12 wk SOF and RBV for 24 wk
AASLD ¼ American Association for the Study of Liver Diseases; BOC ¼ boceprevir; FDA ¼ Food and Drug Administration; IDSA ¼ Infectious Diseases Society of America; INF ¼ interferon; LIV ¼ Liver Institute of Virginia; NA ¼ not approved; NR ¼ no recommendation; PEGINF ¼ peginterferon; RBV ¼ ribavirin; SMV ¼ simeprevir; SOF ¼ sofosbuvir; TPV ¼ telaprevir.
America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.
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.40 In the United States, genotypes 4 through 6 are uncommon and rarely seen except in immigrants from the aforementioned regions of the world. 6
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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
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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.41 In our opinion, the risk that this poor outcome could also occur with a 12-week PEGINF and RBVecontaining 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 Mayo Clin Proc. n XXX 2014;nn(n):1-9 www.mayoclinicproceedings.org
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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 SOFcontaining regimen.14 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
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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. Abbreviations and Acronyms: BOC = boceprevir; FDA = Food and Drug Administration; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HIV = human immunodeficiency virus; PEGINF = peginterferon; RBV = ribavirin; RVR = rapid virologic response; SMV = simeprevir; SOF = sofosbuvir; SVR = sustained virologic response; SVR-4 = HCV RNA undetectable 4 weeks after stopping treatment; TPV = telaprevir Potential Competing Interests: Dr Shiffman has participated in advisor meetings with Achillion Pharmaceuticals, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Gen-Probe, Inc, Globeimmune Inc, GlaxoSmithKline, Janssen Pharmaceutical Companies, Merck & Co, Inc, Novartis Corp, Genentech, Inc, and Vertex Pharmaceuticals Inc; is on the speakers’ bureau for Bayer AG, Gilead Sciences, Janssen Pharmaceutical Companies, Merck & Co, Inc, Genentech, Inc, and Vertex Pharmaceuticals Inc; and receives grant support from Abbott Laboratories, Achillion Pharmaceuticals, Inc, Beckman Coulter, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Globeimmune Inc, Idenix Pharmaceuticals, Inc, Intercept Pharmaceuticals, Inc, Merck & Co, Inc, Mochida Pharmaceutical Co, Inc, Novartis Corp, and Genentech, Inc. Ms Long has participated in advisor meetings with AbbVie Inc, Gilead Sciences, Janssen Pharmaceutical
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Companies, Kadmon Pharmaceuticals, Merck & Co, Inc, and Vertex Pharmaceuticals Inc and is on the speakers’ bureau for Merck & Co, Inc, GlaxoSmithKline, Kadmon Pharmaceuticals, Salix Pharmaceuticals, Inc, and Vertex Pharmaceuticals Inc. Ms James has participated in advisor meetings with Gilead Sciences and Janssen Pharmaceutical Companies and is on the speakers’ bureau for Janssen Pharmaceutical Companies. Mr Alexander has participated in advisor meetings with Gilead Sciences. Correspondence: Address to Mitchell L. Shiffman, MD, Liver Institute of Virginia, Bon Secours Health System, 5855 Bremo Rd, Ste 509, Richmond, VA 23226 ([email protected]).
REFERENCES 1. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-714. 2. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. 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(2):513-521. 3. Moyer VA; 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(5):349-357. 4. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 19451965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. 5. Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology. 2010; 139(5):1593-1601. 6. Manns MP, Pockros PJ, Norkrans G, et al. Long-term clearance of hepatitis C virus following interferon a-2b or peginterferon a-2b, alone or in combination with ribavirin. J Viral Hepat. 2013;20(8):524-529. 7. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009;49(3):729-738. 8. Shiffman ML, 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(suppl 1):S52. 9. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593. 10. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic response reduces risk of allcause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol. 2011;9(6):509-516.e1. 11. Morgan TR, Ghany MG, Kim HY, et al; HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52(3):833-844. 12. Ferenci P. Treatment of chronic hepatitis Cdare interferons really necessary? Liver Int. 2012;32(suppl 1):108-112. 13. You DM, Pockros PJ. Simeprevir for the treatment of chronic hepatitis C. Expert Opin Pharmacother. 2013;14(18):2581-2589. 14. Shiffman ML, Benhamou Y. Patients with HCV and F1 and F2 fibrosis stage: treat now or wait? Liver Int. 2013;33(suppl 1):105-110. 15. Koff RS. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the
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16.
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treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther. 2014;39(5):478-487. Kowdley KV, 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(3):222-232. Lawitz E, Poordad FF, Pang PS, 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 openlabel, randomised, phase 2 trial [published correction appears in Lancet. 2014;383(9920):870]. Lancet. 2014;383(9916): 515-523. Everson GT, Sims KD, 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(2): 420-429. Lawitz E, Hezode C, Gane E, et al. Efficacy and safety of MK5172 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(suppl 1):S25-26. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369(7):630-639. Talwani R, Heil EL, Gilliam BL, Temesgen Z. Simeprevir: a macrocyclic HCV protease inhibitor. Drugs Today (Barc). 2013;49(12):769-779. Moreno C, Hezode C, Marcellin P, et al. Simeprevir with peginterferon/ribavirin in treatment-naïve or -experienced patients with chronic HCV genotype 4 infection: a phase III study. Paper presented at: 14th European AIDs Conference; October 1619, 2013; Brussels, Belgium. Manns M, Marcellin P, Poordad FPF, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial [abstract 1413]. J Hepatol. 2013; 58(suppl 1):S568. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype1 infection in treatment-naïve patients: results from QUEST-1 a phase III trial [abstract 1425]. J Hepatol. 2013;58(suppl 1):S574. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial [published online ahead of print March 3, 2014]. Gastroenterology. http://dx.doi.org/10.1053/j.gastro.2014.02.051. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146(2):430-441. Thompson AJ, Muir AJ, Sulkowski MS, et al. IL28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139(1):120-129.e18. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013; 368(20):1878-1887. Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in
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patients without treatment options. N Engl J Med. 2013; 368(20):1867-1877. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir þ ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial [AASLD abstract 1085]. Hepatology. 2013;58(4, suppl):733A. 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) [AASLD abstract 212]. Hepatology. 2013;58(4, suppl):313A. Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation [AASLD abstract 213]. Hepatology. 2013;58(4, suppl):314A. Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study [AASLD abstract LB2]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC. Forns X, Fontana RJ, Moonka D, et al. Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV following liver transplantation [AASLD abstract 1084]. Hepatology. 2013;58(4, suppl):732A. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and noncirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study [AASLD abstract LB3]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC. Restivo L, Zampino R, Guerrera B, Ruggiero L, Adinolfi LE. Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-a-2a plus ribavirin and RVR. J Viral Hepat. 2012; 19(5):346-352. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study [AASLD abstract LB4]. Paper presented at AASLD annual meeting, November 4, 2014, Washington DC. American Association for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for Testing, Managing, and Treating Hepatitis C. http://www. hcvguidelines.org/full-report-view. Revised March 21, 2014. Accessed April 19, 2014. Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc; December 2013. http://www.gilead.com/w/media/Files/pdfs/ medicines/liver-disease/sovaldi/sovaldi_pi.pdf. Nguyen MH, Keeffe EB. Chronic hepatitis C: genotypes 4 to 9. Clin Liver Dis. 2005;9(3):411-426. Hézode C, Fontaine H, Dorival C, et al; CUPIC Study Group. Triple therapy in treatment-experienced patients with HCVcirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol. 2013;59(3):434-441.
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My Treatment Approach to Chronic Hepatitis C Virus Mitchell L. Shiffman, MD; April G. Long, NP; Amy James, FNP; and Phillip Alexander, NP 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. ª 2014 Mayo Foundation for Medical Education and Research
C
hronic hepatitis C virus (HCV) affects an estimated 4 million persons in the United States and 300 million persons worldwide.1 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.2 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.3,4 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.”5,6 Patients who achieve an SVR have improvement in liver histologic features and regression of fibrosis.7,8 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.9-11 For the past 15 years, interferon and then peginterferon (PEGINF) have been the backbone
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of HCV treatment on which ribavirin (RBV) and more recently HCV protease inhibitors have been added.12 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 1.13 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.15 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 1).16-20 Two of these treatments have
Mayo Clin Proc. n XXX 2014;nn(n):1-9 n http://dx.doi.org/10.1016/j.mayocp.2014.04.013 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
From the Liver Institute of Virginia, Bon Secours Health System, Richmond, and Newport News, VA.
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TABLE 1. Interferon-Free All-Oral Combination Therapies for Patients With HCV Genotype 1 That Are Anticipated to Be Available During 2015 Company
Protease inhibitor
Polymerase inhibitor
NS5A replication complex inhibitor
AbbVie Inc Gilead Sciences Boehringer-Ingelheim Bristol-Myers-Squibb Merck & Co, Inc
ABT-245/r . Faldaprevir Asunaprevir MK-5172
. Sofosbuvir . . .
ABT-267 Ledipasvir Deleobuvir Daclatasvir MK-8742
Non-nucleotide polymerase inhibitor
Anticipated approval
ABT-333 . . 791325 .
4th quarter, 2014 3rd quarter, 2014 2nd quarter, 2015 3rd quarter, 2015 4th quarter, 2015
Ellipses indicate not applicable.
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. SIMEPREVIR Simeprevir is a pangenotypic NS3/4A protease inhibitor that is effective in vitro against HCV genotypes 1 through 6.21 To date, clinical trials have been completed only in patients with genotype 1. A study in patients with HCV genotype 4 is currently under way. Preliminary data from this study suggest that PEGINF, SOF, and RBV could achieve SVR rates approaching 80%.22 Simeprevir is highly effective and has been approved by the FDA for treatment of patients with chronic HCV genotype 1. Simeprevir binds to the same site as TPV and BOC. It has not been studied in patients in whom TPV or BOC treatment failed or resistance to TPV or BOC developed. Given its mechanism of action, it is unlikely to be effective and should not be used in these patients.13 Simeprevir is used as triple therapy with PEGINF and RBV for 12 weeks, followed by an additional 12 weeks of PEGINF and RBV (total duration of therapy, 24 weeks) in all patients who are treatment naive or who have had a relapse while taking PEGINF and RBV, including those with cirrhosis. Approximately 2
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80% of patients achieve a rapid virologic response (RVR), and HCV RNA is undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately 90%.23-25 As opposed to TPV and BOC, for which the duration of therapy is adjusted on the basis of whether an RVR is achieved, response-guided therapy is not necessary with SMV. In patients who have no response to PEGINF and RBV, 12 weeks of SMV, PEGINF, and RBV is followed by 36 weeks of PEGINF and RBV (total duration of therapy, 48 weeks). The SVR rate in these patients is 53% to 65%.26 All patients with HCV RNA levels greater than 25 IU/mL at weeks 4, 12, or 24 should stop treatment. Although controlled clinical trials comparing the SVR rates of the 3 protease inhibitors have not been conducted, each has been evaluated against a placebo control with PEGINF and RBV. Comparison of the improvement in SVR over control for the 3 protease inhibitors suggests that RVR and SVR rates are somewhat higher with SMV compared with TPV or BOC.13 Simeprevir offers considerable advantages over TPV and BOC, the most important of which is that SMV does not cause additional anemia compared with PEGINF and RBV.23-26 In phase 2 and 3 clinical trials, patients treated with SMV, PEGINF, and RBV did not have any adverse events with greater frequency than those taking PEGINF and RBV. Simeprevir is taken as a single once-daily tablet, no special diet is required, and far fewer drug-drug interactions have been observed. The success in patients treated with SMV, like other protease inhibitors, is dependent on an effective interferon response, which is modulated by IL28B genotype.27 In treatmentnaive patients, the SVR approaches 90% in patients with IL28B CC genotype and declines in
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patients with the CT and TT genotypes.23,24 In patients with a previous nonresponse to PEGINF and RBV, the SVR rates during retreatment with SMV triple therapy follow a similar trend of interferon responsiveness: higher rates of SVR with a previous partial response and lower SVR rates in previous nonresponders.26 The primary limitation of SMV is that a sequence variation at the Q80K loci of HCV significantly limits the antiviral efficacy of this protease inhibitor and reduces SVR to values that are similar to that achieved with PEGINF and RBV.23-26 This sequence variation is present in about 40% of patients with HCV genotype 1a. It is not present in HCV genotype 1b. The FDA has suggested that all patients with genotype 1a undergo resistance testing for the presence of the Q80K sequence variation in HCV and that the physician strongly consider using a treatment other than SMV if this sequence variation is present. The Q80K sequence variation has the greatest impact and considerably lowers SVR in patients who are genetically less sensitive to PEGINF. In contrast, patients with IL28B CC genotype, who are highly sensitive to interferon, have similar SVR rates regardless of the presence or absence of the Q80K sequence variation.23-26 We therefore disagree with the FDA recommendations somewhat and strongly believe that patients with HCV genotype 1a and Q80K who have IL28B CC genotype could be treated successfully with SMV, PEGINF, and RBV. We do not recommend and we do not treat our patients who have HCV genotype 1 with SMV, PEGINF, and RBV. However, if a physician or payer chooses this regimen, our recommendation would be to test those patients with genotype 1a for IL28B genotype. If the patient has IL28B CC genotype, then no viral resistance testing is necessary. If the patient has IL28B CC or TT genotype, the patient would then need to be tested for Q80K, and if absent, they could also be treated with SMV, PEGINF, and RBV. In contrast, if the patient has IL28B CT or TT genotype and Q80K sequence variation, we would not recommend SMV. SOFOSBUVIR Sofosbuvir is the first polymerase inhibitor to be approved by the FDA for the treatment of chronic HCV.15 It is a nucleotide analogue Mayo Clin Proc. n XXX 2014;nn(n):1-9 www.mayoclinicproceedings.org
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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.28-30 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 6.28 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 characteristicsdMetavir fibrosis score of F3 or F4, high viral load, IL28B non-CC genotypedthe 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
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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 3.28-30 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.29 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 treatmentnaive patients without cirrhosis and 21% to 34% in patients with cirrhosis.28-30 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 4
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rate of 85% in patient without cirrhosis but only 60% in patients with cirrhosis.30 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).31 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 posteliver 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.32 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 posteliver transplant population.33,34 One study included patients with stable normal graft function at least 6 months after transplant.33 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
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patients with severe HCV recurrence after transplant.34 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.15 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.29 In the 5 phase 3 clinical trials, the drop-out rate due to adverse events was greatest in the placebo-treated group (4%); the dropout 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 1.35 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%. Mayo Clin Proc. n XXX 2014;nn(n):1-9 www.mayoclinicproceedings.org
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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 3.36 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%.28-30 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.37 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.38 These recommendations and the FDA recommendations for use of SOF39 are summarized in Table 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 2). In several situations, we believe the American Association for the Study of Liver Diseases/Infectious Diseases Society of
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TABLE 2. 2014 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 PEGINF, SOF, and RBV for 12 wk cirrhosis INF intolerant, no cirrhosis SOF and SMV RBV for 12 wk SOF and RBV for 24 wk INF intolerant, cirrhosis Genotype 1: Prior PEGINF and RBV nonresponse INF tolerant, no cirrhosis or compensated SOF and SMV RBV for 12 wk PEGINF, SOF, and cirrhosis INF intolerant, no cirrhosis SOF and SMV RBV for 12 wk SOF and RBV for 24 wk INF intolerant, cirrhosis Genotype 1: Prior treatment with PEGINF, RBV, and TPV or BOC INF tolerant, no cirrhosis or compensated SOF for 12 wk, PEGINF and RBV PEGINF, SOF, and cirrhosis for 12-24 wk INF intolerant, no cirrhosis NR SOF and RBV for 24 wk INF intolerant, cirrhosis Genotype 2 Treatment naive or PEGINF-RBV relapse, SOF and RBV for 12 wk SOF and RBV for 12 wk no cirrhosis or compensated cirrhosis Prior PEGINF-RBV nonresponse, no SOF and RBV for 12 wk cirrhosis 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 Prior PEGINF-RBV, INF tolerant, no cirrhosis or compensated cirrhosis Prior PEGINF-RBV, INF intolerant, no cirrhosis Prior PEGINF-RBV, INF intolerant, cirrhosis Genotype 4 INF tolerant PEGINF, SOF, and RBV for 12 wk INF intolerant SOF and RBV for 24 wk Genotypes 5 and 6 INF tolerant PEGINF, SOF, and RBV NA for 12 wk INF intolerant NR NA
Defer treatment SOF and SMV for 12 wk RBV for 12 wk Defer treatment SOF and SMV for 12 wk RBV for 12 wk Defer treatment SOF and SMV for 12 wk SOF and RBV for 12 wk
SOF and RBV for 24 wk PEGINF, SOF, and RBV for 12 wk Defer treatment SOF and RBV for 24 wk
SOF and SMV for 12 wk PEGINF, SOF, and RBV for 12 wk SOF and RBV for 24 wk
AASLD ¼ American Association for the Study of Liver Diseases; BOC ¼ boceprevir; FDA ¼ Food and Drug Administration; IDSA ¼ Infectious Diseases Society of America; INF ¼ interferon; LIV ¼ Liver Institute of Virginia; NA ¼ not approved; NR ¼ no recommendation; PEGINF ¼ peginterferon; RBV ¼ ribavirin; SMV ¼ simeprevir; SOF ¼ sofosbuvir; TPV ¼ telaprevir.
America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.
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.40 In the United States, genotypes 4 through 6 are uncommon and rarely seen except in immigrants from the aforementioned regions of the world. 6
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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
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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.41 In our opinion, the risk that this poor outcome could also occur with a 12-week PEGINF and RBVecontaining 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 Mayo Clin Proc. n XXX 2014;nn(n):1-9 www.mayoclinicproceedings.org
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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 SOFcontaining regimen.14 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
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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. Abbreviations and Acronyms: BOC = boceprevir; FDA = Food and Drug Administration; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HIV = human immunodeficiency virus; PEGINF = peginterferon; RBV = ribavirin; RVR = rapid virologic response; SMV = simeprevir; SOF = sofosbuvir; SVR = sustained virologic response; SVR-4 = HCV RNA undetectable 4 weeks after stopping treatment; TPV = telaprevir Potential Competing Interests: Dr Shiffman has participated in advisor meetings with Achillion Pharmaceuticals, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Gen-Probe, Inc, Globeimmune Inc, GlaxoSmithKline, Janssen Pharmaceutical Companies, Merck & Co, Inc, Novartis Corp, Genentech, Inc, and Vertex Pharmaceuticals Inc; is on the speakers’ bureau for Bayer AG, Gilead Sciences, Janssen Pharmaceutical Companies, Merck & Co, Inc, Genentech, Inc, and Vertex Pharmaceuticals Inc; and receives grant support from Abbott Laboratories, Achillion Pharmaceuticals, Inc, Beckman Coulter, Inc, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead Sciences, Globeimmune Inc, Idenix Pharmaceuticals, Inc, Intercept Pharmaceuticals, Inc, Merck & Co, Inc, Mochida Pharmaceutical Co, Inc, Novartis Corp, and Genentech, Inc. Ms Long has participated in advisor meetings with AbbVie Inc, Gilead Sciences, Janssen Pharmaceutical
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Companies, Kadmon Pharmaceuticals, Merck & Co, Inc, and Vertex Pharmaceuticals Inc and is on the speakers’ bureau for Merck & Co, Inc, GlaxoSmithKline, Kadmon Pharmaceuticals, Salix Pharmaceuticals, Inc, and Vertex Pharmaceuticals Inc. Ms James has participated in advisor meetings with Gilead Sciences and Janssen Pharmaceutical Companies and is on the speakers’ bureau for Janssen Pharmaceutical Companies. Mr Alexander has participated in advisor meetings with Gilead Sciences. Correspondence: Address to Mitchell L. Shiffman, MD, Liver Institute of Virginia, Bon Secours Health System, 5855 Bremo Rd, Ste 509, Richmond, VA 23226 ([email protected]).
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