June 14, 2014

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By Press Association, 9 June 2014 11.00pm. Updated: 10 June 2014 5:41am.

The Scottish Medicines Consortium (SMC) has approved sofosbuvir for restricted use within the NHS.

The SMC said its use addresses an unmet treatment need, while campaigners welcomed the move as a "step in the right direction."

Hepatitis C is a blood-borne virus thought to affect more than 200,000 people in the UK. It can cause cirrhosis and liver cancer but more than half of those living with the condition are believed to be undiagnosed.

There is no vaccine but treatment can clear the virus in most patients.

Sofosbuvir is the first medicine in a new class and stops the virus from multiplying, according to The Hepatitis C Trust.

It must be given in combination with other medication and is taken in tablet form once a day.

In the absence of other treatment options, the relatively high cost of the drug was deemed acceptable by the SMC, given the expected benefits of the treatment, the charity said.

Petra Wright, Scottish officer for The Hepatitis C Trust said: "The Trust welcomes the SMC's advice that sofosbuvir should be made available to NHS patients in Scotland, in what we hope to be the first of many emerging therapies for Hepatitis C.

"The advent of these 'patient friendly' medications will reduce treatment duration and the severity of side effects experienced by those affected.

"This is a step in the right direction which we hope will hasten the elimination of Hepatitis C from Scotland."

Stelios Karagiannoglou, UK general manager of drug manufacturer Gilead Sciences Ltd, said: "We are pleased that the SMC have recognised the significant efficacy and safety profile demonstrated by sofosbuvir in clinical studies and therefore agree it is a valuable use of NHS resources given the high unmet need in hepatitis C."

Source

Gilead Sciences Policy Position

Key points:

  • Approved by the U.S. Food and Drug Administration in December 2013 and by the European Commission in January 2014, Gilead’s Sovaldi (sofosbuvir) represents a therapeutic advance in the treatment of appropriate patients with hepatitis C
  • Sovaldi, in combination with other agents, offers a cure with a short-term course of treatment, an important consideration when comparing the cost of a drug to the lifetime cost of chronic disease
  • Gilead is working with public and private payers around the world to help ensure patient access to Sovaldi as quickly as possible

For 75-85 percent of people who contract the hepatitis C virus, it becomes a chronic infection that can lead to serious and life-threatening complications including liver failure, liver cancer or liver transplantation. Beyond the devastating impact on the lives of patients, the cost and burden to societies of managing these conditions is enormous. Once a patient achieves a cure for chronic hepatitis C, the threat of these complications, along with their accompanying costs, is thought by the medical community to be greatly reduced.

Unlike long-term or indefinite treatments for other chronic diseases, Sovaldi, in combination with other agents, is a short-term therapy that resulted in high cure rates in Phase 3 clinical trials. Patients who achieve sustained virologic response 12 weeks after treatment (SVR12) are considered cured of hepatitis C. Sovaldi was priced such that the total regimen cost is comparable to the previous standard of care regimen for genotype 1 patients with hepatitis C. However, in addition to a higher cure rate, Sovaldi provides a shorter treatment duration and improved tolerability, thereby potentially reducing total treatment costs for hepatitis C when taking into account the cost of medications (including those for side effects of less effective treatment or complications from side effects) and healthcare visits.

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Facilitating Patient Access in the U.S. and Beyond

Gilead offers a number of support services for patients in the United States who are uninsured, underinsured or who need financial assistance to pay for their medicine. These include the Sovaldi Co-pay Coupon Program, which limits monthly out-of-pocket costs for eligible patients with private insurance to no more than $5 per month; and the Support Path Patient Assistance Program, which provides Sovaldi at no charge for eligible patients with no other insurance options.

On a worldwide basis, Gilead is working on programs and partnerships to help ensure patients for whom treatment with Sovaldi may be appropriate have access to it. A key component of the company’s treatment expansion efforts is tiered pricing based on a country’s ability to pay. Gilead also considers an individual country’s HCV burden, treatment needs and economic means when setting prices. Learn more about Gilead’s developing world access program.

Source

Article in Press

Mitchell L. Shiffman, MD, April G. Long, NP, Amy James, FNP, Phillip Alexander, NP

Published Online: May 24, 2014

DOI: http://dx.doi.org/10.1016/j.mayocp.2014.04.013

Publication stage: In Press Corrected Proof

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 personsworldwide.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, 10, 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.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, 17, 18, 19, 20 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.

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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 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 approximately90%.23, 24, 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, 24, 25, 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 treatment-naive patients, the SVR approaches 90% in patients with IL28BCC genotype and declines in 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, 24, 25, 26This 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, 24, 25, 26 We therefore disagree with the FDA recommendations somewhat and strongly believe that patients with HCV genotype 1a and Q80K who haveIL28B 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 hasIL28B 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 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, 29, 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, and6.28 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 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 3.28, 29, 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 treatment-naive patients without cirrhosis and 21% to 34% in patients with cirrhosis.28, 29, 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 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 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.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 post–liver 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 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 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 1.35 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%.

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 3.36Sustained 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, 29, 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 America treatment guidelines are overly aggressive, are too costly, and have no clinical trial data to substantiate the recommendation.

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 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

AASLD = American Association for the Study of Liver Diseases; BOC = boceprevir; FDA = Food and Drug Administration; IDSA = Infectious Diseases Society of America; INF = interferon; LIV = Liver Institute of Virginia; NA = not approved; NR = no recommendation; PEGINF = peginterferon; RBV = ribavirin; SMV = simeprevir; SOF = sofosbuvir; TPV = telaprevir.

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.

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.41 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.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 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.

References

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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 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.

© 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

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Jun 13, 2014

NORTH CHICAGO, Ill., June 13, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced today that the New Drug Application (NDA) for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection has been accepted by the U.S. Food and Drug Administration (FDA) and has been granted priority review.

The NDA was submitted on April 21, 2014 and is supported by data from a large clinical program including six Phase III studies of more than 2,300 GT1 patients in over 25 countries. The regimen was granted a Breakthrough Therapy designation by the FDA in May 2013, a status given to investigational treatments for serious or life-threatening conditions with preliminary clinical evidence demonstrating substantial improvement on at least one clinically significant endpoint compared to available therapy.

In May 2014, AbbVie submitted marketing authorization applications (MAAs) for regulatory approval in the European Union.

About AbbVie's Investigational HCV Regimen
The AbbVie investigational regimen consists of ABT-450/ritonavir co-formulated with ombitasvir (ABT-267), and dasabuvir (ABT-333) with or without RBV. The combination of three different mechanisms of action interrupts the hepatitis C virus replication process with the goal of optimizing sustained virologic response rates across different patient populations.

Additional information about AbbVie's Phase III studies can be found on www.clinicaltrials.gov.

AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral regimen with and without ribavirin with the goal of producing high sustained virologic response rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C virus protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission.

AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

SOURCE AbbVie

For further information: Media: Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com , Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com , Investor Relations: Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

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