Hepatitis C Antiviral Therapy

Transcription

1 MEDICAL POLICY POLICY RELATED POLICIES POLICY GUIDELINES DESCRIPTION SCOPE BENEFIT APPLICATION RATIONALE REFERENCES CODING APPENDIX HISTORY Hepatitis C Antiviral Therapy Number Effective Date January 1, 2016 Revision Date(s) 12/08/15; 11/10/15; 09/08/15; 08/11/15; 04/14/15; 01/27/15; 12/22/14; 11/10/14; 04/14/14; 12/09/13; 06/12/12; 05/10/11; 05/11/10; 05/12/09; 02/12/08; 01/09/07; 11/14/06; 05/01/06 Replaces Policy [TOP] Prioritizing Patients for Treatment for Chronic Hepatitis C New direct-acting antiviral agents (DAA) are revolutionizing treatment for Hepatitis C. Within a few months, we expect to see FDA-approved all-daa regimens for every genotype. Clinical trials for these regimens have demonstrated sustained viral response rates (SVR) of greater than 90% except in the most complicated patients. Combined AASLD and IDSA guidelines for the treatment of chronic hepatitis C are available on the Internet at Since they are updated regularly, prescribers should visit the Web site periodically to check for changes in the recommendations. These guidelines acknowledge the need to prioritize patients for treatment based on the large potential target population and the high cost of these new drugs and form the basis of this policy. Treatment for chronic active hepatitis C with regimens selected from the appropriate table below (initial treatment table; retreatment table) according to viral genotype and patient circumstances may be considered medically necessary, except as noted under EXCEPTIONS below. Treatment will be approved for the number of weeks shown in the table for the selected regimen, based on viral genotype, relevant mutations in viral genes and patient status (treatment-naïve, experienced, etc.) Per guideline recommendations, 48 weeks of treatment will be approved for patients awaiting liver transplantation. Re-treatment after all- DAA regimen: All cases will be considered individually. The following information must be submitted with a request for retreatment: o Notes indicating prior treatment regimen- including response and timelines o Lab report of testing for resistance mutations Medical necessity will be based on expert recommendations that members not be re-treated with a regimen containing a drug they have failed or relapsed on: o Patients having failed a regimen containing an NS3/4A protease inhibitor (boceprevir, telaprevir, simeprevir or paritaprevir) should not be re-treated with a regimen containing one of these agents. o Ledipasvir/sofosbuvir (Harvoni) is suitable for retreatment in such cases unless contraindicated Patients receiving post-transplant treatment for hepatitis C should receive weeks of therapy, or as currently recommended by the guidelines.

2 RECOMMENDED REGIMENS FOR TREATMENT-NAÏVE PATIENTS (AASLD/IDSA Current Guidelines and/or Product Label) Hyperlinks to genotypes for initial treatment: 1a, 1b, 1 regardless of subtype, 2, 3, 4, 5 or 6 Genotype 1a Initial Treatment Agents (Treatment Naïve) Harvoni (preferred agent) or Cirrhosis? Duration in Weeks No 12 Daklinza + Sovaldi No 12 Daklinza + Sovaldi with or w/o RBV Viekira Pak + RBV No 12 Viekira Pak + RBV Olysio + Sovaldi No 12 Olysio + Sovaldi with or w/o RBV without Q80K polymorphism 1b Harvoni (preferred agent) No 12 Daklinza + Sovaldi No 12 Daklinza + Sovaldi with or w/o RBV Viekira Pak No 12 Olysio + Sovaldi No 12

3 Olysio + Sovaldi with or w/o RBV 1, Regardless of subtype Daklinza + Sovaldi + RBV 12 Daklinza + Sovaldi (RBV intolerant or ineligible) 2 (Note: Harvoni is not approved for this genotype) Harvoni + RBV Sovaldi + RBV No 12 Sovaldi + RBV Daklinza + Sovaldi No 12 Daklinza + Sovaldi + RBV 12 3 (Note: Harvoni is not approved for this genotype) Sovaldi + RBV Sovaldi + RBV + PEG-IFN (when interferon tolerant) Sovaldi + RBV (when interferon intolerant) 48 No 12 No Daklinza + Sovaldi No 12 Daklinza + Sovaldi with or w/o RBV Daklinza + Sovaldi + RBV 12 4 Sovaldi + RBV Harvoni (preferred agent) 48 No 12 Technivie + RBV No 12

4 Sovaldi + RBV No Sovaldi + RBV + PEG-IFN (when interferon tolerant) No 12 Daklinza + Sovaldi + RBV 12 Daklinza + Sovaldi (RBV intolerant or ineligible) 5 or 6 Harvoni + RBV Harvoni (preferred agent) 12 No 12 Sovaldi + RBV + PEG-IFN (when interferon tolerant) No 12 RECOMMENDED REGIMENS FOR PATIENTS IN WHOM PREVIOUS TREATMENT HAS FAILED (AASLD/IDSA Current Guidelines and/or Product Label) Hyperlinks to genotypes for retreatment: 1a, 1b, 1a or 1b, 1b Q80K variant negative, 1 regardless of subtype, 2, 3, 4, 5 or 6 Genotype 1a If Failed Treatment with..then Recommended Retreatment per the AASLD Guidelines or Cirrhosis? Duration in Weeks Daklinza + Sovaldi No 12 Harvoni No 12 Viekira Pak + RBV No 12 Sovaldi + Olysio No 12 1b Daklinza + Sovaldi No 12 Harvoni No 12 Viekira Pak No 12

5 Sovaldi + Olysio No 12 1a or 1b Daklinza + Sovaldi with or w/o RBV Harvoni Harvoni + RBV 12 Viekira Pak + RBV Viekira Pak (no RBV) 12 1b, Q80K variant negative 1, regardless of subtype Sovaldi + RBV with or w/o PEG-IFN Sovaldi + Olysio with or w/o RBV Harvoni + RBV No 12 Sovaldi Harvoni + RBV Sovaldi-based treatment Harvoni + RBV NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + PEG- IFN + RBV Daklinza + Sovaldi No 12 NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + PEG- IFN + RBV Harvoni No 12

6 Sovaldi + Olysio (No prior NS5A treatment) Harvoni + RBV No 12 NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + Daklinza + Sovaldi with or w/o RBV NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + combination of Sovaldi and Olysio Daklinza + Sovaldi with or w/o RBV NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + Harvoni NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + combination of Sovaldi and Olysio Harvoni + RBV NS3 protease inhibitor (examples telaprevir, boceprevir, or simeprevir) + Harvoni + RBV 12

7 NS5A inhibitor (including Daklinza + Sovaldi, Harvoni, or Viekira Pak) For patients with minimal liver disease, deferral of treatment is recommended, pending availability of data. For patients who are cirrhotic or otherwise require urgent treatment testing for resistanceassociated variants that confer decreased susceptibility to NS3 protease inhibitors and NS5A inhibitors is recommended. The specific drugs using the treatment regimen should be tailored to the results of this testing. Addition of ribavirin can be recommended. N/A 2 PEG + RBV Sovaldi + RBV No 16 or PEG + RBV Sovaldi + RBV + PEG-IFN (interferon tolerant) No 12 Sovaldi + RBV Daklinza + Sovaldi with or w/o RBV (interferon intolerant) No Sovaldi + RBV Sovaldi + RBV + PEG-IFN (interferon tolerant) No 12 3 Daklinza + Sovaldi No 12 Sovaldi + RBV + PEG-IFN (interferon tolerant) No 12 Sovaldi + RBV Daklinza + Sovaldi + RBV (interferon intolerant) No

8 Sovaldi + RBV Sovaldi + RBV + PEG-IFN (interferon tolerant) No 12 4 Harvoni No 12 Technivie + RBV No 12 Sovaldi + RBV + PEG-IFN (interferon tolerant) No 12 Sovaldi + RBV No Sovaldi-based treatment Harvoni + RBV 5 or 6 Harvoni No 12 ASLDD does not specify exact prior treatment failure Sovaldi + RBV + PEG-IFN (interferon tolerant) No 12 Indicated treatment durations are for the direct-acting agent(s) in each regimen. PEG and/or RBV may be continued for to 48 weeks, as specified in the guidelines. Abbreviations: RBV = ribavirin, PEG = pegylated alfa interferon Viekira approval requires failure, intolerance or contraindication to Harvoni, except as noted below. FDA approved the 12-week course of therapy; however, based on clinical trials an 8-week course may be considered in patients with baseline viral load of less than 6 million units/ml For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present. For Daklinza, SVR rates are reduced in patients with. This agent has to be used in combination with sofosbuvir. For Technivie, patient must NOT have (i.e. fibrosis stage F 0 to 3 is non-cirrhotic; F 4 is indicative of.). In addition, this agent is not recommended in patients with moderate hepatic impairment (Child-Pugh B). Technivie is contraindicated in patients with severe hepatic impairment (Child- Pugh C). Contraindications to ribavirin also apply to this combination regimen. For complete list of contraindications please see package insert. Technivie is to be used in combination with ribavirin. For patients unable to tolerate ribavirin, Technivie without ribavirin for 12 weeks may be considered for treatment-naïve patients. Technivie approval requires failure, intolerance or contraindication to Harvoni, except as noted below. As additional DAA agents are approved by the FDA, these may be considered medically necessary when used according to their labeled indications until this policy is updated. Harvoni (ledipasvir/sofosbuvir) is the preferred agent and should be used first line wherever recommended by the guidelines, unless there are contraindications to its use.

9 EXCEPTIONS These drugs are exceptions to the above policy statement: The use of Viekira Pak (paritaprevir/ritonavir/ombitasvir/dasabuvir combination) may be considered medically necessary to treat Genotype 1 and 4 patients meeting the above criteria with failure or intolerance to Harvoni (ledipasvir/sofosbuvir). The use of Viekira Pak (paritaprevir/ritonavir/ombitasvir/dasabuvir combination) may be considered medically necessary to treat Genotype 1 and 4 patients meeting the above criteria that have not been treated with Harvoni but have a creatinine clearance (CrCl) < 30 ml/min. The use of the combination of simeprevir (Olysio ) and sofosbuvir (Sovaldi ) to treat Hepatitis C is considered not medically necessary, since an equally or more effective alternative, ledipasvir/sofosbuvir (Harvoni ) is available at a much lower cost. All other uses of DAA agents are considered investigational. Pegylated interferons (Pegasys PEGIntron ) and ribavirin no longer require prior authorization. Use in accordance with current guidelines is recommended. Incivek (telaprevir) or Victrelis (boceprevir) are not recommended in current guidelines. These agents have been superseded by simeprevir and are no longer in common use; therefore, prior authorization for them is no longer required. Coverage will be provided for patients currently receiving an older regimen to complete their prescribed course of therapy. For HCV testing, see Policy Guidelines, below. Related Policies None [TOP] Policy Guidelines [TOP] Viral Genotyping Genotyping of hepatitis C virus is considered medically necessary as a technique to determine duration of therapy. HCV genotype is required with requests for coverage of the following regimens. Patients with genotype 1a must have a negative test for the NS3 Q80K mutation to be approved for treatment with an NS3/4A inhibitor. Currently available NS3/4A inhibitors are: Olysio (simeprevir). The current recommended testing sequence should be followed when screening and diagnosing patients with hepatitis C. (See Resistance Mutations Genetic testing for resistance mutations is commercially available and is considered medically necessary to guide the selection of a patient-specific DAA regimen for retreatment in patients that have failed a prior DAA-containing regimen. Prior authorization for such testing is not required. Test results should be submitted along with the request to approve the retreatment regimen.

10 Description [TOP] Hepatitis C Approximately 4 million Americans have been infected with hepatitis C virus (HCV), of whom 74% have chronic infection. Most patients are diagnosed based on elevated liver transaminases and the presence of hepatitis C virus ribonucleic acid (HCV RNA). Hepatitis C is a major cause of liver-related morbidity and mortality. Although the disease typically progresses without symptoms for several decades, 20% to 30% of infected individuals develop within 10 to 20 years and 5% to 10% develop end stage liver disease. After development of, the annual risk of development of hepatocellular carcinoma is 1% to 4%. Chronic hepatitis C is also the most common indication for liver transplantation in the United States. Treatment may be considered for patients at increased risk of developing. These individuals include those with: Detectable HCV RNA levels higher than 50 IU/mL A liver biopsy with portal or bridging fibrosis and at least moderate inflammation and necrosis. However, many patients with chronic hepatitis C meeting these criteria may still not be considered candidates for therapy. Common exclusionary factors are severe psychiatric illness, alcohol or substance abuse, and renal disease. Providers considering initiation of therapy should consult the current AASLD/IDSA guidelines for specific advice. (See There are 6 known genotypes and over 50 subtypes of hepatitis C virus. These genotypes vary by as much as 34% in their genetic sequencing and subtypes are known to differ by 20% to 23%. This genetic heterogeneity has known implication for therapeutic management and its effectiveness. Genotypes 1 and 4 are associated with less chance of achieving a sustained virologic response (SVR) or the clearance of HCV RNA by qualitative analysis weeks after therapy cessation. Although SVR is a surrogate endpoint which has not yet been correlated with improved survival, it is the current standard measure of response to therapy. A pegylated interferon (PegIntron [pegylated interferon alfa-2b], Schering or Pegasys [pegylated interferon alfa-2a], Roche) plus ribavirin is currently considered the best available therapy and standard of care for the treatment of chronic hepatitis C infection, except where contraindicated. However, this pharmacotherapeutic combination is only effective in about 55% of treatment naïve patients and is poorly tolerated. Major adverse effects of interferon-based therapy include neuropsychiatric symptoms, influenza-like symptoms, and hematologic abnormalities. In phase 3 trials, adverse events occurring with the combination of a pegylated interferon and ribavirin resulted in dose reductions in up to 42% and therapy discontinuation in up to 14% of patients. Recently five newer direct-acting oral agents in two pharmacologic classes have been approved. Direct acting agents are administered orally, tend to have fewer side effects and achieve higher SVR rates with shorter courses of therapy: Non-alcoholic Fatty Liver Disease (NAFLD) NAFLD is a buildup of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat. However, if more than 5% to 10% of the liver s weight is fat, then it is called a fatty liver (steatosis). Non-Alcoholic Steatohepatitis (NASH) NASH causes the liver to swell and become damaged. NASH can progress to fibrosis/, and lead to ESLD, while NAFLD is much less likely to do that, if kept under control. NASH is one of the leading causes of in adults in the United States. Up to 25% of adults with NASH may have. NS3/4A Protease Inhibitors (simeprevir) This class is currently approved for use only in genotype 1 disease. Presence of the Q80K polymorphism in the NS3 sequence of subtype 1a appears to reduce the clinical benefit of simeprevir.

11 NS5B Polymerase Inhibitors (sofosbuvir, dasabuvir) This class has demonstrated very encouraging results and has activity against other genotypes. NS5A Inhibitors (ombitasvir) This is the newest class of antiviral agents to treat hepatitis C. In combination with paritaprevir and dasabuvir it produces very high rates of viral clearance and sustained viral response in genotype 1 patients. Simeprevir/sofosbuvir combination therapy With the FDA approval of the new ledipasvir/sofosbuvir product (Harvoni ) to treat all genotype 1 patients on October 10, 2014, there is no longer reason to use the off-label combination of simeprevir and sofosbuvir. Use of this combination was based on evidence from one small Phase 2 trial, whereas the safety and efficacy of Harvoni is has been convincingly demonstrated in a robust Phase 3 trial program that led to its approval. (See evidence summary in the 2014 update below.) Paritaprevir/ritonavir/ombitasvir/dasabuvir combination therapy With the FDA approval of this new product (Viekira Pak ) to treat genotype 1 patients on December 19, 2014, another alternative is added. This combination has several disadvantages, including a more complex regimen, numerous significant drug interactions and greater potential for resistance, compared to Harvoni. (See evidence summary in the 2015 update below.) Therefore, it is relegated to second-line use. Scope [TOP] Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer services representative to determine whether there are any benefit limitations applicable to this service or supply. This policy does not apply to Medicare Advantage. Benefit Application [TOP] This policy is applicable to enrollees who are managed by the Company s Pharmacy Formulary. It does not apply to enrollees managed under the Express Scripts Formulary. Rationale [TOP] Treatment Efficacy-Pegylated Interferon + Ribavirin Two multi-center, randomized, double-blind, controlled trials have demonstrated pegylated interferons to be more effective for achievement of an SVR than non-pegylated interferons in treatment-naïve patients with chronic hepatitis C virus (HCV). Randomized, double-blind controlled trial evidence also supports the combination of interferon or a pegylated interferon with ribavirin to be substantially more effective for achievement of a SVR than interferon or peginterferon monotherapy. The two currently available pegylated interferons in combination with ribavirin indirectly appear to be equally efficacious (SVR rates of 54% to 56%) and modestly more efficacious than non-pegylated interferon plus ribavirin (SVR rates as high as 43%).

12 Sustained Virologic Response-Chronic Hepatitis C Although sustained virologic response (SVR) is a surrogate endpoint, it has recently been correlated with improved survival, and it is the current gold standard measure of response to chronic HCV pharmacotherapy. An SVR is the clearance of HCV RNA by qualitative analysis weeks after therapy cessation. Pretreatment factors associated with achievement of SVR include lower body mass indexes (body weight <75 kg), milder histology on liver biopsy (Metavir fibrosis stage 0 or 1), genotype 2 or 3, and lower initial viral titers (HCV RNA level <2 million copies/ml or 800,000 IU/mL). During treatment, factors associated with achievement of an SVR include rapid or early virologic response, therapy adherence, and lack of HIV co-infection. Achievement of an SVR has been associated with resolution of liver injury, reduction in hepatic fibrosis, a low likelihood of relapse, and survival. Adherence-Chronic Hepatitis C Adherence is important to chronic HCV treatment success. A retrospective analysis of data from a phase 3, randomized, controlled trial of pegylated interferon plus weight-based ribavirin (1000 mg daily for patients <75 kg and 1200 mg daily for patients 75 kg) in genotype 1 patients showed that patients that were adherent to therapy (defined as 80% of the pegylated interferon dose and 80% of the ribavirin dose for 80% of the recommended duration of therapy) had substantially higher SVR rates (63%) compared with patients who received the same dose but were not adherent (34%, P=.01). Early Virologic Response-Chronic Hepatitis C Early virologic response (EVR) is defined as clearance of HCV-RNA during the first 12 weeks of therapy. A partial response is defined as a minimum 2-log decrease in hepatitis C viral load after 12 weeks of therapy. An analysis of the pivotal randomized controlled trials for pegylated interferon plus ribavirin suggests that patients who do not achieve an EVR have a 3% chance of achieving an SVR. Use of EVR could spare patients 12 to 36 weeks of additional often poorly tolerated treatment. In an economic analysis, Wong et al (2003) found the use of an EVR reduced morbidity and decreased costs by 45% compared with a full course of therapy. Relapse and Non-Response-Chronic Hepatitis C Relapse is defined as initial achievement of an SVR that is not sustained over time. Non-response is defined as never achieving an SVR. Guidelines for retreatment of this population are evolving rapidly. See Transplantation-Chronic Hepatitis C Hepatitis C frequently recurs in the transplant setting. Guidelines for retreatment of this population are evolving rapidly. See Update When Hepatitis C patients receive a liver transplant, allograft infection is universal, and recurrent hepatitis C progresses at an accelerated rate. Preemptive antiviral therapy after transplantation has been disappointing. However, treatment of established histological disease with a combination of pegylated interferon and ribavirin is associated with sustained virologic response (SVR) in roughly 25% of cases. A recent meta-analysis reported a pooled SVR rate of 27% (range 23-31%). Stable and improved fibrosis scores can be expected in most patients who achieve SVR. While these rates are not impressive, pegylated interferon plus ribavirin remains the best available treatment and represents the current standard of care. Further research in this area is clearly needed Update A literature search of the MEDLINE database did not identify any additional published studies that would prompt reconsideration of the policy statement, which remains unchanged Update A literature search of the MEDLINE database from May 2008 to March 2009 and the 2008 AASLD annual meeting proceedings did not identify any additional published studies that would result in major reconsideration of

13 the policy statement, excepting results from the EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis) study. EPIC 3 is a multinational, open-label trial assessing the efficacy and safety of peginterferon alfa-2b 1.5 mcg/kg/wk in combination with weight-based ribavirin for 48 weeks in the retreatment of chronic hepatitis C patients with fibrosis (METAVIR F2-F4) unresponsive to or relapsing after standard or pegylated interferonalfa/ribavirin combination treatment. Overall, SVR rates were 7%, 6%, and 18% in Peg-2b, Peg-2a, and standard interferon combination therapy nonresponders and 32%, 34%, and 43% in Peg-2b, Peg-2a, and standard interferon combination therapy relapsers. Undetectable HCV-RNA at week 12 was the most important predictor of SVR in this population. Overall, 56% achieved SVR if HCV-RNA was undetectable vs. 5% achieved SVR if only a 2 log decrease in HCV-RNA was observed at week 12). High-dose Therapy and Extended Treatment Intervals REPEAT (REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy) is an international, Phase III, randomized, parallel group study that included 942 adult patients with HCV unresponsive to at least 12 weeks of combination peginterferon/ribavirin therapy. Patients were randomized to: 1) Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for an additional 60 weeks (n=317); 2) Pegasys 360 mcg/week x 12 weeks, followed by 180 mcg/week x 36 weeks (n=156); 3) Pegasys 180 mcg/week for 72 weeks (n=156); or 4) Pegasys 180 mcg/week x 48 weeks (n=313). All patients also received 1000/1200 mg ribavirin daily based on weight. Patients were followed for an additional weeks after the end of therapy. Baseline demographics and patient characteristics were similar between study groups. Most patients were infected with genotype 1 (91%) and were Caucasian (89%). Primary study endpoint was SVR. A total of 28-33% of all patients had response at end of treatment. However, 49%-78% of patients relapsed. Overall SVR rates were 16% in the induction dosing and 72- week treatment duration group, 7% in the induction dosing and 48-week treatment duration group, 14% in the standard dosing and 72-week treatment duration group, and 9% in the standard dosing and 48-week treatment duration group. Pooled data showed patients treated for a longer duration (72 weeks) had higher SVR rates than those treated for 48 weeks [16% vs. 8%, P=0.0006, OR 2.22 (95% CI )]. However, overall rates of SVR continued to be low. Induction dosing did not provide additional benefit vs. standard dosing. Tolerability of induction and standard dosing was generally similar. The profile and frequency of adverse events in all treatment groups was also similar, while the number of treatment discontinuations due to adverse events was lower in patients treated for 48 weeks rather than 72 weeks. Children and HCV Baker and colleagues reported their observations on the treatment of 10 adolescent patients with Chronic Hepatitis C receiving pegylated interferon and ribavirin for 48 weeks. 1 patient did not complete the course of treatment and 1 patient with HCV type 3a received treatment for weeks. The period of observation continued from November 2002 to December The authors reported that all but 1 patient had a viral response (no detectable virus) at some time during or after treatment. Three patients achieved sustained viral response (no detectable virus 6 months after the therapy). One patient who previously failed interferon therapy was among the sustained responders. The authors concluded that children with HCV achieve results similar to those seen in adults Update A literature search did not identify any additional published studies that would require reconsideration of the policy statement. The Policy Guidelines dealing with slow responders and also requests for more than 2 courses of retreatment per year were added based on expert consultation Update A literature search did not identify any additional published studies that would require reconsideration of the policy statement Update Added criteria for Hepatitis C protease inhibitors telaprevir and boceprevir, based on a review of the primary literature.

14 2014 Update Two new antiviral agents were approved in late These agents are rapidly changing the standard of care for treating Hepatitis C Update One additional prioritization criteria was added to the list. A brief description of NASH and NAFLD has been added to the discussion section. Two new antiviral agents (Technivie and Daklinza ) were approved at the end of July, Sofosbuvir In the treatment-naïve population, the FISSION, NEUTRINO, and VALENCE trials demonstrated the noninferiority of sofosbuvir combination compared to the standard of treatment, PegIFN/ribavirin, in HCV genotypes 1-4. The VALENCE trial demonstrated that 12 weeks of treatment for HCV genotype 2 and weeks of treatment for genotype 3 were optimal. In the treatment-experienced population, the POSITRON, FUSION, and VALENCE trials demonstrated that sofosbuvir in combination with ribavirin for the treatment of HCV genotypes 2 and 3 provided adequate SVR12 rates. Those who were cirrhotic achieved lower SVR rates than those without. The SVR rates were, however, higher in the sofosbuvir treatment than in the standard of care treatment. The PHOTON-1 trial demonstrated the efficacy of sofosbuvir/ribavirin combination in HCV/HIV-1 coinfected patients. Sofosbuvir demonstrates less drug interactions with HIV antiviral regimens than the older protease inhibitors on the market. In the pre-transplant population, sofosbuvir/ribavirin combination shows promise as a neo-adjuvant treatment with 64% of the subjects thus far achieving undetectable HCV RNA at 12 weeks post-transplant. In the post-transplant populations who have been reinfected with HCV, the sofosbuvir/ribavirin combination is also showing promise with SVR4 rates of 77%. Both of these trials are ongoing and the full data is not yet available. Simeprevir In QUEST-1, QUEST-2, and PROMISE, patients were randomized in 2:1 to simeprevir (150 mg once a day) plus pegylated interferon plus ribavirin (PegIFN/RBV) for 12 weeks followed by PegIFN/RBV or placebo plus PegIFN/RBV for 48 weeks. Total treatment duration was or 48 weeks in the simeprevir group based on response-guided criteria (HCV RNA < 25 IU/mL week 4 and undetectable week 12). Because both QUEST-1 and QUEST-2 trials were performed in an HCV-treatment-naïve population and employed nearly identical study design, results were pooled for efficacy analysis. The pooled SVR12 was 80% in the simeprevir combination arm and 50% in the placebo/pegifn/rbv arm. The PROMISE trial was performed in patients who had relapsed after previous PegIFN/RBV treatment for chronic HCV infection. The SVR12 rate was 79% in the simeprevir combination arm and 36% in the placebo/pegifn/rbv arm. Patients receiving simeprevir-containing regimens compared with patients receiving PegIFN/RBV regimens had fewer treatment failures and treatment relapses. The percentages of patients who failed treatment in the simeprevir arms of QUEST-1, QUEST-2 and PROMISE were 9%, 7%, and 3%, respectively. The corresponding percentages in placebo-treated arms were 34%, 32%, and 27%, respectively. The percentage of patients who relapsed in the simeprevir arm in QUEST-1, QUEST-2, and PROMISE were 9%, 13%, and 19%, respectively. The corresponding percentages in placebo-treated arms were 21%, %, and 48%, respectively. The Q80K polymorphism in HCV genotype 1a infected patients is a factor that adversely affects treatment outcome of the simeprevir but no that of the PegIFN/RBV arms. In the pooled data from the QUEST-1 and QUEST-2 trials, the SVR12 rates in patients with Q80K polymorphism were substantially lower than those without Q80K polymorphism (58% versus 84%, respectively). Further, among patients with Q80K polymorphism, SVR12 rates were similar between simeprevir and placebo arms (58% versus 55%, respectively). A similar trend was seen in the PROMISE trial. Ledipasvir/sofosbuvir combination product (Harvoni ) In the 3 Phase III clinical trials (the ION trials), the SVR rates of sofosbuvir/ledipasvir were found to be efficacious

15 in treatment naïve patients at 8 weeks (SVR rate 94%, 95% CI 90 to 97 in patients without ), 12 weeks (SVR rate 99%, 95% CI 96 to 100), and weeks (SVR rate 98%, 95% CI 95 to 99). However in the patients who received 8 week treatment, a 10% relapse rate was seen in patients who had a baseline HCV RNA load 6 million IU/mL leading to the FDA only recommending considering 8 week treatment in treatment naïve patients whose viral load is < 6 million IU/mL. Treatment with sofosbuvir/ledipasvir was also found to be efficacious in treating patients who are treatment experienced (treatment experienced = patients who tried and failed pegifn and ribavirin ± a NS3/4a protease inhibitor) at 12 weeks and weeks; SVR rates 94% (95% CI 87-97) and 99% (95% CI ), respectively. In all of the studies, the addition of ribavirin added no significant increase in efficacy while generally increasing the AEs experienced in each patient group. In regards to, treatment naïve patients who were cirrhotic at baseline achieved similar response rates as those who had no at 12 and weeks of sofosbuvir/ledipasvir treatment. Cirrhotic patients were not part of the 8 week trial for treatment naïve patients. The only distinguishing factor of predicting treatment response in treatment experienced patients was. Patients with baseline and treated with 12 weeks of sofosbuvir/ledipasvir had an SVR rate of 92% (95% CI 84 to 97) compared to an SVR rate of 98% (95% CI 96 to 99) for patients without. There are currently studies underway to evaluate sofosbuvir/ledipasvir in different HCV genotypes (1-6) and in patients who have advanced liver disease and in patients who have undergone liver transplant. There is also a study not yet in the recruiting phase designed to test the efficacy of sofosbuvir/ledipasvir in patients co-infected with HIV. Currently there are no guidelines for the off-label use of sofosbuvir/ledipasvir in the above populations. Sofosbuvir is considered pan-genotypic in combination with ribavirin and pegifn in all HCV genotypes (1-6). There are no trials currently which compare the use of sofosbuvir/ledipasvir to current recommended sofosbuvir, ribavirin, and pegifn. However, as stated in the studies, the typical SVR rate seen with standard therapy range around 60-70% for HCV genotype 1. In all sofosbuvir/ledipasvir studies, the SVR rates were >97% for the use of the product for the duration FDA has approved in each patient group. Sofosbuvir/ledipasvir was generally safe over varying treatment lengths with the shorter the length of treatment resulting in fewer AE. More AE were seen in treatment arms of the studies that included ribavirin. No patients discontinued treatment early due to AE in ION-2 (440 patients). 10 patients (out of 865) in ION-1 discontinued treatment early due to AE, 4 from the sofosbuvir/ledipasvir week arm and 6 from the sofosbuvir/ledipasvir + ribavirin week arm. There was no early discontinuation in either 12 week arm. In ION-3 (647 patients), 3 patients discontinued sofosbuvir/ledipasvir due to AE; 1 in the 8 week arm (due to road accident), 2 in the 12 week arm of sofosbuvir/ledipasvir (1 due to arthralgia and 1 due to lung cancer). Out of a total of 1952 patients exposed to sofosbuvir/ledipasvir 13 patients (<1%) discontinued treatment early due to AE. This is much lower than the standard discontinuation rate of interferon based therapy. Mild to moderate AE were common across all trials (67 to 92% of patients reported at least one AE). The most common AE were fatigue, headache, nausea, diarrhea, and insomnia Update (August) A new direct acting antiviral agent combination product was approved in December This product, Viekira Pak, consists of three active ingredients, paritaprevir (boosted by ritonavir), ombitasvir and dasabuvir. Paritaprevir Paritaprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, paritaprevir inhibited the proteolytic activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes with IC50 values of 0.18 nm and 0.43 nm, respectively. Paritaprevir inhibited the activity of NS3/4A enzymes from single isolates of genotypes 2a, 2b, 3a, and 4a with IC50 values of 2.4 nm, 6.3 nm, 14.5 nm, and 0.16 nm, respectively. The activity of paritaprevir is boosted by the addition of low dose ritonavir. This addition is responsible for many of the drug interactions reported with Viekira. Ombitasvir Ombitasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of ombitasvir has been characterized based on cell culture antiviral activity and drug

16 resistance mapping studies. Dasabuvir Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. In a biochemical assay, dasabuvir inhibited a panel of genotype 1a and 1b NS5B polymerases with median IC50 values of 2.8 nm (range 2.4 nm to 4.2 nm; n = 3) and 3.7 nm (range 2.2 nm to 10.7 nm; n = 4), respectively. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a nonnucleoside NS5B-palm polymerase inhibitor. Dasabuvir had reduced activity in biochemical assays against NS5B polymerases from HCV genotypes 2a, 2b, 3a and 4a (IC50 values ranging from 900 nm to > 20 nm. The efficacy and safety of Viekira Pak was evaluated in six randomized, multicenter, clinical trials in 2,308 subjects with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including one trial exclusively in subjects with with mild hepatic impairment. In SAPPHIRE-I and -II, subjects without were randomized to Viekira Pak in combination with ribavirin for 12 weeks or to placebo. Subjects in the placebo arm received placebo for 12 weeks, after which they received open-label Viekira Pak in combination with RBV for 12 weeks. In PEARL- II, -III and -IV, subjects without were randomized to receive Viekira Pak with or without RBV for 12 weeks of treatment. In the open-label TURQUOISE-II trial, subjects with compensated (Child-Pugh A) who were either treatment-naïve or pegylated interferon/rbv (pegifn/rbv) treatment experienced were randomized to receive Viekira Pak in combination with RBV for either 12 or weeks of treatment. Subjects who previously failed therapy with a treatment regimen that included Viekira Pak or other direct-acting antiviral agents were excluded. In these six clinical trials, the ombitasvir, paritaprevir, ritonavir dose was 25/150/100 mg once daily and the dasabuvir dose was 250 mg twice daily. Doses of drugs in Viekira Pak were not adjusted. For subjects who received RBV, the RBV dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg. RBV dose adjustments were performed according to the RBV labeling. Ombitasvir, paritaprevir, ritonavir (Technivie ) See description of ombitasvir and paritaprevir above. Ritonavir is a protease inhibitor, which in the setting of HCV acts as a pharmacokinetic booster of other protease inhibitors. The efficacy and safety of Technivie was evaluated in a single clinical trial in subjects with genotype 4 (GT4) chronic hepatitis virus (HCV) infection. PEARL-I was a randomized, global, multicenter, open-label trial that enrolled 135 adults with HCV GT4 infection without who were either treatment-naïve or did not achieve a virologic response with prior treatment with pegylated interferon/ribavirin (pegifn/rbv). Previous exposure to HCV direct-acting antivirals was prohibited. Treatment-naïve subjects were randomized in a 1:1 ratio to receive one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule once-daily with food with or without ribavirin for 12 weeks. PegIFN/RBV treatment-experienced subjects received one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule once-daily with food in combination with ribavirin for 12 weeks. The ribavirin dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg. The primary endpoint was sustained virologic response defined as HCV RNA below the lower limit of quantification (<LLOQ) 12 weeks after the end of treatment (SVR12) using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, which has an LLOQ of 25 IU per ml. HCV GT4-infected subjects had a median age of 51 years (range: 19 to 70); 64% were treatment-naïve, 17% were prior pegifn/rbv null responders; 7% were prior pegifn/rbv partial responders, 13% were prior pegifn/rbv relapsers; 65% were male; 9% were Black; 14% had a body mass index at least 30 kg/m2; 70% had baseline HCV RNA levels at least 800,000 IU/mL; 79% had IL28B (rs ) non-cc genotype; 7% had bridging fibrosis (F3).

17 SVR12 for HCV Genotype 4-Infected Subjects without Cirrhosis Treatment Outcome Ombitasvir + Paritaprevir + Ritonavir with RBV for 12 weeks Ombitasvir + Paritaprevir + Ritonavir for 12 weeks Overall SVR12 Treatment-naïve Treatment-experienced Treatment -naive % (n/n) % (n/n) % (n/n) 100% (42/42) 100% (49/49) 91% (40/44) Outcome for subjects without SVR12 Ontreatment 0% (0/42) 0% (0/49) 2% (1/44) VF Relapse 0% (0/42) 0% (0/49) 5% (2/42) Other 0% (0/42) 0% (0/49) 2% (1/44) The safety assessment of Technivie is based on data from a clinical study that included 135 HCV genotype 4- infected subjects without, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects without who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks (PEARL-I). The majority of adverse reactions in PEARL-I were mild in severity. None of the subjects who received ombitasvir, paritaprevir and ritonavir with ribavirin experienced a serious adverse reaction. None of the subjects receiving ombitasvir, paritaprevir and ritonavir with or without ribavirin discontinued treatment due to an adverse reaction. Selected Adverse Reactions (All Grades) with 5% Frequency Reported in Subjects Treated with Ombitasvir, Paritaprevir, and Ritonavir, with or without Ribavirin for 12 weeks. PEARL-I Adverse Reaction Ombitasvir, paritaprevir, ritonavir + RBV Ombitasvir, paritaprevir, ritonavir Asthenia 12 weeks 12 weeks Fatigue N=91 N=44 Nausea % % Insomnia Pruritus* 15 7 Skin reactions** 14 9 Daclatasvir (Daklinza ) Daclatasvir is an inhibitor of HCV NS5A protein, and is thus direct-acting antiviral agent against HCV.IT binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. The efficacy and safety of DAKLINZA in combination with sofosbuvir were evaluated in the Phase III ALLY-3 (AI ) clinical trial. ALLY-3 was an open-label trial that included 152 subjects with chronic HCV genotype 3 infection and compensated liver disease who were treatment-naive (n=101) or treatment-experienced (n=51). Most treatment-experienced subjects had failed prior treatment with peginterferon/ribavirin, but 7 subjects had been treated previously with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational cyclophilin inhibitor. Previous exposure to NS5A inhibitors was prohibited. Subjects received DAKLINZA 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for weeks post treatment.hcv RNA values were measured during the clinical trial using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per ml. Sustained virologic response (SVR) was the primary endpoint and was defined as HCV RNA below the LLOQ at post-treatment week 12 (SVR12).The 152 treated subjects in ALLY-3 had a median age of 55 years (range, -73); 59% of the subjects were male; 90% were white, 5% were Asian, and 4% were black. Most subjects (76%) had baseline HCV RNA levels greater than or equal to 800,000 IU/mL; 21% of the subjects had compensated, and 40%

18 had the IL28B rs CC genotype.svr and outcomes in subjects without SVR in ALLY-3 are shown by patient population in Table 8. For SVR outcomes related to the baseline NS5A Y93H polymorphism, see Microbiology (12.4). SVR rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. Treatment Outcomes in ALLY-3: Daklinza in Combination with Sofosbuvir in Subjects with HCV Genotype 3 Infection Treatment Outcomes Treatment-Naïve SVR ALL No With Outcomes for subjects without SVR On-treatment virologic failure Relapse n=101 90% (91/101) 98% (80/82) 58% (11/19) 1% (1/101) 9% (9/100) Treatment-Experienced n=51 86% (44/51) 92% (35/38) 69% (9/13) 0 14% (7/51) Total N=152 89% (135/152) 96% (115/120) 63% (20/32) 0.7% (1/152) 11% (16/151) References [TOP] 1. Kim WR. The burden of hepatitis C in the U.S. Hepatology. 2002; 36(5 suppl 1):S30-S Yano M et al. The long-term pathological evolution of chronic hepatitis C. Hepatology. 1996; 23: Pearlman BL. Hepatitis C treatment update. Am J Med. 2004; 117: Anon. National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002 June Hepatology. 2002; 36(5 suppl l):s3-s Muir AJ, Provenzale D. A descriptive evaluation of eligibility for therapy among veterans with chronic hepatitis C virus infection. J Clin Gastroenterol. 2002; 34: Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001; 358: Fried MW, Shiffman ML, Redd R et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347: Centers for Disease Control. HBV Disease Burden Last accessed September, Centers for Disease Control. HBV Disease Burden Last accessed September, El-Surag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med. 2000; 160: United Network for Organ Sharing/Organ Procurement Transplant Network. last accessed on September, Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology. 2001; 34: Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B: update of recommendations. Hepatology. 2004; 39(3): Lindsay KL et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001; 34: Zeuzem S et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000; 343: Poynard T, Marcellin P, Lee SS et al. Randomized trial of interferon alpha-2b plus ribavirin for 48 weeks or for weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998; 352:

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