The end of the beginning for hepatitis C treatment

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"The development of an oral regimen of DAA's that can produce SVR in a high proportion of patients is the grail that we seek. It will prolong life and prevent death from liver disease, just as the epidemic reaches crisis proportions. The two studies in this issue of Hepatology bring us much closer to providing the answer to the epidemic."

1. Douglas Dieterich Mt Sinai Hosp NYC
Hepatology Jan 2012

Accepted Article (Accepted, unedited articles published online for future issues)

THE END OF THE BEGINNING FOR HEPATITIS C TREATMENT

"Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning." Winston Churchill.

These are extraordinary times in the history of HCV drug development. We waited 13 years between the approval of ribavirin in 1998 and the approval of telaprevir and boceprevir in 2011. The trajectory of drug discovery and clinical trials has gone from exponential to warp speed since the EASL meeting in April 2011, and these two articles are perfect examples of what has changed the world of hepatitis C; interferon-free combination therapy and in one of the trials, leading to eradication of the virus. The first demonstration in man of IFN-free combination therapy with direct acting antivirals (DAA's) was the INFORM-1 trial presented first at EASL 2009 and published in 2010(1) It showed that a nucleoside analogue polymerase inhibitor (now known as mericitabine) and a protease inhibitor (now known as danoprevir (now boosted with ritonavir) together without PEG or RBV could reduce HCV viral load by 5·1 log10 IU/mL in 14 days with no sign of resistant virus. This was the proof of principle that two DAA's by themselves could render most patients undetectable without PEG or RBV. This combination hit a snag with some danoprevir toxicity issues, and development has slowed. Those issues were successfully resolved with ritonavir boosting and the follow up study to INFORM is now proceeding apace and data will be forthcoming from that trial in 2012 or 2013.

The Zeuzem study published in this journal (2) compared an all-oral combination of tegobuvir a nonnucleoside polymerase inhibitor given twice daily plus GS 9256 an NS3 serine protease inhibitor with and without ribavirin in two arms for 28 days, at which point they received peginterferon and ribavirin standard of care. The third arm used quadruple therapy with both DAA's plus peginterferon and ribavirin for 28 days and then peginterferon and ribavirin alone. All patients with viral rebound of >.5 log10 from nadir or non response defined as < 2.0 log10 decline at day 5 received peginterferon and ribavirin immediately. Median maximal reductions in HCV RNA were -4.1log10 IU/ml, -5,1 log10 IU/ml and -5.7 log10 IU/ml for tegobuvir plus GS 9256, tegobuvir , GS9256 plus ribavirin and the tegobuvir, GS9256, peg and ribavirin arms. The results were quite instructive. RVR for the two DAA's alone was 7%, for the two DAA's plus ribavirin 38% and for the quadruple therapy arm 100%. The importance of ribavirin in preventing resistance is very clear with this combination and reemphasizes the continuing value of using ribavirin in all oral regimens of DAA's. It also demonstrates the real, but weak antiviral activity of ribavirin (3). Why was this result so much different than that of INFORM where virtually all patients were undetectable at 14 days of dual therapy? The answer lies in the barrier to resistance (4). The nucleoside/nucleotide analogues in general have a very high barrier to resistance and the INFORM study used the nucleoside mericitabine. The barrier to resistance for protease inhibitors is relatively low, and lower still for genotype 1a as opposed to genotype 1b, since the 1a virus only requires one mutation to generate resistance to protease inhibitors, while the 1b virus requires two. Most nonnucleoside polymerase inhibitors have a relatively low barrier to resistance. When you combine two DAA's with relatively low barriers to resistance, it is easy for the virus to produce the double mutants that are resistant to both drugs. Ribavirin slows this down somewhat, but does not add enough antiviral activity to prevent resistance over 60% of the time with tegobuvir and GS 9256. There is one other factor involved in preventing resistance and that is the activity of the DAA. Extremely potent agents, which drop the viral load down to undetectable rapidly, also prevent resistance. A good example of this is the combination study of BI 201335 and BI 207127 (5). This study compared two groups: BI201727 400 mg or 600 mg given thrice daily plus BI 201335 and ribavirin 1000-1200 mg for 4 weeks. In the 400 mg group, the RVR was 73 %( with better response in genotype 1b than 1a, as one would expect with a protease inhibitor in the regimen). In the 600 mg group, the RVR was 100% and did not differ between genotype 1a and 1b. From this data one can infer that the potency of either the protease inhibitor or the nonnucleoside polymerase inhibitor was different, since the same two classes of drugs, plus ribavirin yielded a much higher RVR. To be fair, there was no arm without ribavirin in this study and, of course, it is hard to compare results between studies. The designs of both studies are elegant, simple and easy to understand and advance the field enormously. Gilead is now aggressively addressing the issue of potency by adding a third DAA to tegobuvir and GS 9256 with and without ribavirin. (6)

The other study in this issue of Hepatology (7) advances the field dramatically further. Not only does it move us from RVR without interferon to SVR, but it does it in null responders! This represents a giant step towards the "Holy Grail" of HCV therapy: once daily, oral interferon-free treatment. The world of HCV treatment changed forever in April of 2011 when the first interferon-free SVR's were presented using an NS5A inhibitor and a protease inhibitor, the same two drugs used in the Chayama paper. (8) The 100% SVR with quadruple therapy was overshadowed by the all-oral double DAA combination, without ribavirin that resulted in a 36% SVR. This was the long awaited proof of principle that HCV could be eradicated without interferon. Of note in the all-oral arm was that both of the genotype 1b patients achieved an SVR, but only 2/9 of the genotype 1a patients achieved an SVR demonstrating the differences in activity of protease inhibitors in genotypes 1a and 1b.

The Chayama study in this issue examined the combination of the NS5A BMS-790052 60 mg qd ( now called daclatasvir) and the protease inhibitor BMS-650032 600mg (now called asunaprevir) in null responders, but only in genotype 1b, the most common genotype in Japan. Ten patients received both drugs for 24 weeks. Of the nine patients who completed the study, all achieved an SVR. HCV RNA remained undetectable in the patient who discontinued treatment after two weeks. This is truly a remarkable achievement in the field of HCV treatment. It is only partially applicable to genotype 1a patients around the world, but nonetheless brings us closer to what we seek in HCV therapy: all oral highly effective treatment. This publication marks a turning point in the HCV drug development world. It demonstrates that a protease and an NS5A inhibitor together can achieve an extremely high SVR in null responders, at least in genotype 1b. It is the second trial to show that an SVR is possible without either interferon or ribavirin in null responders.

In the patois of HCV drug development, we often speak of an all-oral regimen as the "Holy Grail" we all seek. In history that term has had many meanings, particularly in Arthurian legends beginning in the late 12th century. The meaning that comes closest, though to what we really intend, is in Wolfram von Eschenbach's Parzival. In it he portrays the grail as a stone that prevents anyone who sees it from dying. The development of an oral regimen of DAA's that can produce SVR in a high proportion of patients is the grail that we seek. It will prolong life and prevent death from liver disease, just as the epidemic reaches crisis proportions. The two studies in this issue of Hepatology bring us much closer to providing the answer to the epidemic.

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Treatment of chronic hepatitis C – are interferons really necessary?

Liver International

Special Issue: Proceedings of the 5th Paris Hepatitis Conference. International Conference of the Management of Patients with Viral Hepatitis: Special Edition Hepatitis C

Volume 32, Issue Supplement s1, pages 108–112, February 2012

Review Article

Peter Ferenci

Article first published online: 29 DEC 2011

DOI: 10.1111/j.1478-3231.2011.02705.x

© 2012 John Wiley & Sons A/S

Abstract

Due to the side effect profile of pegylated interferons interferon treatment has become the holy grail of drug development for chronic hepatitis C. The precise role of interferon in treatment of hepatitis C is not fully understood, besides its antiviral effects interferon is an immune modulator. Nevertheless, recent proof of concept studies indicated, that cure of chronic hepatitis C can be achieved without interferon. Various compounds achieved this goal, like the polymerase inhibitor PSI 7977, the combination of NS5a inhibitor (daclatasvir) and a protease inhibitor (asunaprevir) and the cyclophillin antagonist alisporivir. Various other combinations are investigated currently. Providing that phase 3 studies will confirm these exciting data, direct acting antivirals or host targets will replace peginterferon/ribavirin combination therapy.

The current standard of care (SoC) for treatment of chronic hepatitis C is still a combination of a pegylated interferon-α2 (PEG-IFN) with ribavirin (RBV) [1]. Recently, the first two direct-acting antivirals (DAA) were licensed in the USA and the European Union. In combination with PEG-IFN/RBV, telaprevir and boceprevir significantly increases the rate of cure of chronic hepatitis C, genotype 1, both in naïve and treatment-experienced patients [2, 3, 4]. Nevertheless, treatment is still restricted to patients who can tolerate PEG-IFN and RBV. As many as 50% of patients, including those with the greatest need of effective treatment such as those with advanced liver disease, cannot receive the new triple therapy. Thus, an interferon-free treatment regimen is required .

Investigation of DAA combination regimens has exploded in the last 12 months. This is possible because of the diversity of antiviral mechanisms besides protease inhibitors that are now in Phase II of the drug development pipeline for hepatitis C [5]. Diverse mechanisms are important because they often have different resistance profiles, and antiviral combinations are being assembled with new compounds with non-overlapping profiles to provide a greater barrier to antiviral resistance. Other factors that are important when assembling optimal combinations include the safety and tolerability profile of each agent, compatible pharmacokinetic profiles and a low potential for unfavourable drug–drug interactions.

The role of interferon in the treatment of chronic hepatitis C

Although interferon (IFN) has been used to treat chronic hepatitis C for more than 25 years, its precise role in eradicating the hepatitis C virus (HCV) still remains unknown. Determining the mechanism(s) involved in an IFN-induced cure is mandatory if IFN-free treatment regimens are to be developed. IFNs play a pivotal role in the outcome of a viral infection. IFNs are a family of pleiotropic cytokines that typically exhibit antiviral, antiproliferative, antitumour and immunomodulatory properties. The first response of an organism to intruding pathogens is an inflammatory reaction that includes secretion of cytokines and chemokines. These signalling molecules activate or attract innate immune cells, such as neutrophils, macrophages, natural killer (NK) cells, and dendritic cells (DCs), to orchestrate an effective response at the site of infection. Induction of innate immune mechanisms is not pathogen-specific, but is dependent upon interactions between pathogenic factors and host-cell determinants. During viral infection, some of the most prominent cytokines produced are IFNs. The importance of IFNs goes beyond their antiviral activities and includes numerous immunoregulatory functions that affect both innate and adaptive immunity [6]. IFN-induced clearance of HCV is both cytolytic (clearance of HCV-infected hepatocytes) and non-cytolytic (intra-cytoplasmic destruction of HCV without cell injury).

Innate immunity can be principally affected by HCV at the level of both: (i) type I IFN production by infected hepatocytes and (ii) the signals provided by the relative receptors (IFNAR-1/2) once they are engaged by soluble type I IFNs (mainly produced by plasmacytoid dendritic cells). If these defects are combined with a low viral load or infection by HCV strains that are highly susceptible to the antiviral effects of IFN, the spread of the HCV virus is contained, and the functions of dendritic cells, NK, B and T cells would not be heavily affected. Induction of type I IFN production in HCV-infected cells (i.e. hepatocytes) either on contact with TLR3 in the endosomal compartments, or upon recognition of the polyuridine motif of the HCV 30 untranslated region (UTR) by the retinoid acid-inducible gene I (RIG-I) in the cytoplasm, may be affected by HCV [7, 8, 9]. Thus, the initial response to HCV infection might not be sufficient to induce effective primary or secondary CD8 T-cell responses [10]. In chronic HCV infection, two major pathways, T-cell exhaustion and viral escape, contribute to CD8⁺ T-cell failure. In vivo models of HCV infection demonstrate selective impairment of T cells infiltrating HCV-infected livers because of the high concentrations of viral proteins produced at the site of infection, which may play a role in HCV persistence by affecting local adaptive immune responses [9].

The immunomodulatory activity of PEG-IFN-α and RBV induced T-cell immune responses may be important to eliminate chronic HCV infection [11]. In a prospective study, the kinetics of T-cell responses to HCV antigens (NS3-4 and core) correlated with virological outcome in patients undergoing PEG-IFN-α2a/RBV therapy. NS3-4-directed T helper cell type 1 (Th1) responses were detected in 77% of patients with a significant decline in viremia at treatment week 4, but were not detected in those with a slower viral decline. HCV-specific T-cell reactivity was uncommon at baseline, but increased markedly during antiviral therapy, peaking at around treatment weeks 4–8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production [12]. The detectability of NS3-4-directed Th1 responses was associated with faster viral clearance, was short-lived and was not associated with the final treatment outcome [13]. This may be explained because HCV abolishes the blockade of the adaptative immune response by inhibiting viral replication. T-cell activation was transient, but not always sufficient to clear infected hepatocytes. Thus, if rapid inhibition of HCV replication by DAA is sufficient to restore adaptative immunity, exogenous IFN administration may not be necessary.

The other important role of IFN is the inhibition of viral replication. In drugs with a low genetic barrier such as first generation protease inhibitors, IFN and RBV are required to block the emergence of DAA resistant viral strains [14, 15]. Potential strategies to overcome this problem are: (i) DAA combinations including polymerase inhibitors with a high barrier to resistance; (ii) triple DAA therapy; and (iii) combinations of two DAAs with a lower genetic barrier to resistance plus RBV. A mathematical model by Perelson et al. [16] suggests that IFN-free regimens will need to contain three or four distinct antiviral mechanisms to obtain a sustained viral response (SVR) before the development of resistance.

Proof-of-concept studies

The first published trial with an all-oral combination treatment with two experimental anti-HCV drugs [mericitabine, a nucleoside polymerase inhibitor (NI); and danoprevir, an NS3/4A protease inhibitor] in patients with chronic HCV infection was the INFORM-1 study [17]. Patients with chronic hepatitis C, genotype 1, received up to 13 days of oral combination treatment with mericitabine (500 or 1000 mg twice daily) and danoprevir (100 or 200 mg every 8 h or 600 or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or a web response system to either active treatment or placebo. The primary outcome was a change in HCV RNA concentrations from baseline to day 14 in patients who received 13 days of combination treatment. Eighty-eight patients were randomly assigned to a drug treatment regimen (n = 74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n = 14, all of whom received at least one dose). The median change in HCV RNA concentrations from baseline to day 14 ranged from −3.7 to −5.2 log₁₀ IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentrations from baseline to day 14 was −5.1 log₁₀ IU/mL in treatment-naive patients and −4.9 log₁₀ IU/mL in previous SoC non-responders. The combination of RG7128 and danoprevir was well tolerated with no severe treatment-related or adverse events, no grade 3 or 4 changes in laboratory parameters and no safety-related treatment discontinuations. Virological breakthrough, with the selection of resistant variants, has not yet been observed in short-term clinical studies of the NS3/4A protease inhibitor danoprevir plus the NI, mericitabine, suggesting that inclusion of an NI in DAA combination therapy may be an attractive strategy. However, additional efficacy (SVR) and safety data from longer term treatments are still required. A phase 2a study is ongoing (Matterhorn study).

In another study [18], the combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127 and RBV was shown to have a rapid and strong activity against HCV genotype-1 with no severe adverse events. Thirty-two treatment-naïve patients with chronic HCV genotype-1 infection were randomly assigned to groups that were administered 400 or 600 mg BI 207127, three times a day (TID), plus 120 mg BI 201335, once a day and 1000–1200 mg RBV per day for 4 weeks. The primary efficacy endpoint was virological response (HCV RNA < 25 IU/mL at week 4). The virological response rates were 47, 67 and 73% at days 15, 22, and 29, respectively, in the group receiving BI 207127 400 mg TID; a higher response rate was observed in patients with genotype-1b compared with genotype-1a. The virological response rates were 82, 100 and 100%, respectively, in the group receiving BI 207127 600 mg TID, and did not differ among genotypes. One patient in the group receiving 400 mg TID had a virological breakthrough [≥1 log [10] rebound in HCV RNA] at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash and photosensitivity. There were no severe or serious adverse events; none of the patients discontinued treatment early.

The results of a proof-of-concept study for SVR with a PEG-IFN-free treatment regimen in HCV patients was recently reported. Four of eleven genotype 1 patients, who were non-responders to PEG-IFN/RBV treatment, achieved a SVR after 24 weeks of treatment with the combination of an NS5A inhibitor and an NS3/4A protease inhibitor, with only one relapse in this cohort [19], especially in patients with genotype 1b [20]. This suggests that HCV can be eradicated in chronically infected patients with a PEG-IFN-free DAA combination regimen, and supports investigations of various DAA combinations to improve SVR rates without PEG-IFN.

These observations provide a proof-of-concept for an oral approach to the treatment of HCV, including a combination of DAA without PEG-IFN.

ZENITH is an ongoing Phase 2 study of multiple 12- and 24-week response-guided treatment regimens with VX-222 (400 or 100 mg), a polymerase inhibitor in development, in combination with telaprevir [21]. The all-oral treatment arms (VX-222 400 or 100 mg plus telaprevir 1125 mg BID) were discontinued because of a pre-defined stopping rule in relation to viral breakthrough. The two treatment arms including PEG-IF and RBV (quadruple therapy) could stop all treatments at week 12, if hepatitis C virus was undetectable at weeks 2 and 8. Twenty-six of fifty-nine (44%) patients qualified for 12 weeks of therapy, and 88.4% of these had a SVR. The remaining patients received an additional 12 weeks of PEG-IFN/RBV. SVR was achieved in 96%. The overall SVR rate was 86.4%.

Another approach is the combination of nucleoside polymerase inhibitors (PSI-7997 with PSI-938) [22] with promising initial data. The approach of combining three non-cross resistant DAAs with a lower genetic barrier to resistance, i.e. an NNI plus a NS3/4A protease inhibitor and an NS5A inhibitor, is well supported by mathematical analyses. Rong et al. demonstrated that resistant variants against the three drug classes are unlikely to pre-exist before treatment initiation, and emergence is unlikely to occur during therapy [23]. However, drug–drug interaction and overlapping safety profiles remain an issue.

A third highly attractive strategy is to combine two DAA with a lower genetic barrier to resistance, plus RBV. A trial evaluating GS-9256 plus tegobuvir, with or without RBV demonstrated the central role of RBV in the decrease in HCV RNA and the reduction of viral breakthroughs for DAA combinations with a low barrier to resistance. Unfortunately, this study was interrupted because of safety concerns (Table 1).

Finally, a new class of drugs called cyclophilin inhibitors may be used in an IFN-free approach. Alisporivir (DEB025) is the first in this class of drugs, and is currently under investigation. Unlike other compounds under development that target the virus directly, Alisporivir is a host targeting antiviral that targets host proteins essential for the replication of HCV. As these proteins play a key role in the replication of all types of HCV, alisporivir may offer an effective treatment option for a broad range of HCV forms and be effective against other common HCV genotypes. High SVR rates were obtained in combination with PEG-IFN/RBV [24]. INF-free regimens in patients with genotypes 2 and 3 were recently presented [25, 26]. Alisporivir as IFN-free therapy achieves early on-treatment viral response in up to half of G2/3 patients by treatment week 6 and in most patients who reached end of treatment [25]. In a phase 2a study PSI 7977 in combination with ribavirin reached a 100% cure rate in just 12 weeks [26].

Summary

As a result of the side effects of IFN, there is ongoing search for interferon-free antiviral approaches to cure chronic hepatitis C. The FDA, EMA as well as patient advocacy groups are strong proponents of investigating antiviral drug combinations prior to approval of individual components. Although proof-of-concept studies confirm that such approaches may be feasible, at present, only oral combinations together with PEG-IFN/RBV offer the best chances for cure even in non-responders to SoC treatment. The best drug combinations must prevent the emergence of drug resistant viral strains, have a high degree of safety and efficacy, an easy treatment algorithm and short treatment duration. The treatment should work for all genotypes. Although the ideal drug has not yet been found there is an urgent medical need because patients with advanced liver disease or organ transplant patients (excluding liver transplants) cannot tolerate IFN and are in great need of effective treatment.

Conflicts of interest

Dr Ferenci is a member of the global advisory board and of the speaker bureau of ROCHE. He also receives an unrestricted research grant from ROCHE Austria. He is also member of the global advisory boards of Vertex/Tibotec, Böhringer-Ingelheim, MSD and Rottapharm-Madaus, and serves as advisor to Pfizer, Novartis, Achilleon, GSK.

References

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Merck Announces Initiation of Clinical Development Collaboration with Roche To Evaluate Investigational Combination Regimens for the Treatment of Chronic Hepatitis C Genotype 1 Infection

Posted December 16, 2011

New Clinical Trial Will Evaluate an Investigational Therapeutic Regimen with VICTRELIS^TM (boceprevir)

WHITEHOUSE STATION, N.J., Dec. 15, 2011 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that Merck, in collaboration with Roche (SIX: RO, ROG; OTCQX: RHHBY), has initiated the first of a series of planned clinical trials to examine novel combinations of marketed and investigational medicines to expedite the availability of potential new treatment regimens for patients with chronic hepatitis C virus (HCV) genotype 1 infection. Clinical development collaboration is part of the overarching strategic agreement between Merck and Roche to improve treatment, diagnosis and awareness of chronic HCV in developed and emerging markets.

"VICTRELIS is the first in a new class of medicines for the treatment of chronic HCV genotype 1 infection, and when used in combination with peginterferon alfa, can significantly increase a patient's chance of achieving undetectable levels of the virus," said Eliav Barr, M.D., vice president, Infectious Diseases Project Leadership and Management, Merck Research Laboratories. "The start of this new study is an important milestone in our collaboration with Roche as we work to build on the innovative platform VICTRELIS provides by evaluating it in combination therapy with new investigational medicines for the treatment of chronic HCV genotype 1 infection, and also emphasizes our ongoing commitment to seeking novel treatment options for patients with chronic HCV."

The first trial is designed to provide clinical data on the use of VICTRELIS^TM (boceprevir), an oral HCV NS3/4A protease inhibitor, in combination with mericitabine (RO5024048), Roche's investigational oral HCV NS5B nucleoside polymerase inhibitor, Pegasys® (pegylated interferon alfa-2a) and Copegus® (ribavirin), in adult patients with chronic HCV genotype 1 infection who had a null response to prior peginterferon alfa and ribavirin therapy (less than a 2 log HCV-RNA decline at treatment week 12). The Phase II study, called DYNAMO 1, plans to recruit patients at 25 sites globally. For further details of the clinical trial please visit www.clinicaltrials.gov , or contact (888) 662-6728 or Genentechclinicaltrials@drug info.com.

Indications and usage for VICTRELIS
VICTRELIS was approved by the U.S. Food and Drug Administration (FDA) on May 13, 2011 for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (P/R), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:

VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.

VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.

VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to peginterferon alfa and ribavirin therapy.

Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin.

Important safety information about VICTRELIS
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and neutropenia have been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.

Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis care.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

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