Methadone programs can be key in educating, treating patients with hepatitis C virus infection

Research by Andrew Talal shows that people who inject drugs want to be educated about hepatitis C and are willing to be treated.

More effective, new medications for HCV infection with fewer side effects also are causing a shift in patients’ attitudes

By Ellen Goldbaum

Release Date: May 16, 2014

People who inject drugs and are enrolled in a drug treatment program are receptive to education about, and treatment for, hepatitis C virus, according to a study by researchers at several institutions, including the University at Buffalo.

That finding, published online this week in the Journal of Addiction Medicine will be welcome news to health care providers. The paper notes that injection drug use is a primary mode of infection, making for an HCV infection prevalence as high as 80 percent among people who inject drugs.

"One of the most important findings of this work is that people who inject drugs do want to be educated about the disease and that education is associated with willingness to be treated," says senior author Andrew H. Talal, MD, professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at UB and adjunct associate professor of medicine at Weill Cornell Medical College. First author is Marija Zeremski, PhD, senior research associate in medicine at Weill Cornell Medical College and research assistant professor of medicine at UB.

Talal and colleagues previously demonstrated that treatment of addiction significantly enhances the ability of people who use drugs to complete HCV therapy.

"These new findings support the premise that addiction-treatment facilities can help provide sustained HCV treatment for this population," Talal says. "These facilities have the added advantage of being able to link HCV care to drug treatment, allowing for closer patient evaluation, which will likely lead to improved adherence to treatment regimens."

HCV infection often is asymptomatic, but 75 to 80 percent of those infected will develop chronic infection that can progress to liver cirrhosis and/or liver cancer, potentially requiring liver transplantation as a life-saving intervention. However, in order to be considered for a liver transplant, people who use drugs must remain "clean" for at least six months.

The study was based on a survey of 320 patients enrolled in a New York City-based methadone treatment program (START Treatment and Recovery Centers). Nearly half of them reported that they had tested positive for HCV infection.

Seventy-eight percent of respondents expressed willingness to participate in HCV-related education and to receive treatment for HCV. More than half of those surveyed correctly responded to at least five of seven questions assessing their knowledge about HCV.

"People who inject drugs have always wanted to be treated for hepatitis C, but there have been a variety of barriers at the patient, provider and institutional levels," says Talal. "Most importantly, there has been a lack of education about the disease, a fear of side effects of interferon, discomfort in conventional health care venues and a lack of awareness of the status of the infection."

In some cases, the percentage of HCV-infected people who use drugs that show up for HCV-related medical appointments is as low as 10 percent, according to Talal.

In the current research, patients cited fear of side effects from interferon, which remains as part of the standard treatment regimen for genotype 1 infection, as a key barrier to their willingness to accept HCV treatment. Interferon can cause multiple side effects, ranging from fatigue, fever, nausea, anorexia, muscle pain and hair loss, to insomnia, depression and irritability. In addition, interferon-based therapies are only effective in eliminating infection in half of those who take it.

"A major change in the attitudes of people who use drugs is due to knowledge about greatly improved treatment efficacy and the ability to provide HCV treatment at the same site as the substance abuse treatment," says Talal.

Talal adds that the New York State law mandating that all individuals born between 1945 and 1965 be offered HCV screening is increasing the number of people diagnosed with the infection, thereby also making them more receptive to HCV education and treatment.

This study, funded by the Viral Hepatitis Action Coalition and performed in collaboration with the Centers for Disease Control and Prevention, documents the initial phase of a project called Prevention, Evaluation and Treatment of Hepatitis C in Opiate Agonist Treatment (PET-C). Led by Talal, the project's goal is to assess how telemedicine can be used to evaluate a model of HCV treatment for people who inject drugs and are enrolled in a drug treatment program.

Talal conducts research on HCV in UB's Clinical and Translational Research Center and he sees patients as a physician with UBMD, the practice plan of the UB School of Medicine and Biomedical Sciences. He previously served on the advisory board for Abbott Molecular, received support from Gilead Sciences and disclosed a prior relationship with Vertex Pharmaceuticals, all of which helped sponsor the study.

Media Contact Information
Ellen Goldbaum Senior Editor, Medicine
Tel: 716-645-4605
goldbaum@buffalo.edu
Twitter: @egoldbaum

Source

Public health boards fail to prioritise hepatitis C

Alistair Kleebauer

Nursing Standard. 28, 37, 0-0. http://dx.doi.org/10.7748/ns.28.37.0.2837992

Published online: 16 May 2014

Health and wellbeing boards in England are failing to make the hepatitis C virus (HCV) a priority despite an increase in hospital admissions and deaths from the virus, according to the HCV Action network and the charity Hepatitis C Trust.

Both groups said the failure constituted a ‘serious public health issue’ and that their evidence showed just three of the top ten areas with the highest prevalence have a detailed needs assessment of hepatitis C, which is recommended by the National Institute for Health and Care Excellence.

Their report found that 52 per cent of health and wellbeing boards fail to mention hepatitis C at all in their joint strategic needs assessments or in their joint health and wellbeing strategies.

Public Health England (PHE) data show that deaths from hepatitis C-related end-stage liver disease and hepatocellular carcinoma, a hepatitis C-related cancer, are rising year-on-year, from 89 in 1996 to 326 in 2012.

HCV Action’s chair and consultant hepatologist at Nottingham University Hospitals NHS Trust Stephen Ryder said: ‘The report highlights the alarming gap between the prevalence of hepatitis C and the way health and wellbeing boards prioritise the diagnosis and treatment of the virus.’

For read the full report, go to: www.hepctrust.org.uk/Resources/HepC%20New/Documents/Hepatitis%20C%20in%20JSNAs%20Final%20Report%20May%2014%20PDF.pdf

To comment on this story email letters@rcnpublishing.co.uk

Source

Hepatitis C Virus Therapy in the Direct Acting Antiviral Era

Current Opinion in Gastroenterology

Mitchell L. Shiffman

Curr Opin Gastroenterol. 2014;30(3):217-222.

Abstract and Introduction

Abstract

Purpose of review: The evolution of treatment for patients with chronic hepatitis C virus (HCV) is evolving at a rapid pace. Two new oral antiviral agents, simeprevir and sofosbuvir, have already been approved and are now available for treatment of patients with chronic HCV. Other antiviral agents will be available during 2014.

Recent findings: The protease inhibitor simeprevir was recently approved for use with peginterferon (PEGINF) and ribavirin (RBV) in patients with chronic genotype 1. About 80% of patients achieve a rapid virologic response and can be treated for 24 weeks. The sustained virologic response (SVR) in treatment-naive patients is about 80%. Sofosbuvir, the first polymerase inhibitor, is effective in all HCV genotypes. When utilized with peginterferon and RBV for 12 weeks in treatment-naive patients with genotypes 1, 4, 5 and 6, an SVR of 90% is observed. Sofosbuvir and RBV have also been studied without interferon and represent the first interferon-free therapy for chronic HCV.

Summary: It is now possible to cure chronic HCV in the vast majority of patients with chronic HCV and in many patients without interferon.

Introduction

The treatment of chronic hepatitis C virus (HCV) continues to evolve at an accelerating pace. In 2011, the first two protease inhibitors, telaprevir and boceprevir, were approved to be utilized with peginterferon (PEGINF) and ribavirin (RBV) to treat chronic HCV genotype 1.^[1–5] The addition of a protease inhibitor to PEGINF and RBV represented a huge advance in HCV treatment and increased sustained virologic response (SVR) in the treatment-naive population with HCV genotype 1 from about 40% to 70–75%. The main limitation of these first-generation protease inhibitors was side-effects, particularly anemia, which were more severe than observed with PEGINF and RBV. These adverse events are even more severe and increase the risk of hepatic decompensation in patients with cirrhosis. In a study that included only patients with advanced fibrosis or cirrhosis, many of whom had previously failed PEGINF and RBV, nearly half of all patients treated with either telaprevir or boceprevir developed serious adverse events, 25% discontinued treatment, over half developed severe anemia and required a hematopoetic growth factor and 1–2% died as a result of hepatic decompensation.^[6] The patients at greatest risk to develop hepatic decompensation included those with thrombocytopenia and a low serum albumin.^[7] The SVR in this cohort was only 40%. In the subset of patients with cirrhosis who failed previous therapy, the SVR was under 20%.^[6,7] Results like these caused many physicians who were treating HCV to pause and wait for a better alternative.

In late 2013, another protease inhibitor simeprevir and the first polymerase inhibitor, sofosbuvir, were approved for HCV treatment. These two antiviral agents offer significant advantages compared with telaprevir and boceprevir when treating patients with HCV genotype 1; the duration of therapy is shorter, the adverse effect profile is superior and the SVR is higher. In addition, sofosbuvir is effective against all genotypes and when utilized with RBV represents the first interferon-free treatment for chronic HCV.

During the past few years, several oral antiviral agents, which inhibit various HCV proteins, have been developed at a rapid pace. These include protease inhibitors, nucleotide and nonnucleotide polymerase inhibitors, NS5A inhibitors and cyclophilin inhibitors. Two or more oral antiviral agents from different classes have been combined and their evaluation in phase 3 clinical trials is well underway.^[8–11] During 2015 multiple oral antiviral combinations are expected to be available to treat chronic HCV (Table 1). The rapid evolution of these treatments will make any recommendations for how to treat HCV in 2014 tentative at best. The treatments that will be available during 2014 are illustrated in Fig. 1. The rapid evolution of HCV treatment has also occurred at a pace that far exceeds the appearance of peer-reviewed publications. The vast majority of cited references are therefore abstracts, which have been presented at national and international meetings during 2013.

Figure 1.

Treatment regimens for patients with chronic hepatitis C virus (HCV) utilizing the two newest antiviral agents simeprevir (SPV) and sofosbuvir (SOF). Treatment of patients with HCV genotype 1 includes SPV, peginterferon (PEGINF) and ribavirin (RBV) for 24–48 weeks, SOF, PEGINF and RBV for 12 weeks, SOF plus RBV for 24 weeks or SOF and SPV for 12 weeks. The treatment of patients with HCV genotype 2 is SOF plus RBV for 12 weeks. The treatment of patients with HCV genotype 3 is SOF plus

Simeprevir and Faldaprevir

Both simeprevir and faldaprevir are NS3–4A protease inhibitors.^[12–16] Both act at the same binding site as telaprevir and boceprevir and are only effective in patients with HCV genotype 1. As a result, neither of these agents is likely to be effective in patients with resistance to telaprevir or boceprevir.

Simeprevir was approved for use in patients with HCV genotype 1 in late 2013 and faldaprevir is expected to be approved in early 2014. Both of these protease inhibitors will be utilized as triple therapy with PEGINF and RBV for 12 weeks followed by an additional 12–36 weeks of PEGINF and RBV. In patients who are treatment-naive or who have had prior relapse with PEGINF and RBV, the recommended total duration of therapy when utilizing simeprevir is 24 weeks, that is 12 weeks of simeprevir, PEGINF and RBV followed by an additional 12 weeks of PEGINF and RBV. Approximately, 80% of these patients will achieve a rapid virologic response (RVR) and be HCV RNA undetectable within 4 weeks of initiating treatment. The SVR in these patients is approximately 90%.^[12,13] It is recommended that patients with HCV RNA more than 25 IU/ml at either weeks 4, 12 or 24 stop treatment. In patients with prior nonresponse to PEGINF and RBV, the total duration of therapy is 48 weeks, that is 12 weeks of simeprevir, PEGINF and RBV followed by an additional 36 weeks of PEGINF and RBV. The SVR rate in these patients is 53–65%.^[14] It is recommended that patients with HCV RNA more than 25 IU/ml at either weeks 4, 12 or 24 also stop treatment. It is anticipated that the recommendations for faldaprevir will be quite similar.

Simeprevir and faldaprevir offer significant advantages over telaprevir and boceprevir. The most important of these is that neither of these agents cause additional anemia compared with PEGINF and RBV.^[12–16] All of these agents are dosed as a single once daily tablet, no special diet is required during dosing and no significant drug-drug interactions have been observed. Simeprevir was not noted to have any adverse events with greater frequency than PEGINF and RBV.^[12–14] Faldaprevir was noted to have a slightly higher incidence of rash.^[15,16] However, the rash was graded as only mild or moderate in all cases and no grade 3 rashes were observed. Faldaprevir was also associated with a mild increase in total bilirubin without elevations in liver transaminases or alkaline phosphatase.

Controlled clinical trials comparing the various antiviral agents utilized for treatment of patients with HCV genotype 1 have not been conducted. As such, no direct comparison regarding the relative effectiveness of these agents can be made. Both simeprevir and faldaprevir triple therapies were evaluated against a placebo control with PEGINF and RBV. As a result, the improvement in SVR with the protease inhibitor over control could be compared for all of the available protease inhibitors.^{[1–5,12–16]} Such a comparison suggests that RVR and SVR rates are somewhat higher in patients treated with simeprevir or faldaprevir compared with telaprevir and boceprevir. The high RVR rates observed with simeprevir and faldaprevir allow 80% of patients to be treated for only 24 weeks and lead to the higher SVR rates.

The success of treatment in patients treated with simeprevir or faldaprevir, like other protease inhibitors, is dependent upon an effective interferon response and this is modulated by interleukin-28B genotype. In treatment-naive patients, the SVR approaches 90% in patients with interleukin-28B genotype CC and declines in patients with the CT and TT genotypes.^[12,13,15] In patients with prior nonresponse to PEGINF and RBV, the SVR rates during retreatment with simepreivr or faldaprevir triple therapy follow a similar trend of interferon responsiveness; higher rates of SVR with prior partial response and the lowest SVR rates in prior null responders.^[14,16]

The primary limitation of simeprevir is that a mutation at the Q80K loci of HCV adversely impacts the antiviral efficacy of simeprevir and leads to a significant reduction in SVR.^[12,13,17] This mutation is present in about 40% of patients with HCV genotype 1A. The Q80K mutation is only rarely seen in HCV genotype 1B. The Q80K mutation in HCV has the greatest impact and significantly lowers SVR in patients who are genetically less sensitive to interferon. In contrast, patients with interleukin-genotype CC, who are highly sensitive to interferon, have similar SVR rates even if the HCV Q80K mutation is present.^[12,13] When treating patients with genotype 1A, it is therefore important that the patient is interleukin-28 genotype CC or that HCV does not contain the Q80K mutation. Testing the patient for their IL28B genotype and/or evaluating HCV for the presence of this mutation should be strongly considered if simeprevir is to be utilized. Patients with HCV genotype 1 and the Q80K mutation who are IL28B genotype CT or TT are best treated by an alternative antiviral agent.

Sofosbuvir

Sofosbuvir is the first polymerase inhibitor to be approved for the treatment of chronic HCV. It is a nucleotide analog, which inhibits the NS5B polymerase and is effective in all HCV genotypes. It is incorporated into the growing RNA sequence during replication and acts as a chain terminator. The appearance of resistance to sofosbuvir is extremely limited and when this does occur the viral species is unable to persist.

Sofosbuvir was studied as triple therapy with PEGINF and RBV for just 12 weeks in patients with genotypes 1, 4, 5 and 6^[18**] This was a single arm study with no comparison with PEGINF and RBV because of the marked differences in the duration of treatment. Over 90% of patients treated with sofosbuvir triple therapy were HCV RNA undetectable within 2 weeks and virtually all patients achieved a RVR. The overall SVR rate was 90%: 89% in patients with genotype 1 and 96% in patients with genotype 4. In patients with cirrhosis, the SVR rate was 80%. All seven of the patients with HCV genotypes 5 and 6 achieved SVR. Sofosbuvir triple therapy has not been evaluated in patients who failed either PEGINF and RBV or triple therapy with a protease inhibitor.

The combination of sofosbuvir and RBV represents the first interferon-free regimen approved for use to treat patients with chronic HCV. This combination was initially studied and is approved for use in patients with HCV genotypes 2 and 3.^[18**,19**] In patients with HCV genotype 2, sofosbuvir and RBV yielded superior SVR rates compared with PEGINF and RBV. In treatment-naive patients, 12 weeks of sofosbuvir and RBV achieved SVR rates of 91 and 98% in patients with and without cirrhosis respectively. In patients who had previously failed PEGINF and RBV SVR rates of 96 and 60% were observed with 12 weeks of treatment. Extending the duration of treatment from 12 to 16 weeks did increase the SVR in this subgroup of patients to 78%. The recommended duration of sofosbuvir and RBV for patients with HCV genotype 2 is 12 weeks.

In patients with genotype 3, treatment with sofosbuvir and RBV for 12 weeks yielded an SVR rate of only 61% in patients without cirrhosis and 34% in patients with cirrhosis.^[18**,19**] These SVR rates are very similar to that observed with PEGINF and RBV. Extending the duration of sofosbuvir and RBV to 16 and 24 weeks increased the SVR rate in all patients with genotype 3 to about 62 and 84%, respectively.^[19**,20,21] As a result, the recommended duration of sofosbuvir and RBV for patients with genotype 3 is 24 weeks.

Sofosbuvir and RBV were also studied in patients with genotypes 1, 2 and 3 who had co-infection with HIV.^[22] The duration of treatment for patients with genotypes 1 and 3 was 24 and 12 weeks for patients with HCV genotype 2. SVR rates of 76, 92 and 88% were observed for patients with genotype 1, 2 and 3, respectively. This study led to the approval of sofosbuvir and RBV for the treatment of HCV in patients co-infected with HIV.

Sofosbuvir and RBV have also been studied without interferon in patients with HCV and liver cancer awaiting liver transplant and in patients with post-liver transplant recurrent HCV.^[23,24] The duration of sofosbuvir and RBV in all of these studies was for 24 weeks. SVR rates of about 75% were achieved in each of these populations. These studies led to the recommendation that sofosbuvir and RBV be utilized in patients with HCV genotype 1 who were unable to receive PEGINF. The recommended duration of therapy in these patients was 24 weeks.

Sofosbuvir is a well tolerated antiviral agent with minimal side-effects. In a study in which sofosbuvir and RBV were compared with placebo in patients who could not take PEGINF and RBV, the only side-effects with increased frequency above placebo were anemia and pruritus, both of which were attributed to RBV.^[19**]

Mixing and Matching Antiviral Agents

Both simeprevir and sofosbuvir are currently approved and available for treatment of chronic HCV. The combination of simeprevir and sofosbuvir with or without RBV for either 12 or 24 weeks was evaluated in about 160 patients with HCV genotype 1. Many of these patients had prior nonresponse to PEGINF and RBV and about half had advanced fibrosis or cirrhosis.^[25] Over 93% of all patients achieved SVR. Treating for 24 weeks or using RBV was no more effective than 12 weeks of treatment with just simeprevir and sofosbuvir alone, without RBV. The SVR rate in patients with genotype 1B or genotype 1A without the Q80K mutation was 100%. Patients with genotype 1A and the Q80K mutation had an SVR rate of about 90%. Although the regulatory authorities did not specifically approve the combination of simeprevir and sofosbuvir for the treatment of patients with HCV, the approval by the US Food and Drug Administration states that simeprevir and sofosbuvir are 'indicated for the treatment of chronic HCV infection as part of a combination antiviral regimen'. This opens the door for the use of these agents along to treat patients with HCV genotype 1 and provides a cheaper, shorter and probably superior SVR than 24 weeks of sofosbuvir and RBV.

Identification of Patients With Hepatitis C Virus

An estimated 4 million persons in the United States and 300 million persons worldwide are infected with HCV.^[1] In the United States, the vast majority were infected in the 1960–1980s through the transfusion of blood products and injection drug use. Many of these patients are asymptomatic and have evaded detection for many years. The need to identify these patients is why the Center for Disease Control and the US Preventive Services Task Force has recommended that all persons born between the years of 1945–1965 be screened for HCV.^[26*,27*] If all persons in these birth cohort years were screened, it is estimated that 75% of all persons with HCV in the United States would be identified.

Conclusion

It is now possible to cure HCV in the vast majority of patients with chronic HCV. SVR rates of 80–90% can be routinely achieved in patients with all HCV genotypes in as little as 12–24 weeks. Of the antiviral agents currently available, sofosbuvir appears to be the easiest to manage, the most efficacious and the antiviral agent with the broadest of indications. Patients with HCV genotypes 1, 4, 5 and 6 can be treated with sofosbuvir, PEGINF and RBV for 12 weeks. SVR rates of 90% or better are achieved. Patients with genotype 1 who are unable to tolerate PEGINF and patients with HCV genotype 3 can be treated with sofosbuvir and RBV for 24 weeks. SVR rates in these patients range from 75 to 83%. Patients with genotype 2 can be treated with sofosbuvir and RBV for 12 weeks with an SVR exceeding 90%. Simeprevir offers an SVR of about 80%, but requires 24 weeks of PEGINF and RBV. Patients with HCV genotype 1A and the Q80K mutation have SVR rates that are significantly reduced. Perhaps the best use for simeprevir is with sofosbuvir for 12 weeks in patients with HCV genotype 1. Our ability to eradicate HCV is on the horizon. However, this cannot be achieved unless patients are recognized and this will require screening in those persons at greatest risk, which is now defined by the year of their birth.

References

1. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206.

2. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405–2416.

3. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217.

4. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428; 8.

5. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365:1014–1024.

6. Fontaine H, Hezode C, Dorival C, et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French early access program (anrs co20-CUPIC). J Hepatol 2013; 58 (Suppl 1):S27.

7. Bourlie` re M, Wendt A, Fontaine H, et al. How to optimize HCV therapy in genotype 1 patients with cirrhosis. Liver Int 2013; 33 (Suppl 1):46–55.

8. Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333+/_ ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol 2013; 58 (Suppl; abstr 3).

9. Everson GT, Sims KD, Rodriguez-Torres M, et al. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. J Hepatol 2013; 58 (Suppl; abstr 1423).

10. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl j Med 2013; 369:630–639.

11. Gane E, Hyland R, Ding X, et al. ELECTRON: 100% Suppression of Viral Load through 4 Weeks' Posttreatment for Sofosbuvir + Ledipasvir (GS-5885) + RBV for 12 Weeks in Treatment-naive and –experienced Hepatitis C Virus GT 1 Patients. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA, 2013. Abstract 41LB.

12. Manns M, Marcellin P, Poordad FPF, et al. Simeprevir (TMC435) with pegylated interferon/ribavirin for the treatment of chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-2, a phase 3 trial. J Hepatol 2013; 58 (Suppl; abstr 1413).

13. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatmentnaive patients: results from QUEST-1 a phase III trial. J Hepatol 2013; 58 (Suppl 1):S574.

14. Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: Final SVR24 results of the ASPIRE trial. J Hepatol 37:56. (suppl abstract 2).

15. Sulkowski MS, Asselah T, Lalezari J, et al. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype 1 HCV: SILEN-C1 trial. Hepatology 2013; 57:2143–2154.

16. Sulkowski MS, Bourlie` re M, Bronowicki JP, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013; 57: 2155–2163.

17. Palanisamy N, Danielsson A, Kokkula C, et al. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 2013; 99:12–17.

18. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.
**This is the first study to demonstrate the effectiveness of sofosbuvir for the treatment of patients with chronic HCV.

19. Jacobon IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotypes 2 or 3 in patients without treatment options. N Engl J Med 2013; 368:1867–1877.
**This is the first manuscript to demonstrate that an all oral interferon-free regimen can lead to SVR for patients with chronic HCV.

20. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology 2013; 58 (Suppl Abstract 1085).

21. Lawitz E, Poordad F, Brainard DM, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 Study. Hepatology 2013; 58 (Suppl Abstract LB4).

22. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected With HIV (PHOTON-1). Hepatology 2013; 58 (Suppl Abstract 212).

23. Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013; 58 (Suppl); Abstract 213.

24. Charlton MR, Gane EJ, Manns MP, et al. Sofosbuvir and ribavirin for the treatment of established recurrent hepatitis C infection after liver transplantation: preliminary results of a prospective, multicenter study. Hepatology 2013; 58 (Suppl Abstract LB2).

25. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once daily regimen of simeprevir plus sofosbuvir with or without ribavirin in cirrhotic and noncirrhotic HCV genotype treatment naive and prior null-responder patients. The COSMOS study. Hepatology 2013; 58 (Suppl AASLD abstract LB3).

26. Moyer VA, and the U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2013; 159:349–357.
*This study demonstrates the importance of baby boomer cohort screening to detect persons infected with HCV.

27. Smith BD, Morgan RL, Beckett GA, et al. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med 2012; 157:817–822.
* This study demonstrates the importance of baby boomer cohort screening to detect persons infected with HCV.

Source

Simeprevir approved in the European Union for the treatment of adults with hepatitis C genotype 1 and 4 infection

• OLYSIO™ (Simeprevir) provides a new triple therapy treatment option, as well as the first ever 12-week interferon-free and ribavirin independent treatment regimen, in combination with sofosbuvir, for appropriate patients in Europe

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that simeprevir has been granted marketing authorisation by the European Commission (EC) for the treatment of adults with genotype 1 and 4 chronic hepatitis C in combination with other medicinal products.

“The approval of simeprevir in Europe is a further step in our partner's global strategy to enable an improved treatment for hepatitis C patients. This also means that Medivir will now be able to offer this treatment to patients in the Nordic region, where we have the marketing rights“, says Maris Hartmanis, CEO, Medivir.

This marketing authorisation represents a significant milestone in the development of new triple therapy hepatitis C (HCV) treatment options for genotype 1 and 4 patients. It also includes simeprevir as part of an all oral 12-week interferon-free direct-acting antiviral (DAA) regimen with or without ribavirin (RBV), in genotype 1 or 4 patients, who are intolerant to or ineligible for IFN treatment.

* Treatment-naïve and prior relapse patients with cirrhosis who are co-infected with HIV should receive 48 weeks of treatment. Treatment with simeprevir must be initiated in combination with PegIFN + RBV and administered for 12 weeks and then followed by an additional 36 weeks of PegIFN + RBV.

The EC approval for simeprevir with PegIFN + RBV is based on a clinical trial programme involving three pivotal phase III studies, with over 1000 patients. The trials; QUEST-1, QUEST-2 and PROMISE, explored the use of simeprevir in combination with PegIFN/RBV in treatment-naïve patients and patients who have relapsed after prior interferon-base treatment. All three studies met their primary endpoints and demonstrated that simeprevir in combination with PegIFN/RBV, achieves significant cure rates when compared with PegIFN/RBV alone.

The EC approval for the combination of simeprevir and sofosbuvir also contains the phase II study, COSMOS. This was based upon prior null responder and treatment-naïve patients.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.00 CET on 16 May 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S. and in March 2014 in Russia. Following the EMA approval, it is anticipated that simeprevir will be available across a number of European Union countries in conjunction with reimbursement, in the second half of 2014.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

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Helping Patients with Liver Disease Choose Wisely

As in every field of medicine, there are certain tests and procedures that patients with liver disease and their physicians should discuss to ensure they are truly necessary and will improve care. The AASLD is proud to partner with the ABIM Foundation's Choosing Wisely® campaign to identify specific tests, procedures, and treatments that may be unnecessary and may even cause harm.

AASLD has made recommendations on a wide range of liver conditions that affect patients with:

• Cirrhosis and small varices
• Hepatitis encephalopathy
• Hepatitis C virus
• Benign focal liver lesions

View the specific recommendations [PDF]

AASLD's list was developed by a group of experts to broadly represent varying practice settings and subspecialty expertise within the field of hepatology after soliciting the input of the entire AASLD membership. The recommendations that AASLD made are based on the most current evidence found in scientific literature.

Health care in America often includes practices that may provide little, if any, benefit to patients. Some estimate that up to 30 percent of health care spending goes toward duplicative or unnecessary interventions. The Choosing Wisely® campaign of the ABIM Foundation is one way of encouraging conversations between physicians and patients to avoid these unnecessary tests or procedures and improving overall health.

Since launching in April 2012, nearly 100 national, regional and state medical specialty societies, health collaboratives and consumer groups have become Choosing Wisely partners. The campaign has released 54 lists covering more than 250 tests and procedures that the specialty society partners say are overused or inappropriate.

“AASLD is pleased to be working with the ABIM Foundation to help streamline the care of our patients with liver disease and spark conversations with their physicians about the care that is best for them,” said Adrian M. Di Bisceglie, AASLD president.

To view the specific recommendations, click here. [PDF]To learn more about Choosing Wisely and to view the complete lists and additional detail about the recommendations and evidence supporting them, visit www.ChoosingWisely.org.

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About the ABIM Foundation
The mission of the ABIM Foundation is to advance medical professionalism to improve the health care system. We achieve this by collaborating with physicians and physician leaders, medical trainees, health care delivery systems, payers, policy makers, consumer organizations and patients to foster a shared understanding of professionalism and how they can adopt the tenets of professionalism in practice. To learn more about the ABIM Foundation, visit www.abimfoundation.org, read our blog blog.abimfoundation.org, connect with us on Facebook or follow us on Twitter.

About Choosing Wisely®
First announced in December 2011, Choosing Wisely® is part of a multi-year effort led by the ABIM Foundation to support and engage physicians in being better stewards of finite health care resources. Participating specialty societies are working with the ABIM Foundation and Consumer Reports to share the lists widely with their members and convene discussions about the physician's role in helping patients make wise choices. Learn more at www.ChoosingWisely.org.

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U.S. health officials urge use of HIV pill for at-risk individuals

CHICAGO Wed May 14, 2014 7:11pm EDT

(Reuters) - U.S. health officials on Wednesday issued new recommendations urging healthcare workers to consider offering an HIV prevention pill to healthy individuals who are at substantial risk for HIV infection.

The guidelines, issued by the U.S. Centers for Disease Control and Prevention and the U.S. Public Health Service, involve the use of pre-exposure prophylaxis or PrEP, a strategy in which at-risk individuals take a daily dose of an antiretroviral drug to reduce their risk of HIV infection.

The strategy builds on a landmark 2010 study that found Gilead Sciences Inc's Truvada - a pill already widely used to treat the human immunodeficiency virus - was more than 90 percent effective at preventing HIV infections among test subjects who took the drug as prescribed.

According to the new guidelines, healthcare providers should consider PrEP for anyone who meets specific risk criteria, such as being in a relationship with an HIV-infected partner or having sex without condoms with partners known to be at risk for HIV, such as injecting drug users.

The guidelines offer the first comprehensive guidance from the CDC, replacing interim guidance that emerged after studies showed PrEP to be effective in different patient populations.

The CDC now estimates as many as 275,000 uninfected gay men and 140,000 heterosexual couples, in which one partner is HIV-infected, could benefit from PrEP.

Some 1.2 million people in the United States live with HIV, and new infections are estimated at 50,000 each year.

(Reporting by Julie Steenhuysen; Editing by Tom Brown)

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Eradication of hepatitis C on the horizon

Originally published in the The Washington Times

By Lenny Bernstein May 12 at 7:00 am

Darryl Kato, research scientist for Gilead Sciences Inc., works on the synthesis of a potential hepatitis C virus drug candidate at the company’s lab in Foster City, California in 2012. (David Paul Morris/Bloomberg)

It’s an easy and reliable applause line for budget cutters to find some basic medical research and complain that it’s a complete waste of money, especially if those dollars are put up by taxpayers, as they often are. And let’s face it, those who feel otherwise don’t always do the best job of arguing the opposite position.

One exception I recently read is an article by two physicians, Raymond T. Chung and Thomas F. Baumert, with the lofty title: “Curing Chronic Hepatitis C — The Arc of a Medical Triumph.” Their analysis in an April issue of the New England Journal of Medicine shows exactly how valuable such research and a cooperative government can be.

For those who are not aware, the piece points out that 130 million to 170 million people — three percent of the world’s population —  are infected with the virus that causes hepatitis C. In the United States, Chung and Baumert note, chronic hepatitis C is the leading cause of death from liver disease and the top reason for liver transplants. It also recently passed HIV infection as a cause of death. According to the Centers for Disease Control and Prevention, for every 100 people in the United States infected by the hepatitis C virus, one to five will die from cirrhosis of the liver or liver cancer.

Unfortunately,  70 percent to 80 percent of people with the virus have no symptoms and many have no idea they are infected. Most at risk are injection drug users, dialysis patients, people who get tattoos or body piercings with non-sterile instruments, some health-care workers, people with HIV and children born to mothers with hepatitis C, according to the CDC.

But the good news is that today the development of anti-viral drugs “has revolutionized [hepatitis C] treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection in humans,” according to the the authors, who are affiliated with Harvard Medical School and Massachusetts General Hospital. “This success can be traced to important scientific, clinical, and regulatory developments.”

At the risk of oversimplifying the piece, the authors note that the virus was discovered 25 years ago using new scientific approaches, and further research led to the discovery that the virus “requires continuous replication for its existence — an observation that would be leveraged for the design of strategies to permanently clear” it. Then, guided by the experience of developing the drugs used against HIV, researchers developed therapies that use more than one anti-viral agent.

The Food and Drug Administration then agreed to an unusual design of clinical trials that fast-tracked the testing of the drugs, which proved successful more than 90 percent of the time.

The result, Chung and Baumert say, is that “it may now be possible to imagine the global eradication of [hepatitis C]” if issues of cost, early detection and re-infection can be overcome — a potential landmark in public health progress, brought about by the system created to accomplish just that.

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To curb hepatitis C, test and treat inmates

PUBLIC RELEASE DATE: 14-May-2014 Contact: David Orenstein
david_orenstein@brown.edu
401-863-1862
Brown University

PROVIDENCE, R.I. [Brown University] — Problematic as it is for society, the high incarceration rate in the United States presents an important public health opportunity, according to a new "Perspective" article in the New England Journal of Medicine. It could make staving off the worst of the oncoming hepatitis C epidemic considerably easier.

Nearly 4 million Americans may be infected with the hepatitis C virus (HCV). Many of them don't know they carry HCV, which can take decades to make them ill with cirrhosis, cancer, or liver failure. About a million people could die because of HCV by 2060, the authors wrote, and many who are saved will have required critical and costly treatments, including liver transplants.

"We know this is going to come crashing down on us," said lead author Dr. Josiah D. Rich, professor of medicine and epidemiology at Brown University and director of the Center for Prisoner Health and Human Rights at The Miriam Hospital. "It's already starting to come crashing down. The next 10 to 20 years are going to be ugly."

The single best setting for fighting the epidemic is U.S. prisons and jails, where more than 10 million people cycle through each year. In part because a major means of HCV transmission is through injection drug use, a large portion of the nation's infected population passes through the criminal justice system. In the journal, for example, Rich and his coauthors estimate that one in six inmates is infected and one in three infected Americans ends up locked up for at least a little time in their lives.

"We can head off a lot of disease and expense if we invest now," Rich said. "How do we do that most efficiently and effectively? What we're arguing in the paper is that we do it using the criminal justice system infrastructure."

Worth the considerable cost

The key barrier, Rich readily acknowledges, is the very high cost of hepatitis C drugs. A 12-week course of Sovaldi, made by Gilead Sciences, costs $84,000 a person. Treating all current inmates with HCV would therefore cost $33 billion, the authors estimate. Treating just half the people who cycle through prisons and jails in a given year would cost $77 billion.

But drug costs don't have to be nearly so high if state prison systems can negotiate reasonable discounts with drug makers, as the federal government does for its prisoners.

And while prisons have a clear disincentive to spend money to treat people who may well be released before they become sick, the money cannot and need not come solely from their budgets.

"The criminal justice system cannot be expected to shoulder the prohibitive costs of hepatitis C treatments alone," said co-author Dr. Brie A. Williams, associate professor of Medicine at the University of California–San Francisco. "Recognizing that infectious disease epidemics cannot be contained behind prison walls, we must develop a national strategy for responding to them that includes financial support and an infrastructure to test and treat prisoners, both within prisons and jails and after they return to our communities."

U.S. society as a whole will pay the costs of an inadequately addressed HCV epidemic, the authors said. Helping prisons to provide this treatment will also curb the need for litigation by prisoner advocates to a community standard of HCV care for prisoners, said co-author Dr. Scott A. Allen, professor of medicine at the University of California–Riverside.

"Even with the high cost, the drugs appear to be cost-effective," Allen said. "Private insurers in the community appear to be covering it. That establishes a clear community standard, and prisons will be held to that standard by the courts. The public policy question isn't whether or not we pay for hepatitis C care but how we pay for it."

A potential model already exists in the Ryan White Care Act, the three authors note. Congress could consider replicating that achievement of funding widespread HIV services and treatment for people who couldn't obtain them otherwise them. An HCV version could include programs and grants for prisons and jails, as well as programs to prevent reinfection of inmates after they are released.

"Seizing this opportunity for timely care will require leaders to consider the criminal justice system as part of the fabric of U.S. health care," the authors concluded. "This step will help to change the perception of the HCV epidemic in the criminal justice system, transforming it from a legal liability to a critical opportunity to change the course of HCV in the United States."

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The research for the article required no direct funding, but Rich disclosed an honorarium he received from Gilead for speaking at a meeting in 2012.

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Video: Interferon-free regimens for HCV patients highlighted

Provided by Healio

May 13, 2014

CHICAGO — Bruce R. Bacon, MD, James F. King, MD, Endowed Chair in Gastroenterology, St. Louis University School of Medicine, discusses the advances in hepatitis C demonstrated by studies presented at Digestive Disease Week, and the results from the SAPPHIRE-II and ION studies that showed high cure rates across many patient groups.

“One of the most exciting concepts that’s going around at this meeting and a few weeks ago at the EASL meeting is the tremendous advances in treatment of viral hepatitis with the new interferon-free regimens,” Bacon told Healio.com. “These medicines were very well tolerated without any significant side effects, short duration of treatment and high efficacy.”

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AbbVie Eyes Hepatitis C Cure with New Regimen

Provided by Drug Discovery & Development

Wed, 05/14/2014 - 1:47pm

Christina Jakubowski, News Editor

AbbVie is tossing its metaphorical hat into the quickly growing and highly competitive hepatitis C treatment ring with an experimental, all-oral, interferon-free regimen – one that is boasting sustained viral response rates 12 weeks post treatment (SVR12 rates) that range from 90 to 100%.

While the research-based biopharmaceutical company, which split from parent company Abbott Laboratories in early 2013, may be a relative newcomer, the folks behind the pipeline are no strangers to virology.

“AbbVie has a longstanding history of development work in virology dating back to the early 90s. We introduced one of the first protease inhibitors for HIV in 1996 and followed that with Kaletra in 2000,” says Barry Bernstein, MD, AbbVie’s vice president of infectious disease development. “Early in the last decade, we then turned our attention to start work on hepatitis C, using much of what we’d learned from the HIV development activities. Our work was expanded through a collaboration with Enanta, which was formed in 2006. Since then, we’ve advanced a number of different compounds into the clinic.”

The culmination of that hard work came in mid-April of this year, when AbbVie submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the use of its experimental regimen in patients with chronic genotype 1 (GT1) hepatitis C virus (HCV). That was quickly followed by the submission of multiple marketing authorization applications (MAAs) for the same regimen, and the same use, to the European Union (EU) in early May.

Both submissions are backed by a breakthrough Phase 3 clinical trial program. The pivotal TURQUOSE-II trial showed viral response rates of 91.8% and 95.9% after 12 and 24 weeks of treatment, respectively. These rates are in patients considered to be a “difficult-to-treat” population: those who have GT1 HCV and compensated liver cirrhosis.

“The Phase 3 program involved six different clinical trials which were targeted to different populations. They ranged from patients who had not received prior treatment, they had no evidence of cirrhosis, to patients who had advanced disease with compensated cirrhosis and who had failed prior therapy with interferon- and ribavirin-based regimens. So, it was a broad spectrum of patients, which we think reflects the population currently infected with the hepatitis C virus,” says Bernstein. “The studies enrolled rapidly, I think reflecting, in part, a great deal of excitement about the potential for these interferon-free therapies to really transform the face of HCV treatment.”

Bernstein was “pleased” with these overall response rates. “We felt that they reflected the new regimen’s potential to [help] a vast majority of patients with HCV infection,” he says.

He added: “We had previously performed a Phase 2b trial, the AVIATOR study, and in that study we achieved SVR rates as high as 99% in some populations. This Phase 3 program expanded on that, to additional populations including cirrhosis, and overall we saw similar response rates confirming the Phase 2b data. So, response rates in the various arms of the study ranged from 90 to 100%.”

While awaiting approval in both the United States and EU, AbbVie will continue to make strides in other areas of its hepatitis C program. According to Bernstein, the company currently has a Phase 3 program in Japan, and is looking to initiate work in China soon. Perhaps most promising is AbbVie’s recently presented data out of Egypt, where genotype 4 HCV is endemic.

“[In Egypt], we enrolled both treatment-naïve and treatment-experienced genotype-4-infected patients,” Bernstein says. “There, we saw SVR rates as high as 100%, so we are very encouraged by those results.”

Abbvie’s regimen, which consists of the fixed-dose combination of ABT-450 and ritonavir, co-formulated with ABT-267 (ombitasvir), dosed once daily, and ABT-333 (dasabuvir) – with or without ribavirin – dosed twice daily, faces tough competition if approved. Gilead’s Sovaldi (which carries a controversial price tag) was approved by the FDA in December 2013 and by the European Medicines Agency (EMA) in January. In the pipeline at Bristol-Myer Squibb is a dual regimen of daclatasvir and asunaprevir, which has received Breakthrough Therapy Designation from the FDA. An NDA for the BMS treatment is also pending.

So what sets AbbVie’s treatment apart?

“We feel the most important characteristic of a regimen is its ability to cure patients. This is a devastating disease and it has a tremendous impact on patients’ quality of life as well as morbidity and mortality. So, the ability to cure is by far the most important characteristic of the regimen,” Bernstein says. “We’ve focused our development program on maximizing the SVR (or cure) rates that we can achieve with our therapy. So, we have targeted different populations with slightly different regimens to meet that objective and we feel that with the SVR rates that we are seeing in Phase 3, our regimen will provide an important option for patients with hepatitis C.”

With hopeful expectations for U.S. approval of the new regimen by the end of 2014, Bernstein is also looking to the pipeline for future hepatitis C drug development. There, he sees potential next-generation treatments, which have already progressed to Phase 2 at AbbVie, for patients with all genotypes.

“There are other genotypes, genotype 4 and genotype 3 in particular, where there is still significant unmet medical need. We are working on next-generation compounds that will address those needs,” he says. “These compounds include a protease inhibitor and an NS5A inhibitor with activity against all genotypes, as well as activity against many of the resistance-variants that emerge with first-generation therapy use. So, we feel that these will have utility there.”

Yet despite all the excitement surrounding the pharma companies that are developing hepatitis C compounds and regimens, Bernstein adds that it’s important to remember the people who are truly benefitting from these drug discoveries.

“It’s a particularly exciting time for patients in need of improved therapies,” he says. “We’re very, very happy to be contributing to that effort – to improve treatments for hepatitis C.”

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Abbvie TV Commercial -- Hepatitis C Awareness

Abbvie TV Commercial, 'Hepatitis C'

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Janssen Submits Supplemental New Drug Application to U.S. FDA for OLYSIO™ (Simeprevir) for Once-Daily Use in Combination with Sofosbuvir for 12 Weeks for the Treatment of Adult Patients with Genotype 1 Chronic Hepatitis C

Filing Includes Data from Treatment-Naïve Patients with Advanced Fibrosis and Null Responders with All Stages of Liver Fibrosis

RARITAN, New Jersey – May 7, 2014 – Janssen Research & Development, LLC (Janssen) today announced it has submitted a Supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for simeprevir, an NS3/4A protease inhibitor marketed as OLYSIO™ in the United States, in combination with the nucleotide analog NS5B polymerase inhibitor sofosbuvir developed by Gilead Sciences, Inc. This regulatory submission is for the treatment of genotype 1 chronic hepatitis C (HCV) in adult treatment-naïve patients with advanced fibrosis and null responders with all stages of liver fibrosis.

OLYSIO™ is currently approved for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. OLYSIO™ efficacy has been established in combination with peginterferon alfa and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis.

“Hepatitis C places a significant burden on the lives of those infected and if left untreated may cause significant damage to the liver, including cirrhosis and complications such as liver failure,” said Gaston Picchio, Hepatitis Disease Area Leader, Janssen Research & Development. “This filing brings us closer to potentially offering these patients a once-daily all-oral treatment combination that includes the direct-acting antiviral agents simeprevir and sofosbuvir.”

The regulatory submission for OLYSIO™ and sofosbuvir is supported by data from the Phase 2 COSMOS study which included treatment-naïve patients with advanced fibrosis (METAVIR F3 to F4 scores) and null-responder patients with all stages of liver fibrosis (METAVIR F0 to F4 scores).

In April 2014, Janssen announced initiation of the Phase 3 OPTIMIST trials examining the safety and efficacy of simeprevir and sofosbuvir without interferon or ribavirin for the treatment of chronic genotype 1 HCV infection.  In the first trial, known as OPTIMIST-1, the combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naive or treatment experienced.  In the second trial, known as OPTIMIST-2, the combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naive or treatment experienced.   For more information please visit www.clinicaltrials.gov.

About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver that affects approximately 3.2 million people in the United States and is a leading cause of chronic liver disease. Approximately 150 million people are infected with hepatitis C worldwide and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver, including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About OLYSIO™ (simeprevir)
OLYSIO™ is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S., and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.

Important Safety Information

What Is OLYSIO™?

• OLYSIO™ (simeprevir) is a prescription medicine used with other antiviral medicines, peginterferon alfa and ribavirin, to treat genotype 1 chronic (lasting a long time) hepatitis C in adults with stable liver problems.
• OLYSIO™ must not be taken alone. The efficacy of OLYSIO™ in combination with peginterferon and ribavirin is greatly decreased in patients who have genotype 1a Q80K. Please talk to your doctor about testing for genotype 1a Q80K and using a different therapy when genotype 1a Q80K is present.
• It is not known if OLYSIO™ is safe and effective in children under 18 years of age.

What is the most important information I should know and who should not take OLYSIO^™ (simeprevir)?

• OLYSIO^™, in combination with peginterferon alfa and ribavirin may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, or plans to become pregnant, do not take these medicines. You or your sexual partner should not become pregnant while taking OLYSIO^™ with peginterferon alfa and ribavirin and for 6 months after treatment is over.
  • Females and males must use two effective forms of birth control during treatment and for 6 months after treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy. Talk to your healthcare provider about forms of birth control that may be used during this time.
  • Females must have a pregnancy test before starting treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy, every month while being treated, and every month for 6 months after your treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy is over.
  • If you or your female sexual partner becomes pregnant while taking OLYSIO^™, peginterferon alfa, and ribavirin combination therapy or within 6 months after you stop taking these medicines, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes ribavirin while she is pregnant.
• OLYSIO^™ in combination with peginterferon alfa and ribavirin may cause rashes and skin reactions to sunlight. These rashes and skin reactions to sunlight can be severe and you may need to be treated in a hospital. Rashes and skin reactions to sunlight are most common during the first 4 weeks of treatment, but can happen at any time during treatment with OLYSIO^™, peginterferon alfa, and ribavirin combination therapy.
  • Use sunscreen, and wear a hat, sunglasses, and protective clothing when you will be exposed to sunlight during treatment with OLYSIO^™.
  • Limit sunlight exposure during treatment with OLYSIO^™.
  • Avoid use of tanning beds, sunlamps, or other types of light therapy during treatment with OLYSIO^™.
  • Call your healthcare provider right away if you get any of the following symptoms:
    • burning, redness, swelling or blisters on your skin
    • mouth sores or ulcers
    • red or inflamed eyes, like "pink eye" (conjunctivitis)
• Do not take OLYSIO^™ alone. OLYSIO^™ should be used together with peginterferon alfa and ribavirin to treat chronic hepatitis C infection.

What should I tell my healthcare provider before taking OLYSIO^™?

• Before taking OLYSIO^™, tell your healthcare provider if you:
  • have liver problems other than hepatitis C virus infection
  • have taken the medicines telaprevir (Incivek^®) or boceprevir (Victrelis^®)
  • had a liver transplant
  • are receiving phototherapy
  • have any other medical condition
  • are of East Asian descent
  • are breastfeeding. It is not known if OLYSIO^™ passes into your breast milk. You and your healthcare provider should decide if you will take OLYSIO^™ or breastfeed. You should not do both.

• Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
• OLYSIO^™ and other medicines may affect each other. This can cause you to have too much or not enough OLYSIO™ or other medicines in your body, which may affect the way OLYSIO™ or your other medicines work, or may cause side effects. Do not start taking a new medicine without telling your healthcare provider or pharmacist.
• Especially tell your healthcare provider if you take any of the following medicines:
  amiodarone (Cordarone^®, Pacerone^®), amlodipine (Norvasc^®), atazanavir (Reyataz^®), atorvastatin (Lipitor^®, Caduet^®), carbamazepine (Carbatrol^®, Epitol^®, Equetro^®, Tegretol^®), cisapride (Propulsid^®, Propulsid Quicksolv^®), clarithromycin (Biaxin^®, Prevpac^®), cobicistat-containing medicine: (Stribild^®), cyclosporine (Gengraf^®, Neoral^®, Sandimmune^®), darunavir (Prezista^®), delavirdine mesylate (Rescriptor^®), dexamethasone (when administered by injection or when taken by mouth), digoxin (Lanoxin^®), diltiazem (Cardizem^®, Dilacor XR^®, Tiazac^®), disopyramide (Norpace^®), efavirenz (Sustiva^®, Atripla^®), erythromycin (E.E.S.^®, Eryc^®, Ery-Tab^®, Erythrocin^®, Erythrocin Stearate^®), etravirine (Intelence^®), felodipine (Plendil^®), flecainide (Tambocor^®), fluconazole (when taken by mouth or when administered by injection) (Diflucan^®), fosamprenavir (Lexiva^®), indinavir (Crixivan^®), itraconazole (when taken by mouth) (Sporanox^®, Onmel^®), ketoconazole (when taken by mouth) (Nizoral^®), lopinavir (Kaletra^®), lovastatin (Advicor^®, Altoprev^®, Mevacor^®), mexiletine (Mexitil^®), midazolam (when taken by mouth), milk thistle (Silybum marianum) or products containing milk thistle, nelfinavir (Viracept^®), nevirapine (Viramune^®, Viramune XR^®), nicardipine (Cardene^®), nifedipine (Adalat CC^®, Afeditab CR^®, Procardia^®), nisoldipine (Sular^®), oxcarbazepine (Trileptal^®), phenobarbital (Luminal^®), phenytoin (Dilantin^®, Phenytek^®), pitavastatin (Livalo^®), posaconazole (when taken by mouth) (Noxafil^®), pravastatin (Pravachol^®), propafenone (Rythmol SR^®), quinidine (Nuedexta^®, Duraquin^®, Quinaglute^®), rifabutin (Mycobutin^®), rifampin (Rifadin^®, Rifamate^®, Rifater^®), rifapentine (Priftin^®), ritonavir (Norvir^®), rosuvastatin (Crestor^®), saquinavir mesylate (Invirase^®), sildenafil (Revatio^®, Viagra^®), simvastatin (Zocor^®, Vytorin^®, Simcor^®), sirolimus (Rapamune^®), St. John’s wort (Hypericum perforatum) or products containing St. John’s wort, tacrolimus (Prograf^®), tadalafil (Adcirca^®, Cialis^®), telithromycin (Ketek^®), tipranavir (Aptivus^®), triazolam (when taken by mouth) (Halcion^®), verapamil (Calan^®, Covera-HS^®, Isoptin^®, Tarka^®), voriconazole (when taken by mouth or when administered by injection) (Vfend^®), warfarin (Coumadin^®)
• This is not a complete list of medicines that could interact with OLYSIO^™. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.
• Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

What are the most common side effects of OLYSIO^™?

• The most common side effects of OLYSIO^™ when used in combination with peginterferon alfa and ribavirin include skin rash, itching, nausea.
• Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
• These are not all of the possible side effects of OLYSIO^™. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please see full Prescribing Information, including Patient Information for more details.

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(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in new product development, including obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; general industry conditions including trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 29, 2013, including in Exhibit 99 thereto, and our subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.)

Media contacts:
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Phone: (609) 730-2823

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AbbVie Submits for EU Marketing Authorization its Investigational, All-Oral, Interferon-Free Therapy for the Treatment of Chronic Hepatitis C

May 8, 2014

-- Submission based on the largest Phase III program in genotype 1 (GT1) hepatitis C patients conducted to date^[1]

-- European Medicines Agency has granted AbbVie's request for accelerated assessment

NORTH CHICAGO, Illinois, May 8, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) submitted marketing authorization applications (MAAs) to the European Medicines Agency (EMA) seeking approval for the company's investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection. The MAAs are supported by data from the largest all-oral, interferon-free clinical program in GT1 patients conducted to date^[1], which consists of six Phase III studies that include more than 2,300 patients in over 25 countries.

"These regulatory submissions bring us closer to offering adult genotype 1 chronic hepatitis C patients an all-oral, interferon-free regimen which has the potential to provide a promising advancement for the hepatitis C community in the European Union," said Scott Brun, M.D., vice president, Pharmaceutical Development, AbbVie. "This regulatory milestone, on the heels of our submission of a New Drug Application in the U.S., represents an important step for our pipeline."

Accelerated Assessment Granted
The EMA has granted AbbVie's request for accelerated assessment for ABT-450/ritonavir, ombitasvir (ABT-267), and dasabuvir (ABT-333), a designation that is granted to new medicines of major public health interest. Review of AbbVie's MAAs will be conducted under the centralized licensing procedure which, when finalized, provides one marketing authorization in all 28 member states of the European Union (EU). Although accelerated assessment could shorten the EMA's review time by approximately two months, it does not guarantee a positive opinion from the EMA's Committee for Medicinal Products for Human Use (CHMP) or final approval by the European Commission. If approved, ABT-450/ritonavir, ombitasvir (ABT-267), and dasabuvir (ABT-333) could be available for marketing in the EU in the first quarter of 2015.

Globally, approximately 160 million people are chronically infected with hepatitis C^[2] and an estimated 3 million to 4 million people are newly infected each year.^[3] In Europe, approximately 17.5 million people have chronic hepatitis C,^[4] with GT1 as the predominant genotype.^[4]

About AbbVie's Investigational HCV Regimen
The AbbVie investigational regimen consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ombitasvir (ABT-267) 25mg, dosed once daily, and dasabuvir (ABT-333) 250mg with or without ribavirin (weight-based), dosed twice daily. 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.

^[1] Comparison based on review of data from www.clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013. 
^[2] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.
^[3] World Gastroenterology Organisation. World Gastroenterology Organisation Global Guidelines: Diagnosis, Management and Prevention of Hepatitis C. April 2013. http://www.worldgastroenterology.org/assets/export/userfiles/WGO_Hepatitis%20C_Final%20Version.pdf. Accessed April 25, 2014.
^[4] EASL Clinical Practice Guidelines: management of hepatitis C virus infection. European Association for the Study of the Liver. J Hepatol. 2014;60:392-420.

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

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A supplemental New Drug Application has been submitted to the U.S. FDA for Simeprevir in combination with Sofosbuvir

• The Supplemental New Drug Application for OLYSIO™ (simeprevir) for once-daily use in combination with sofosbuvir is for 12 Weeks treatment of adult patients with genotype 1 chronic hepatitis C.
• The filing includes data from treatment naïve patients with advanced liver fibrosis and prior null responders with all stages of liver fibrosis.

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announces that Janssen has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Association (FDA) for simeprevir, an NS3/4A protease inhibitor marketed as OLYSIO™ in the United States, in combination with the nucleotide analogue NS5B polymerase inhibitor sofosbuvir developed by Gilead Sciences, Inc.

“It is of great importance to continue to improve the treatments for hepatitis C. The supplemental filing of the data available on the combination of simeprevir and sofosbuvir is an important step towards making an efficacious once daily all-oral treatment available for these patients“, says Charlotte Edenius, EVP Development, Medivir.

OLYSIO™ is currently approved in the U.S. for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. OLYSIO™ efficacy has been established in combination with peginterferon alfa and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis.

This regulatory submission is for the treatment of genotype 1 chronic hepatitis C (HCV) in adult treatment-naïve patients with advanced fibrosis and null responders with all stages of liver fibrosis.

The regulatory submission for OLYSIO™ and sofosbuvir is supported by data from the phase II COSMOS study which included treatment-naïve patients with advanced fibrosis (METAVIR F3 to F4 scores) and prior null-responder patients with all stages of liver fibrosis (METAVIR F0 to F4 scores).

Our partner, Janssen R&D Ireland Ltd initiated in April 2014 the phase III OPTIMIST (Optimal Treatment with a simeprevir and sofosbuvir Therapy) trials examining the safety and efficacy of simeprevir and sofosbuvir without interferon or ribavirin for the treatment of chronic genotype 1 HCV infection. In the first trial, known as OPTIMIST-1, the combination will be administered once daily for 8 or 12 weeks in chronic HCV genotype 1 infected patients without cirrhosis who are HCV treatment naive or treatment experienced. In the second trial, known as OPTIMIST-2, the combination will be administered once daily for 12 weeks in HCV genotype 1 infected patients with cirrhosis who are HCV treatment naive or treatment experienced.

For more information please visit www.clinicaltrials.gov.

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR, mobile: +46 708 537 292

Medivir is required under the Securities Markets Act to make the information in this press release public. The information was submitted for publication at 13.50 CET on 7 May 2014.

About Simeprevir
Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB and indicated for the treatment chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1 and 4 infected patients with compensated liver disease, including cirrhosis.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis in September 2013 in Japan, in November 2013 in Canada and the U.S. and in March 2014 in Russia. A Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) in April 2013 by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C and the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending Marketing Authorisation in the European Union for the use of simeprevir in combination with other medicinal products for the treatment of chronic HCV. This application is under review by the EMA.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

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Directly observed therapy for chronic hepatitis C: A randomized clinical trial in the prison setting

Gastroenterol Hepatol. 2014 Apr 28. pii: S0210-5705(14)00081-8. doi: 10.1016/j.gastrohep.2014.03.004. [Epub ahead of print]

Saiz de la Hoya P¹, Portilla J², Marco A³, García-Guerrero J⁴, Faraco I⁵, Antón J⁶, de Juan J⁷, Pozo E⁸.

Abstract

BACKGROUND: The diagnosis and treatment of chronic hepatitis C are major concerns in prisons.

OBJECTIVES: The aim of this randomized clinical trial was to determine the extent to which directly observed therapy (DOT) improved the efficacy of the standard treatment for chronic hepatitis C in the prison setting.

PATIENTS AND METHODS: A randomized clinical trial was carried out to evaluate the efficacy of a DOT compared with a self-administered therapy in prison inmates who underwent standard treatment for chronic hepatitis C (based on pegylated interferon alpha-2a and ribavirin).

RESULTS: A total of 252 inmates were randomized, of which 244 were analyzed: 109 in the DOT group and 135 in the non-DOT group. The mean age was 35.88 years (SD 6.54), 94.3% were men, 72.1% reported intravenous drug use, 21.3% were HIV co-infected, and 55.3% had genotype 1 or 4. The patients received the study treatment for a median time of 33.9 weeks in the overall sample. Sustained virological response was achieved in 60.6% (95% CI, 51.17-69.22) of the DOT group and in 65.9% (95% CI, 57.59-73.38) of the standard therapy group (risk ratio=0.92; 95% CI, 0.76-1.12). The mean proportion of patients continuing the treatment was 83% (SD=31). Adverse events were reported in 93.4% of the patients, and serious adverse events were reported in 8.2%, with no significant differences between groups.

CONCLUSIONS: Sustained virological response was remarkably high, although there were no differences between groups, probably due to high treatment adherence.

Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

KEYWORDS: Chronic hepatitis C, Directly observed therapy, HCC, HCV, Hepatitis C crónica, Interferón pegilado, Pegylated interferon, Ribavirin, Ribavirina, Tratamiento directamente observado

PMID: 24786935 [PubMed - as supplied by publisher]

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