This blog is all about current FDA approved drugs to treat the hepatitis C virus (HCV) with a focus on treating HCV according to genotype, using information extracted from peer-reviewed journals, liver meetings/conferences, and interactive learning activities.
Risk Of Developing Liver Cancer After HCV Treatment
The MD Magazine Hepatitis C condition center provides clinical news and articles, information about upcoming conferences and meetings, updated clinical trial listings, and other resources.
Here is a list of the latest headlines for August starting with todays update. RNA Assessment Predicts Hepatitis C Relapse Two Weeks into Treatment Aug 31, 2016 | Caitlyn Fitzpatrick Published in the Journal of Hepatology, the results showed that hepatitis C RNA levels in people with HCV genotype 3 who achieved sustained virologic response (SVR) were significantly lower during the first four weeks of SOF/RBV treatment than the levels observed in those who ended up relapsing.
Exploring Treatment Failure Among Hepatitis C Patients
Although direct acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV), a small fraction of patients still experience treatment failure
Studying Faldaprevir and Deleobuvir Use in NS3/4A and NS5B Amino-acid Variants of Hepatitis C
Faldaprevir and deleobuvir resistance-associated variants (RAVs) are more common among virologic failures than at baseline in patients with treatment emergent NS3/4A and NS5B amino-acid variants of hepatitis C virus (HCV), according to the results of a recent study. Published on the website PLOSOne, the study was conducted by Kristi Berger, PhD, of Boehringer Ingelheim Pharmaceuticals, in Ridgefield Connecticut, and colleagues.
Aug 29, 2016 | ARTICLES | Caitlyn Fitzpatrick
It’s no secret that excessive alcohol consumption is dangerous to the liver; that’s exactly why patients with hepatitis C are advised to steer clear of it.
Interferon Combo Regimen for HCV GT2,3?
Aug 22, 2016 | ARTICLES | Dava Stewart
Despite the arrival of direct acting antivirals, there are limit options for patients with genotypes 2 and 3 of HCV infection. A drug combo using interferon appears to work, a study finds.
Study Looks at Barriers to Hepatitis C Treatment
Aug 19, 2016 | ARTICLES | Catherine Kolonko
Beyond high cost, people with hepatitis C face several barriers to treatment, and those arise from various sources. Doctors, Medicaid, private health insurance companies, and intravenous drug use can all be obstacles, according to a university study out of Massachusetts that examined treatment approvals for two new drugs.
Are Pan-Genotypics a Panacea for HCV?
Aug 18, 2016 | ARTICLES | Kenneth Bender
The list of effective drugs for the once incurable illness of hepatitis C infection keeps growing. But some physicians are frustrated. Here's why.
How Did Kids in Princeton Get HCV?
Aug 16, 2016 | ARTICLES | Gale Scott
The news that physicians in Princeton, NJ were confronting an outbreak of hepatitis C in young people who were also using heroin shocked this affluent, mostly white community. Ronald Nahass, MD, talks about how it occurred and what needs to happen next.
Boehringer Ingelheim exits hepatitis C field, pulls regulatory filings for faldaprevir
June 20th, 2014
By: Joe Barber
Boehringer Ingelheim on Friday announced that following a strategic review the company has decided against moving forward in the field of hepatitis C. As such, the drugmaker indicated that it will withdraw all regulatory filings for faldaprevir, which had been granted accelerated assessment by the European Medicines Agency, and will discontinue further development of the protease inhibitor.
The company noted that "the HCV treatment environment has significantly and rapidly evolved" since filing faldaprevir, adding "there are now several new treatment options available for patients and additional all-oral options are expected to be approved in 2014." Boehringer Ingelheim added that as a result, an unmet medical need no longer exists for the faldaprevir interferon-based regimen that was the subject of the regulatory filings.
In February, Gilead Sciences submitted its all-oral hepatitis C treatment combination of the nucleotide analogue polymerase inhibitor Sovaldi (sofosbuvir), which was cleared in the US in December and in Europe earlier this year, and the NS5A inhibitor ledipasvir for FDA approval. Meanwhile, the FDA recently granted priority review to AbbVie's interferon-free regimen of the protease inhibitor ABT-450 boosted by ritonavir and co-formulated with the polymerase inhibitor dasabuvir and the NS5A inhibitor ombitasvir. In addition, Johnson & Johnson has applied for FDA marketing authorisation for the NS3/4A protease inhibitor Olysio (simeprevir), which was approved in the US last year and in Europe in May, in combination with Sovaldi. Earlier this year, Bristol-Myers Squibb's all-oral regimen of the NS5A replication complex inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir attained FDA breakthrough therapy status.
Boehringer Ingelheim indicated that it remains committed to developing new treatment options and will focus its efforts on the development of drugs for immunology, cardiovascular, respiratory, and metabolic diseases, central nervous system disorders and oncology.
Hepatitis C Virus Therapy in the Direct Acting Antiviral Era
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.
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.
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.
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.
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.
Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428; 8.
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.
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.
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.
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).
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).
Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl j Med 2013; 369:630–639.
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.
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).
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.
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).
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.
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.
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.
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.
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.
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).
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).
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).
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.
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).
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).
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.
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.
Boehringer Ingelheim Announces Phase 3 SVR12 Results in HCV/HIV Co-Infected Patients Treated with Faldaprevir
Additional drug-drug interaction data for faldaprevir combined with commonly prescribed HIV medications also presented at CROI 2014
Faldaprevir NDA has been accepted for review by U.S. FDA as part of a combination regimen for patients with chronic hepatitis C
For media outside of the US, the UK & Canada only
Ingelheim, Germany and Ridgefield, CT, March 6, 2014 – Today Boehringer Ingelheim announced results from STARTVerso®4 in patients with HCV/HIV co-infection. Hepatitis C viral cure 12 weeks after the conclusion of treatment (SVR12) was achieved by 72% of all patients in the trial. Patients were enrolled in either 120mg or 240mg faldaprevir dose groups. Further, 80% of all patients were eligible for randomization to a shortened duration of treatment (24 versus 48 weeks) because they achieved protocol-defined early treatment success (ETS)* and 86% of these patients achieved SVR12. STARTVerso®4 is a Phase 3 trial that enrolled 308 hepatitis C (HCV) treatment-naïve or experienced patients with HCV/HIV co-infection and evaluated the efficacy and safety of the investigational compound faldaprevir in combination with pegylated interferon and ribavirin (PegIFN/RBV).
"The SVR12 data from STARTVerso®4 are encouraging, especially given the inclusion of patients with cirrhosis," said Peter Piliero, MD, vice president, Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "Comprehensive data from our STARTVerso® clinical trial program, including data from patients with HCV/HIV co-infection, have been filed with the FDA as part of our New Drug Application for faldaprevir."
In each faldaprevir dose group, 71% (120mg) and 72% (240mg) of patients achieved SVR12. SVR12 results were consistent across patients regardless of HCV genotype-1 subtype (GT1a or GT1b), presence of compensated cirrhosis, dose and duration of faldaprevir, and duration of PegIFN/RBV. In a post hoc analysis, 75% of patients with the Q80K variant achieved SVR12 compared with 71% of patients who did not have the variant.
Serious adverse events (AEs) were reported in 32 patients (10%). To date, 24 patients have prematurely discontinued faldaprevir due to AEs. The most frequent AEs in STARTVerso®4 were nausea (37%), fatigue (34%), diarrhea (27%), headache (25%) and weakness (23%). Patients will be followed to 24 weeks after the conclusion of treatment (SVR24).
In separate poster presentations at CROI, investigators described the results from analyses that evaluated drug-drug interactions of faldaprevir with common HIV medications, including: efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir and tenofovir. In each of these analyses, there was no clinically relevant effect of faldaprevir on the pharmacokinetics of any of the HIV medications studied. Patients in STARTVerso®4 already taking ritonavir-boosted HIV protease inhibitors (darunavir or atazanavir) or efavirenz were enrolled into the 120mg and 240mg faldaprevir groups, respectively.
Boehringer Ingelheim HCV Development Update The New Drug Application (NDA) for faldaprevir has been accepted for filing by the U.S. Food and Drug Administration (FDA). Faldaprevir is currently under review as a component of a combination antiviral treatment regimen for the treatment of chronic HCV infection in adult patients who are treatment-naïve or have been previously treated with interferon-based treatment, as well as those with compensated liver disease, cirrhosis, or HCV/HIV co-infection. The FDA target action date for faldaprevir is in the fourth quarter of 2014.
The NDA submission for faldaprevir is supported by Boehringer Ingelheim’s STARTVerso® (NCT01343888, NCT01297270, NCT01358864, NCT01399619) clinical trial program, a multi-study Phase 3 trial program that evaluated faldaprevir for 12 or 24 weeks in combination with pegylated interferon and ribavirin (PegIFN/RBV). The four trials that make up this program studied treatment-naïve, treatment-experienced, and HCV/HIV co-infected patients with chronic genotype-1 (GT1) HCV. The primary efficacy endpoint of each STARTVerso® trial is viral cure 12 weeks after the conclusion of treatment (SVR12).
In November 2013, Boehringer Ingelheim announced that the faldaprevir application for marketing authorization is under review by the European Medicines Agency (EMA). If authorized by the European Commission, faldaprevir could be available for marketing in the EU in the second half of 2014.
Following an assessment of the blinded Phase 3 trial data from HCVerso® 1 and 2 for the combination of deleobuvir, faldaprevir and ribavirin, Boehringer Ingelheim has decided to halt further development of deleobuvir-containing HCV regimens. Ongoing regulatory reviews of faldaprevir are not affected by the decision on the deleobuvir-containing regimens.
About Faldaprevir Faldaprevir is an investigational, oral protease inhibitor that is specifically designed to target viral replication in the liver. Faldaprevir is an investigational compound that has not been approved by the FDA; its safety and efficacy have not been established.
The biggest story thus far is the FDA approval of Olysio (simeprevir) and Solvadi (sofosbuvir), two new oral drugs to treat hepatitis C, or is it?
In 2013 we found ourselves with a prolific HCV pipeline of direct-acting anti-viral agents which have improved: 1. Efficacy - overall 90% cure rates, 2. Tolerability - less side effects and 3. Convenience - shorter treatment duration, less pill burden. Wow.
In this short 2013 review we count down twelve months of news, research and breakthroughs that made a significant difference in the lives of people living with hepatitis C.
January
BMS-986094 Lawsuit
We heard more on the lawsuit involving 15 patients who were tragically hurt - one died- during the company-sponsored clinical trials of the hepatitis C drug BMS-986094. The Wall Street Journal reported that Bristol-Myers Squibb agreed to pay $80 million to 15 patients who either died or were hospitalized while participating in the study.
The Canadian Liver Foundation (CLF) recommended hepatitis C screening among all persons born between 1945 and 1965
The Canadian Liver Foundation (CLF) urged general practitioners (GPs) to immediately begin recommending a one-time blood test for all adults born between 1945 and 1975.
2013-Guide to Clinical Trials for People with Hepatitis C
*Pegylated interferon alfa-2a (Pegasys) and alfa-2b (PegIntron)
A paper published in BMC suggested standard doses of pegylated interferon alfa-2a and alfa-2b, administered with ribavirin, were similarly effective in patients with chronic hepatitis C genotype 1.
Updated Practice Guideline: Treatment of Genotype 1 Chronic HCV Virus Infection
Sexual transmission of HCV rare among long-term, monogamous couples
(The HCV partners study)
Patients with chronic hepatitis C in long-term, monogamous relationships are at a very low risk for transferring the virus to their partner via sexual contact.
The company has elected not to continue its clinical development program for IDX184, a nucleotide polymerase inhibitor in phase IIb testing for the treatment of hepatitis C virus (HCV) infection, or to continue its development of IDX19368, an HCV nucleotide polymerase inhibitor
The two Idenix drugs, IDX184 and IDX19368, as well as another drug from Bristol-Myers Squibb Co. called BMS-986094, work in similar ways. All three products are nucleotide inhibitors, meaning they are designed to prevent the hepatitis C virus from making copies of itself.
In August *2012 Bristol-Myers halted testing of BMS-986094 after one patient in the clinical trial died of heart failure following treatment. The drugmaker eventually abandoned development of the product.
Idenix has said there are important differences between the drugs, but the Food and Drug Administration placed IDX184 on clinical hold Aug. 16. At the time, it was Idenix's most advanced experimental drug. The FDA also had placed a hold on IDX19368, which hadn't begun patient dosing. March
Mortality risk greater among patients with HCV who moderately drank alcohol
For people with the chronic liver infection hepatitis C, heavy drinking is an obvious no-no, but a new study links even modest alcohol consumption with an increased risk of death - and not just from liver disease.
"What this study shows is... truly, even what might be considered a moderate and safe amount of alcohol use in people without hepatitis C is dangerous to your health if you have hepatitis C," said Rae Jean Proeschold-Bell, a hepatitis C researcher at Duke University in Durham, North Carolina, who was not involved in the study.
The International Liver Congress 2013 of the
European Association for the Study of the Liver (EASL), took place April 24
to 28 in Amsterdam, The Netherlands.
Dr. Maheshwari urges caution among clinicians in the administration of telaprevir, and stresses the need for rigorous side-effect management protocol and adequate long-term follow-up for patients with HCV receiving this treatment.
In December 2012 telaprevir included a “black box” warning that fatal and non-fatal serious skin reactions have been reported in patients taking INCIVEK
DDW 2013 - May 18-21, 2013 - Orlando, FL
Digestive Disease Week - The conference will showcase the latest advances in GI research, medicine and technology in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery View Media and DDW Updates
DDW 2013 - Coverage @ GI & Hepatology News
Aug 12 2013 - DDW 2013 The AGA Report Download PDF | Digital Edition
June
US Preventive Services Task Force recommended hepatitis C screening among all persons born between 1945 and 1965
In June 2013, the US Preventive Services Task Force updated recommendations to include hepatitis C screening among all persons born between 1945 and 1965.
The USPSTF had initially recommended a "C" rating for this birth cohort (1945 and 1965) in a draft proposal, conflicting with the CDC recommendation and creating confusion in the primary care community. The change from a "C" to a "B" rating gives primary care clinicians the absolute clarity of the hepatology community -- early detection of HCV allows for the drastically greater possibility of treatment success for patients. The new "B" rating allowed for testing without a copayment by both Medicare and private insurers.
The recommendation statement was published online June 24 in the Annals of Internal Medicine.
A Science First: Japanese researchers grow human liver using stem cells
It could herald a giant leap forward for the field of human regenerative medicine.Japanese researchers say they have grown a tiny human liver, only five millimetres long,from reprogrammed human skin cells.
July
JAMA - Deaths from liver disease increased from 1990 to 2010
The most common causes of both cirrhosis and liver cancer are viral hepatitis, alcoholism, and obesity-related fatty liver disease. However, it is hepatitis C that is the most likely cause of the emergence of liver disease as a growing threat to American lives. According to a July 10, 2013 article published in the Journal of The American Medical Association – “The State of US Health, 1990-2010: Burden of Diseases, Injuries, and Risk Factors” deaths from liver disease increased from 1990 to 2010. Liver disease also rose as a contributor to premature mortality.
Cirrhosis -- damaged liver tissue and the loss of liver function due to a variety of liver diseases -- has risen substantially from the 14(th) most frequent cause of death in 1990 to the 8(th) most frequent cause of death in 2010. In the same time period, liver cancer went from the 39(th) to the 30(th) most frequent cause of death in the US. The prognosis of liver cancer is particularly poor with the medical community's limited ability to treat patients with liver cancer, with death most often occurring within six months.
August
Documentary - Breaking the Silence: Voices of Chronic Hepatitis C
As once a hepatitis C patient myself, I was deeply touched while viewing this awe inspiring documentary from Janssen Therapeutics. For 17 minutes the viewer with hepatitis C is not alone, for 17 minutes normal people just like you and me share their story, diagnosis and family struggles. Support of family and friends is critical, but no matter how much our loved ones may empathize with us - connecting with other people living with the virus is invaluable.
There isn't really a diet for people with hepatitis C, but research has shown people with HCV that are obese have a higher risk for developing fibrosis, scarring, and cirrhosis of the liver.
In the August issue of "Nutrition Journal" researchers suggest exercise, low-fat or low-calorie diets can improve fibrosis, steatosis and insulin resistance in people living with chronic hepatitis C.
For the hands on reader, in this September video Dr. Galati answers the common question about diet and liver health.
Additionally, a podcast on the effects of acetaminophen and alcohol on the liver is hosted by Dr. Galati, check out Part One and Part Two
September
Surgeons at New York-Presbyterian/Columbia University Medical Center Report Successful Laparoscopic Living Donor Liver Retrieval for Adult Recipients
A team of surgeons at New York-Presbyterian/Columbia University Medical Center is the first in the country to report a fully laparoscopic hepatectomy — the removal of a portion of the liver — from a living adult donor for adult and teenage recipients. The procedure advances transplant surgery and offers hope for addressing the significant shortage of liver donors.
The timing of the book couldn't be more perfect. With screening strategies in place by the CDC and Task Force which recommend all people born from 1945 through 1965 get tested one time for hepatitis C, and new drugs moving through the final stages of FDA approval - the need for a guide during HCV therapy is paramount.
This comprehensive book provides tips for people starting hepatitis C treatment while slowly dissipating the fear of the unknown.
November
OLYSIO™ Simeprevir FDA Approved
OLYSIO™ (simeprevir) Receives FDA Approval for Combination Treatment of Chronic Hepatitis C
Johnson & Johnson's protease inhibitor OLYSIO (Simeprevir) is approved for the treatment of HCV genotype 1, in combination with peginterferon alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are treatment-naïve or who have failed previous interferon therapy (pegylated or non‑pegylated) with ribavirin.
OLYSIO™ (simeprevir) not effective in patients with HCV Q80K variant
OLYSIO improved tolerability, has a lower pill burden and appears to be slightly more effective than the standard of care, curing 80 percent of treatment-naïve patients, but there are some drawbacks. Before starting treatment patients with HCV genotype 1a need to be screened for Q80K polymorphism, alternative therapy should be considered for people with the mutation, according to simeprevir prescribing information
Hepatitis C: Boehringer Ingelheim's faldaprevir granted accelerated assessment from European Medicines Agency
“Faldaprevir* has been studied with pegylated interferon and ribavirin in a broad range of more than 3,300 patients typical of those that doctors see in every day clinical practice. Faldaprevir* has demonstrated strong efficacy and a robust safety profile while also offering the convenience of once-daily dosing and no food restrictions,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim. “The acceptance for accelerated assessment by the EMA supports our position that if approved, faldaprevir* will provide an important alternative to currently available hepatitis C treatments.”
For full results see the STARTVerso™ press release here.
The 64th Annual Meeting of the American Association for the Study of Liver Diseases
The meeting took place in Washington, DC; November 1-5, 2013, highlights include new data on FDA approved and experimental therapies for hepatitis C.
In HCV Advocate's December newsletter, information on key breakthough therapies presented at this years AASLD is offered in an easy to digest summary.
AASLD 2013 Internet Symposium
AASLD 2013 Internet Symposium -ViralEd
The 1.5 hour symposium discussing key studies on current and HCV future drugs, featuring 4 well-known and recognized thought leaders in the HCV field; Fred Poordad, MD ( looking hot in his bow tie), K. Rajender Reddy, MD., Mark Sulkowski, MD., and Nezam H. Afdhal, MD.
Faculty will be discussing information about pharmaceutical agents that is outside of U.S. Food and Drug Administration approved labeling. The following off-label uses are discussed: simeprevir, sofosbuvir, daclatasvir, asunaprevir, ABT-450, ABT-267, MK-5172, MK-8742, faldaprevir, deleobuvir, PPI-668, and ledipasvir
The successful development of targeted therapies for patients with chronic hepatitis C virus (HCV) was clearly evident. Several companies are jockeying to be the first to offer an all-oral, interferon (IFN)-free strategy. On the near horizon is the promise that a cocktail of agents, constructed on the basis of synergistic mechanisms of action, will be available for clinicians to wisely, effectively, and safely treat patients with HCV infection. A major advance, in my opinion, is the validation of regimens that are devoid of IFN and, in some cases, ribavirin.
Daclatasvir plus Asunaprevir HCV Regimen: No Interferon, No Ribavirin, No Problem
Patients who failed to respond to standard treatment for hepatitis C virus (HCV) infection achieved greater than 80% sustained virologic response at 24 weeks with an all-oral regimen that eschewed both interferon and ribavirin, researchers reported here.
Among 135 patients who were either ineligible for interferon therapy or who were intolerant of the treatment, 87.4% achieved a sustained virologic response -- basically a treatment cure, reported Kazuaki Chayama, MD, PhD, professor of medicine and director of Hiroshima University Hospital.
In his plenary session report at the annual meeting of the American Association for the Study of Liver Diseases, Chayama also reported that 80.5% of 87 previous non-responders or partial responders achieved a sustained virologic response at 24 weeks.
The two investigative agents attack the virus in different ways. Daclatasvir is a potent NS5A replication complex inhibitor with pan-genotypic antiviral activity. Asunaprevir is a potent NS3 protease inhibitor with antiviral activity against genotypes 1, 4, 5, and 6. Chayama said the phase III study he described follows successful phase II studies showing a strong impact on patients with genotype 1b.
The median age of the 222 participants in the trial was 62.5, about 35% were men, and about 10% were diagnosed with cirrhosis. Baseline factors, including male gender, advanced age, high baseline hepatitis C virus RNA, and cirrhosis, did not appear to have an impact on response rates, Chayama said.
The Japanese population mainly had genotype 1b infections, he said. Yet the success rate in achieving sustained virologic response was greater than 80%. "When I first started treating hepatitis C virus infection in the 1990s we were getting sustained virologic response rate in the 7% area, and to be getting response in the 80% to 90% levels we are seeing today is phenomenal."
He acknowledged that historically genotype 1 hepatitis C infection has been considered a more difficult disease to treat than genotypes 2 or 3, but in studies presented at The Liver Meeting 2013, "What has emerged is that genotype 3 is the new genotype 1. With these new drugs I think there has been a surprise that we get suboptimal results with genotype 3."
December Gilead's Sovaldi (Sofosbuvir) Is FDA Approved On December 6, 2013, Sovaldi, a polymerase inhibitor was approved to treat HCV genotypes 1 and 4 treatment-naïve adults in combination with PEG-IFN and ribavirin and the first approved interferon-free treatment regimen for people with HCV genotypes 2 and 3. Overall cure rates are at 80%, response rates and treatment duration varies, depending on genotype, viral and host factors.
Gilead states that Sovaldi in combination with ribavirin alone for 24 weeks can be considered for patients with genotype 1 infection who are interferon ineligible. Additionally, Sovaldi should be used in combination with ribavirin for treatment of HCV patients with hepatocellular carcinoma awaiting liver transplantation for up to 48 weeks or until liver transplantation to prevent post-transplant hepatitis C infection.
Lynda Dee, co-chair of Fair Pricing Coalition, called Sovaldi a “very safe and highly effective drug” but noted that it must be used in combination with other drugs to treat different Genotypes, or strains, of Hepatitis C.
She said that although the other drugs – pegylated interferon and ribavirin – are not as expensive as Sovaldi, the price tag for combination therapy with Sovaldi comes to $93,000 and $168,000 for various treatment regimens for a single person living with Hepatitis C.
“Gilead has set the bar dangerously high as other companies determine prices for similar Hepatitis C drugs as they enter the market,” Dee said.
In a statement released at the time the U.S. Food and Drug Administration approved Sovaldi for patient use on Dec. 6, Gilead said it had put in place a patient assistance program to ensure that people with Hepatitis C have access to Sovaldi regardless of their ability to pay for it.
1. Simeprevir + sofosbuvir for 12 weeks.PROS: More than 90% cure rate in the COSMOS study.
Two pills once daily (it’s amazing even to write that.)
CONS: The COSMOS study was very small. Simeprevir can lead to photosensitivity and has many drug-drug interactions. The Q80K polymorphism may reduce response to simeprevir.
This regimen is not “FDA approved.” Cost = $145,000.
2. Sofosbuvir + ribavirin for 24 weeks.
PROS: Cured 76% of HIV/HCV co-infected patients in the PHOTON-1 study. May well do better in HCV mono-infected. Regimen is “FDA approved” for interferon-ineligible patients, which could help get insurance coverage.
CONS. Ribavirin, and all its side effects. 24 weeks seems long compared to 12 weeks. Response rate is lower than other options listed here, which would require re-treatment.
Cost (not including ribavirin) = $160,000.
3. Sofosbuvir + interferon + ribavirin for 12 weeks:
PROS: 90% cure rate in the NEUTRINO study. Only 12 weeks of interferon and ribavirin.
All are a lot better than what we had just last week. All of them contain sofosbuvir. And all are expensive.
The Next Big Thing Is Sofosbuvir and Ledipasvir
Sofosbuvir and Ledipasvir Amazing Late-stage Hepatitis C Data
The excitement builds with the one pill two trick pony. Can I say that? Well I did.
The buzzword is "nukes", the drug is Sovaldi, a nucleotide analog polymerase inhibitor that works by blocking an enzyme the hepatitis C virus needs to copy itself, the drug is potent and has antiviral activity against HCV genotypes 1-6. Ledipasvir, an NS5A inhibitor, has potency against genotypes 1a and 1b.
SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients
Gilead tested its promising combination pill - consisting of both agents,Sovaldi and Ledipasvir in various treatment durations, with and without ribavirin. Physicians and patients were excited to see high cure rates without ribavirin. A drug that has side effects including rash, cough and anemia. Here are those SVR rates;
In ION-1, which looked at 865 treatment-naïve patients, including 136 participants in the study with cirrhosis, after 12 weeks of therapy 97.7 percent reached SVR- or 97.7 percent of patients were cured.
In ION 2 - the study included 440 treatment-experience or difficult to treat patients, these participants failed therapy in the past. Included in the trial were 88 people with cirrhosis - SVR rates were at 93.6 percent after 12 weeks of therapy - while the cure rate rose to 99.1 percent with 24 weeks of treatment.
Finally, in ION-3 - 647 treatment-naïve patients without cirrhosis were treated for 8 weeks, 94 percent achieved SVR. In patients who treated longer, for 12 weeks, SVR was a bit higher at 95.4 percent.
AbbVie Demonstrates 96 percent SVR(12) in its Phase III Study of Treatment-Experienced Patients with Genotype 1 Hepatitis C
Next up we have AbbVie, results of phase III trials were recently released for a three drug regimen plus ribavirin which consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333.
In the 394-patient SAPPHIRE-II study 96 percent of genotype 1 patients with no evidence of liver cirrhosis who previously failed standard treatment, including approximately 49 percent prior null responders, achieved sustained virologic response (SVR12) with the 12-week regimen.
An important factor here is that the majority of patients were genotype 1a, which is considered a difficult-to-treat subtype. The SVR12 rate for genotype 1a and genotype 1b were at 96 percent and 97 percent, respectively.
Virologic relapse or breakthrough was seen in 2 percent of patients receiving the regimen. In addition, the discontinuation rate due to adverse events was 1 percent.
In TURQUOISE-II naïve and experienced patients with compensated cirrhosis are included, those results are expected in January 2014.
Faldaprevir effective even in patients with HCV Q80K variant
Hepatitis C: Phase III data show Boehringer Ingelheim’s faldaprevir* is effective even in patients with common drug-resistant viral variant
Summary: Naturally occurring mutations in the hepatitis C virus (HCV) are common and many lead to reduced efficacy of antiviral treatments. Faldaprevir* has now been shown to be effective even in patients with the common HCV Q80K variant,1 which affects an estimated 700,0002,3,4 patients in the USA alone. Faldaprevir* is being studied in combinations both with and without interferon. The EMA recently granted accelerated assessment for faldaprevir* as part of an interferon-based regimen and a decision on marketing authorisation is anticipated next year.5,6 Read press release here....
'Serial Infector' Gets 39 Years
The FBI released a story this month describing the criminal investigation into the HCV outbreak at Exeter Hospital.
David M. Kwiatkowski, a former healthcare worker at Exeter Hospital stole syringes intended for hospital patients containing the narcotic Fentanyl. After injecting himself with the narcotic, he replaced the syringes of Fentanyl with saline to use on future patients, 45 people became infected because of the drug diversion tactic. Kwiatkowski pleaded guilty to diverting and obtaining the controlled substance fentanyl as well as to product tampering. He was sentenced earlier this month to 39 years in prison.
Its Not The First Time Fentanyl Was Diverted By Healthcare Workers
Similar to the Exeter Hospital outbreak, from 2008-2010 three case scenarios of drug diversion took place at the following medical facilities: Rose Medical Center in Denver, Mayo Clinic in Florida and Riverside Regional in Virginia, a complete summary is available here on this blog.
At the three facilities employees admitted to stealing syringes filled with Fentanyl, injecting themselves with the drug and replacing the syringes with saline to be used on future unsuspecting patients. The employees, like Kwiatkowski, also traveled around taking jobs at various clinics and hospitals.
EASL - Revised clinical practice guidelines for management of hepatitis C
Current standard of care and developing therapies;
Diagnosis of acute and chronic hepatitis C;
Goals and endpoints of HCV therapy;
Indications for treatment and who should be treated;
Treatment strategies for different viral genotypes;
Treatment monitoring including virological response-guided triple, and dual therapy;
Monitoring treatment safety; and
Treatment of special groups including HIV co-infection, hepatitis B co-infection and patients with other co-morbidities such as severe liver disease
Learn More?
An interactive course on hepatitis C was launched online this year which offers newly diagnosed patients an opportunity to learn more about the management of HCV, to take part in the learning activity, begin here.
*The project is brought to you from the University of Washington and includes a
collaboration with the International Antiviral Society-USA (IAS-USA). Funded by a grant
from the Centers for Disease Control and Prevention
Well, that's all folks
Wishing You All A Very Merry Christmas And A Safe New Year !
The Changing Treatment Armamentarium for HCV: From Today to 2016
Release Date: December 12, 2013
Hello folks,
If you have time to spare during this busy holiday jump over to Clinical Care Options (CCO) for an in-depth review of approved and future HCV drugs, presented by Nezam H. Afdhal, MD, FRCPI.
**Free registration is required
The online activity explores the most critical areas of HCV research, topics include;
The Goal of Combination Regimens Simeprevir and Faldaprevir: Second-Generation PI-Based Therapy Novel Classes With Peginterferon/Ribavirin in Genotype 1 HCV The Advent of All-Oral HCV Therapy Three- and Four-Drug Oral Regimens: Pros and Cons Can Two-Drug Regimens Be Effective? Treatment of Patients With HCV Genotype 2 or 3 Infection Summary: Predicting the Future of HCV Treatment
Excerpt: The Advent of All-Oral HCV Therapy
Ideally, treatment approaches for HCV infection would comprise all-oral regimens. Many studies are currently evaluating regimens that comprise different combinations of oral agents. Many of these regimens include ribavirin, but given the hematologic toxicities of this agent, future HCV regimens will likely consist of combinations of oral DAAs.
NS5B PIs are the class of DAAs with which clinicians currently have the greatest experience, albeit predominantly in combination with peginterferon/ribavirin. The approval of telaprevir and boceprevir in 2011 represents the first recent advance in HCV therapy. In addition, the next-generation PIs faldaprevir and simeprevir (the latter approved in November 2013) are in advanced clinical development. These agents have high efficacy, with ≥ 4 log reductions in HCV RNA levels.
However, this class of drugs predominantly targets genotype 1 only (although some of them show efficacy against other genotypes). In addition, PIs have relatively low barriers to resistance.
NS5A inhibitors (eg, daclatasvir and ledipasvir) feature efficacy, genotype specificity, and resistance barriers that are similar to the PIs. However, the nucleotide NS5B polymerase inhibitors, such as sofosbuvir, offer good efficacy with the advantages of pangenotypic activity and high barriers to resistance; in fact, there has been almost no resistance reported in patients who have been treated with sofosbuvir. By contrast, the NS5B nonnucleoside inhibitors provide the weakest efficacy, are very genotype specific, and have an extremely low barrier to resistance; however, they may retain some utility in combination regimens despite these shortcomings.
The class of cyclophilin inhibitors includes oral interferon inducers and other host-targeting agents. The strengths of these drugs include their pangenotypic activity and high resistance barrier. Cyclophilin inhibitors that are currently in development include alisporivir and Debio 025, although the former is on clinical hold. The usefulness of these agents in HCV treatment remains to be determined.
In December 2013, the first all-oral regimen for HCV, sofosbuvir plus ribavirin, received Food and Drug Administration approval for treatment of patients infected with HCV genotype 2 or genotype 3. In 2014 and 2015, other all-oral HCV treatment regimens may be approved. Many therapeutic combinations are possible, but with the approval of both sofosbuvir and simeprevir, there is likely to be interest in exploring the off-label combination of these agents, in light of promising preliminary data. By 2016, truly pangenotypic all-oral therapies for HCV infection should be available; the most significant advance will be the development of pangenotypic NS3/4A PIs and NS5A inhibitors that have higher barriers to resistance. Such regimens should allow patients with all HCV genotypes and subtypes to be treated successfully.
Hepatitis C: Phase III data show Boehringer Ingelheim’s faldaprevir* is effective even in patients with common drug-resistant viral variant
INGELHEIM, Germany--(BUSINESS WIRE)-- Data show that Boehringer Ingelheim’s second-generation protease inhibitor faldaprevir*, when used in combination with pegylated interferon and ribavirin, was effective even with the presence of naturally-occurring mutant variants of the hepatitis C virus (HCV), such as the NS3 Q80K polymorphism. The Q80K mutant was detected in 23% (49/127, STARTVerso™1) and 40% (159/398, STARTVerso™2) of genotype-1a infected patients. Its presence was found to have no effect on the chances of viral cure (SVR12) in genotype-1 infected hepatitis C patients treated with faldaprevir* plus pegylated interferon and ribavirin.1 These data were presented last week at HEP DART 2013, taking place in Big Island, Hawaii.
“These data are encouraging as they demonstrate that HCV genotype-1 infected patients irrespective of the presence of the common HCV Q80K variant may benefit from faldaprevir*,” said Christoph Sarrazin, M.D., Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. “In some parts of the world, the Q80K mutation is present in almost 50% of genotype-1a infected patients, who will potentially require additional screening prior to using some HCV protease inhibitors. With faldaprevir’s* efficacy against HCV Q80K, physicians should be able to avoid screening for this mutation prior to treatment of genotype-1a infected patients.”
The HCV NS3/4A protease is essential for viral replication and is a key target for direct acting antiviral (DAA) treatments such as faldaprevir*. The NS3 Q80K variant is the most commonly observed NS3 polymorphism in genotype-1a HCV and has been reported in up to 47% of genotype-1a infected patients. The variation in frequency is influenced by the geography, with the prevalence of Q80K being particularly high in the USA.4
Faldaprevir* is the core component of Boehringer Ingelheim’s investigational hepatitis C pipeline and is being studied in combinations both with and without interferon. Faldaprevir* was recently granted accelerated assessment by the European Medicines Agency. If approved by the European Commission, faldaprevir* could be available for marketing in the EU in the second half of 2014 as part of an interferon-based regimen. In addition, Boehringer Ingelheim aims to deliver one of the first interferon-free regimens for the treatment of hepatitis C infection. Pivotal Phase III HCVerso® data for the interferon-free regimen of faldaprevir*, deleobuvir* and ribavirin will be available in 2014.
Additional data from Boehringer Ingelheim at HEP DART
Data presented last week as part of the ‘oral abstract session II’ show a high rate of virologic response in patients treated with a 12 week all-oral combination of Boehringer Ingelheim’s faldaprevir* and deleobuvir* and Presidio’s PPI-668* with and without ribavirin.7 Results from the ongoing Phase II trial were recently presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
*Faldaprevir, deleobuvir and PPI-668 are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established.
The Boehringer Ingelheim NewsHome: An innovative resource for journalists
The Boehringer Ingelheim hepatitis C www.newshome.com is the one-stop-shop for clear, concise and easy to understand information about hepatitis C for media.
Hepatitis C: Boehringer Ingelheim's faldaprevir granted accelerated assessment from European Medicines Agency
Accelerated assessment reserved for medicinal products of major interest from the viewpoint of public health and therapeutic innovation1
Submission based on comprehensive development programme including the Phase III STARTVerso™ data aiming to demonstrate the efficacy and safety of faldaprevir* + PegIFN/RBV in a broad range of genotype-1 infected hepatitis C patients2,3,4
“The acceptance for accelerated assessment by the EMA supports our position that if approved, faldaprevir* will provide an important alternative to currently available hepatitis C treatments.”
The application for European marketing authorisation of faldaprevir*, a potent second generation oral protease inhibitor, has been fully validated and granted accelerated assessment by the European Medicines Agency (EMA).5,6 Boehringer Ingelheim is seeking marketing approval of faldaprevir* in combination with pegylated interferon and ribavirin (PegIFN/RBV) for the treatment of a broad range of patients with genotype-1 (GT-1) hepatitis C, including difficult-to-cure populations such as those with HIV co-infection or advanced liver disease.
“Faldaprevir* has been studied with pegylated interferon and ribavirin in a broad range of more than 3,300 patients typical of those that doctors see in every day clinical practice. Faldaprevir* has demonstrated strong efficacy and a robust safety profile while also offering the convenience of once-daily dosing and no food restrictions,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim. “The acceptance for accelerated assessment by the EMA supports our position that if approved, faldaprevir* will provide an important alternative to currently available hepatitis C treatments.”
Accelerated assessment status does not automatically lead to a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) or the granting of a marketing authorization by the European Commission.1 If approved by the European Commission, faldaprevir* could be available for marketing in the EU in the second half of 2014.
The EMA Marketing Authorisation Application is based on a comprehensive clinical development programme for faldaprevir* with a particular focus on the Phase III STARTVerso™ trial data, recently presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). These studies include data for faldaprevir* in:
Treatment naïve patients with the majority having benefited from shorter treatment duration and achieved viral cure2
Difficult-to-cure patient populations such as those with HIV co-infection4 or advanced liver disease2,3
Patients with the Q80K polymorphism (this mutation is considered to affect the efficacy of other second generation protease inhibitors)2
Treatment experienced patients who have relapsed, partially responded or failed to respond to previous therapy3
For full results see the STARTVerso™ press release here.
Faldaprevir* is the foundation of Boehringer Ingelheim’s hepatitis C treatment pipeline and is being developed in combinations both with and without interferon. In addition to the interferon-based faldaprevir* regimen that has been submitted for marketing approval, Boehringer Ingelheim aims to deliver one of the first interferon-free regimens for the treatment of hepatitis C infection. The goal is to make an interferon-free future a reality for a broad range of hepatitis C patients. Pivotal Phase III HCVerso® data for the interferon-free regimen of faldaprevir*, deleobuvir* and ribavirin will be available in 2014.
* Faldaprevir and deleobuvir are investigational compounds and not yet approved. Their safety and efficacy have not yet been fully established.
Nov 26 - Now FDA Approved Olysio (simeprevir) - The New Kid On The Block OLYSIO (Simeprevir) Cost? - Janssen has priced Olysio at a wholesale acquisition price of $22,120 per bottle of 28 capsules (150 mg capsules), which is an approximately one-month supply. That's roughly $66,360 for a three-month course.
AASLD-What Is The Minimum costs to produce Hepatitis C Direct Acting Antivirals
A third wave of anti HCV DAA agents are currently moving through the pipeline, two new DAAs have already been reviewed by the Antiviral Drugs Advisory Committee, Gilead's Sofosbuvir and Johnson & Johnson's Simeprevir.
The result of the whole process is expected to be decided by the FDA in early December for Sofosbuvir and late November for Simeprevir.
Additionally, other new DAAs in Phase III clinical trials are able to increase SVR and shorten therapy in a significant
proportion of both treatment-naïve and treatment-experienced chronic HCV
infected patients.
However the drugs are expected to be expensive, patients in the US could pay anywhere from $60,000 - $100,000 per treatment. The cost for these life saving drugs will be out of reach for patients in developing countries and the uninsured.
Analysis Of Predicted Minimum Costs To Produce Hepatitis C Direct Acting Antivirals
At this months AASLD, Andrew Hill of Liverpool University and colleagues presented a new analysis of predicted minimum costs to produce Direct Acting Antivirals for the treatment of hepatitis C. The minimum cost of 12 weeks of treatment with each DAA(see below) was calculated assuming a production cost per gram of HCV DAA between 1-10 times the equivalent HIV antiretroviral and based on compound properties including chemical structure, complexity of synthesis, and daily dose. The analysis was also presented earlier this year at the 7th IAS Conference
Predicted Minimum Costs
Theanalysis predicted $20-63 for a 12-week treatment of ribavirin, $10-30 for daclatasvir, $68-136 for sofosbuvir, $100-210 for faldaprevir and $130-270 for simeprevir see charts below.
The complete analysis is available for downloading here or view the predicted costs/slides provided below.
AASLD, Washington DC
Minimum costs to produce Hepatitis C Direct Acting Antivirals
Andrew Hill and Saye Khoo, Department of Pharmacology and
Therapeutics, Liverpool University, UK
Bryony Simmons, Imperial College, London, UK
Nathan Ford, University of Cape Town, South Africa
64th Annual Meeting of AASLD, Washington DC, United States of
America, November 2013 [Poster 1097]
TREATMENT COVERAGE IS LOW EVEN IN DEVELOPED COUNTRIES
Despite the long term morbidity & mortality associated with untreated hepatitis C, data suggests that relatively few patient are being treated.
In Europe only 3.5% of infected individuals received antiviral treatment by the end of 2010 (ranging from 16% in France to <1% in Poland)
In the USA only 21% of infected individuals had received treatment by the end of 2007
Reasons for under
-
treatment:
•
Under
-
diagnosis (80% of HCV cases are asymptomatic)
•
Limitations of currently available medication
•
The very high prices of drug treatment
THE
STIMATED
COST
OF
CURRENT
TREATMENT
(UK & US
ESTIMATES
)
HEPATITIS C GLOBAL PREVALENCE BY COUNTRY (2010)
HEPATITIS C GLOBAL PREVALENCE BY COUNTRY(2010)
PATENT EXPIRY DATES
DAA COMBINATIONS : INTERFERON - FREE REGIMENS
Several combinations of two DAAs (with or without RBV) can cure HCV (SVR) in the
majority of treatment
-
naïve, genotype 1 patients, without the use of interferon:
Continued......
RATIONALE
DAAs for HCV infection have similar mechanisms of action and chemical structures to antiretrovirals for HIV infection.
Generic antiretrovirals are currently manufactured at very low cost, for treatment of over ten million people with HIV in low and middle income countries.
Minimum costs of HIV antiretrovirals are 0.2-0.9/g of drug for nucleoside analogues, 0.5/g for nucleotide analogues, and 0.7-2.1/g for protease inhibitors.
For widespread treatment of HCV in developing countries to be feasible, we need short-course of antiviral treatment available at very low cost.
Using the cost of HIV drugs as a framework, we can make estimates for the potential cost of HCV DAAs
