Faldaprevir–Deleobuvir - Hepatitis C Virus Genotype-1b-Infected Patients w-Cirrhosis and Moderate Hepatic Impairment

Research Article

In conclusion, in this small study in treatment-naïve and treatment-experienced patients with chronic HCV genotype-1b infection and mild or moderate hepatic impairment, the response to 24 weeks of treatment with faldaprevir, deleobuvir and ribavirin was not durable, with 74% of patients achieving SVR4 but only 57% achieving SVR12. Since this study was initiated, the HCV field has changed rapidly with the advent of new DAAs and all-oral DAA combinations. Because of this and based on the results of the phase 3 HCVerso1 and HCVerso2 trials [16], the development of the faldaprevir–deleobuvir combination has been terminated.

HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment
Christoph Sarrazin , Michael Manns, Jose Luis Calleja, Javier Garcia-Samaniego, Xavier Forns, Renee Kaste, Xiaofei Bai, Jing Wu, Jerry O. Stern

Abstract
This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL^-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL^-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL^-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis.
Trial Registration: ClinicalTrials.gov NCT01830127.

Discussion Only
View Full Text Research Article Here
In this small study in treatment-naïve and treatment-experienced patients with chronic HCV genotype-1b infection and mild or moderate hepatic impairment, the overall safety and efficacy profiles for 24 weeks of treatment with deleobuvir and faldaprevir in combination with ribavirin were generally consistent with the safety and efficacy profiles observed in non-cirrhotic patients [16].

Overall the majority of patients achieved SVR4 (74%) and SVR12 (57%); however, response rates were lower than rates achieved with other all-oral DAA regimen in HCV-infected patients with cirrhosis (>90% SVR12) [18, 19]. Notably, the trough concentrations of deleobuvir and faldaprevir over 4 weeks of treatment were not substantially different between the CPA and CPB groups and similar proportions of patients achieved SVR4 and SVR12. The proportion of patients who were SVR4 but not SVR12 responders was higher than reported in phase 3 studies in non-cirrhotic patients. In non-cirrhotic patients, 95% of patients achieving SVR4 went on to achieve SVR12 [16]; whereas, in the present study, only 77% (20/26) of patients with SVR4 also achieved SVR12 (Table 2).

This is consistent with data from other all-oral combinations that require longer treatment durations (24 weeks rather than 12 weeks) to achieve SVR in patients with cirrhosis than in those without cirrhosis [2, 18, 19]. Response at treatment Week 4 appeared to predict SVR12 after 24 weeks of treatment, although the small number of patients precluded statistical analysis. This was particularly notable in patients with moderate hepatic impairment (CPB), where none of the 4 patients having Week 4 HCV RNA <25 IU.mL-1, but with target detected, achieved SVR12, whereas 8/9 (89%) of those with undetectable HCV RNA at Week 4 achieved SVR12. It is conceivable that the combination of faldaprevir and deleobuvir with ribavirin is not sufficient to prevent on-going viral replication in patients where residual virus is detected at Week 4. Of note, with more potent DAA combinations, detectable Week 4 HCV RNA is not predictive of treatment failure [2, 18, 19]. Consistent with a more severe disease state, discontinuations, AEs and SAEs were more common in patients with moderate hepatic impairment than in those with mild hepatic impairment. The higher rates of AEs in CPB patients is likely related to these patients having more severe liver disease and a more unstable condition. SAEs reported in CPB patients were primarily related to worsening of the underlying disease (including hepatic cirrhosis, acute hepatic failure, hepatic encephalopathy, ascites, haemorrhage and general physical health deterioration).

In conclusion, in this small study in treatment-naïve and treatment-experienced patients with chronic HCV genotype-1b infection and mild or moderate hepatic impairment, the response to 24 weeks of treatment with faldaprevir, deleobuvir and ribavirin was not durable, with 74% of patients achieving SVR4 but only 57% achieving SVR12. Since this study was initiated, the HCV field has changed rapidly with the advent of new DAAs and all-oral DAA combinations. Because of this and based on the results of the phase 3 HCVerso1 and HCVerso2 trials [16], the development of the faldaprevir–deleobuvir combination has been terminated.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168544

MD Magazine August/ RNA Assessment Predicts Hepatitis C Relapse Two Weeks into 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.

Continue reading..

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.

Even Light Drinking Spikes Cancer Risk in Hepatitis C-Related Cirrhosis

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.

Comprehensive New Database an “Efficient and Helpful Tool” for Accessing HCV Research
Aug 16, 2016 | ARTICLES | Dava Stewart
“Each entry contains contextual information pertaining to the entry such as the HCV genotypic background and links to the original publication,” say the authors.

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.

Study Explores Marijuana Use and Fibrosis in Women with HIV and Hepatitis C
Aug 12, 2016 | ARTICLES | Catherine Kolonko
A study in women coinfected with hepatitis C and HIV found that use of marijuana was not associated with progression to advanced liver fibrosis.

Traditional Chinese Medicine Kuan-Sin-Yin Found to Improve Liver Function in Hepatitis C Patients
Aug 09, 2016 | ARTICLES | Dava Stewart
In study, GPT and GOT levels significantly decreased in the Kuan Sin Yin group as compared to the placebo group, by 29.7% and 24.4% respectively.

Boehringer Ingelheim exits hepatitis C field, pulls regulatory filings for faldaprevir

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.

For related analysis, see ViewPoints: Competitor dynamics shift in hepatitis C market. For more information on the hepatitis C market, see Hepatitis C: KOL Insight and Consensus Outlook.

To read more Top Story articles, click here.
http://www.firstwordpharma.com/node/1218888?tsid=1#axzz35CbMw1sg

Hepatitis C Virus Therapy in the Direct Acting Antiviral Era

Current Opinion in Gastroenterology

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.

Source - Medscape

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.

Interferon-Free Regimen for HCV Genotype 1 Infection: Closer Still

Interferon-Free Regimen for HCV Genotype 1 Infection: Closer Still

Atif Zaman, MD, MPH reviewing Zeuzem S et al. N Engl J Med 2013 Aug 15.                                   

Despite promising findings, including higher response rates with inclusion of ribavirin in a triple-therapy regimen, response rates are still too low in this group to forgo interferon.

Atif Zaman, MD, MPHInterferon-free regimens should be available soon for hepatitis C virus (HCV) genotype 2 infection and probably genotype 3 infection. For now, the next-generation regimen for genotype 1 infection will be shorter and more tolerable but will still include interferon.

To continue the search for an effective, interferon-free regimen for HCV genotype 1 infection, researchers conducted an industry-funded, multicenter, randomized, open-label, phase IIb study in 362 treatment-naive patients. Patients received faldaprevir (120 mg once daily) plus deleobuvir (600 mg 2 or 3 times daily) with or without ribavirin (1000–1200 mg daily) for 16, 28, or 40 weeks. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12).

SVR12 did not differ by treatment duration (16 weeks, 59%; 28 weeks, 59%; 40 weeks, 52%) or by deleobuvir dose (69% for twice daily and 59% for three times daily). SVR12 was higher in ribavirin users versus nonusers (59% vs. 39%, P=0.03). SVR12 rates were numerically higher in patients with genotype 1b versus 1a (range across treatment groups, 56% to 85% vs. 11% to 47%) and in patients with IL28B genotype CC versus non-CC (range across treatment groups, 58% to 84% vs. 33% to 64%). Of 75 patients with virologic breakthrough, 73 had resistant HCV variant strains. Discontinuation rates ranged from 5% to 25% across treatment groups; the most common adverse events were rash, photosensitivity, nausea, vomiting, and diarrhea.           

Comment
We are getting closer to an interferon-free regimen for genotype 1 hepatitis C virus infection, but we are not there yet. Ribavirin will likely still be needed as a part of the regimen. Also, multiple interferon-free regimens might be required, with choice of regimen based on predictors of response such as genotype 1 subtype and IL28B status. Finally, until their sustained virologic response rates approach 80%, interferon-free regimens will likely only be an option for patients for whom interferon-based regimens are intolerable or contraindicated. -

See more at:
http://www.jwatch.org/na31807/2013/08/14/interferon-free-regimen-hcv-genotype-1-infection-closer#sthash.S00ZLRnv.dpuf

Related:
Interferon-Free Regimen Works in Over 50% of Patients

Boehringer Ingelheim’s investigational Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Boehringer Ingelheim completes patient enrolment of two pivotal Phase III interferon-free hepatitis C clinical trials

Boehringer Ingelheim completes patient enrolment of two pivotal Phase III interferon-free hepatitis C clinical trials

15 August 2013

Boehringer Ingelheim announces full patient enrolment for two of its pivotal Phase III interferon-free hepatitis C clinical trials

• Over 950 patients have now been successfully enrolled in the pivotal Phase III HCVerso™1 and 2 trials
• The Phase III study programme includes treatment naïve patients, including those ineligible for interferon and patients with liver cirrhosis
• The milestone coincides with the New England Journal of Medicine publication of SOUND-C2: one of the largest interferon-free studies in genoytpe-1 HCV published to date, forming the basis of the HCVerso™ trials

INGELHEIM, 15 August 2013 – Boehringer Ingelheim today announced that enrolment of over 950 treatment naïve genotype-1b patients in the pivotal Phase III interferon-free HCVerso™ 1 and 2 trials is complete.1,2 The trials are investigating the efficacy and safety of Boehringer Ingelheim’s second generation protease inhibitor faldaprevir* and NS5B polymerase inhibitor deleobuvir (BI 207127)*, in combination with ribavirin. HCVerso™ 1 and 2 include difficult-to-treat patient populations such as those who are ineligible for interferon or those with liver cirrhosis.

For media outside USA, UK and Canada only

This important developmental milestone coincides with today’s publication of Boehringer Ingelheim’s Phase IIb interferon-free SOUND-C2 study in the New England Journal of Medicine (NEJM).3 SOUND-C2 showed viral cure rates (sustained virological response, SVR) of up to 85% in patients infected with genotype-1b (GT-1b) hepatitis C virus (HCV). SOUND-C2 investigated the efficacy and safety of faldaprevir* and deleobuvir* plus ribavirin in treatment-naïve patients with genotype-1a and 1b HCV, the most common types of HCV globally. The study included patients with liver cirrhosis (9%), who showed similar rates of viral cure as patients without cirrhosis.4

Professor Klaus Dugi,
Senior Vice President
Medicine at Boehringer Ingelheim

"We are proud to announce the completion of patient recruitment in two of our pivotal HCVerso™ trials. This is an important step towards our goal of delivering an effective and well tolerated cure that will enable patients and doctors to consider an individualised approach for interferon-free HCV therapy," said Professor Klaus Dugi, Senior Vice President Medicine at Boehringer Ingelheim. "The publication of the SOUND-C2 study in the NEJM as well as the speedy recruitment into our pivotal trials provide an indication of the high relevance of interferon-free regimens for the future treatment of HCV. We look forward to the first Phase III results of faldaprevir*, deleobuvir* plus ribavirin in 2014 and the opportunity to explore wider patient populations in the future."

Results from the Phase IIb SOUND-C3 study were also recently presented at the APASL Liver Meeting in Singapore. This follow-up study to SOUND-C2 aimed to further optimise the dosing regimen containing faldaprevir* and deleobuvir* plus ribavirin in treatment-naïve patients (including patients with cirrhosis and those who could not tolerate interferon). SVR rates of 95% were observed in GT-1b infected patients after 16 weeks of treatment.5 The regimen tested in the SOUND-C3 study is now under Phase III evaluation in the HCVerso™ 1 and 2 trials.

Overall tolerability in the SOUND-C trials was good. In the dose-finding study SOUND-C2, 44 of the 362 patients included in the analysis discontinued due to adverse events.3 In SOUND-C3, mild rash and nausea were the most common side-effects. Adverse events of a moderate or higher intensity were rare, with anaemia (16%), fatigue (9%), vomiting (9%) and nausea (9%) being the most frequent adverse events.5

The decision to focus on GT-1b in HCVerso™1 and 2 was based on the higher efficacy seen in this population compared to GT-1a infected patients in the SOUND-C studies (SVR12 in GT-1a patients in SOUND-C2 and SOUND-C3: 58/148 and 2/11 of patients, respectively).3

As part of Boehringer Ingelheim’s long-term commitment to hepatitis C, the company is also evaluating other combinations of investigational hepatitis C compounds that work in different ways. Boehringer Ingelheim’s recent collaboration with Presidio Pharmaceuticals, Inc. for a Phase II clinical study investigating an interferon-free, all-oral combination in GT-1a is part of the company’s continued exploration to discover and develop innovative options for the treatment of HCV.

Related: Hepatitis C: Interferon-Free Regimen Works in Over 50% of Patients

Boehringer Ingelheim’s investigational Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Related: Hepatitis C: Interferon-Free Regimen Works in Over 50% of Patients - Faldaprevir and Deleobuvir for HCV Genotype 1 Infection
"While it is important to show that responses in the 50% to 60% range can be obtained without interferon, it is unlikely that these drugs will have much impact in the near future," said Gary L. Davis, MD, director of general and transplant hepatology at Baylor University Medical Center, Baylor HealthCare System, Dallas, Texas, in an interview with Medscape Medical News.....


More Drugs Show Promise in Fighting Hepatitis C

Faldaprevir and deleobuvir are part of effort to develop treatments that avoid harsh side effects

By Amy Norton
HealthDay Reporter

WEDNESDAY, Aug. 14 (HealthDay News) -- An experimental drug duo may cure some cases of the liver disease hepatitis C, without the severe side effects of standard therapy, a new clinical trial suggests.

The study, of 362 people with chronic hepatitis C, found that the new drugs -- combined with one older drug -- cleared the virus from up to 69 percent of patients. And that was without having to use interferon, a difficult-to-take injection drug that is part of the current therapy.

Experts said the findings, published in the Aug. 15 issue of the New England Journal of Medicine, are another step forward in vastly improving hepatitis C treatment.

Dozens of drugs are in development, and some are currently being considered for approval by the U.S. Food and Drug Administration (FDA).

"These are very exciting times in hepatitis C treatment," said Dr. Michael Saag, an infectious disease specialist at the University of Alabama at Birmingham who was not involved in the new study.

Hepatitis C is a liver infection usually passed through contact with infected blood. For most people, the infection becomes chronic, which can eventually lead to scarring of the liver (cirrhosis) or liver cancer years later.

That happens only in a minority of people. "But we have no way of knowing in advance who will develop cirrhosis or cancer," Saag said.

The current drug regimen for chronic hepatitis C includes interferon, plus an older oral drug called ribavirin, and either one of two drugs just approved in the last couple of years, called telaprevir and boceprevir. That combo cures about 68 percent to 75 percent of people with the most common strain of hepatitis C, called genotype 1.

The problem is, treatment lasts for months and almost always causes substantial side effects.

Interferon is especially hard to take, with side effects ranging from sleep problems and mood swings, to nausea and diarrhea, to muscle pain, fever and fatigue.

"There is a great desire to be able to cure hepatitis C without interferon," said Saag, who also serves on the Infectious Diseases Society of America's hepatitis task force.

In the new study, funded by drugmaker Boehringer Ingelheim, German researchers tested two experimental drugs called faldaprevir and deleobuvir against hepatitis C genotype 1.

The investigators randomly assigned 362 patients to one of five groups. Each group received the two new drugs. Four groups also took ribavirin, while the fifth did not.

In the end, the ribavirin proved necessary, Saag pointed out. Three months after their treatment ended, anywhere from 52 percent to 69 percent of patients on all three drugs were hepatitis free, depending on the dose and how long they took the medications.

In contrast, only 39 percent of patients who did not take ribavirin were free of the virus.

The benefits also depended on which virus subtype patients had. Of those with genotype 1b, up to 85 percent were hepatitis free three months after treatment. That compared with no better than 47 percent of patients with type 1a.

"That's to be expected," Saag said. "Type 1b is just easier to treat in general."

There are still questions, and later-stage trials of the new drugs are continuing, said study leader Dr. Stefan Zeuzem, of Goethe University Medical Center, in Frankfurt.

The ideal treatment time, for example, is not clear. The study patients took the drugs for 16 to 40 weeks. But for patients with type 1b, 16 weeks might be enough, according to Zeuzem.

That compares with up to 48 weeks with standard treatment.

As for side effects, nearly all of the study patients had some, including rash, nausea, vomiting and diarrhea. But for most, those problems were mild, Zeuzem's team noted.

"Interferon side effects are certainly worse than side effects observed with faldaprevir and deleoprevir," Zeuzem said.

"It looks like severe side effects were not common," Saag agreed. But, he said, "the main problem with these drugs is that you still have to use ribavirin."

Ribavirin is more tolerable than interferon, but it destroys red blood cells and can cause serious fatigue and other problems.

"Ideally, you'd like drug regimens without ribavirin," Saag said. The good news, he added, is that those are on the way.

Between 50 and 60 new hepatitis C drugs are currently in the pipeline, Saag said, and a couple are already under review by the FDA. One is sofosbuvir: In a recent trial, researchers found that sofosbuvir, along with ribavirin, cured about three-quarters of patients with genotype 2 or 3 hepatitis C.

But Saag predicted that in the next year or two, there will be oral drug regimens that bypass interferon and ribavirin altogether.

"There should be a lot of new options for hepatitis C patients in the next couple years," he said. These new findings, Saag added, "are an important step. But they are not the final step."

In the United States, an estimated 3.2 million people are living with chronic hepatitis C -- most of whom do not know it. Because of that, the U.S. Centers for Disease Control and Prevention recommends that baby boomers (people born between 1945 and 1965) be tested for the virus.

Injection drug abuse is now the top risk factor. But people who had a blood transfusion before 1992 are also at risk, because that predated widespread hepatitis C screening. In a small number of cases, the virus is transmitted during sex.

More information

The U.S. Centers for Disease Control and Prevention has more on hepatitis C.

SOURCES: Stefan Zeuzem, M.D., professor, medicine, Goethe University Medical Center, Frankfurt; Michael Saag, M.D., professor, medicine, University of Alabama at Birmingham; Aug. 15, 2013, New England Journal of Medicine

Last Updated: Aug. 14, 2013

Hepatitis C: Interferon-Free Regimen Works in Over 50% of Patients - Faldaprevir and Deleobuvir for HCV Genotype 1 Infection

Medscape Medical News

HCV: Interferon-Free Regimen Works in Over 50% of Patients

Troy Brown

Aug 14, 2013

More than half (52% - 69%) of patients with hepatitis C virus (HCV) genotype 1 who received interferon-free treatment with faldaprevir combined with deleobuvir plus ribavirin had sustained virologic response 12 weeks after treatment completion, according to a phase 2b, randomized open-label trial of 362 patients.

Stefan Zeuzem, MD, from Johann Wolfgang Goethe University Medical Center in Frankfurt am Main, Germany, and colleagues report their findings in an article published in the August 15 issue of the New England Journal of Medicine.

HCV genotype 1 is the most prevalent and hard-to-cure genotype. Current treatment involves the use of protease inhibitors combined with pegylated interferon and ribavirin, which have high rates of adverse effects and discontinuation. Many patients also have contraindications to pegylated interferon. Faldaprevir is a protease inhibitor, and deleobuvir is a polymerase inhibitor.

In the current trial, investigators randomly assigned previously untreated patients to 1 of 5 groups: faldaprevir 120 mg once daily and deleobuvir 600 mg 3 times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir 120 mg once daily and deleobuvir 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir 120 mg once daily and deleobuvir 600 mg 3 times daily, without ribavirin, for 28 weeks (TID28W-NR).

Among patients in the TID16W group, 59% achieved the primary end point of sustained virologic response 12 weeks after therapy completion as did 59% in the TID28W group, 52% in the TID40W group, 69% in the BID28W group, and 39% in the TID28W-NR group. There were no significant differences in sustained virologic response according to treatment duration or deleobuvir dosage.

Sustained virologic response rates were higher among those who received ribavirin compared with those who received the same regimen without ribavirin (59% in the TID28W group vs 39% in the TID28W-NR group; P = .03).

The investigators found that genotype 1b, IL28B CC genotype, female sex, ribavirin-containing treatment regimens, and normal baseline γ-glutamyl transferase levels were associated with a higher rate of sustained virologic response 12 weeks after therapy completion. They adjusted the analyses for age, sex, body mass index, presence or absence of cirrhosis or diabetes, baseline alanine aminotransferase and γ-glutamyl transferase levels, viral subtype, IL28B genotype, and baseline HCV RNA level.

After adjustment for IL28B genotype, sustained virologic response rates were higher among those with HCV genotype 1b infection compared with patients with HCV genotype 1a infection in all groups except the TID40W group (BID28W, P < .001; TID16W and TID28W-NR, P = .001; TID28W, P = .03; and TID40W, P = .38).

After adjustment for viral subtype, patients with the IL28B CC genotype had higher sustained response rates compared with those with non-CC genotypes in the BID28W and TID28W-NR groups (P = .05 and P = .02, respectively).

Of the 75 patients who had virologic breakthrough during the trial, 50 had HCV genotype 1a infection. Relapse occurred in 19% of those in the TID16W group, 2% of those in the TID28W group, 2% of those in the TID40W group, 0% of those in the BID28W group, and 10% of those in the TIDW-NR group.

Overall, 94% of patients experienced adverse events, 9% of which were severe. The most common adverse events were gastrointestinal and dermatologic: nausea, vomiting, diarrhea, rash, and photosensitivity.

"While it is important to show that responses in the 50% to 60% range can be obtained without interferon, it is unlikely that these drugs will have much impact in the near future," said Gary L. Davis, MD, director of general and transplant hepatology at Baylor University Medical Center, Baylor HealthCare System, Dallas, Texas, in an interview with Medscape Medical News.

"First, this is a phase 2b trial, and their phase 3 study is still ongoing," said Dr. Davis, who was not involved in the trial. "Second, these results are not really competitive with other interferon-free regimens in phase 3 or the combination of sufosbuvir and simeprevir (2 drugs that are likely to be approved by the end of the year; although these 2 drugs will not be approved as a combination, the phase 2 trial with this combination showed 100% [sustained virologic response])," Dr. Davis explained.

"Thus, [Boehringer Ingelheim's] strategy moving forward would probably be to add another drug to this regimen. In looking at clinicaltrials.gov, it appears that they are recruiting such a study now (includes PPI-668, an NS5A inhibitor like daclatasvir and GS5885). Finally, I am concerned about the amount of side effects and whether such a poorly tolerated regimen would ever be competitive," Dr. Davis added. "The poor response with genotype 1a is problematic, but again this might be overcome with PPI-668 in their new study."

The study was supported by Boehringer Ingelheim. The authors report a variety of relationships with pharmaceutical companies that make treatments for HCV, including consulting, expert testimony, board membership, employment, serving on speaker's bureaus, payment for development of educational presentations, and receipt of grant funding. A complete list can be found on the journal's Web site. Dr. Davis is on the Data Safety and Monitoring Boards for Gilead and BMS.

N Engl J Med. 2013;369:630-639.

http://www.medscape.com/viewarticle/809449

Related
Study lends support for interferon-free treatment of hepatitis C
Patients with hepatitis C genotype 1 treated with a combination of faldaprevir, deleobuvir and ribavirin achieved sustained virologic response rates up to 69%....