Wednesday, July 31, 2013

Engineered mice act as hepatitis C model

Hepatitis C particles (yellow) infect liver cells, causing disease and cancer.

Engineered mice act as hepatitis C model

Rodents may eventually replace chimpanzees in vaccine research.

Beth Mole
Researchers have created the first strain of mouse that is completely vulnerable to hepatitis C. The advance, reported today in Nature1, promises to aid efforts to develop a vaccine against the virus, which causes liver disease and cancer. 
Chimpanzees have been the primary animal model for studying hepatitis C infection over the last several decades. But in the past few years scientists have begun phasing out chimp experiments, a process accelerated by the US government’s decision to retire most of its research chimps. That has created a need for alternative models to test potential drugs and vaccines.  
Enter the mouse, which is naturally immune to hepatitis C. To transform the rodent into a model organism for studying infections with the virus, researchers genetically altered the animals to hamper their natural immune response. The team also engineered the animals to produce proteins found on the outside of human liver cells

Continue Reading @ Nature....

Durability of sustained virologic response in chronic hepatitis C.

Gut Liver. 2013 Jul;7(4):458-61. doi: 10.5009/gnl.2013.7.4.458. Epub 2013 Jun 20.

Durability of sustained virologic response in chronic hepatitis C

Uyanikoglu A, Kaymakoglu S, Danalioglu A, Akyuz F, Ermis F, Pinarbasi B, Demir K, Besisik F, Cakaloglu Y.

Department of Gastroenterology, Harran University Faculty of Medicine, Sanliurfa, Turkey.


The aim of this study is to investigate the rate of sustained virologic response (SVR) in chronic hepatitis C patients receiving antiviral treatment.

The files of patients with chronic hepatitis C treated with interferon±ribavirin between 1995 and 2009 were reviewed retrospectively. Six months after the end of treatment, patients with negative hepatitis C virus (HCV)-RNA (<50 IU/mL, as determined by the polymerase chain reaction method) were enrolled in the study.

The mean age of 196 patients (89 males) was 46.13±11.10 years (range, 17 to 73 years). In biopsies, the mean stage was 1.50±0.94; histological activity index was 7.18±2.43. In total, 139 patients received pegylated interferon (IFN)+ribavirin, 21 patients received classical IFN+ribavirin, and 36 patients received IFN alone. The HCV genotypes of 138 patients were checked: 77.5% were genotype 1b, and 22.5% were other genotypes. After achievement of SVR, the median follow-up period was 33.5 months (range, 6 to 112 months), and in this period relapse was only detected in two patients (1.02%) at 18 and 48 months after treatment.

In total, 98.9% of patients with SVR in chronic hepatitis C demonstrated truly durable responses over the long-term follow-up period of 3 years; relapsed patients had intermittent or low-grade viremia.

Chronic hepatitis C, Interferons
PMID: 23898387 [PubMed]

Discussion Only
Full Text Available Here

Regular and long-term follow-up of patients with SVR was not well documented. The current study evaluates the long term results of SVR. In standard interferon or IFN/ribavirin combination therapies, HCV-RNA was negative for 92% to 100% of patients during the follow-up of 1 to 12 years following SVR in patients with chronic hepatitis C.

Recent studies reported that cure for HCV infection was achieved with SVR. Additionally, histological improvement was detected in 94% of the patients and persistently normal ALT levels were detected in 93%.

Our results also confirmed these data and HCV-RNA level was not detectable in the long term for 99.4% of the patients. ALT was determined to be within normal limits for 153 patients (94%) in the final control.

The available data was relatively less for PEG-IFN/ribavirin combination. In a study by Swain et al follow-up of 845 patients who achieved SVR with interferon alpha 2a±ribavirin revealed that HCV-RNA was detected in only seven patients (<1%) within 391 to 1,076 days after treatment. For treatments based on PEG-IFN, it was concluded that late relapse was rare after achievement of SVR. More than half (65%) of our patients received PEG-IFN/ribavirin treatment, with results supporting this study. PEG-IFN + ribavirin treatment appears to have good long term results.

In chronic hepatitis C treatment, it is still uncertain whether complete elimination is achieved as a result of the treatment or whether a small number of viruses persist. In former studies using less sensitive tests, 95% of the patients with SVR had undetectable levels of HCV-RNA in the liver within 1 to 2 years after treatment. Only two of the seven patients with HCV-RNA detected in the liver after treatment relapsed after 4 years. In another study, none of the 17 patients with negative HCV-RNA detected in the liver after treatment relapsed at the end of 12 years.

On the other hand, only two of the 17 patients with negative HCV-RNA resulting from IFN+ribavirin had negative HCV-RNA in all of their body components including hepatocyte, serum, peripheral blood mononuclear cell, lymphocyte, and macrophage cultures. This suggests that there is a probability of relapse after many years.

The clinical significance of low-level HCV-RNA persistence is unknown and further studies must be performed for this issue. For two of our 196 patients with SVR, HCV-RNA was determined to be positive at a low level at months 18 and 48; however, when both observations were repeated after 3 months they were noted to be negative. The exact reason for transient positivity of HCV-RNA was not clear. It was determined that patients with SVR demonstrated truly durable viral responses and relapsed patients had intermittent and low-grade viraemia.

SVR presumably prevents HCC development. None of our patients with SVR demonstrated HCC on long term follow-up. Improvements in liver fibrosis, biochemical indicators, fatigue, and life quality
were detected with SVR. In our batch, no data was available concerning improvements in fibrosis, as there were no adequate end-of-therapy control liver biopsies.

When pretreatment ALT levels were compared with ALT on the last control (101.72±78.84 IU/mL [range, 12 to 465 IU/mL] vs 22.52±11.73 IU/mL [range, 8 to 84 IU/mL]), further improvement was observed (p<0.05).

In conclusion, it was found that patients with SVR in chronic hepatitis C demonstrated truly durable responses in the long term follow-up period of 3 years on average and that there was no complication related with liver disease throughout this period

Gut and Liver 2013 Jul; 7(4): 458-461/ Download Full Text

Effects of metabolic syndrome on fibrosis in chronic viral hepatitis

Gut Liver. 2013 Jul;7(4):469-74. doi: 10.5009/gnl.2013.7.4.469. Epub 2013 Jun 20.

Effects of metabolic syndrome on fibrosis in chronic viral hepatitis

Yoon H, Lee JG, Yoo JH, Son MS, Kim DY, Hwang SG, Rim KS.

Department of Internal Medicine, CHA University, Seongnam, Korea.

Key Words: Metabolic syndrome; Hepatitis B; Hepatitis C; Liver cirrhosis

Various studies have already reported the association between liver fibrosis and metabolic syndrome in nonalcoholic fatty liver disease (NAFLD) and found that the components of metabolic syndrome are independent risk factors of liver fibrosis.

There are relatively less data on chronic viral hepatitis, however. With regards to chronic hepatitis C (CHC), studies have reported that type 2 DM and other components of metabolic syndrome negatively affects the efficiency of antiviral treatments. According to previous report, the prevalence of diabetes and metabolic syndrome were raised in CHC patients, with accelerated progression of liver fibrosis. There are even less information regarding chronic hepatitis B (CHB) than CHC. Only a few preliminary data suggested association between the components of metabolic syndrome—obesity, diabetes, hypertension, and hyperlipidemia—and liver fibrosis in CHB.

The aim of this study was to determine the association between metabolic syndrome and liver fibrosis in CHB and CHC.....

Original Article- Full Text Available Here

Metabolic syndrome, comprising diabetes, hypertension, central obesity, and dyslipidemia, is increasingly prevalent worldwide. We aimed to study the relationship between metabolic syndrome and the risk of liver fibrosis in patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC).

In total, 954 patients (CHB, 850; CHC, 104 patients) with liver biopsy were included in the retrospective analysis. Extensive clinical and histological data were available. Metabolic syndrome was defined using the International Diabetes Federation definition of metabolic syndrome, 2006 criteria. Histological lesions were evaluated according to the histology activity index system.

Metabolic syndrome was present in 6% of patients and significantly more prevalent in patients with CHC than in patients with CHB (5% vs 13%, p<0.001). Patients with metabolic syndrome were older among patients with CHB and patients with CHC, and, as expected, were mainly overweight or obese. Fibrosis was significantly more severe in patients with metabolic syndrome than in those without, regardless of whether they had CHB and CHC (CHB, 3.3±2.1 vs 2.4±1.3, p=0.025; CHC, 2.6±1.5 vs 1.3±0.7, p=0.006). Liver fibrosis (stages 3 to 4) was independently associated with increased age, higher transaminase level and metabolic syndrome (odds ratio, 2.421; p=0.017).

Metabolic syndrome is associated independently with severe fibrosis in patients with chronic viral hepatitis B and C.

 Gut and Liver 2013 Jul; 7(4): 469-474/ Download PDF Here

COMMENTARY ON: Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.

Sofosbuvir-based interferon-free therapy for patients with HCV infection

26 July 2013
Tarik Asselah
Download PDF (335 KB)

(In Press Accepted Manuscript)

Accepted Manuscript
International hepatology

Sofosbuvir-based interferon-free therapy for patients with HCV infection

Tarik Asselah PII: S0168-8278(13)00534-5
Reference: JHEPAT 4806

To appear in: Journal of Hepatology
Received Date: 23 May 2013
Revised Date: 8 July 2013
Accepted Date: 10 July 2013

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain

Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.

Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. N Engl J Med. 2013 Jan 3;368( 1):34-44. doi: 10.1056/NEJMoa1208953.

Copyright © 2013.
Abstract reprinted with permission from Massachusetts Medical Society.

BACKGROUND: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon- sparing and interferon-free regimens for the treatment of HCV infection.

METHODS: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy fo r 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks after therapy.

RESULTS: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa -2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia.

CONCLUSIONS: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection.

(Funded by Pharmasset and Gilead Sciences; Clinical number, NCT01260350) © European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

For the treatment of HCV infection, several direct-acting antivirals (DAAs), including NS3 protease inhibitors, nucleoside/nucleotide analogue and non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A inhibitors, are under development [1].

Among them, Sofosbuvir is a potent HCV-specific nucleotide analog (chain terminator). It is given orally, once daily, without food effect. So far, no safety signal in preclinical/clinical studies has been observed with this compound. Sofosbuvir has a high barrier to resistance with no virologic breakthrough to date. It has a pangenotypic antiviral effect, although it might be less efficient in genotype 3 (G3).

The ELECTRON study goal was to evaluate the safety and efficacy of sofosbuvir as a backbone of combination antiviral therapy in patients with chronic HCV genotype 1, 2 and 3 infections, including both treatment-naïve and treatment-experienced patients [2]. The design of the trials and the results are provided in Fig. 1.

Fig. 1: Electron trial design and results [2].
ELECTRON is an open-label study with eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for12 weeks. Three of these groups also received PegIFNα-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus PegIFNα-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. The rate of sustained virologic response 24 weeks after therapy is reported.

Sofosbuvir combined with ribavirin (RBV) for 12 weeks was associated with sustained virological response (SVR) in 100% of G2/G3 HCV infected patients. For G1 HCV infected patients, 12 weeks sofosbuvir plus RBV provided SVR12 in 84% of treatment-naïve, but only in 10% of null responders.

For G2/3, when sofosbuvir was given alone, SVR rate was 60%. The authors concluded that sofosbuvir plus RBV may be an effective treatment in all previously untreated patients with G2 or G3

HCV infections and also in the majority of G1 HCV naïve infected patients.

What have we learned and what are the questions raised?

First, can we predict relapse with early viral kinetics with sofosbuvir based regimen?

No, unfortunately. Previous studies with pegylated-interferon (PegIFN) based therapy demonstrated that early kinetics may help to predict SVR [4]. However, in this sofosbuvir plus RBV trial, HCV RNA levels in all patients declined rapidly after the initiation of treatment (Fig. 2B).

Fig. 2. Mean change from baseline in hepatitis C virus (HCV) RNA level during treatmentAll patients with HCV genotype 2 or 3 infection completed the 12 weeks of treatment. All patients had an HCV RNA level below the limit of detection (i.e., <15 IU/ml) from week 4 until the end of treatment.

By week-2 of treatment, the majority of patients from all groups had an undetectable level of HCV-RNA. By week-4 of treatment, all 95 patients in the study had an undetectable level of HCV RNA, which was maintained until the end of treatment.

Second, is RBV useful?

Yes. Results from the 10 patients with G2 or G3 HCV infection who received sofosbuvir alone strongly suggest a role for RBV in the maintenance of an antiviral response. The exact mechanism by which RBV acts remains unknown.

Third, can we extrapolate these data to phase 3 data or real-world practice?

No, we still have to be cautious for several reasons: the number of patients is limited; they are selected as they have no cirrhosis, no comorbidities. We have to wait for more data, with a larger number of patients, including difficult-to-cure patients with cirrhosis and previous non-response.

For G1, since sofosbuvir and ribavirin is not a reasonable option, two strategies have been developed (1) 12 weeks sofosbuvir, PegIFN/RBV and (2) new IFN-free regimens with sofosbuvir and ledipasvir (NS5A inhibitor).

Interestingly, several phase 3 studies with sofosbuvir based regimen have been published since then.

The NEUTRINO trial was a single-group, open-label study of sofosbuvir plus PegIFN/RBV in 327 patients infected with HCV genotype 1, 4, 5, or 6 [5]. All patients received sofosbuvir, PegIFN α -2a for 12 weeks. Most of the patients who were included in the study had HCV G1 (89%); 9% had G4, and 2% had G5 or 6. Sofosbuvir was given orally at a dose of 400 mg, once a day, along with RBV, also given orally in a dose bas ed on body weight. Patients who weighed less than 75 kg received 1000 mg/d, and heavier patients received 1200 mg/d. Patients received PegIFN α -2a subcutaneously once a week at a dose of 180 μ g. A total of 295 of the 327 patients (90%) reached SVR after 12 weeks of treatment. According to the HCV genotype: 89% for patients with G1 (92% for G1a and 82% for G1b) and 96% (27/28) for those with G4 had SVR. The single patient with G5 and all six patients with G6 in this trial had a SVR.

The FISSION trial was a randomized, open-label, active-control study of sofosbuvir plus RBV in patients with G2 or G3 HCV infection; patients with the two genotypes were enrolled in an approximately 1:3 ratio, respectively [5]. Patients were randomly assigned in a 1:1 ratio to receive either 12 weeks of sofosbuvir plus RBV or 24 weeks of PegIFN/RBV. The doses of sofosbuvir and RBV were the same as those administered in the Neutrino trial. The dose of RBV for patients in the PegIFN/RBV group was 800 mg daily. Sofosbuvir–RBV was shown to be non-inferior to PegIFN/RBV. At 12 weeks, the rates of SVR for patients receiving 12 weeks of sofosbuvir–RBV and those receiving 24 weeks of PegIFN/RBV were each 67%. A SVR occurred in 97% of patients with G2 and in 56% of those with G3 in the group receiving sofosbuvir–RBV, as compared with response rates of 78% and 63%, respectively, in the group receiving PegIFN/R BV. Among patients with cirrhosis at baseline, 47% of those receiving sofosbuvir–RBV had a SVR, as compared with 38% of those receiving PegIFN/RBV.

The POSITRON trial was a double blinded, placebo-controlled study that compared 12 weeks of treatment with sofosbuvir and RBV with matching placebo in patients who had previously discontinued IFN -therapy owing to unacceptable adverse events, who had a concurrent medical condition precluding therapy with an IFN-containing regimen, or who had decided against treatment with an IFN-containing regimen [6]. The most common reasons that IFN treatment was not an option were clinically significant psychiatric disorders (in 57% of patients) and autoimmune disorders (in 19%).

The rate of SVR at 12 weeks after treatment was 78% among patients receiving sofosbuvir-RBV, as compared with 0% among those receiving placebo (p<0.001). Among patients who received sofosbuvir-RBV, 93% of patients with G2 HCV infection had a SVR, as compared with 61% of those with G3 HCV infection. Likewise, 81% of patients without cirrhosis (92% of patients with G2 HCV infection and 68% of those with G3 HCV infection) had a SVR, as compared with 61% of patients with cirrhosis (94% of patients with G2 HCV infection and21% of those with G3 HCV infection).

The FUSION study was a blinded, active-control study involving patients who had not had a response to prior treatment with an IFN-containing regimen. Approximately 75% of the previously treated patients enrolled had either virologic breakthrough during the prior treatment or virologic relapse afterward; the remainder did not have a response. The rates of SVR achieved were superior to the historical control rate of 25%, with rates of 50% in the12-week group and 73% in the 16-week group (p <0.001 for each comparison). Rates of SVR between the groups showed that patients receiving 16 weeks of treatment had a significantly higher rate of SVR than patients receiving 12 weeks of treatment (p <0.001).

The rates of SVR among patients with G2 HCV infection who received 12 weeks of treatment and those who received 16 weeks of treatment were 86% and 94%, respectively, as compared with 30% and 62% for 12 and 16 weeks of treatment, respectively, among patients with G3 HCV infection. Cirrhosis was associated with a decreased rate of SVR, particularly among patients with G3HCV infection who received 12 weeks of treatment. Among patients with cirrhosis who received 12 weeks of treatment, the rate of SVR was 31% (60% with G2 HCV infection and 19% with G3 HCV infection), as compared with 61% among patients without cirrhosis (96% with G2 HCV infection and 37% with G3 HCV infection). Among patients with cirrhosis who received 16 weeks of treatment, the rate of SVR was 66% (78% with G2 HCV infection and 61% with G3 HCV infection) as compared with 76% among patients without cirrhosis (100% with G2 HCV infection and 63% with G3 HCV infection).

So can we summarize these data?

Yes, we can (Table 1). Summary

What are the key messages?

First, for G1 HCV naïve patients, sofosbuvir with PegIFN-RBV triple therapy appears a reasonable option. Of course, we will need to increase the number of patients with cirrhosis; and also data from genotype 1 experienced patients. There are ongoing phase 3 studies to investigate the efficacy and safety of sofosbuvir/ledipasvir fixed-dose combination with orwithout RBV for 8 or 12 weeks in treatment-naive G1 HCV chronic infection. Ledipasvir is anNS5A replication complex inhibitor ledipasvir (previously GS-5885).

Second, for G4 naïve patients, the data are excellent but limited (n = 28 patients) and we need larger studies for this specific G4 HCV population. There is a major medical need since standard of care remains PegIFN-RBV for 48 weeks with low SVR in “difficult-to-cure” patients population (IL28B non CC; patients with cirrhosis, experienced patients, etc;..).

We urge for studies in G4 HCV, naïve but also experienced patients.

Third, for G2 HCV naïve patients, sofosbuvir-RBV provide excellent results. We have to recall obvious evidence: G2 HCV is not G3, and we need separate studies. In past PegIFN/RBV dual therapy, for statistical issues, HCV G1 and G4, and HCV G2 and G3,were respectively pooled. For DAAs, we need individual study for each genotype. For G2HCV treatment experienced and cirrhosis, we need more data.

Four, data were disappointing regarding G3 HCV naïve patients, in particular those with cirrhosis. The question is how to treat HCV G3 infected patients in the near future. There will be several options:

(1) PegIFN plus RBV, with satisfactory results, but with IFN side effects.
(2) Sofasbuvir plus RBV for 16 weeks: (better tolerated, possible in case of IFN contraindication, but not better than PegIFN plus RBV, and even worse in cirrhotics).
(3) Sofosbuvir plus RBV for 24 weeks; however, SVR results will be given by the ongoing VALENCE study
(4) Triple therapy (Sofosbuvir plus PegIFN-RBV) with a short duration of 12 weeks, using the neutrino regimen, but without data with G3!

Moreover, it is believed that clinical trials provide best evidence when they are randomized to controlled arms with large number of patients [7]. Several of the trials discussed here lack controlled arms or large number of patients.

It may be argue that controlled arms are not necessary when they expose patients to side effects. Furthermore, we need data for «difficult-to-cure» patients, those with cirrhosis, previous non response, comorbidities, etc...

Impressive data have been reported with sofosbuvir based therapy, with high SVR rates and a favorable safety profile so far. A pilot study demonstrated that addition of ledipasvir increased efficacy of sofosbuvir plus RBV, without additional safety issues, and without virologic failures. Gilead recently initiated the first Phase 3 trial (ION-I) evaluating a fixed-dose combination of sofosbuvir and lepidasvir in treatment-naïve G1 HCV infected patients. This four-arm study is evaluating the fixed-dose combination with and without RBV for 12-and 24-week durations in 800 patients, 20 percent of whom have evidence of cirrhosis. Finally, there is a realistic hope for patients with HCV infection, since several IFN-free trials are ongoing with promising early data [8-10].

We do hope that the majority of patients with HCV infection will become «easy-to-cure», and there will be increase in access to treatment.

Conflict of interest
Tarik Asselah is a speaker and investigator for BMS, Boehringer-Ingelheim, Janssen,Gilead, Roche and MSD.

[1] Asselah T, Marcellin P. Interferon-free therapy with direct acting antivirals for HCV. Liver Int. 2013; 33 Suppl 1:93-104.
[2] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide
polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44.
[3] Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of
fibrosis and treatment response. J Hepatol 2012;57:1110–1125.
[4] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 Apr 23.
[5] Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al.
Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment option. N Engl J Med. 2013
Apr 23.
[6]. Asselah T, De Muynck S, Broet P, Masliah-Planchon J, Blanluet M, Bieche I, epolymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol, 2011;56:527-532.
[7] Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical controls for clinical trials. Am J
Med. 1982;72:233-240.
[8] Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013;368:45-53.
[9] Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson D, Zeuzem S, 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 1): A3. [10] Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Mullhaupt B, et al.
Efficacy of the protease inhibitor BI201335, polymerase inhibitor BI 207127, and ribavirin
in patients with chronic HCV infection. Gastroenterology 2011;141:2047–2055

Hepatitis C Treatment: Price, Profits, and Barriers to Access

Hepatitis C Treatment: Price, Profits, and Barriers to Access

A new report (.pdf) from the Open Society Foundations, titled, “Hepatitis C Treatment: Price, Profits, and Barriers to Access,” examines “the difference in price of a 48-week course of hepatitis C treatment in low- and middle-income countries, and detail[s] breakthroughs that have been made in countries like Egypt and Thailand to negotiate lower prices and increase access to this lifesaving medicine,” according to the report summary.

The WHO “estimates that as many as 185 million people, or three percent of the world’s population, are infected with the hepatitis C virus,” the summary states, adding, “Though it is curable, the vast majority of people living with hepatitis C reside in low- and middle-income countries where treatment is virtually inaccessible” (Momenghalibaf, July 2013).

Related work: 
Hepatitis C Treatment: Price, Profits, and Barriers to Access
July 29, 2013
by Azadeh Momenghalibaf

Tuesday, July 30, 2013

Study finds evidence of nerve damage in around half of fibromyalgia patients

Study finds evidence of nerve damage in around half of fibromyalgia patients

Small study could lead to identification of treatable diseases for some with chronic pain syndrome

About half of a small group of patients with fibromyalgia – a common syndrome that causes chronic pain and other symptoms – was found to have damage to nerve fibers in their skin and other evidence of a disease called small-fiber polyneuropathy (SFPN).

Unlike fibromyalgia, which has had no known causes and few effective treatments, SFPN has a clear pathology and is known to be caused by specific medical conditions, some of which can be treated and sometimes cured. The study from Massachusetts General Hospital (MGH) researchers will appear in the journal Pain and has been released online.

"This provides some of the first objective evidence of a mechanism behind some cases of fibromyalgia, and identifying an underlying cause is the first step towards finding better treatments," says Anne Louise Oaklander, MD, PhD, director of the Nerve Injury Unit in the MGH Department of Neurology and corresponding author of the Pain paper.

The term fibromyalgia describes a set of symptoms – including chronic widespread pain, increased sensitivity to pressure, and fatigue – that is believed to affect 1 to 5 percent of individuals in Western countries, more frequently women. While a diagnosis of fibromyalgia has been recognized by the National Institutes of Health and the American College of Rheumatology, its biologic basis has remained unknown. Fibromyalgia shares many symptoms with SFPN, a recognized cause of chronic widespread pain for which there are accepted, objective tests.

Designed to investigate possible connections between the two conditions, the current study enrolled 27 adult patients with fibromyalgia diagnoses and 30 healthy volunteers. Participants went through a battery of tests used to diagnose SFPN, including assessments of neuropathy based on a physical examination and responses to a questionnaire, skin biopsies to evaluate the number of nerve fibers in their lower legs, and tests of autonomic functions such as heart rate, blood pressure and sweating.

The questionnaires, exam assessments, and skin biopsies all found significant levels of neuropathy in the fibromyalgia patients but not in the control group. Of the 27 fibromyalgia patients, 13 had a marked reduction in nerve fiber density, abnormal autonomic function tests or both, indicating the presence of SFPN. Participants who met criteria for SFPN also underwent blood tests for known causes of the disorder, and while none of them had results suggestive of diabetes, a common cause of SFPN, two were found to have hepatitis C virus infection, which can be successfully treated, and more than half had evidence of some type of immune system dysfunction.

"Until now, there has been no good idea about what causes fibromyalgia, but now we have evidence for some but not all patients. Fibromyalgia is too complex for a 'one size fits all' explanation," says Oaklander, an associate professor of Neurology at Harvard Medical School. "The next step of independent confirmation of our findings from other laboratories is already happening, and we also need to follow those patients who didn't meet SFPN criteria to see if we can find other causes. Helping any of these people receive definitive diagnoses and better treatment would be a great accomplishment."

Source: Massachusetts General Hospital

Posted July 23 - Faster, simpler diagnosis for fibromyalgia may be on the horizon

The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers

The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers

G Y Lai, S J Weinstein, D Albanes, P R Taylor, K A McGlynn, J Virtamo, R Sinha and N D Freedman

Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations.

We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27037 Finnish male smokers, aged 50–69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models.

Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73–0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48–0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee.

These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered.

Full Text Sources
Nature Publishing Group

Interferon-free treatment for genotype-1b hepatitis C patients: an interview with Professor Wulf Boecher, Boehringer Ingelheim -

Interferon-free treatment for genotype-1b hepatitis C patients: an interview with Professor Wulf Boecher, Boehringer Ingelheim

Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)

Please can you give a brief introduction to genotype-1b hepatitis C and how it differs from subtype 1a?

Genotype 1 is, worldwide, the most prevalent genotype of the hepatitis C virus. It accounts for around seventy percent of all hepatitis C infections. With the introduction of protease inhibitors, it became known that the subtypes 1a and 1b make a difference in terms of treatment response. Subtypes 1a and 1b are genetically closely related. They share seventy to eighty percent of their genome. However, 1a turned out to be more difficult to treat than 1b, which is easier to treat. That was also the case with the already approved protease inhibitors, and still is the case with the second generation of protease inhibitors (PIs) like faldaprevir or other second generation PIs that are in late stage development. And it applies for interferon based as well as interferon-free treatments

Faldaprevir’s target in viral polyprotein processing. *Please note faldaprevir (BI 201335) is an investigational compound and not yet approved. Its safety and efficacy has not yet been fully established.

Do genotypes 1a and 1b affect equal numbers of people, or is one more common than the other?

It is regionally very different. In the US, genotype 1a is more prevalent where it accounts for roughly seventy percent of genotype 1 infections. In Europe, there is slightly more genotype 1b. So therea€™s roughly a sixty-forty split, with sixty percent being genotype 1b, forty percent 1a. If you go further East the prevalence of 1b becomes nearly the only genotype 1. So in Japan, in China, and in large parts of Asia, genotype 1b is basically the vastly prevailing or the only genotype 1 subtype.

Hepatitis C virus travelling in the bloodstream.

Why is eliminating injectable interferon from HCV treatment regimens highly desirable?

I have been working on hepatitis C treatment for many years and it is not only subcutaneous injections that make patients uncomfortable. Interferon really makes patients sick for the whole course of treatment and with current treatments this can be as long as twenty four or forty eight weeks, so nearly one year. Patients feel like they have the flu, with fever, myalgia, chills, and many other symptoms. Also their neuro-cognitive function is reduced. They have low blood cell count that can lead to infections and to severe bleedings. They suffer from psychiatric side effects like severe depression. There are suicides associated with treatment with interferon.

So interferon is really a trouble-maker for patients; it makes patients sick for the duration of their treatment and it is less effective than the oral treatments that are to come. Treatment lasts longer and there is a high chance patients won a€™t be cured at the end. In contrast, current triple therapies the next generation triple therapies, as well as the future interferon-free treatments, offer shorter treatment duration and higher cure rates.

Faldaprevir* Protease Inhibitior Mode of Action.

Please note faldaprevir (BI 201335) is an investigational compound and not yet approved. Its safety and efficacy has not yet been fully established.
Source: Boehringer Ingelheim

How did your interferon-free combination treatment originate and what stage of development is it currently at?

It's actually based on the knowledge of HIV and tuberculosis treatment; where by combining different oral drugs with a different mode of action it is possible to control or eliminate the virus or mycobacteria. In HCV, we had two different mode-of-action drugs in late stage development that we combined. We had actually thought we may possibly have a forty-five percent cure rate, which would still have been a very attractive cure rate for patients without any treatment options.

Up to fifty percent of hepatitis c patients right now do not tolerate interferon or have contra-indications against interferon. But then in our phase two studies we found out that by focusing on the easier-to-treat genotype 1b patients, eighty five to ninety five percent of patients can be cured. This makes this combination very attractive as an alternative to replace interferon-based treatments. And with this interferon-free treatment, we are currently in phase III development.

Please can you tell us about the recent Phase IIb study into the efficacy and safety of this combination treatment?

This is our second phase IIb trial. Initially (in the SOUND-C2 trial) we tested our interferon-free treatment regimen of faldaprevir, deleobuvir and ribavirin in a large study. We had 362 patients, including patients with liver cirrhosis and all stages of liver disease. We found that genotype 1a patients are indeed difficult to treat, achieving lower cure rates. That would have been attractive maybe three, four years ago, but not nowadays.

But in this study genotype 1b patients had a cure rate of eighty-five percent. Then we modified the regimen. We shortened treatment from twenty eight to sixteen weeks in SOUND-C3, which is the study we just published at the Asian Pacific Liver Conference (APASL) in June. We also dropped a so-called induction dose. So in the old regimen, we had a high dose of our polymerase inhibitor and this was not so well tolerated, as we found out. So we dropped this, we shortened treatment and we found in genotype 1b patients ninety five percent achieved viral cure. But it turned out that in the more difficult to treat population of genotype 1a patients, only two of seventeen patients were cured. And that confirmed our decision to focus on genotype 1b patients with this regimen.

Progression of liver damage caused by infection with hepatitis C.
Source: Boehringer Ingelheim

What were the results of this study and what do they indicate?

The very high cure rates of ninety five percent confirm our decision to focus on genotype 1b patients with this regimen. We dropped genotype 1a patients from this regimen. However we are currently investigating a third compound in combination with our interferon free combination with which we strive to address genotype 1a patients. The tolerability was very good. This was as expected from interferon-free treatment. We saw only minor effects on the red blood cells, which was due to the ribavirin component of the regimen, but we didn't see any effects on white blood cells or platelets. We did see mostly mild adverse events like mild rashes or nausea, which were the most common side effects. Did any patients experience serious adverse events during the trial? Only two patients had to discontinue treatment for adverse events and only one patient reported a serious adverse event (SAE). So overall, I think we can say that this is very good tolerability.

What serious adverse event did the patient experience?

The SAE patient was a patient who had severe dehydration. He was hospitalized to get some infusions and discontinued HCV treatment early after 6 weeks of treatment. However the condition was managed and resolved and the patient recovered completely from the event but also from his hepatitis C.

What are your plans for the future?

For genotype 1b patients we are in the middle of our phase III evaluations. We are expecting results early next year. We have three on-going phase III trials:- One in treatment-naive genotype 1b patients.

One in a treatment-naive population that includes interferon ineligible patients, which are patients who have contra indications to interferon based treatments. So these patients have currently no treatment option at all. We have a third trial that goes to the highest unmet medical need population, which are patients with decompensated liver cirrhosis. The first two trials also include patients with compensated liver cirrhosis, but the third trial really addresses the late stage liver cirrhosis, or decompensated liver cirrhosis.

These are patients that will die if they do not receive a liver transplant. All studies are on-going as we speak. Our trials are comprehensively designed and address the real-world patients that physicians see every day in clinical practice. Through robust science, our goal is to provide a safe and highly effective interferon-free treatment for genotype-1b patients.

How do you think the future of genotype-1b hepatitis C treatments will progress?

From a patient and a prescriber or physician'€™s perspective, the future is very bright. There are several companies and there will be several regimens available to physicians to pick the best treatment option for a given patient. There are many factors that need to be considered when prescribing HCV treatments, so there will be no one-size-fits-all approach. In the future individualized treatment will become a reality. Physicians will be able to pick the best treatment option for a given patient depending on: the virus genotype and patient genetics on individual patient conditions age gender co-morbidities co-medications.

Everything will play into this and there will be several interferon-free treatment options that can be really tailored individually to a given patient. It is exactly our strategy to provide tailored therapy which is optimal for specific patient populations. I think this is where we believe we will excel in. The treatment landscape will become more complex. In the past, we had only to pick between prescribing pegylated interferon for twenty four, or forty eight weeks, and ribavirin in eight hundred, one thousand or twelve hundred milligrams. This was very easy, no drug-drug interactions. The future looks like it will be more individualized, with physicians choosing which regimen to provide based on the individual patient'€™s profile. But this is in fact a luxury situation and a great opportunity.

Where can readers find more information?

Readers can find more information on Boehringer Ingelheim at:

About Professor Wulf Boecher

Wulf trained and worked more than 15 years at Mainz University Hospital in Germany as a Gastroenterologist/ Hepatologist and Infectious Diseases Specialist, where he lectures as an Associate Professor for Internal Medicine. His main scientific focus has been immune pathogenesis and new treatments of HBV, HCV and HIV infection. Wulf joined Boehringer Ingelheim for the clinical development of new HCV treatments in 2007 and currently holds the position of Associate Therapeutic Area Head Virology.

Saturday, July 27, 2013

WHO: over 350 000 people die each year from hepatitis C-related diseases

WHO: over 350 000 people die each year from hepatitis C-related diseases

Azerbaijan, Baku, July 26/ Trend, S.Ahmadova/

Every year, about 1.4 million people experience chronic illness from their infection with hepatitis A, approximately 2 billion - with Hepatitis B and around 150 million people - with Hepatitis C, The United Nations Department of Public Information Office in Azerbaijan reported.

World Hepatitis Day is celebrated on July 28 every year. This year's World Hepatitis Day slogan is: "It's closer than you think".

Under the World Hepatitis Day theme WHO is urging governments to strengthen efforts to fight viral hepatitis that kills about one million people every year and an estimated 500 million people experience chronic illness from their infection with hepatitis. It is a major cause of liver cancer and liver cirrhosis.

The campaign focuses on raising awareness of the different forms of hepatitis: what they are and how they are transmitted; who is at risk; and the various methods of prevention and treatment.

"The vast majority of people infected with hepatitis are unaware, undiagnosed and untreated," says Dr Sylvie Briand of WHO's Pandemic and Epidemic Disease Department. "Only by increasing awareness of the different forms of hepatitis, and how they can be prevented and treated, can we take the first step towards full control of the disease and save thousands of lives."

Given the scale of the epidemic - with 1 in 12 people chronically infected - and recent advances in prevention and treatment, the World Health Assembly in 2010, Resolution WHA63.18 was adopted at the World Health Assembly, calling for a comprehensive approach to the prevention and control of viral hepatitis and designated 28 July as World Hepatitis Day. The Day serves to promote greater understanding of hepatitis as a global public health problem and to stimulate the strengthening of preventive and control measures against infection in countries throughout the world.

There are five main types of viral hepatitis: A, B, C, D, E. Hepatitis A and E are typically caused by ingestion of contaminated food or water. Hepatitis B, C and D are typically caused by contact with contaminated blood or body fluids.

The global burden of disease due to acute hepatitis B and C, and cancer and cirrhosis of the liver, accounts for about 2.7% of all deaths. This is expected to increase further in the next two decades.

An estimated 57% of liver cirrhosis and 78% of primary liver cancer are due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

In total, about 2 billion people have been infected with HBV; about 600 000 people die each year due to the consequences of hepatitis B.

About 150 million people are chronically infected with HCV (about 10 times higher than HIV estimates); more than 350 000 people die each year from hepatitis C-related liver diseases.

Hepatitis B and C cause a high burden of disease in the WHO European Region, especially among key populations. Only 1 in 5 persons exposed to the hepatitis B and C virus develops acute symptoms, but chronic infection is common. Hepatitis B and C each is estimated to affect up to 2% of the population in the Region (13.3 million people living with chronic hepatitis B, 15 million with chronic hepatitis C); together, they cause over 120 000 deaths per year. Two-thirds of infected persons live in Eastern Europe and central Asia. Co-infection of HCV and HIV is common, especially among people who inject drugs.
In preparation for this year's World Hepatitis Day, WHO is launching a new global framework to tackle the disease. The Prevention and control of viral hepatitis infection: Framework for global action describes four areas of work to prevent and treat hepatitis infection.

Raising awareness, together with promoting partnerships and mobilizing resources constitute the first of the four priorities in WHO's new framework.

The World Health Organization is the United Nations specialized agency for health. It was established on 7 April 1948. WHO's objective, as set out in its Constitution, is the attainment by all peoples of the highest possible level of health. Health is defined in WHO's Constitution as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.

WHO is governed by 193 Member States through the World Health Assembly. The Health Assembly is composed of representatives from WHO's Member States.

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Fever after interferon injection for HCV predicts treatment success

Fever after interferon injection for HCV predicts treatment success

Last Updated: 2013-07-25 15:20:15 -0400 (Reuters Health)

By Will Boggs, MD

NEW YORK (Reuters Health) - Patients with chronic hepatitis C virus (HCV) who become febrile after peginterferon alfa-2a (PEG-IFN) injection are more likely to have a virological response than those who don't, a retrospective study suggests.

"Many patients find it difficult to complete interferon-based regimens because of the side-effects," Dr. Yaron Rotman from National Institutes of Health, Bethesda, Maryland told Reuters Health by email. "Clinicians can use our findings as a tool to encourage patients who suffer from side effects, to let them know that these actually suggest they are responding, and to help convince them to persist and maintain their compliance and adherence to treatment."

Fever commonly follows PEG-IFN injection, but the factors that predict the magnitude of this febrile response and its association with the antiviral efficacy of PEG-IFN are unknown.

To explore this issue, Dr. Rotman and colleagues reviewed data from a prospective trial of 60 treatment-na�ve adults with chronic HCV.

Most (57%) were infected with genotype 1, and their average age was 52 years.

As reported online July 11th in the Journal of Hepatology, oral temperature rose above 38.0 C in 20 patients (33%) at a median of 12.5 hours after injection.

The maximum temperature increase correlated strongly with the first phase virological decline, with a 0.49 C increase for each 1 log10 decline in viral levels.

Temperature increases did not differ significantly by gender. The link between temperature increase and virological decline also didn't differ by gender, nor by the presence or absence of cirrhosis or the viral genotype.

The maximum temperature change was higher for patients with the IL28B-related SNP rs12979860 CC genotype, and the correlation of maximum temperature increase with virological decline was limited to patients with the CC genotype.

Despite the link of temperature change with virological response, maximum temperature change did not predict either rapid or sustained virological response very well, and it was only a weak predictor of early virological response.

"Since the spike of fever is independent of virological predictors of response, it could potentially serve in the research setting as a tool to tease out host interferon-responsiveness from viral- and liver-related factors," the researchers say.

"The clinical importance of the study is in the novel appreciation that medication side-effects are closely linked to its efficacy," Dr. Rotman said.

"Of course," he continued, "the interferon-induced fever is not causing viral clearance, and we are not claiming that, but its occurrence early on (in the first 24 hours) can give patients and their doctors an inclination that the drug is actually doing its job."

Dr. Hans Van Vlierberghe from Ghent University Hospital in Belgium, who has published work on chronic HCV treatment, told Reuters Health by email, "This is a very nice and elegant study, monitoring temperature after peginterferon administration and linking the rise in temperature to response. However, treatment of hepatitis C is evolving more and more to an interferon-free combination schedule, making the observation by the authors less and less relevant."

Dr. Rotman added, "I would have to credit the first author, Hwalih Han, BSN, BS, the research nurse specialist, who has done a significant amount of the work on this study under my mentorship. Research nurses are not typically involved in the analysis and writing of clinical trial manuscripts; our work shows how physicians and nurses can work in synergy not only in clinical care, but also in research, especially in areas that straddle both disciplines."


J Hepatol 2013.

Friday, July 26, 2013

Marijuana may not exacerbate liver disease in at-risk patients

Marijuana may not exacerbate liver disease in at-risk patients

Last Updated: 2013-07-25 9:00:15 -0400 (Reuters Health)

By Rob Goodier

NEW YORK (Reuters Health) - Marijuana smoking doesn't appear to accelerate liver disease progression in HIV patients with hepatitis C coinfection, a new prospective study from Canada has found.

"Based on previous studies, physicians have counseled patients that marijuana is harmful to their livers," Dr. Marina Klein, of McGill University Health Centre in Montreal, told Reuters Health by email.

"The results of our study suggest that physicians can reassure their patients that marijuana use, while it may have other deleterious effects, likely will not make their liver disease progress more rapidly," said Dr. Klein, who led the study, published online June 28 in Clinical Infectious Diseases.

Patients in Canada can apply for permission to use marijuana for medicinal purposes. The United States has conflicting marijuana laws. The federal government outlaws it, but 18 states allow for medicinal use, including two, Colorado and Washington, that also allow for recreational use.

The researchers followed up with 690 patients at 17 Canadian HIV clinics for an average of 2.7 years. The patients had HIV-hepatitis C coinfection at baseline, but did not have significant liver fibrosis (aspartate aminotransferase-to-platelet ratio (APRI) < 1.5).

At baseline, more than half of the patients said they had smoked marijuana in the past six months (median, seven joints per week) and 40% of those did so daily. A similar proportion said they used the drug for symptom relief.

In the course of the study, 19% of the patients reached an APRI score of 1.5, and 15% percent progressed to a score of 2. Eight patients, representing 1.2% of the study group, developed cirrhosis and 11, or 1.6%, developed end-stage liver disease (ESLD).

On multivariate analysis, there was no link between marijuana smoking and progression to liver disease based on the APRI score.

The researchers did find an association between marijuana use and progression to a clinical diagnosis of cirrhosis, with a hazard ratio of 1.33 per 10 additional joints per week. But when they reevaluated the findings using a lagged model of marijuana exposure, the association became statistically insignificant.

The lagged model measured marijuana use six to 12 months before the period during which liver disease developed, while the main model measured marijuana use during the same time that liver disease was diagnosed.

"The idea, really, was to make sure that smoking started before the participants got a liver problem and using the exposure and outcome at the same interval doesn't allow that (e.g. patients may have simply increased their use because they had symptoms of a disease that was already present). When we did this, it no longer looks as though marijuana is associated with any of the outcomes we investigated," Dr. Klein said.

That bias may explain some of the associations found between marijuana use and liver disease in past studies, she added.


Clin Infect Dis 2013.

Thursday, July 25, 2013

VX-135 -Vertex Sees Liver Toxicity With Emerging Hep C Drug, Faces FDA Hold

UPDATE 1-U.S. FDA puts hold on Vertex hepatitis study

Bill Berkrot

July 25 (Reuters) - Vertex Pharmaceuticals Inc said U.S. health regulators placed a partial clinical hold on its mid-stage study of an experimental oral hepatitis C treatment because of potential liver problems, sending its shares sharply lower on Thursday.

Vertex said the U.S. Food and Drug Administration took the action on the Phase II study of its VX-135 in combination with the standard hepatitis drug ribavirin after elevated liver enzymes were observed in three patients taking the 400 milligram dose of its drug.

As a result of the hold, the U.S. biotechnology company said it was unable to evaluate results of the trial, even for those patients who had been getting the 200 mg dose of VX-135.

"We are committed to continuing to work closely with the FDA to provide the data needed to support evaluation of a 200 mg dose of VX-135 in the U.S.," Robert Kauffman, Vertex's chief medical officer, said in a statement.

The halted trial was being conducted in Europe. The 400 mg arm of the study was discontinued and the patients' liver enzymes returned to what they had been prior to entering the trial, Vertex said.

A U.S. study evaluating 100 mgs of VX-135 was not affected, the company said.

VX-135 is also being studied at 100 mg and 200 mg in combination with Bristol-Myers Squibb Co's daclatasvir, a highly promising hepatitis drug from a different class of oral medicines.

Vertex has the market leading hepatitis C treatment with Incivek. But that drug must be taken with the difficult to tolerate injected drug interferon to provide high cure rates.

Incivek sales have been declining sharply as patients wait for new all oral treatment regimens that promise very high cure rates without the need for interferon and the miserable flu-like symptoms that come with it.

The first of those are expected to become available in 2014 from other companies and Vertex has been playing catch-up.

"With our ongoing studies in the U.S., Europe and now New Zealand with VX-135 and daclatasvir, our strategy in hepatitis C is unchanged - to develop an all-oral therapy that provides a high cure rate across multiple hepatitis C genotypes," Kauffman said.

Vertex shares were down more than 9 percent at $80 in after hours trading after closing at $87.62 on Nasdaq.

Vertex Press Release

July 25, 2013

Vertex Provides Update on Ongoing All-Oral Studies of VX-135 in Hepatitis C

-U.S. Study: FDA places partial clinical hold on ongoing Phase 2 U.S. study of VX-135, preventing evaluation of 200 mg dose following observation of elevated liver enzymes in patients receiving 400 mg of VX-135 in combination with ribavirin in Phase 2 study in Europe; evaluation of 100 mg dose continues in U.S.-

-European Study: 12-week dosing complete in 100 mg and 200 mg VX-135 dose groups in combination with ribavirin in Phase 2 study; 70% and 80%, respectively, of patients achieved undetectable HCV RNA by week 4 and treatment was well tolerated with no discontinuations or serious adverse events reported through 12 weeks-

-New Zealand Study: dosing ongoing in Phase 2 study of 100 mg and 200 mg of VX-135 in combination with daclatasvir, an NS5A replication complex inhibitor-

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the company has received notice from the U.S. Food and Drug Administration (FDA) that a partial clinical hold has been placed on Vertex's ongoing Phase 2 U.S. study of the nucleotide analogue hepatitis C virus (HCV) polymerase inhibitor VX-135. The partial clinical hold prevents evaluation of a 200 mg dose of VX-135 in the U.S. study following observation of reversible elevated liver enzymes in patients receiving 400 mg of VX-135 in combination with ribavirin in a Phase 2 study in Europe. Evaluation of a 100 mg dose of VX-135 in combination with ribavirin as part of the 12-week Phase 2 study in the U.S. is continuing as planned.

Vertex recently completed dosing of 100 mg and 200 mg of VX-135 in combination with ribavirin as part of the 12-week Phase 2 study in Europe, and both doses were well tolerated with no discontinuations. No serious adverse events have been reported and no liver or cardiac safety issues have been identified. Vertex also recently initiated dosing of 100 and 200 mg of VX-135 in combination with daclatasvir as part of a Phase 2 study in New Zealand.

"Developing safe and effective medicines for patients is our goal," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "We are committed to continuing to work closely with the FDA to provide the data needed to support evaluation of a 200 mg dose of VX-135 in the U.S."

Ongoing Studies of VX-135

Multiple studies of VX-135 as part of all-oral treatment regimens are ongoing, including:
U.S. Study of VX-135 in Combination with Ribavirin: Dosing of 100 mg of VX-135 in combination with ribavirin as part of a 12-week Phase 2 study in the United States is ongoing, and evaluation of this dose group is continuing as planned. Ten patients with genotype 1 hepatitis C are enrolled in this dose group, and all patients have now completed at least 10 weeks of treatment. Complete safety and efficacy results from the 100 mg arm of the study are expected to be available in the second half of 2013. Under the partial clinical hold, Vertex plans to complete evaluation of the 100 mg dose of VX-135 but will not evaluate a 200 mg dose of VX-135 in the United States without authorization from the FDA. At the request of the FDA, Vertex expects to complete submission of additional clinical, preclinical and pharmacokinetic data from ongoing VX-135 studies in the fourth quarter.
European Study of VX-135 in Combination with Ribavirin: Dosing of 100 mg and 200 mg of VX-135 in combination with ribavirin as part of a 12-week Phase 2 study in Europe is complete, and all patients are in the post-treatment follow-up period. Ten patients with genotype 1 hepatitis C were enrolled in each dose group and all 20 patients completed 12 weeks of treatment. Both the 100 mg and 200 mg doses were well tolerated, no serious adverse events have been reported and no liver or cardiac safety issues have been identified. All patients achieved undetectable HCV RNA during the 12-week dosing period, and 70 percent and 80 percent of patients in the 100 mg and 200 mg dosing arms, respectively, had undetectable HCV RNA within four weeks of initiating treatment. HCV RNA was undetectable at the end of the treatment period in all patients with available data. Complete safety and efficacy results from the 100 and 200 mg arms of the study are expected to be available in the second half of 2013. Following completion of enrollment in the 100 mg and 200 mg arms of the European study, the study was amended to evaluate a 400 mg dose of VX-135 in combination with ribavirin in ten patients. Elevated liver enzymes were observed in three of ten patients in this dose group, including one serious adverse event, and the 400 mg arm of the study was discontinued. Following the discontinuation of dosing, liver enzyme levels returned to baseline in all three patients.
Study of 100 and 200 mg Doses of VX-135 in Combination with Daclatasvir: Vertex and Bristol Myers Squibb Company (BMS) recently initiated dosing in New Zealand in a Phase 2 study of VX-135 in combination with daclatasvir, an NS5A replication complex inhibitor being developed by BMS. This first part of the study is evaluating 100 mg and 200 mg doses of VX-135 in combination with daclatasvir as part of 12-week treatment regimens in approximately 20 people with genotype 1 hepatitis C. Pending data from the initial cohort of patients, Vertex and BMS plan to expand the study to enroll additional patients with both genotypes 1 and 3. Safety and efficacy results from the first part of the study are expected to be available in early 2014.

VX-135 in Combination with Simeprevir: A drug-drug interaction study of VX-135 in combination with simeprevir in healthy volunteers is complete. A combination study of VX-135 and simeprevir is planned for the second half of 2013 in patients with genotype 1 hepatitis C, pending availability of additional data. Simeprevir (TMC435) is a once-daily investigational hepatitis C protease inhibitor being jointly developed by Janssen R&D Ireland and Medivir AB.
Termination of Collaboration with GlaxoSmithKline (GSK): In June, Vertex and GSK mutually decided to cease the collaboration for a Phase 2 study of VX-135 and GSK-2336805 and prioritize other projects. The preclinical and early-stage clinical data support continued development of VX-135 and of GSK-2336805.

About VX-135

VX-135 is a uridine nucleotide analogue pro-drug designed to inhibit the replication of the hepatitis C virus by acting on the NS5B polymerase. Vertex gained worldwide rights to ALS-2200, known as VX-135 in Phase 2 studies, through an exclusive licensing agreement signed with Alios BioPharma, Inc. in June 2011.

About Vertex

Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences.

Vertex Special Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman's statements in the third paragraph of the press release and statements regarding (i) Vertex's expectation that it will complete submission of additional clinical, preclinical and pharmacokinetic data in the fourth quarter of 2013; (ii) the plan to complete the evaluation of the 100 mg dose of VX-135 in the United States; (iii) the timing of availability of data from the U.S. and European studies of VX-135 in combination with ribavirin and from the first part of the study of VX-135 in combination with daclatasvir; (iv) the plan to expand the study of VX-135 and daclatasvir to enroll additional patients with both genotypes 1 and 3 HCV infection; and (v) the planned combination study of VX-135 and simeprevir. While Vertex believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the partial clinical hold prevents evaluation of the 200 mg dose of VX-135 in the United States, that the clinical development program for VX-135 may be delayed by the partial clinical hold, that the FDA may not lift the partial clinical hold on VX-135 or allow the company to pursue further development of VX-135 in the United States, that the outcomes of Vertex's planned and ongoing clinical studies of VX-135 may not be favorable, that VX-135 may not be safe or efficacious and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the company's website at Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

Vertex Contacts:
Media: Zach Barber, 617-341-6470
or Investors: Michael Partridge, 617-341-6108
or Kelly Lewis, 617-961-7530
Source: Vertex Pharmaceuticals Incorporated
News Provided by Acquire Media

Vertex Sees Liver Toxicity With Emerging Hep C Drug, Faces FDA Hold 
Luke Timmerman

Vertex Pharmaceuticals suffered a meaningful setback today in its bid to remain a long-term player in the treatment of hepatitis C.

The Cambridge, MA-based biotech company (NASDAQ: VRTX) said today that the FDA has stopped the company from giving certain doses of its VX-135 drug candidate for hepatitis C in a mid-stage U.S. study, after seeing evidence of liver toxicity in patients in Europe. The FDA put a hold on Vertex’ plans to deliver 200-milligram doses of VX-135 in the U.S., but has allowed the study to continue enrolling patients on a lower, 100 milligram dose.

That decision was made after researchers saw liver toxicity in three of 10 European patients who got 400 milligrams of the Vertex drug, before they stopped enrolling patients in that group. The liver toxicity, measured in an increase in liver enzymes, was reversible once patients quit taking the drug, Vertex said. Vertex said that patients on the 100 and 200-milligram doses were able to tolerate the drug well, and none of those dropped out of 12-week study in Europe because of side effects.

“Developing safe and effective medicines for patients is our goal,” said Robert Kauffman, Vertex’s chief medical officer, in a statement. “We are committed to continuing to work closely with the FDA to provide the data needed to support evaluation of a 200 mg dose of VX-135 in the U.S.”

Vertex shares fell 11 percent, to $78 a share, in after-hours trading following the announcement.

The clinical hold is just the latest setback for Vertex in hepatitis C. Although the company blazed a new trail in the field by winning FDA approval in 2011 with its protease inhibitor telaprevir (Incivek), that treatment still must be given in combination with injectable interferon alpha, which causes flu-like side effects. Competitors such as Gilead Sciences (NASDAQ: GILD) and AbbVie (NYSE: ABBV) are both ahead in late-stage development with all-oral combination regimens that have increased hepatitis C cure rates without subjecting people to interferon. The results with competing drugs have been so compelling the past couple years that many hepatitis C patients have elected to wait until the new compounds are approved by the FDA instead of taking the currently available compound from Vertex.

VX-135, a nucleotide polymerase inhibitor, represents one of Vertex’s best chances to remain competitive in a landscape dominated by all-oral therapy. Vertex got the rights to this molecule through a collaboration with South San Francisco-based Alios Biopharma in 2011.

Vertex outlined a list of studies that remain ongoing with VX-135 in today’s statement. The drug is still being tested in combinations with compounds from Bristol-Myers Squibb and Johnson & Johnson, although Vertex said today that a VX-135 collaboration with GlaxoSmithKline ended last month.

Hepatitis C in the UK: 2013 report

Hepatitis C in the UK: 2013 report

Authors: PHE, HP Scotland, PH Wales, HSC

Publication date: July 2013

Download: Hepatitis C in the UK: 2013 report (PDF, 3.9 MB)


The most recent national estimates suggest that around 215,000 individuals are chronically infected with hepatitis C (HCV) in the UK; most of this infection (~90%) is genotype 1 and genotype 3.

Injecting drug use continues to be the most important risk factor for HCV infection in the UK. Data from the Unlinked Anonymous Monitoring (UAM) survey of people who inject drugs (PWID) suggest that levels of infection in this group remain high in 2012 (49% in England, 34% in Northern Ireland and 33% in Wales); in 2011/12, 53% of PWID surveyed in Scotland tested positive for antibodies to hepatitis C.

While it is acknowledged that both hospital episode statistics and death certification underestimate true numbers of admissions and deaths from HCV-related end stage liver disease (ESLD) and hepatocellular carcinoma (HCC) national data shows that levels of both are continuing to rise in the UK.

Hospital admissions have risen from 612 in 1998 to 2268 in 2011, while deaths have risen from 98 in 1996 to 381 in 2011. An overall increase in registrations for liver transplants with a primary code of post-hepatitis C cirrhosis has been observed from 45 in 1996 to 124 in 2012, although figures have been relatively stable over the last five years.

To help tackle HCV infection, public health programmes need to make progress in the following four action areas:

*prevention of new infections
*increasing awareness of infection
*increasing testing and diagnosis
*getting diagnosed individuals into treatment and care

Download full publication

Last reviewed: 24 July 2013

U.S. drugmakers cheer 'speed lane' for breakthrough therapies

WASHINGTON, July 24 | Wed Jul 24, 2013 7:53pm EDT

(Reuters) - A new regulatory pathway could shave years off the traditional drug approval process in the United States, according to some companies whose drugs have been given "breakthrough therapy" designation by the U.S. Food and Drug Administration.

Speaking at a briefing in Washington to raise awareness of the drug review process, Dr. Jay Siegel, head of global regulatory affairs at Johnson & Johnson, said he expects two years to be knocked off the time it would typically take the FDA to review ibrutinib, the company's experimental cancer drug.

To be granted breakthrough designation, an experimental drug must show early indication of clinical improvement over existing therapies, even if the clinical trial is small. It might apply, for example, to a new type of cancer drug that shows strong early promise.

J&J's ibrutinib, which it is developing with Pharmacyclics Inc, would be the first in a class of oral medicines that block a protein known as Bruton's tyrosine kinase. It is being developed for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and for patients with mantle cell lymphoma, both cancers of the blood.

Dr. Jeffrey Leiden, the chief executive of Vertex Pharmaceuticals Inc, who also spoke at the briefing and whose cystic fibrosis drug Kalydeco was approved under the designation, said his company's experience working with the FDA was dramatically different from the normal drug approval process.

Under breakthrough designation, he said, "everything is on the table" for discussion in order to move the process along as quickly as possible. Communications that might typically take weeks and months, under the breakthrough pathway take minutes.

"We pick up the phone and talk in real time," Leiden said. "It makes the process immeasurably smoother."

The breakthrough pathway was spearheaded by Friends of Cancer Research, a patient advocacy organization. It received bipartisan support in Congress and was signed into law in July 2012. As of July 12, the FDA had received 67 requests for breakthrough designation. It had granted 24 and denied 18.

Dr. Janet Woodcock, director of the FDA's drugs division, said during the discussion that the breakthrough pathway was designed to accommodate new science, particularly targeted therapies that may work in people with certain genetic mutations. She noted that just because the review process is speeded up there is no guarantee of approval.

In the 1990s, she said, the agency was not seeing drugs whose promise could be detected in early clinical trials.

"We didn't see these therapies in Phase I or II where you said 'bingo,' you've got a likely winner," she said.

Still, there are challenges associated with speeding up a drug's development timeline. For one thing, other nations might not be willing to approve the products based on the FDA's more flexible clinical trial standards under the breakthrough designation.

"Our hope is that foreign regulators will catch up," Siegel said.

Moreover, he said, it is not clear that insurers will pay for drugs if the data do not show improved survival or other clear benefit they are used to seeing when drugs are approved. One task, he said is to figure out "how to bring payors on board."

The panelists did not discuss what happens once a drug reaches the market under the breakthrough designation.

Under a separate pathway known as "accelerated approval" drugs may be approved based on a so-called surrogate endpoint - a measure, such as tumor shrinkage - that might reasonably be expected to confer a clinical benefit such as improved survival.

Companies that win approval for a product under the accelerated approval process are required subsequently to prove through further clinical trials that the surrogate measure does in fact correlate with improved survival or a reduction in disease symptoms.

"A discussion on this topic is reckless if it doesn't discuss the next stage after the drug reaches the market," said Sidney Wolfe, co-founder and senior adviser to Public Citizen's Health Research Group, a watchdog organization that has frequently criticized the FDA for approving, or failing to withdraw, drugs it considers unsafe.

Woodcock said the FDA is now working to develop a mechanism to speed the development of breakthrough diagnostics that can be used in conjunction with new drugs to help identify which patients will respond to a particular therapy.

WHO urges governments to act on hepatitis threat

WHO urges governments to act on hepatitis threat
World Hepatitis Day 2013

24 July 2013 | GENEVA - On World Hepatitis Day (28 July), WHO is urging governments to act against the five hepatitis viruses that can cause severe liver infections and lead to 1.4 million deaths every year. Some of these hepatitis viruses, most notably types B and C, can also lead to chronic and debilitating illnesses such as liver cancer and cirrhosis, and in addition to, loss of income and high medical expenses for hundreds of millions of people worldwide.

Viral hepatitis is referred to as a ‘silent epidemic’ because most persons do not realize that they are infected and, over decades, slowly progress to liver disease. Many countries are only now realizing the magnitude of the disease burden and devising ways to address it.

“The fact that many hepatitis B and C infections are silent, causing no symptoms until there is severe damage to the liver, points to the urgent need for universal access to immunization, screening, diagnosis and antiviral therapy,” says Dr Keiji Fukuda, WHO Assistant Director-General for Health Security and the Environment.

"Many of the measures needed to prevent the spread of viral hepatitis disease can be put in place right now, and doing so will offset the heavy economic costs of treating and hospitalizing patients in future."

Dr Sylvie Briand, Director, WHO Pandemic and Epidemic Diseases 

This year, in the run up to World Hepatitis Day, the Organization is releasing its first-ever country hepatitis survey, covering 126 countries. The WHO "Global policy report on the prevention and control of viral hepatitis in WHO Member States" identifies successes as well as gaps at country level in the implementation of four priority areas. The priority areas are raising awareness, evidence-based data for action, prevention of transmission, and screening, care and treatment.

The findings show that 37% of the countries have national strategies for viral hepatitis, and more work is needed in treating hepatitis. It also highlights that while most of the countries (82%) have established hepatitis surveillance programmes, only half of them include the monitoring of chronic hepatitis B and C, which are responsible for most severe illnesses and deaths.

“Many of the measures needed to prevent the spread of viral hepatitis disease can be put in place right now, and doing so will offset the heavy economic costs of treating and hospitalizing patients in future,” says Dr Sylvie Briand, Director, Pandemic and Epidemic Diseases at WHO. “The findings underline the important work that is being done by governments to halt hepatitis through the implementation of WHO recommended policies and actions.”

The challenges posed by hepatitis were formally acknowledged by the World Health Assembly in 2010 when it adopted its first resolution on viral hepatitis, and called for a comprehensive approach to prevention and control. This has promoted a new era of awareness with more governments proactively working to address the disease. Reinforcing that call for action, WHO has been collaborating closely with countries and partners to build a strong global response. As a result, the new report notes, 38% of countries observe World Hepatitis Day (an annual event that began in 2010) with even more countries expected to mark the day this year.

In addition to collaborating closely with countries, WHO has been working on developing networks and mechanisms that can deliver results. The Organization is exploring with international funding agencies avenues that could allow hepatitis to be included in their current programme of activities. In June 2013, WHO launched the Global Hepatitis Network. One of its aims is to support countries with planning and implementation of viral hepatitis plans and programmes.

WHO is currently developing new hepatitis C screening, care and treatment guidelines, which will provide recommendations on seven key areas such as testing approaches; behavioural interventions (alcohol reduction); non-invasive assessment of liver fibrosis; and the selection of hepatitis C drug combinations.

”New, more effective medicines to prevent the progression of chronic hepatitis B and C are in the pipeline. However, these will be expensive and therapy will require monitoring with sophisticated laboratory tests. To cure and reduce the spread of these viruses, medicines must become more accessible,” says Dr Stefan Wiktor, Team lead of WHO’s Global Hepatitis Programme.
Additional background information

The complexity of hepatitis disease lies in the existence of different types of viruses. Hepatitis A and E are foodborne and waterborne infections which cause millions of cases of acute illness every year, sometimes with several months needed for a person to fully recover.

Hepatitis B, C, and D are spread by infected body fluids including blood, by sexual contact, mother-to-child transmission during birth, or by contaminated medical equipment. Hepatitis B and C have a greater health burden in terms of death because they can cause life-long infection (called chronic infection), which can lead to liver cirrhosis and cancer. In fact, chronic hepatitis is the leading cause of liver cirrhosis and cancer.

WHO-approved vaccines are available to prevent hepatitis A and B, while screening of blood donors, assuring clean needle and syringes, and condom use can prevent bloodborne and sexual transmission.
Hepatitis B can be prevented by reaching every child with immunization programmes that include hepatitis B vaccine. There is no vaccine for hepatitis C. In addition, infections can be prevented by protecting against mother-to-child transmission of the virus and ensuring the safety of blood, transfusion services, organ donation and injection practice (treatment can include antiviral medications if needed).

Hepatitis A and E can be prevented by avoiding contaminated food and water; in addition, there is an effective WHO approved vaccine for hepatitis A.

Hepatitis medicines are now included in the WHO Essential Medicines List, which Member States are encouraged to adopt. Essential medicines are selected based on disease prevalence, safety, efficacy, and comparative cost-effectiveness. The WHO Model List can be used by countries as a guide for the development of their own national list.
For more information please contact:

Mr Glenn Thomas
Communications Officer
WHO, Geneva
Telephone: +41 22 791 3983
Mobile: +41 79 509 0677