Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis

Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis

Alimentary Pharmacology & Therapeutics

J. H. Hoofnagle1,*, M. L. Van Natta2, D. E. Kleiner3, J. M. Clark2, K. V. Kowdley4, R. Loomba5, B. A. Neuschwander-Tetri6, A. J. Sanyal7, J. Tonascia2, the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN)
Article first published online: 29 MAY 2013 DOI: 10.1111/apt.12352

Volume 38, Issue 2, pages 134–143, July 2013

Discussion Only

Full Text Available @ Alimentary Pharmacology & Therapeutics

Discussion

Non-alcoholic fatty liver disease has become the most common cause of liver test abnormalities adults in the Western world and is estimated to affect up to 30% of the adult population.[17-19] This condition is also increasing in frequency among children and adolescents.[20] NAFLD is often benign and nonprogressive and associated with few, if any, symptoms. On the other hand, a proportion of patients with NAFLD develop progressive liver disease that can result in cirrhosis, end-stage liver disease, need for liver transplantation, hepatocellular carcinoma and death.[21-25] Patients with progressive disease usually have NASH on liver biopsy with the typical findings of centrizonal (zone 3) cellular injury (also called ballooning degeneration), inflammation, and fibrosis in addition to steatosis.[22] The separation of simple steatosis from NASH non-invasively can be difficult and is not predicted by serum aminotransferase levels, thus leading to the need for liver biopsy to decide upon interventions.[26, 27] These findings suggest that serum ALT and AST are unreliable markers for the degree of activity or severity, stage or degree of fibrosis and ultimate progression of NASH to end-stage liver disease.
 

In this secondary analysis of the PIVENS trial, however, serum ALT levels, if elevated at baseline, were found to have reasonable reliability in detecting improvement in the underlying liver disease, at least as assessed by liver biopsy and a validated histological scoring system. Over 80% of patients treated with vitamin E whose serum ALT levels fell to 40 U/L or less and by at least 30% of baseline had histological improvement. Importantly, none of these patients had evidence of worsening. In contrast, patients who did not achieve this degree of improvement in serum liver biochemical tests were less likely to show histological improvement and a significant proportion worsened.

This reanalysis of the PIVENS trial also showed the important and confounding effects of weight change on serum ALT levels as well as histological features of disease. Indeed, in patients who lost weight (using a cut point of only 2 kg over a 2-year period), the proportion of patients with histological improvement was similar in vitamin E and placebo groups (71% vs. 64%), although the quantitative degree of improvement in NAS score was greater with vitamin E than placebo (−2.8 vs. −1.9 points). Perhaps more strikingly, patients who gained weight were less likely to improve with vitamin E therapy, and those receiving placebo were likely to worsen. Weight gain was indeed associated with significant worsening of hepatic fibrosis in the placebo-treated patients. In contrast, patients who received placebo and who lost or did not gain weight and those who received vitamin E were unlikely to demonstrate progression of fibrosis scores over the 2-year period of this study whether or not ALT levels improved. These results provide strong and evidence-based support for dietary recommendations in patients with NASH. A first priority should be weight loss. But, perhaps more important is strict avoidance of further weight gain, which is closely associated with worsening of fibrosis, a surrogate, but convincing marker for disease progression.
 

The demonstration that vitamin E resulted in decreases in ALT levels and histological improvements in NASH was shown in the initial publication of the PIVENS trial [13] and was reinforced by several features in this study. First, there was a rapid and statistically significant decline in ALT levels in the vitamin E-, but not placebo-treated patients. The proportion of patients with an ALT response was three or more times higher in the vitamin E than placebo group, both at 24 weeks (39% vs. 7%) and 96 weeks (48% vs. 16%). Improvements in ALT levels were associated with improvements in histology scores and this was most evident in the vitamin E-treated subjects. Finally, discontinuation of vitamin E was followed by a prompt relapse and loss of the ALT response in 42% of patients.

Shortcomings of this post hoc analysis include the small sample size of the controlled study, which was adequate to assess the primary endpoint, but was somewhat limited for extensive secondary analyses. In addition, the definitions of ALT and histological responses were made a priori with only limited analysis of the dataset. However, both definitions are based upon clinical understanding of NAFLD and were easy to apply. The numbers of patients in the study were too few to attempt to generate statistically based algorithms for defining an ALT or histological responses; however, in preliminary analyses, modification of the criteria, such as dropping the requirement for a 30% decline in ALT from baseline, decreasing the criteria for an ALT response from ≤40 to ≤30 U/L, and using AST rather than ALT values did not improve the area under the curve in predicting histological responses (Table S1). Finally, this study was carried out in nondiabetic patients and the findings may not be applicable to patients with diabetes, who typically have more severe disease. Furthermore, only half of patients (48%) responded to vitamin E therapy and most relapsed when it was stopped.

In summary, these results show that vitamin E therapy is associated with improvements in serum aminotransferase levels, and that decreases of ALT values into the normal range (to ≤40 U/L and by 30% of baseline) are usually associated with histological improvement in disease activity (steatosis, inflammation, cell injury). Weight loss can also achieve these endpoints, but importantly weight gain has definite negative implications for the natural history and outcome of this common and increasingly important form of liver disease. The effects of vitamin E and weight loss on both ALT and histological responses were separate and independent, so that even patients who lost weight benefitted from vitamin E therapy.

Clinical Trial Number: NCT00063622.

1. Summary
2. Introduction
3. Methods
4. Results
5. Discussion
6. Authorship
7. Acknowledgements
8. References
9. Supporting Information

 

Scientists score stem-cell victory with lab-grown liver tissue

Scientists score stem-cell victory with lab-grown liver tissue

July 5, 2013 | By Ryan McBride

Score one for stem cell scientists in the hunt to regenerate human livers. A group from Yokohama City University in Japan has reported that lab-grown human liver "buds" were injected into mice and performed the detoxification functions.

Scientists have many questions to probe about the approach, and the use of such methods in humans could be years away. Yet the approach opens the door to further exploration and provides some hope that stem cell science could yield breakthroughs for patients with ailing livers.

When a mixture of induced pluripotent stem cells matured into liver buds, which represent the organ in an early state, the Japanese scientists were totally "gobsmacked" by the unexpected result, a lead scientist told reporters from the BBC and other media outlets through a translator. They injected the liver buds into mice with chronic liver disease, showing that the buds seemed to function and improve the survival of the animals.

"We just simply mixed three cell types and found that they unexpectedly self-organize to form a three-dimensional liver bud--this is a rudimentary liver," said Professor Takanori Takebe, as quoted by the BBC. "And finally we proved that liver bud transplantation could offer therapeutic potential against liver failure."

Livers take a beating from Western diets and diseases such as hepatitis, driving up demand for new treatments and transplants. A regenerative therapy could prolong the function of diseased livers.
However, lab-grown liver buds could find use sooner as ways to assess the toxicity of drugs before they are tested in humans. Drug hunters have already turned to stem cell science for models of human disease, as mice offer limited evidence of how treatments impact humans.

- read the BBC's coverage
- and the report from The Toronto Star

http://www.fiercebiotech.com/story/scientists-score-stem-cell-victory-lab-grown-liver-tissue/2013-07-05

Related
Video
June 25 2013
A Science First: Japanese researchers grow human liver using stem cells

Durability of SVR in HCV patients treated with peg/riba and a direct-acting anti-viral

Durability of SVR in chronic hepatitis C patients treated with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral

K. Rutter1, H. Hofer1, S. Beinhardt1, M. Dulic2, M. Gschwantler2, A. Maieron3, H. Laferl4, A. F. Stättermayer1, T.-M. Scherzer1, R. Strassl5, H. Holzmann5, P. Steindl-Munda1, P. Ferenci1,* Article first published online: 26 MAY 2013 DOI: 10.1111/apt.12350 

Alimentary Pharmacology & Therapeutics
Volume 38, Issue 2, pages 118–123, July 2013

Summary
Background
The introduction of direct-acting anti-virals has increased sustained virological response (SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking.

Aim
To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals.

Methods
Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7–64) months.

Results
One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5–49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24–6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance.

Conclusion
Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up.

Introduction
Eradication of HCV is the ultimate goal of anti-viral therapy. The commonly used parameter for viral eradication is a sustained virological response defined by undetectable HCV-RNA 6 months after end of successful therapy. Sustained virological response is commonly considered as parameter for cure of chronic hepatitis C. Long-term follow-up studies in patients treated by peginterferon/ribavirin have shown that HCV eradication is durable with follow-up periods of more than 20 years.[1-5] Achieving a SVR prevents progression to end stage liver disease and occurrence of hepatocellular carcinoma.[6-8] Moreover, successful treatment of HCV is associated with reduced hepatic morbidity, liver related deaths and improvement of health-related quality of life.[7-11] Recent reports even documented a reversal of cirrhosis many years after achieving sustained virological response (SVR).[12-14]

Currently we are witnessing the development of potent anti-viral drugs for treatment of chronic hepatitis C. The first two licensed protease inhibitors almost doubled the rate of SVR both in treatment-naïve[15, 16] and treatment-experienced patients.[17, 18] It is unknown whether the encouraging long-term data of dual combination therapy can be extrapolated to triple therapy with direct-acting anti-virals. So far, no data on the long-term outcome of patients with SVR following triple therapy have been reported. Aim of our study was to analyse virological follow-up of a large cohort of SVR patients participating in phase 2 or 3 trials or an extended access programme treated with peginterferon/ribavirin in combination with different direct-acting anti-virals.

Patients and methods
Patients
Patients participated in prospective randomised trials of treatment with pegylated interferon-alfa, ribavirin (PEGIFN/RBV) with a direct-acting anti-viral[15, 18-20] or in a named patient early access programme for telaprevir and were routinely invited for follow-up examinations.[3] Patients were selected according to the inclusion and exclusion criteria of the respective trial. All patients were Caucasians. Patients receiving placebo or no ribavirin were excluded from this analysis. A total of 103 out of 113 patients (91.2%) with SVR after DAA containing therapy attended follow-up visits at the out-patient clinics of the 4 participating tertiary referral centres. SVR was achieved in 43 patients receiving telaprevir, 30 on faldaprevir,[21, 22] 20 on simeprevir[23], 3 on danoprevir, 5 on ritonavir boosted danoprevir, 5 on mericitabine[24],3 on ritonavir boosted danoprevir and mericitabine and 2 on balapiravir.[25] For details see Table 1.

Table 1. Patients with SVR in triple therapy studies and long-term follow-up
 

Drug	Study	No. recruiteda	All with SVR 24; n (%)	No. with SVR and FUb
EAP, extended access programme. a Only patients receiving PEGIFN/RBV plus a direct-acting anti-viral. b Patients completed treatment and long-term follow-up. Virological test used in the central laboratories of the studies. c Roche COBAS Taqman HCV/HPS assay: limit of quantification <25 IU/mL; limit of detection 10 IU/mL. d Roche COBAS Ampliprep/COBAS, limit of detection 15 IU/mL. e Roche COBAS Taqman version 1.0, limit of quantification 30 IU/mL; lower limit of detection 10 IU/mL.
Telaprevir	Prove 2,[19]e C208,[20]c ADVANCE,[15]c REALIZE,[18]c EAP	53	43 (81.1)	40
Simeprevir	ASPIRE (NCT00980330),c PILLAR (NCT00882908),c	26	20 (77.0)	19
Faldaprevir	SILEN 1,[25]c SILEN 3 (NCT00984620)c	39	30 (76.9)	26
Danoprevir	ATLAS (NCT00869661)d	3	3	3
Ritonavir boosted Danoprevir	DAUPHINE (NCT01220947)c	10	5	5
Mericitabine	PROPEL,[21]d	8	5	5
Ritonavir boosted Danoprevir + Mericitabine	MATTERHORN (NCT01331850)c	9	5	3
Balapiravir [22]d		11	2	2

Routine laboratory parameters like alanine aminotransferase (ALT) and alpha-fetoprotein (AFP) were determined at every follow-up visit. EDTA blood was used for genetic testing. The SNPs for IL28B rs 12979860 were analysed by the StepOnePlus Real time PCR System (Applied Biosystems, Foster City, CA, USA) as described previously.[26] Baseline data are summarised in Table 1.

Virological tests
HCV was quantified during the studies in central laboratories using different PCR assays described in subscript Table 1. During follow-up, viral load of HCV was quantified by real-time PCR (COBAS TaqMan HCV Test Version 2; Roche Diagnostics, Pleasanton, CA, USA) in all patients. Genotyping of HCV was determined by Versant genotype assay (LiPA 2.0; Bayer HealthCare LLC, Subsidiary of Bayer Corporation, Tarrytown, NY, USA). Sequencing of HCV-RNA was performed for one patient by Böhringer-Ingelheim Canada (by Marquis Martin) using the ABI 3730 Genetic Analyzer (Applied Biosystems) detection system. The second sequencing of HCV-RNA was performed by the department of virology (HH) using the ABI 3130XL Genetic Analyzer (Applied Biosystems).

Clinical follow-up
All patients were asked to return to follow-up visits after 6 months and then at least once a year. Out of 113 patients, 103 patients returned to follow-up visits. At the clinical visits, routine blood tests, including alfa-1-fetoprotein and quantitative HCV-RNA determination (by TaqMan HCV Test), were obtained. Patients with pre-treatment cirrhosis were asked to perform a liver ultrasound examination prior to the visit. If necessary [in case of hepatic decompensation or suspicion for hepatocellular carcinoma (HCC)], further examinations were performed as needed. The institutional review board approved this retrospective non-interventional analysis.

Statistical analysis
Database management and statistical analysis were performed using commercially available software systems (Microsoft Office Excel 2010; Microsoft Corporation, USA and SPSS 2006 for Windows version 16). Quantitative variables were expressed as mean with the 95% confidence interval or as median (range). Data were analysed by using Student′s t-test for Gaussian variables, Mann–Whitney U-test for non-Gaussian variables as well as Chi-squared test. To determine, whether variables were normally distributed or not, the Kolmogorow–Smirnow test was applied. All P-values were two-tailed and assumed to be statistically significant if P ≤ 0.05.

Results
Characteristics of patients

A total of one hundred and three patients (f/m = 34/69, age: 47.6 ± 8.7; years ± s.d.) with a sustained virological response (SVR) were evaluated. Patient′s characteristics are shown in Table 2. A total of 23 patients (17 Nonresponder/6 Relapser) were treatment experienced, while 80 were treatment naive.

Table 2. Patient characteristics

	n (%)
a In five patients fibrosis grade was assessed by Fibroscan, none of them had F4. b IL28 rs12979860 was not available in all patients. c Follow-up [months, median (range)] after achieving SVR (=24 weeks after end of treatment).
n (f/m)	103 (34/69)
Age (mean ± s.d.)	47.6 ± 8.7
BMI (kg/m2)	24.7 + 3.6
HCV-Genotype
HCV-1a	34 (33.0)
HCV-1b	67 (65.1)
HCV-4	2 (1.9)
Cirrhosis (liver biopsy available in 98a)	18 (18.4)
Follow-up [mo, median(range)]c	21 (7–64)
IL28 rs12979860 available in 79b
CC	23 (29.1%)
C/T	44 (55.7%)
T/T	10 (12.7%)
Treatment
Protease inhibitor	93 (90.3)
NS5B Polymerase inhibitor	7 (6.8)
Both	3 (2.9)

One hundred and one patients were chronically infected with HCV-genotype 1 (HCV-1a: 34; HCV-1b: 67), two patients with HCV-genotype 4 (both received mericitabine). Ninety-three patients with HCV-genotype 1 received a protease inhibitor, seven patients a NS5B inhibitor (balapiravir or mericitabine) and three patients a combination of protease and NS5B inhibitor together with pegylated interferon-alfa and ribavirin at the four Austrian study sites (for details see Table 1).

Two relapses (2/103, 1.9%) occurred during follow-up after achieving a sustained virological response: One late relapse was seen in a 51-year-old female noncirrhotic patient (Fibroscan: 5.8 ± 0.5 kPa) infected with genotype 1b. She was a carrier of the IL-28B rs12979860 T/C genotype. She was treatment naïve and received triple therapy (3 days lead in with peginterferon/ribavirin followed by peginterferon/ribavirin/faldaprevir 120 mg daily) for 12 weeks and peginterferon/ribavirin for a total of 24 weeks.

HCV-RNA became undetectable at week 4 and remained undetectable throughout the whole therapy. She was HCV-RNA negative after 24 weeks of follow-up (SVR24) and had aminotransferases in normal range. Two months later, she came to the out-patient unit because of abdominal pain. Laboratory test showed detectable HCV-RNA (=8 months after end of treatment; viral load: 1.33 E5 IU/mL). The positive HCH RNA was confirmed several times.

Cloning sequencing in this patient showed the same sequence in the sample taken after relapse as in the sample obtained at screening. Resistance analysis revealed no presence of viral resistance. She received a retreatment with pegIFN/RBV and telaprevir for a total of 24 weeks and was HCV-RNA undetectable at end of treatment. She is currently on treatment-free follow-up.

The second late relapse occurred in a 59-year-old treatment-naïve, cirrhotic, male patient, who was chronically infected by HCV-genotype 1b and carrier of IL-28B genotype rs12979860 T/C. He received triple therapy (peginterferon/ribavirin/faldaprevir 120 mg daily for 24 weeks and peginterferon/ribavirin for a total of 48 weeks). HCV-RNA became undetectable at week 4 and remained undetectable throughout the whole therapy. After 24 weeks of follow-up, HCV-RNA was not detected (SVR24) and aminotransferases were normal. At a routine control examination 12 months after end of treatment, increased ALT was detected. HCV quantification revealed a viral load of 288 IU/mL. The genotype of the pre-treatment and the postrelapse sample was HCV-1b and cloning sequencing revealed identical sequence in both samples. Resistance analysis revealed no presence of viral resistance. No signs of hepatic decompensation or HCC occurrence were observed.

In both patients, HCV-RNA increased to pre-treatment levels within the next months. Of the remaining 101 patients, 90 (89.1%) had aminotransferases within the normal range at the last follow-up. AFP levels were available in 60 patients and were within the normal range in 54/60 (90%) patients. In the patients with slight increase AFP levels abdominal ultrasound revealed no signs of hepatic mass. No patient took immunosuppressive medication in the posttreatment follow-up period.

Discussion
This study confirms that SVR equals permanent HCV eradication by whatever interferon-based anti-viral treatment it was achieved. Our data indicate that the favourable long-term outcome reported after peginterferon/ribavirin combination therapy seems to hold true for patients treated with a triple therapy with peginterferon/ribavirin in combination with a direct anti-viral agent. To the best of our knowledge, this is the first study reporting long-term virological outcomes in patients with hepatitis C after successful anti-viral triple therapy.

There are theoretical concerns regarding the durability of HCV eradication after successful direct-acting anti-viral-based triple therapy. During direct-acting anti-viral treatment resistance-associated variants with reduced replication fitness compared with the wild type virus may emerge. If these resistance-associated variants cannot be eliminated by the required peginterferon/ribavirin backbone, strains with reduced replication fitness may persist in low concentration and may account for late relapses.

In the ADVANCE study, 1 of 357 patients evaluated had a confirmed late relapse after early discontinuation of treatment (randomised to the arm 8 weeks of telaprevir followed by dual therapy) at week 12.[15] In the PROVE 2 study, 2 late relapses were observed 36 and 48 weeks after the end of treatment.[19] In a phase 2 trial of an interferon-free regime (ritonavir boosted protease inhibitor ABT-450 combined with the nonnucleoside inhibitor of HCV NS5B polymerase ABT-072), one patient had a late relapse 36 weeks after end of treatment.[27] Thus data on longer follow-up are of major importance in the era of direct-acting anti-virals in HCV treatment.

In our study, two patients with a sustained virological response (SVR24) experienced a relapse 2 and 6 months later. Both patients completed a full course of anti-viral treatment without dose modifications or discontinuations of medications with peginterferon/ribavirin and faldaprevir. The serum samples of both patients (taken at baseline and after relapse) revealed no viral resistance and showed viral homology to samples collected at screening. Neither of the two patients showed a risk behaviour regarding HCV infection before reappearance of HCV. Thus, in both patients a late relapse rather than a newly acquired infection seems to be the reason for reappearance of hepatitis C virus. Obviously, an ongoing occult HCV infection cannot be excluded with certainty.[28]

Overall, our data show that it seems appropriate to extrapolate the encouraging long- term data of dual combination therapy to triple therapy with direct-acting anti-virals. The late relapse rate was 1.9% (95% CI: 0.24–6.8) as compared to 0.18% (0.004–1.01) in a much larger cohort of patients with SVR after dual therapy.[29] As all patients treated with direct-acting anti-virals in combination with PEGIFN/RBV achieving similar rates of SVR were followed prospectively, a potential selection bias is unlikely. However, in parallel to reported late relapses after successful dual therapy), late relapses after triple therapy – although a rare event – seem to occur within the first months after SVR like in the cases in our cohort. The fact that both relapses were observed in patients receiving faldaprevir occurred possibly just by chance, as the mode of action and the efficacy of the protease inhibitors are similar. Nevertheless, it seems advisable to confirm a successful HCV eradication within the first year of follow-up after achieving a sustained virological response. From our data, no impact on the durability of SVR after interferon-free treatments can be inferred.

In conclusion, our study shows that HCV eradication by triple therapy remains durable and confirms an excellent long-term prognosis of HCV patients with SVR. To assess the long-term clinical benefit of triple therapy, studies with a longer follow-up and larger patient numbers are needed.

Authorship
Guarantor of the article: Peter Ferenci.

Author contributions: Karoline Rutter: data collection, data analysis, writing of the manuscript. Albert Friedrich Stättermayer, Sandra Beinhardt, Thomas-Matthias Scherzer, Melisa Dulic, Michael Gschwantler, Andreas Maieron, Hermann Laferl, Petra Steindl-Munda: acquisition of data, critical revision of the manuscript for important intellectual content. Robert Strassl and Heidemarie Holzmann performed the virological assays. Peter Ferenci and Harald Hofer: study concept and design, analysis and interpretation of data, outlining and revising the manuscript. All authors approved the final version of the article.

Acknowledgements
Declaration of personal interests: The authors would like to thank Kerstin Zinober for her help in data collection and management and Martin Marquis, Böhringer-Ingelheim Canada for clonal sequencing.

Declaration of funding interests: Peter Ferenci is a member of the global advisory board and of the speaker's bureau of ROCHE, Basel CH and Rottapharm-Madaus, Monza, Italy. He is also advisor to Böhringer-Ingelheim, Vertex/Tibotec, Idenix, Achilleon, Glaxo Smith-Kline, Gilead and MSD and receives an unrestricted research grant from ROCHE Austria and MSD Austria. Harald Hofer, Michael Gschwantler, Petra Steindl-Munda and Andreas Maieron serve as speakers for Roche Austria, MSD Austria, Bristol-Myers Squibb and Janssen Austria. Karoline Rutter serves as speaker for Madaus-Rottapharm and MSD, Austria. All other authors have no financial disclosures to report.

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ABT-450/r; ABT-267, and ABT-333 w-RBV-High SVR rates among chronic HCV patients

High SVR rates with DAA regimen among chronic HCV patients

July 5, 2013
Sustained virologic response to a regimen of three antivirals and ribavirin was highly prevalent with or without a ribavirin dose reduction among patients with chronic HCV in a study presented at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur, Malaysia.

Researchers evaluated 247 noncirrhotic patients with chronic HCV genotype 1, including 159 treatment-naive patients and 88 who were nonresponsive to previous interferon-based therapy. Patients were assigned 12 or 24 weeks of treatment with a combination of three direct-acting antivirals (DAA): HCV protease inhibitor ABT-450/r; NS5A inhibitor ABT-267, and non-nucleoside NS5B inhibitor ABT-333, along with weight-based ribavirin (RBV).

Full Story »

Possibility of cracked vials leads to Merck recall of hepatitis B vaccine

Possibility of cracked vials leads to Merck recall of hepatitis B vaccine

July 4, 2013 1:03 pm by Sell, David

Merck & Co., said Wednesday that it was recalling one lot of its hepatitis B vaccine Recombivax HB that was made in West Point, Montgomery County, because of fears that some of the vials could have cracked.

The U.S. Food and Drug Administration posted a notice of the voluntary recall on its website. The medication is delivered via injection.

"Merck's investigation concluded that for certain vials in the affected lot, the potential exists for a crack to have occurred in the vial," the FDA said in its statement. "If the vial was cracked, the integrity of the vial and the sterility of any product remaining in the vial could not be assured."

Merck's facilities in West Point handle some of the company's research and development of medicine, along with some manufacturing.

Read more here

Boceprevir- Adherence to Assigned Dosing Regimen in Chronic Hepatitis C

Adherence to Assigned Dosing Regimen in Chronic Hepatitis C

Discussion Only

Abstract and Introduction

Materials and Methods

Results

Discussion
The present retrospective analysis of two large registration trials indicates that adherence to duration of treatment with P plus R plus BOC is an important factor associated with achieving SVR in patients with chronic hepatitis C genotype 1 infection. In particular, adherence to treatment duration appeared to be more important than adherence to the dosing interval with BOC in achieving SVR in the overall, nonblack and black populations.

Patients who discontinued treatment due to meeting the futility rules would have been defined as having low adherence rates to the duration of treatment. Approximately 9% and 19% of the treatment-naïve patients and those who failed previous treatment met the futility rules, respectively. However, patients who discontinued treatment could still have been defined as having high adherence rates to the t.d.s. dosing interval with BOC. Therefore, protocol-defined discontinuations (or early discontinuations due to adverse events) may have influenced the adherence rates to the duration of treatment, but may not have had an effect on the adherence rates to the t.d.s. dosing interval with BOC.

These results indicate that higher SVR rates were achieved when patients adhered to ≥80% of the treatment duration when compared with <80% of the treatment duration. In SPRINT-2, previously untreated patients with treatment duration adherence of ≥80% and BOC dose adherence of <80% had high SVR rates (78–100%) and in RESPOND-2, SVR rates in patients who had failed previous therapy and had good adherence to the treatment duration of ≥80% were still high (83–100%) even with <80% adherence to the doses of BOC. In addition, black and nonblack patients who adhered to ≥80% of the assigned dosing interval achieved similar SVR rates. It is important to note that non-adherence to the assigned duration of treatment includes patients who met futility rules or discontinued due to adverse events or other reasons.

Although the approved dosing of BOC every 8 h was effective, the present analysis indicates that strict adherence to the 7- to 9-h BOC dosing interval had minimal impact on SVR among patients who were otherwise adherent to the assigned duration of therapy. Specifically, different rates of adherence to the t.d.s. dosing interval with BOC (<60% to >80%) did not impact the SVR rates except for patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC. Different rates of adherence before or after treatment week 8 did not differentially impact SVR rates or the emergence of resistance. Adherence rates above or below 80% did not impact the emergence of resistance.

In these Phase 3 registration trials, it is not surprising that patients had high rates of adherence to the study drug, BOC, and that patients who were adherent to BOC were likewise adherent to both P and R. Accordingly, it was not possible to discern whether adherence to an individual agent within this triple drug regimen, by itself, influenced overall response rates. These findings are consistent with the HCV anti-viral pivotal registration trials of a decade ago,^[2] wherein most patients managed to achieve the goals of 80% adherence to their study medication doses of P and R and treatment durations. At that time, it was conjectured that such high patient motivation and careful management in the context of controlled trials at tertiary referral centres might not be representative of patients treated in the community. Subsequent studies over the past 10 years, however, have confirmed that patients who were treated with P and R in the community were, in fact, largely reflective of the patients treated within clinical trials.^[8] In one small analysis, however, including 23% who were HIV co-infected, 7% of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of R in the last 7 days, with the authors noting that self-reported dose non-adherence to hepatitis C treatment occurs frequently.^[9]
                       
Moreover, often in the real world setting, patients who ordinarily would not be considered candidates for anti-viral therapy are treated with HCV anti-virals, including those with serious psychiatric disorders and those with recent injection drug use. Among a group of 109 Australian patients with recently acquired HCV infection, many of whom were recent injection drug users, an exceptionally high rate of adherence to therapy was observed with the interesting observation that patients with no 'tertiary education' were less likely to have '80/80' P adherence, whereas injection drug use prior to or during treatment, however, did not impact such adherence.^[10] Regarding underlying depression and anxiety, at least two European studies[11, 12] confirmed that aggressive and pre-emptive therapy of such psychiatric conditions allows for the optimisation of adherence and virological efficacy to anti-viral treatment in hepatitis C. Such observations were corroborated by a recent report by Schaefer et al., ^[13] showing that prophylactic therapy with antidepressants may lessen the depression adverse events associated with interferon therapy in patients with hepatitis C infection.

The concept of anti-viral therapy adherence as it relates to efficacy became known in the HIV era, and it was recently emphasised that the term 'non-adherence' differs in how it is used in the HCV from the HIV literature. Weiss et al.^[14] note that in HIV, non-adherence refers primarily to patient-missed doses, whereas in HCV, the term refers primarily to dose reductions by the clinician and early treatment discontinuations. The authors propose that investigators codify such terminology, noting correctly that such compliance measures will become increasingly important to future treatment given the potential for resistant mutations emerging in the HCV direct-acting anti-viral agents.

In a report by Lo Re et al., utilising an adherence calculation that assessed pharmacy refill data, the investigators found that adherence of ≥85% to pegylated interferon and ribavirin was associated with increased HCV suppression and early virological response during the initial phases of HCV anti-viral therapy during the period of rapid virological decay compared with <85% adherence.^[15] Decreases in HCV viral load with adherence levels of 90–99% or 100–109% were similar to that with 85–89% adherence. This indicated that an adherence level of ≥85% achieved the maximal decrease in HCV viral load. Recently, Lo Re et al. reported that early virological response and SVR rates were increased with higher levels of adherence to P and R.^[16]
                       
Moving forward to a new generation of HCV therapy with agents that have specific actions on the replication cycle of the HCV RNA virus has mandated a re-evaluation of the role of patient adherence to such therapy. Using additional agents with defined half-lives reinforces the need for patient adherence to maximise the chance of sustained viral eradication and minimise the possibility of resistance. The present report is reassuring because it validates the continued inherent motivation of the HCV-infected patient to undergo an arduous and sometimes protracted course of therapy. In the absence of serological tags of seroconversion or other markers to denote the point at which no further virological suppression is required to achieve a cure from therapy, duration of on-treatment viral negativity remains a surrogate indicator. The current findings strengthen the need for patient adherence in the new anti-viral era, but distinguish the heightened importance of adherence to duration, with somewhat lesser importance of the need for adherence to the t.d.s. dosing interval with BOC. Future regimens involving therapy with once-daily agents should allow for improved patient compliance and potentially, improved anti-viral outcomes.

http://www.medscape.com/viewarticle/806314_4

Scientists create human liver from stem cells

Scientists create human liver from stem cells

By Kate Kelland

**(This story refiles to fix a typo in the name "Yokohama" in the eighth paragraph)

LONDON | Thu Jul 4, 2013 9:06am IST

LONDON (Reuters) - Scientists have for the first time created a functional human liver from stem cells derived from skin and blood and say their success points to a future where much-needed livers and other transplant organs could be made in a laboratory.

While it may take another 10 years before lab-grown livers could be used to treat patients, the Japanese scientists say they now have important proof of concept that paves the way for more ambitious organ-growing experiments.

"The promise of an off-the-shelf liver seems much closer than one could hope even a year ago," said Dusko Illic, a stem cell expert at King's College London who was not directly involved in the research but praised its success.

He said however that while the technique looks "very promising" and represents a huge step forward, "there is much unknown and it will take years before it could be applied in regenerative medicine."

Researchers around the world have been studying stem cells from various sources for more than a decade, hoping to capitalize on their ability to transform into a wide variety of other kinds of cell to treat a range of health conditions.

There are two main forms of stem cells - embryonic stem cells, which are harvested from embryos, and reprogrammed "induced pluripotent stem cells" (iPS cells), often taken from skin or blood.

Countries across the world have a critical shortage of donor organs for treating patients with liver, kidney, heart and other organ failure. Scientists are keenly aware of the need to find other ways of obtaining organs for transplant.

The Japanese team, based at the Yokohama City University Graduate School of Medicine in Japan, used iPS cells to make three different cell types that would normally combine in the natural formation of a human liver in a developing embryo - hepatic endoderm cells, mesenchymal stem cells and endothelial cells - and mixed them together to see if they would grow.

They found the cells did grow and began to form three-dimensional structures called "liver buds" - a collection of liver cells with the potential to develop into a full organ.

When they transplanted them into mice, the researchers found the human liver buds matured, the human blood vessels connected to the mouse host's blood vessels and they began to perform many of the functions of mature human liver cells.

"To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells," the researchers wrote in the journal Nature.

Malcolm Allison, a stem cell expert at Queen Mary University of London, who was not involved in the research, said the study's results offered "the distinct possibility of being able to create mini livers from the skin cells of a patient dying of liver failure" and transplant them to boost the failing organ.

Takanori Takebe, who led the study, told a teleconference he was so encouraged by the success of this work that he plans similar research on other organs such as the pancreas and lungs.

A team of American researchers said in April they had created a rat kidney in a lab that was able to function like a natural one, but their method used a "scaffold" structure from a kidney to build a new organ.

And in May last year, British researchers said they had turned skin cells into beating heart tissue that might one day be able to be used to treat heart failure.

That livers and other organs may one day be made from iPS cells is an "exciting" prospect, said Matthew Smalley of Cardiff University's European Cancer Stem Cell Research Institute.

"(This) study holds out real promise for a viable alternative approach to human organ transplants," he said.

Chris Mason, a regenerative medicine expert at University College London said the greatest impact of iPS cell-liver buds might be in their use in improving drug development.

"Presently to study the metabolism and toxicology of potential new drugs, human cadaveric liver cells are used, " he said. "Unfortunately these are only available in very limited quantities".

The suggestion from this new study is that mice transplanted with human iPS cell-liver buds might be used to test new drugs to see how the human liver would cope with them and whether they might have side-effects such as liver toxicity.

(This story refiles to fix a typo in the name "Yokohama" in the eighth paragraph)

(Reporting by Kate Kelland; Editing by Janet Lawrence)

http://in.reuters.com/article/2013/07/04/us-liver-stemcells-idINBRE9620Y120130704

Hepatitis C Triple Therapy Scores in Large Clinical Trial

July
Infectious disease special edition

Hepatitis C Triple Therapy Scores in Large Clinical Trial

by Christina Frangou

Patients with the most prevalent type of hepatitis C virus (HCV) infection have a substantially higher likelihood of achieving a sustained virologic response (SVR) with a triple therapy that includes an HCV protease inhibitor, a recent report confirmed. The findings validate triple therapy as the first-line treatment for genotype 1 hepatitis C (Ann Intern Med 2013;158:114-123).

Donald M. Jensen, MD, a professor of medicine and the director of the Center for Liver Diseases at the University of Chicago Medicine, said that the Annals study confirms previous research and an FDA review. “Triple therapy with a protease inhibitor is the current standard of care,” Dr. Jensen said.

After the drugs were approved in 2011, triple therapy quickly became the general practice in urban centers throughout the United States and the regimen has been adopted slowly as standard treatment throughout the rest of the country, added Paul Pockros, MD, the director, Center for Liver Diseases, Scripps Clinic, San Diego. “I think [triple therapy] is widely adopted now,” said Dr. Pockros, who was not involved in the study.

In the report, lead author Roger Chou, MD, from the Division of General Internal Medicine and Geriatrics at Oregon Health & Science University, in Portland, and his colleagues assessed 379 studies identified by searching multiple databases dating between 1947 and August 2012. Their analysis revealed that, for HCV genotype 1 infection, “fair-quality trials” demonstrated that triple therapy with pegylated interferon (PEG-IFN), ribavirin and either boceprevir or telaprevir increases the likelihood for achieving SVR by between 22% and 31% compared with dual therapy not including a protease inhibitor.

Triple therapy for HCV genotype 1 infection also was associated with a shorter duration of treatment, “an important consideration given the high frequency of adverse effects associated with interferon-based therapy,” the authors said.

Their findings also confirm the well-documented increase in adverse events (AEs) for triple-therapy regimens. Compared with dual therapy, triple therapy including boceprevir was associated with a greater risk for hematologic AEs, and triple therapy including telaprevir was linked to higher rates of anemia and rash.

The authors said their findings have important implications for treatment as well as screening because “screening benefits depend in part on the effectiveness of available treatments.”

Precedent-Setting

Further reviewing the trial results, the investigators reported that no study in the past 70 years has focused on long-term clinical outcomes after treatment. Instead, studies rely on SVR as the primary outcome measure. The authors said that it is difficult to evaluate long-term clinical outcomes other than SVR because HCV infections develop over many years.”

50% Mortality Risk Reduction

However, the authors said evidence suggested that SVR is associated with a lower risk for all-cause mortality. The strongest evidence comes from a cohort study published in 2011 that showed SVR was associated with a 30% to 50% reduction in mortality risk, after adjusting for confounders (Clin Gastroenterol Hepatol 2011;9:509-516). Dr. Chou and his colleagues said the study provides “strong evidence” that virologic and clinical outcomes are linked.

That may be the most important finding in the report, commented Andrew J. Muir, MD, MHS, the clinical director of hepatology, Department of Medicine at Duke University in Durham, N.C. “This has been an area of controversy in the field for a number of years,” Dr. Muir said. “With the slow natural history of hepatitis C, it was difficult to demonstrate the benefits in accepted clinical outcomes. The lack of clear clinical benefit also kept some [practitioners] from accepting the value of hepatitis C treatment.”

The investigators also reported that dual therapy with PEG-IFN alfa-2b was associated with a reduced rate of SVR by about 8% compared with PEG-IFN alfa-2a. However, PEG-IFN alfa-2b was associated with a lower risk for serious AEs, “suggesting potential trade-offs between benefits and harms,” said the authors. For patients with HCV genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood for achieving SVR than was therapy for 24 weeks, and lower doses of PEG-IFN alfa-2b were less effective than standard doses, according to evidence from two to four fair-quality trials.

Across all regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis and patients with higher viral load, the researchers noted.

The study was supported by the Agency for Healthcare Research and Quality. The authors reported no relevant conflicts of interest.

http://www.idse.net/ViewArticle.aspx?d=Hepatitis&d_id=213&i=July+2013&i_id=977&a_id=23518