Global policy report on the prevention and control of viral hepatitis

in WHO Member States

Authors:
World Health Organization

Publication details

Number of pages: 220
Publication date: July 2013
Languages: English
ISBN: 978 92 4 156463 2

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Global policy report on the prevention and control of viral hepatitis
July 2013

The periodic evaluation of implementation of the WHO strategy requires an initial baseline survey of all Member States. In mid-2012, WHO, in collaboration with the World Hepatitis Alliance, conducted such a survey, asking Member States to provide information relating to the four axes of the WHO strategy. In particular, Member States were asked whether key prevention and control activities are being conducted. This report presents the results.

The first chapter provides an introduction to viral hepatitis and to the global response to this group of diseases. The second chapter provides a global overview of the survey findings. Chapters three through eight present findings from the six WHO regions, including summaries of data from all responding countries. Additional survey data, study methodology information and the survey instrument can be found in Annexes A–E.

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Citations Highlight Promising New Drugs for Hepatitis C Infection

July 2013

by David W. Sharp

The U.S. Centers for Disease Control and Prevention has recently revised its guidance on testing for infection with hepatitis C virus (HCV). Testing for anti-HCV, recommended for known at-risk groups for the past 15 years (and, in 2012, suggested as routine in the birth cohort 1945-65, the so-called “baby boomers”) does not distinguish between past and ongoing infection. The latest guidance includes tests for HCV RNA; these tests do make the distinction. Another reason for the revision is “significant advances in the development of antiviral agents with improved efficacy against HCV” (MMWR 62[18]: 357-61, 2013). Drawing on exclusive citation data from Thomson Reuters Web of Science, a new Top Ten list, with papers #4 and #8, provides the opportunity for an update on those agents.

What’s Hot in Medicine

Rank	Paper	Citations This Period (Nov-Dec 12)	Rank Last Period (Sep-Oct 12)
1	R. Siegel, et al., “The impact of eliminating socioeconomic and racial disparities on premature cancer deaths,” CA-A Cancer J., 61(4): 212-36, Jul-Aug 2011. [American Cancer Soc., Atlanta, GA]	149	1
2	P.B Chapman, et al., “Improved survival with vemurafenib in melanoma with BRAF V600E mutation,” New Engl. J. Med., 364(26): 2507-16,  30 June 2011. [26 institutions worldwide]	121	2
3	M.R. Patel, et al., “Rivaroxaban versus warfarin in nonvalvular atrial fibrillation,” New Engl. Med., 365(10): 883-91, 8 September 2011. [12 institutions worldwide]	77	4
4	F. Poordad, et al., “Boceprevir for untreated chronic HCV genotype 1 infection,” New Engl. J. Med., 364(13): 1195-1206, 31 March 2011. [12 institutions worldwide]	74	9
5	C.R. Smith, et al., “Transcatheter versus surgical aortic-valve replacement in high-risk patients,” New Engl. J. Med., 364(23): 2187-98, 9 June 2011. [12 institutions worldwide]	67	10
6	C.B. Granger, et al., “Apixaban versus warfarin in patients with atrial fibrillation,” New Engl. J. Med., 365(11): 981-92, 15 September 2011. [26 institutions worldwide]	61	7
7	M. Gerlinger, et al., “Intratumor heterogeneity and branched evolution revealed by multiregion sequencing,” New Engl. J. Med., 366(10): 883-92, 8 March 2012. [7 institutions worldwide]	60	+
8	I.M. Jacobson, et al., “Telaprevir for previously untreated chronic hepatitis C virus infection,” New Engl. J. Med., 364(25): 2405-16, 23 June 2011. [22 institutions worldwide]	59	+
9	M.S. Cohen, et al., “Prevention of HIV-1 infection with early antiretroviral therapy,” New Engl. J. Med., 365(6): 493-505, 11 August 2011. [27 institutions worldwide]	57	3
10	E. Scallan, et al., “Foodborne illness acquired in the United States—Major pathogens,” Emerging Infectious Dis., 17(1): 7-15, January 2011. [Ctrs. Disease Control, Atlanta, Ga.]	55	+
SOURCE: Thomson Reuters Web of Science NB. Only papers indexed by Thomson Reuters since January 2011 are tracked. The “+” sign indicates that the paper was not ranked in the Top Ten during the last period. In the event that two or more papers collected the same number of citations in the most recent bimonthly period, total citations to date determine the rankings

HCV infection is a serious public-health issue. World Health Organization global estimates include 150 million people with chronic HCV infection and 350,000 deaths from HCV-related liver disease and 3 to 4 million new infections annually. Many cases remain undiagnosed; there is currently no vaccine; and available treatments are not ideal. The six known HCV genotypes can respond differently; a mainstay of therapy has been interferon, a tricky drug to manage; and about 60% of patients with HCV genotype 1 infection are not cured by up to 48 weeks of interferon plus ribavirin (J.G. McHutchison et al,  New Engl. J. Med., 361[6]: 580-93, 2009). When ScienceWatch last covered the therapeutic options, the best on offer seemed to be a combination of polyethyleneglycolated interferon (PEG interferon) and the antiviral agent ribavirin. The picture has recently been changing, and rapidly, with the development of compounds that act more directly on HCV. The two current front-runners in terms of both clinical trial activity and publications and citations are boceprevir and telaprevir (#4 and #8, respectively), still given in combination with the former dual therapy, but there is huge interest in second-generation candidates (vaniprevir, sofosbuvir and MK-5172, to name but a few).

INTERFERON IN RETREAT?

There is not yet much long-term clinical experience with any of these new drugs, and issues such as resistance, adverse reactions, and differing response rates for different HCV genotypes will require close attention. However, sustained virologic responses (SVR) are now being reported in 90% or more of patients treated with direct-acting antivirals, and there is the welcome possibility of interferon-free regimens. A New England Journal of Medicine editorial in May of this year, accompanying papers reporting four trials of sofosbuvir, foresaw an imminent radical change in clinical practice, noting that“interferon is in retreat,” although the interferonologist (a reference to the very specialized handling needed for this agent) is not yet down and out (J.P.H. Drenth, New Engl. .J Med., 368[20]: 1931-21, 2013). Other observers, meanwhile, see “the nail in the coffin for HCV” (M.P. Mans., M. Cornberg,, Lancet Infect. Dis., 13[5]: 378-79), or speak of at least interferon-sparing regimens (G. Dusheiko, T. Burney, in a commentary on a phase-2 trial of sofosbuvir published in mid-June [Lancet, 381(9883): 2063-5, 2013). ScienceWatchreaders will want to share this optimism, but while we wait for more evidence on the newest drugs let us focus on the two first-generation agents, both of which have been the subject of large numbers of papers and have been attracting high citation rates in the first half of 2013.

EFFICACY IN THE UNTREATED

The trial on patients with previously untreated HCV infection (#4) should be considered in parallel with the companion paper on the use of boceprevir in those previously treated (B.R. Bacon, et al,. New Engl. J. Med., 364[13]: 1207-17, 2011; 46 citations this period). With interferon/ribavirin as the standard-of-care control, SVR rates were 21% in previously treated patients and 23% and 40% in black and non-black controls who had not been treated before, compared with the much higher responses found when boceprevir was added of around 60% in treated and untreated depending on the drug regimen used (but lower in blacks). Clinical trials with telaprevir have followed a similar pattern and have similar success in terms of SVR data, and again it is the study in untreated patients (#8) that has been receiving the greater number of citations; the findings from the companion trial here were published in 2010 (J.G. McHutchison, et al., New Engl. J. Med., 362[14]: 1292-303, 2010; a report now too “old” for Hot Papers coverage but cited more than 260 times to date). These findings and others (e.g., S. Zeuzem, et al., New Engl. J. Med., 364[25]: 2417-28, 2011; 37 cites this period) certainly are encouraging, but clinicians may be holding back in the expectation of something even better. In the 12 months following the U.S. Food and Drug Administration’s licensing of these two drugs, only 18.7% of HCV patients were on them, perhaps because of “concerns about side effects and recognition that more effective medications could be available in the future” (E.Y. Chen, et al., Clin. Gastroenterol. Hepatol. April 16, 2013; doi 10.1016/j.cgh.2013.03.032).

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A former deputy editor of The Lancet, David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, UK.

The data and citation records included in this report are from Thomson Reuters Web of KnowledgeSM. Web of KnowledgeSM is a registered trademark of Thomson Reuters. All rights reserved.

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Innovative Cancer Treatment Supported by NICE

LONDON, July 24, 2013 /PRNewswire/ --

NEW UK GUIDANCE SHOULD IMPROVE PATIENT ACCESS TO SIR-SPHERES® MICROSPHERES FOR PRIMARY LIVER CANCER

The UK National Institute for Health and Clinical Excellence (NICE) has published guidance to support the routine use of SIRT (Selective Internal Radiation Therapy) for the treatment of patients with primary liver cancer.^[1] This decision is good news for patients with the most-common form of primary liver cancer, called hepatocellular carcinoma or HCC, for whom few effective treatment options are available currently.

SIRT is used for the treatment of inoperable liver tumours and involves injecting millions of tiny radioactive microspheres into the liver via the hepatic artery (blood supply). Each microsphere is coated with a beta-emitting radioactive isotope called yttrium-90. The radiation delivers localised treatment to tumour cells whilst conserving normal liver cells. SIR-Spheres microspheres, a form of SIRT, were approved in Europe in 2002 and more than 35,000 treatments have been supplied worldwide. Over 500 patients have received this treatment in Britain. The NICE guidance, released on 24^th July 2013, confirmed that the scientific evidence of the safety and efficacy of SIRT for patients with HCC is now considered adequate, which means that eligible National Health Service (NHS) patients are now likely to have improved access to this treatment.

Dr Harpreet Wasan, Consultant Oncologist at Hammersmith Hospital, Imperial College, said:

"SIRT is an innovative treatment for patients with inoperable primary liver tumours where few other effective treatment options are available.  It is excellent news that NICE has now published guidance supporting the latest evidence on SIRT in HCC and this should ensure suitable patients can access SIRT on the NHS.  I hope that, as a result, 'postcode prescribing' and treatment delays due to a lengthy funding application and approval process will no longer be a problem for treating eligible NHS patients with SIRT."

About Hepatocellular Carcinoma

HCC occurs most commonly in people whose livers have become severely damaged or cirrhotic, usually due to underlying liver conditions such as previous viral hepatitis infection or alcohol related liver damage. It is one of the ten most-common cancers in the world, with nearly 750,000 cases diagnosed annually, and is the third-leading cause of cancer deaths.^[2] HCC occurs with greatest frequency in regions where hepatitis is most often diagnosed, such as in the Asia Pacific region and Southern Europe.

HCC can be cured only by surgery, either by resecting or ablating the diseased parts of the liver, or by transplantation with a liver from a donor. These interventions, however, are unsuitable for the great majority of patients, whose survival may range from a few months to two or more years depending largely on the state of their liver at the time of their diagnosis and the extent of tumour in the liver.

For Further Information:

SIR-Spheres microspheres are approved for use in Australia, the European Union (CE Mark), New Zealand, Switzerland, Turkey and several other countries for the treatment of unresectable liver tumours.

SIR-Spheres microspheres are also fully FDA PMA-approved and are indicated in the U.S. for the treatment of non-resectable metastatic liver tumours from primary colorectal cancer in combination with intra-hepatic artery chemotherapy using floxuridine.

®SIR-Spheres is a registered trademark of Sirtex SIR-Spheres Pty Ltd.

References:

1. National Institute for Health and Clinical Excellence. Selective internal radiation therapy for primary hepatocellular carcinoma (Interventional Procedure Guidance 460). London: NICE, July 2013.
2. GLOBOCAN. Liver Cancer Incidence and Mortality Worldwide in 2008.

732-EUA-0713

SOURCE Sirtex Medical Limited

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Risk factors of chronic hepatitis in antiretroviral-treated HIV infection, without hepatitis B or C viral infection

Published on: 2013-07-26

Increasing rates of non-AIDS defining illnesses, and in particular liver diseases, have been found after the initiation of highly active antiretroviral therapy. However, there is little evidence concerning the risk factors for and clinical characteristics of liver disease in antiretroviral (ARV)-treated HIV infection, in the absence of hepatitis B or C viral co-infection.

Methods: A nested case--control study of HIV infected volunteers, matched by starting date of anti-retroviral treatment, was conducted in a Thai cohort studied from Nov 2002 - July 2012.

Cases were defined as those subjects with an elevated alanine aminotransferase (ALT >= 40 IU/L) at two consecutive visits six months apart, while controls were defined as individuals who never demonstrated two consecutive elevated ALT results and had a normal ALT result (<40 IU/L) at their last visit. Both groups had normal ALT levels prior to ARV initiation.

Clinical demographics and risk factors for chronic hepatitis including HIV-related illness, ARV treatment and metabolic diseases were collected and analyzed. Conditional logistic regression was used to determine risk factors for chronic hepatitis in HIV infection.

Results: A total of 124 matched pairs with HIV infection were followed over 3,195 person-years.
The mean age (+/-SD) was 33.0 +/- 7.3 years, with 41.1% of subjects being male. The incidence of chronic hepatitis was 5.4 per 100 person-years.

The median time from initiation of ARV to chronic hepatitis was 1.3 years (IQR, 0.5-3.5). From univariate analysis; male sex, plasma HIV-1 RNA level >5 log 10 copies/ml, metabolic syndrome at baseline visit, high BMI >23 kg/m2, abnormal HDL cholesterol at time of ALT elevation and treatment experience with NNRTI plus boosted PI were selected (p value <0.2) to the final model of multivariate analysis.

Male sex had 3.1 times greater risk of chronic hepatitis than the females by multivariate analysis (adjusted OR, 95% CI: 3.1, 1.5-6.3, p =0.002). High BMI >= 23 kg/m2 was also associated with 2.4 times greater risk of chronic hepatitis (adjusted OR, 95% CI: 2.4, 1.2-4.8, p = 0.01).

Conclusions: Chronic hepatitis in ARV-treated HIV-infected patients is common and may lead to a major health care problem.

Male sex and high BMI >= 23 kg/m2 carry higher risks for developing chronic hepatitis in this study. Therefore, these patients should be closely monitored for long-term hepatotoxicity.

Author: Thep ChalermchaiNarin HiransuthikulPisit TangkijvanichSuteeraporn PinyakornAnchalee AvihingsanonJintanat Ananworanich
Credits/Source: AIDS Research and Therapy 2013, 10:21

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Arrowhead starts Phase I trial of hepatitis B therapeutic

Published on July 25, 2013 by Paul Tinder

Arrowhead Research Corporation, a biopharmaceutical company, announced on Tuesday that it started dosing in a Phase I clinical trial of its candidate for the treatment of chronic hepatitis B virus infection.

ARC-520 is a RNA interference-based drug candidate that is meant to treat chronic HBV infection by reducing the expression and release of key viral proteins and new viral particles. The goals of the study are to evaluate pharmacokinetics in healthy volunteers, characterize the safety profile of ARC-520 and determine the maximum tolerated dose.

ARC-520 is the first drug candidate to use Arrowhead’s proprietary dynamic polyconjugate delivery platform.

“This Phase I study will establish a safety profile for ARC-520 as well as provide the first human data for our DPC delivery platform,” Christopher Anzalone, the president and CEO of Arrowhead, said. “This is an important step forward as we seek to advance ARC-520 into HBV patients and build additional RNAi therapeutics based on what we believe is the most potent delivery system in the industry.”

Arrowhead anticipates the Phase I trial will be completed in the fourth quarter of 2013 and will be followed by a Phase IIa trial in chronic HBV patients next year.

Approximately 350 million people around the world are chronically infected with HBV, but there is no available treatment method to reliably achieve meaningful cure rates.

Arrowhead previously presented data generated in rodent models and in a chimpanzee chronically infected with HBV demonstrating ARC-520′s induction of rapid deep and durable knockdown of both circulating HBV DNA and key viral proteins.

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Miriam researcher helps develop global hepatitis C recommendations for injection-drug users

Public release date: 25-Jul-2013
Contact: Jessica Collins Grimes
jgrimes2@lifespan.org
Lifespan

July 28 is World Hepatitis Day

(PROVIDENCE, R.I.) – A Miriam Hospital researcher has joined forces with international colleagues to call for new strategies to better manage and improve assessment and treatment for hepatitis C (HCV) infection in individuals who inject drugs.

Lynn E. Taylor, M.D., an HIV specialist focusing on HIV and viral hepatitis coinfection at The Miriam Hospital, was the only American physician invited to join the expert international panel that issued these first-of-its-kind recommendations. They were published online yesterday by the journal Clinical Infectious Diseases, just ahead of World Hepatitis Day on July 28.

The recommendations are part of a supplement entitled "Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs: Moving the Agenda Forward," developed in collaboration with the International Network on Hepatitis Care in Substance Users.

"In well-resourced parts of the world, most hepatitis C exists among people who currently inject drugs and those who have injected drugs in the past. However, treatment access and uptake among this population remains low – even though we increasingly have effective treatments for hepatitis C, which is a curable disease," said Taylor.

"Research supporting our recommendations – the first international set ever released for treating hepatitis C in people who inject drugs – demonstrates that treatment can be successful when barriers to care are addressed within a supportive environment," she added. "In fact, the burden of liver disease worldwide could be dramatically reduced by increasing treatment for hepatitis C infection among people who inject drugs, by preventing forward transmission."

An estimated five million people in the U.S. have chronic HCV infection, a liver disease that may result in long-term health problems, including liver scarring, liver failure and liver cancer. According to the Centers for Disease Control and Prevention, approximately 12,000 people die every year from HCV-related liver disease.

Until recently, HCV treatment guidelines excluded people who inject drugs, due to concerns about poor adherence, adverse events and re-infection. However, successful HCV treatment studies among this population have challenged this paradigm. The new international guidelines present evidence-based recommendations for treating HCV among individuals who inject drugs with appropriate evaluation and support.

Taylor is also lead author on a separate paper, appearing in the same supplement of Clinical Infectious Diseases, which focuses on the need for improved HCV care of another subset of the HCV-infected population: those who inject drugs and are also infected with HIV.

Chronic HCV infection has become a leading cause of non-AIDS related illness and death among individuals infected with HIV. Due to overlapping routes of transmission, dual infection is common: in the United States, 30 percent of HIV-infected people have chronic HCV, which is spread via contaminated blood, often through injection drug use. However, newer research suggests it may also be transmitted sexually among HIV-infected men who have sex with other men.

"HIV-infected individuals contending with injection drug use are the most likely to be affected by HCV, but the least likely to have access to treatment for HCV," said Taylor. "They should have equal and universal access to HIV/AIDS, HCV and addiction prevention, care and treatment."

She says essential but basic steps include improving prevention and screening for both infections and engaging co-infected individuals who inject drugs in HIV and HCV care early after diagnoses.

"The benefits of therapeutic advances in HCV will be limited for this group until barriers such as cost and access are overcome," she added. "Even with HCV cure rates approaching 100 percent with newer medications, effectiveness at population level will require expanding HCV therapy on large scale. These recommendations are an important step towards the goal of elimination of hepatitis C."

Taylor is also director of the HIV/Viral Hepatitis Program at The Miriam Hospital and an assistant professor of medicine at The Warren Alpert Medical School of Brown University.

###

About The Miriam Hospital

The Miriam Hospital is a 247-bed, not-for-profit teaching hospital affiliated with The Warren Alpert Medical School of Brown University. It offers expertise in cardiology, oncology, orthopedics, men's health, and minimally invasive surgery and is home to the state's first Joint Commission-certified Stroke Center and robotic surgery program. The hospital, which received more than $23 million in external research funding last year, is nationally known for its HIV/AIDS and behavioral and preventive medicine research, including weight control, physical activity and smoking cessation. The Miriam Hospital has been awarded Magnet Recognition for Excellence in Nursing Services four times and is a founding member of the Lifespan health system. Follow us on Facebook and on Twitter (@MiriamHospital).

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Also See:

1. Six Recommended Measures to Prevent Hepatitis C for Young Injection-Drug Users
2. Moving the Agenda Forward: The Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs

Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin

Journal of Viral Hepatitis

Volume 20, Issue 8, pages 524–529, August 2013

Original Article

M. P. Manns^1,*, P. J. Pockros², G. Norkrans³, C. I. Smith⁴, T. R. Morgan⁵, D. Häussinger⁶, M. L. Shiffman⁷, S. J. Hadziyannis⁸, W. N. Schmidt⁹, I. M. Jacobson¹⁰, R. Bárcena¹¹, E. R. Schiff¹², O. S. Shaikh¹³, B. Bacon¹⁴, P. Marcellin¹⁵, W. Deng¹⁶, R. Esteban-Mur¹⁷, T. Poynard¹⁸, L. D. Pedicone^16,†, C. A. Brass^16,†, J. K. Albrecht^16,†, S. C. Gordon¹⁹

Article first published online: 3 MAR 2013

DOI: 10.1111/jvh.12074

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: clinical; cure; eradication; follow-up; longitudinal

Summary

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1–99.7%] for IFN α-2b and 99.4% (95% CI, 97.7–99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

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Nutritional Management of Patients with Cirrhosis and Hepatic Encephalopathy

July 19, 2013

Atif Zaman, MD, MPH reviewing Amodio P et al. Hepatology 2013 Jul.

Consensus recommendations are now available despite continued knowledge gaps in this area.

An expert panel commissioned by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism has recommended that all patients with cirrhosis and hepatic encephalopathy should receive nutritional management similar to that for patients with cirrhosis but without hepatic encephalopathy. Specific recommendations from their consensus document are described below.

Strongest recommendations:

• All patients should undergo baseline nutritional assessment as a part of management. (The authors acknowledged that no clinically practical, well-validated tools to assess nutrition are currently available.)
• Optimal daily energy intake should be 35 to 40 kcal/kg ideal body weight.
• Optimal daily protein intake should be 1.2 to 1.5 g/kg ideal body weight.
• Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrate are ideal.
• Hyponatremia should always be corrected slowly.

Recommendations with less certainty, but with moderate evidence:

• Encourage a diet rich in vegetable and daily protein.
• Branched-chain amino acid supplementation might allow recommended nitrogen intake to be maintained in patients intolerant of dietary protein.
• A 2-week course of a multivitamin could be justified in patients with decompensated cirrhosis.
• Encourage a diet containing 25 to 45 g of fiber daily.
• Avoid long-term treatment with manganese-containing nutritional formulations.

Comment

This thoughtful consensus paper highlights how important it is for clinicians to be cognizant of the nutritional status of their patients with cirrhosis as well as the importance of optimizing daily energy and protein intake in these patients. The panel emphasized that dietary protein restriction is detrimental in this population and should be avoided, yet they observed that this practice is still widespread, which requires urgent attention. They also observed that no evidence shows benefits from zinc supplementation or probiotic use. Finally, the panel noted the continued existence of significant knowledge gaps in nutritional management of patients with cirrhosis that merit further research.

Disclosures for Atif Zaman, MD, MPH at time of publication Speaker&#8217;s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex

Citation(s):

Amodio P et al. The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism consensus. Hepatology 2013 Jul; 58:325. (http://dx.doi.org/10.1002/hep.26370)

PubMed abstract (Free)

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The diagnostic accuracy of Fibroscan® for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response

Journal of Hepatology
Volume 59, Issue 2 , Pages 251-256, August 2013

Roberta D’Ambrosio, Alessio Aghemo, Mirella , Maria Grazia Rumi, Maria Francesca Donato,  Valerie Paradis, Pierre Bedossa, Massimo Colombo

Received 12 December 2012; received in revised form 5 March 2013; accepted 8 March 2013. published online 25 March 2013.

Abstract

Background & Aims

Transient elastography (TE) is a validated non-invasive tool to evaluate hepatic fibrosis in patients with hepatitis C virus (HCV) infection. Whether TE may sense changes of liver fibrosis following therapeutic HCV eradication has never been evaluated.

Methods

37 HCV cirrhotics with paired pre- and post-sustained virological response (SVR) liver biopsies (LB) underwent TE at the time of post-SVR LB. Liver fibrosis was staged with the METAVIR scoring system and the area of fibrosis (%) was assessed morphometrically.

Results

Thirty-three patients had valid TE measurements after 61 (48–104) months from an SVR, and 20 (61%) of them had cirrhosis regression. On post-SVR LB, the median area of fibrosis was 2.3%, being significantly reduced from baseline (p<0.0001). Median TE value was 9.8kPa being lower in regressed vs. not regressed patients (9.1kPa vs. 12.9kPa, p=0.01). TE was <12kPa in 5 (38%) F4 patients and in 19 (95%) F3 patients (p=0.0007). The diagnostic accuracy of TE for diagnosing F4 after treatment was 61% sensitivity, 95% specificity, 12.3 LR+, 0.4 LR−, and AUROC 0.77. A significant correlation was found between TE and both fibrosis stage (r=0.56; p=0.001) and morphometry (r=0.56, p=0.001) as well as between fibrosis stage and area of fibrosis (r=0.72, p=0001).

Conclusions

Following therapeutic eradication of HCV, the predictive power of the viremic cut-off of 12kPa was low as a consequence of liver remodelling and fibrosis reabsorption. LB still remains the only reliable approach to stage liver fibrosis following an SVR.

Abbreviations: SVR, sustained virological response, IFN, interferon, HCV, hepatitis C virus, HBV, hepatitis B virus, LB, liver biopsy, TE, transient elastography, LS, liver stiffness, RBV, ribavirin, LSM, liver stiffness measurement, IQR, interquartile ratio, CI, confidence interval, LR, likelihood ratio

Keywords: Sustained virological response, Hepatitis C virus, Cirrhosis regression, Fibroscan®, Morphometry

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Care coordination for patients with cirrhosis: A “win-win” solution for patients, caregivers, providers, and healthcare expenditures

Journal of Hepatology
Volume 59, Issue 2 , Pages 203-204, August 2013

Phillip S. Ge, Bruce A. Runyon

Received 15 April 2013; accepted 21 April 2013. published online 08 May 2013.

See Article, pages 257–264

Full Text

We receive with great enthusiasm the recently published article by Morando and his colleagues from the University of Padova regarding their experience with a new model of care coordination in the setting of cirrhosis [1]. The burden of chronic disease is greater now than ever. In the absence of a coordinated effort to prevent, diagnose, and better manage chronic disease, we as a society will bear increasing socioeconomic costs over time.

Almost one half of all Americans suffer from one or more chronic diseases [2]. Millions are diagnosed and millions more die annually from a chronic disease. This is a reflection of the changing demographics in the developed world, where mortality from communicable infectious diseases decreases and mortality from non-communicable chronic diseases continues to increase. Enormous scientific advancements in treatment have largely failed to curb this steady rise. Although current health care financing and delivery systems focus on the treatment of acute conditions, 78% of actual healthcare spending is spent on the treatment of chronic conditions [3]. The total burden of chronic diseases on the economy exceeds $1.3trillion annually; of this amount, $277billion is spent annually on treatment, with lost productivity totaling $1.1trillion. At our current pace, by 2023 we can expect a 42% increase in the incidence of chronic disease, totaling $4.2trillion annually in treatment costs and lost economic output [4].

Chronic liver disease and cirrhosis are leading causes of death in the United States and worldwide. In the United States, an estimated 30,000 new cases of cirrhosis are diagnosed each year, and cirrhosis overall accounts for over 150,000 annual hospitalizations [5]. Treatment costs associated with the sequelae of cirrhosis such as variceal bleeding, ascites, encephalopathy, and hepatocellular carcinoma exceed $4billion annually, exclusive of estimates of lost economic output [6]. In stark contrast to most other malignancies, hepatocellular carcinoma is increasing in frequency, with associated expenditures doubling from 1988 to 2000 after adjusting for inflation [7]. Given our society’s struggles with metabolic syndrome and obesity, emerging chronic diseases such as fatty liver disease and non-alcoholic steatohepatitis are predicted to become the most common cause of cirrhosis, and will overtake hepatitis C as the most common indication for liver transplantation in the United States by 2030 [8].

Frequent hospital readmissions for management of fluid overload, hepatic encephalopathy, and/or gastrointestinal hemorrhage are commonplace among patients with cirrhosis. A recent study from Volk and colleagues from the University of Michigan found that 69% of patients with cirrhosis had at least one non-elective readmission, with a median time to first readmission of 67days [9]. In a sobering statistic, 14% of patients were readmitted within one week, and 37% within one month. One patient was readmitted 40times. 22% of readmissions were found to be possibly preventable. The study concluded that readmission among patients with cirrhosis was common, costly, moderately predictable, possibly preventable, and independently associated with mortality [9].

In recent years, care coordination, or “collaborative care”, has emerged as a highly effective concept that can help reduce readmission rates in patients who are known to be at high risk for readmission. The concept of care coordination has been applied in disorders such as depression, coronary artery disease, congestive heart failure, and poorly-controlled diabetes, with studies generally demonstrating improved control of the underlying diseases [10]. In theory, care coordination by specifically trained personnel should result in fewer readmissions, improved outcomes, and reduced expenditures. However, studies have also suggested that viable programs without a strong transitional care component are unlikely to yield significant savings [11].

Current care of patients with cirrhosis is fragmented and poorly coordinated. While many “evidence-supported” practice guidelines have been published in recent years regarding the common complications of cirrhosis, current literature suggests that patients with cirrhosis often fail to receive these evidence and guideline-supported treatments [6], [12]. Furthermore, the hospitalist movement has separated the outpatient physician from the inpatient physician, creating discontinuity at a critical juncture in patient care. A study of physician continuity of care between 1996 and 2006 showed that while continuity of care decreased overall, one-third of this decrease was attributed to the increasing involvement of hospitalists [13]. This and many other reasons have made the process of coordinating care perilous and challenging [14].

It is in this context that the study by Morando and colleagues is highly significant [1]. This study represents the first prospective trial in the cirrhosis population comparing the traditional system involving the family physician and punctual consultation to a specialist, with a new coordinated care system involving close monitoring by a specialized team of nurses, physicians-in-training, and hepatologists. The results clearly favor the care coordination model, both in costs and survival. The study demonstrated reduced 30-day readmission (42% vs. 15%), reduced 12-month readmission (71% vs. 46%), reduced 12-month mortality (46% vs. 23%), and a 46% cost reduction overall. An important point to emphasize is that patients with cirrhosis and ascites who are discharged from the hospital following treatment of an acute decompensation represent a unique population for which follow-up and specialist management is highly relevant, as they are predisposed to developing potentially preventable major complications resulting in readmission or mortality. Expertise is needed for early detection and treatment of these complications. The integration of care coordination at this critical juncture likely explains the impressive results of the study; in other diseases the number of cases required to find significant differences is often much higher.

The study is obviously not without its limitations. Understandably, the study was not randomized as it would be difficult to recruit patients for a randomized study in which they would receive either “standard care” vs. orchestrated care from a multidisciplinary team of specialists and nurses. Further, it was not clear whether the specialists involved in the care coordination group provided a standardized level of care or whether certain specialists had disproportionately better outcomes. It has been shown in a previous study of patients with cirrhosis and ascites in the Veterans Affairs Health System that health care quality was higher in patients who received specialist care from a gastroenterologist [12]. In our opinion, a liver-focused gastroenterologist would probably provide higher quality specialty care as compared to a general gastroenterologist. Finally, the study does not include various non-hospital expenses such as nursing home stays and home caregiving, although the overall savings in reducing emergent hospital readmissions should still make this model economically feasible.

Because the management of cirrhosis and other chronic diseases are multidisciplinary in nature and quickly becoming a high policy priority in the era of healthcare reform, improving care coordination should improve the quality and efficiency of care and provide business opportunities for gastroenterologists [6]. At our current institution, we are investigating efforts to integrate a similar model of care coordination in an attempt to reduce readmissions, reduce expenditures, and improve survival. Our coordinator would help coordinate inpatient-to-clinic transitions, call patients on a routine basis to prevent non-elective visits to the Emergency Department, place “smart-scales” in patient homes to monitor body weight remotely, and facilitate interaction with other healthcare professionals. They would also help facilitate transfers to hospice or skilled nursing facilities, especially for patients who are either unsuitable for transplantation due to medical comorbidities or who are unable to undergo transplantation due to technical reasons or due to organ shortage. Patients in this latter category are left in a challenging situation as they may be “too well for transplant”, yet are extremely sick with a decreased quality of life and decreased life expectancy due to the development of other cirrhosis-related complications. Too many die awaiting liver transplantation [15]. In this setting, care coordination would serve an instrumental role in providing the best possible quality of life in the face of a terminal diagnosis, with seamless timely transitions from “listed for transplant” to palliative care [16].

As our healthcare expenditures continue to grow and the burden of chronic disease continues to increase, care coordination is an obvious solution and a “win-win” situation for patients, caregivers, providers, and healthcare expenditures alike.

Conflict of interest 

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

References

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With baby boomers, show’s over for selective HCV screening

By: BRUCE JANCIN, Family Practice News Digital Network

07/25/13

ESTES PARK, COLO. – The era of selective screening for hepatitis C infection based upon risk factors such as alcoholism or a history of illicit drug use or incarceration has come to an end.

The June 2013 U.S Preventive Services Task Force Grade B recommendation for one-time testing of all baby boomers for hepatitis C infection means that the birth cohort–based testing will be a covered benefit under the Affordable Care Act, Dr. Gregory T. Everson noted at a conference on internal medicine sponsored by the University of Colorado.

The task force’s action was an endorsement of an earlier Centers for Disease Control and Prevention recommendation that all adults born in 1945-1965 should receive one-time testing for HCV without prior assessment of HCV risk (MMWR Recomm. Rep. 2012;61(RR-4):1-32). This is sound policy for several reasons, said Dr. Everson, professor of medicine and director of hepatology at the University of Colorado, Denver.

First, baby boomers account for roughly 75% of all cases of chronic hepatitis C virus (HCV) infection in the United States. Most of these cases remain undiagnosed. The CDC estimates that one-time universal testing of baby boomers would identify 800,000 new cases and prevent more than 120,000 deaths. The prevalence of HCV in the United States isn’t expected to peak until the year 2020.

In addition, recent dramatic advances in the treatment of chronic HCV make it likely that the therapy will move from hepatology clinics to primary care physicians’ offices, where preventive medicine is a priority, Dr. Everson noted.

The screening entails a blood test for HCV antibody. If the results are positive, the next step is to confirm the diagnosis via a polymerase chain reaction–based test for HCV RNA quantification. There is roughly a 75% chance that an HCV antibody–positive patient will be HCV RNA positive, which indicates the patient has a chronic HCV infection. The natural history of HCV infection is roughly a 30-year timeline from acute infection to liver transplantation or death.

Dr. Everson said that for assessing the severity of hepatic fibrosis in patients with HCV, he still relies heavily on liver biopsy, which most experts consider the gold standard.

The Food and Drug Administration has approved ultrasound-based transient elastography via the FibroScan device as a noninvasive alternative. The device, which costs about $130,000, is good at identifying cirrhosis but less accurate in staging intermediate levels of fibrosis, Dr. Everson noted. The same is true of an FDA-approved serologic test for fibrosis, he said.

Dr. Everson is involved in developing new treatments for HCV. He reported that he receives research grants from, serves as a consultant to, or serves as an advisory board member for roughly two dozen pharmaceutical companies.

bjancin@frontlinemedcom.com

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Bristol-Myers Squibb Partners with the Centers for Disease Control Foundation to Increase Awareness of Chronic Hepatitis B on World Hepatitis Day

• Joint effort supports early disease identification to connect at-risk patients to necessary care 
• Local Department of Health estimates up to 40,000 people living in Hawaii have chronic hepatitis B (CHB), and only 1 percent of these people know their status

Tuesday, July 23, 2013 11:00 am EDT

(PRINCETON, N.J., July 23, 2013) – In conjunction with World Hepatitis Day, celebrated annually on July 28, Bristol-Myers Squibb (NYSE: BMY), Viral Hepatitis Action Coalition (VHAC), a partner of the Centers for Disease Control (CDC) Foundation and the Hawaii State Department of Health are convening leading community experts to discuss CHB in Hawaii and key barriers to diagnosis and treatment. This forum is part of Bristol-Myers Squibb’s long-term commitment to raising awareness of CHB and supporting programmatic efforts to reach at-risk communities.

It is estimated that 65 percent of all Americans infected with the hepatitis B virus are unaware of their status. Once infected with hepatitis B, the virus may stay with a person for a lifetime, and the hepatitis B virus can harm the liver, leading to complications. As many people who are infected show no signs or symptoms, they may be at risk for unknowingly passing the virus to others. There are 1.2 million people with this chronic disease in the United States, and 1 out of 12 Asian Americans has CHB.  In Hawaii, over 93 percent of reported CHB cases identify as Asian or Pacific Islander.

To help address the spread of CHB and the unmet need in patient diagnosis, linkage to care and treatment, Bristol-Myers Squibb has awarded the CDC Foundation a grant to help support early disease identification and connect patients to necessary care.

“This panel discussion is part of a critical effort to help the people of Hawaii understand the risks associated with CHB and the importance of early diagnosis. Once diagnosed with CHB, patients need to be linked to care, evaluation and treatment,” said Carol L. Brosgart, M.D., senior advisor on science and policy, VHAC, at the CDC Foundation. “Patients may feel concerned that they will be stigmatized after a diagnosis due to cultural and/or social barriers. Stigma or fear of stigma can prevent patients from seeking appropriate care, counseling and treatment. It is important to come together as communities to educate the public about the risks of disease progression. And, for those who are not infected, testing for hepatitis B can lead to prevention of CHB.”

The panel discussion will include local Asian-American physicians who specialize in the management of CHB and community advocates, who will discuss diagnosis, testing and programs currently under way to educate patients about the disease. The event will take place on July 23 and will include:

• Thaddeus Pham, viral hepatitis prevention coordinator, Hawaii State Department of Health
• Naoky Tsai, M.D., University of Hawaii Cancer Center
• Simon Kim, M.D.

“For the people of Hawaii, there is a significant disparity between those who have CHB and those who know their status,” said Thaddeus Pham, viral hepatitis prevention coordinator at the Hawaii State Department of Health. “Through open dialogue about this disease, we hope to raise awareness about free screening as well as treatment and prevention options that can make a difference.”

About Hepatitis B and Bristol-Myers Squibb

While working at the forefront of treatment advancement in hepatitis B, Bristol-Myers Squibb acknowledges that hepatitis prevention and control programs are multi-faceted and may involve immunization, blood screening, injection safety, public health awareness and education, sexual health programs, surveillance, blood testing and treatment access. As part of this commitment, a series of grassroots educational events hosted by Bristol-Myers Squibb across the country continue to help raise awareness about hepatitis B so local Asian-American communities can better understand the cultural, psychosocial and other barriers that may be keeping patients from seeking care. For more information, visit www.FaceHepB.com.

Grant funding from this event will directly support testing, counseling and referral efforts in Hawaii, where there is a high-density of Asian-Pacific island-born residents and historically limited resources available to provide ongoing, sustainable programs.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit: http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

About the CDC Foundation

Established by Congress, the CDC Foundation helps the U.S. Centers for Disease Control and Prevention (CDC) do more, faster, by forging effective partnerships between CDC and corporations, foundations and individuals to support CDC’s 24/7 work to fight threats to health and safety. The Foundation manages approximately 200 CDC-led programs in the U.S. and in countries around the world. Learn more at www.cdcfoundation.org.

About the Viral Hepatitis Action Coalition

The Viral Hepatitis Action Coalition is a public-private partnership developed by the CDC Foundation to help the Centers for Disease Control and Prevention (CDC) make meaningful advances in the prevention, screening and treatment of viral hepatitis. Learn more at www.viralhepatitisaction.org.

About the Hawaii State Department of Health

The Adult Viral Hepatitis Prevention Program in the Hawaii State Department of Health aims to reduce the burden of viral hepatitis among communities in Hawaii by increasing awareness and enhancing access to hepatitis services (including testing, vaccinations, and linkage to medical care).  The program is committed to achieving these objectives through partnership and collaboration with private and public agencies throughout the state.  For more information on local efforts, go to www.hepfreehawaii.org.

Contact:
Media: Julie Ferguson, 609-252-5597, Julie.Ferguson@bms.com
Media: Carrie Fernandez, 609-252-4831, Carrie.Fernandez@bms.com

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Underestimation of Liver-Related Mortality in the United States

Gastroenterology
Volume 145, Issue 2 , Pages 375-382.e2, August 2013

Presented as an abstract at the Liver Meeting, American Association for the Study of Liver Diseases, Boston 2010.

Sumeet K. Asrani, Joseph J. Larson, Barbara Yawn, Terry M. Therneau, W. Ray Kim

Received 12 December 2012; accepted 3 April 2013. published online 11 April 2013.

Abstract

Background & Aims

According to the National Center for Health Statistics (NCHS), chronic liver disease and cirrhosis is the 12^th leading cause of death in the United States. However, this single descriptor might not adequately enumerate all deaths from liver disease. The aim of our study was to update data on liver mortality in the United States.

Methods

Mortality data were obtained from the Rochester Epidemiology Project (1999−2008) and the National Death Registry (1979−2008). Liver-specific mortality values were calculated. In contrast to the narrow NCHS definition, updated liver-related causes of death included other specific liver diagnoses (eg, hepatorenal syndrome), viral hepatitis, and hepatobiliary cancers.

Results

The Rochester Epidemiology Project database contained information on 261 liver-related deaths, with an age- and sex-adjusted death rate of 27.0/100,000 persons (95% confidence interval: 23.7−30.3). Of these, only 71 deaths (27.2%) would have been captured by the NCHS definition. Of cases for which viral hepatitis or hepatobiliary cancer was the cause of death, 96.9% and 94.3% had liver-related immediate causes of death, respectively. In analysis of data from the National Death registry (2008), use of the updated definition increased liver mortality by >2-fold (from 11.7 to 25.7 deaths/100,000, respectively). Using NCHS definitions, liver-related deaths decreased from 18.9/100,000 in 1979 to 11.7/100,000 in 2008—a reduction of 38%. However, using the updated estimate, liver-related deaths were essentially unchanged from 1979 (25.8/100,000) to 2008 (25.7/100,000). Mortality burden was systematically underestimated among non-whites and persons of Hispanic ethnicity.

Conclusions

Based on analyses of the Rochester Epidemiology Project and National Death databases, liver-related mortality has been underestimated during the past 2 decades in the United States.

Keywords: Hepatocellular Carcinoma, Rate of Death, HCV, HBV, Population

Abbreviations used in this paper: CDC, Centers for Disease Control and Prevention, CI, confidence interval, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, ICD, International Classification of Diseases, NCHS, National Center for Health Statistics, REP, Rochester Epidemiology

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

July 25, 2013

-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 www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

VRTX — GEN

Vertex Contacts:
Media:
Zach Barber, 617-341-6470
mediainfo@vrtx.com
or
Investors:
Michael Partridge, 617-341-6108
or
Kelly Lewis, 617-961-7530

Source: Vertex Pharmaceuticals Incorporated

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Moving the Agenda Forward: The Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs

Clin Infect Dis. (2013) 57 (suppl 2): S29-S31. doi: 10.1093/cid/cit264

This article appears in:Prevention and Management of Hepatitis C Virus Infection Among People Who Inject Drugs: Moving the Agenda Forward

Jason Grebely1, Philip Bruggmann2, Markus Backmund3,4, and Gregory J. Dore1

+ Author Affiliations

The majority of hepatitis C virus (HCV) occurs among people who inject drugs (PWID) [1], and the burden of HCV-related liver disease is still increasing [2]. HCV treatment is safe and effective among PWID [3], and international guidelines encourage HCV treatment in this group [4, 5], but HCV treatment uptake remains low among PWID [6, 7], mainly due to patient-, practitioner- and systems-related barriers to care. However, strategies have emerged to improve the prevention and management of HCV infection among PWID.

To foster the dissemination of knowledge in the field of viral hepatitis among PWID, the International Network on Hepatitis in Substance Users (INHSU) was established. INHSU established the International Symposium on Hepatitis in Substance Users (held every 2 years), focused on the management of viral hepatitis among PWID, specifically HCV infection. The first symposium was held in Zurich, Switzerland, in 2009 and the second was held in Brussels, Belgium, in 2011. The symposium is attended by researchers, practitioners, and community members and includes sessions on the epidemiology and natural history of viral hepatitis, clinical applications of basic science research, management of medical comorbidities and social science– and community-based perspectives. At the meeting in 2011, a panel of international experts was assembled in collaboration with the European Liver Patients Association to develop the first international recommendations for the management of HCV among PWID. This supplement presents original research from the most recent meeting, highlights recent advances in the field, and presents recommendations for the clinical management of HCV infection among PWID.

HCV PREVENTION AMONG PWID

It is estimated that 10 million PWID were HCV antibody positive in 2010, with a global HCV prevalence of 67% among PWID [8]. HCV incidence also remains high among PWID [9].

In the first article of this supplement, Page et al review and highlight the challenges of behavioral interventions for HCV prevention [9]. The authors demonstrate that harm-reduction programs successful in preventing human immunodeficiency virus (HIV) infection among PWID have been less effective for preventing HCV infection and that combined strategies are likely required [9]. Martin et al use mathematical modeling to project the impact of combining opiate substitution treatment (OST), high-coverage needle and syringe programs (NSPs), and HCV treatment on HCV prevalence and incidence among PWID [10]. Data from their study suggest that large reductions (>45%) in HCV chronic prevalence over 10 years requires HCV antiviral treatment, with the scale-up of combined interventions, including OST and NSPs, substantially reducing the treatment rate required to achieve specific HCV prevalence reductions. An alternative way of preventing HCV infection would be through the availability of an HCV vaccine. Cox and Thomas highlight the need for an HCV vaccine for PWID, demonstrate that protective immunity against persistent HCV infection is possible, and summarize recent advancements in HCV vaccine research, including recent phase 1/2 trials of an HCV candidate vaccine among PWID [11].

ENHANCING HCV ASSESSMENT AMONG PWID

Although HCV treatment is successful among PWID [3], assessment and uptake remain low [6, 7]. Understanding the barriers and facilitators of HCV care is critical in the design of strategies and programs for effectively increasing the proportion of PWID assessed and treated for HCV.

In this supplement, Treloar et al discuss barriers to HCV care and stigmatization, considering components required for the design programs to effectively engage PWID in HCV care [12]. Bruggmann et al review the spectrum of HCV care models among PWID, highlighting that “one size does not fit all” and that when barriers are systematically addressed within a supportive environment, HCV assessment and treatment among PWID can be very successful [13]. This is consistent with data from Alavi et al from the Enhancing Treatment for Hepatitis C in Opioid Substitution Settings (ETHOS) Study, demonstrating that when HCV nursing and specialist support are integrated into existing OST or community health clinics, a high proportion of PWID with chronic HCV assessed by a nurse can be engaged in HCV care [14]. Another setting with opportunity for expanding HCV assessment and treatment is prisons. Post et al review the considerable burden of HCV in prisons, highlight potential challenges, and illustrate programs that have successfully integrated HCV screening, assessment, and treatment for prisoners with HCV [15]. One important consideration as we move forward with the development of new models of care is the involvement of the affected community. In this supplement, Crawford et al review different peer support models [16] and highlight the importance of involving community-based groups early into the design and implementation of these programs to achieve the greatest opportunity for engagement by PWID.

ENHANCING HCV TREATMENT AMONG PWID

It has been clearly demonstrated that PWID can be successfully treated [3]. However, the populations studied are often heterogeneous (combination of current and former PWID) and there are few data on HCV treatment outcomes among active PWID. Further, few prospective trials have evaluated strategies to enhance adherence and response to treatment among PWID.

In a systematic review and meta-analysis of treatment for HCV infection among active PWID, Aspinall et al demonstrate an overall sustained virologic response (SVR) of 56% [17]. This is the first systematic review of HCV treatment among those with ongoing drug use at the time of treatment and illustrates that active PWID can respond favorably to therapy. In the first randomized controlled trial performed to date among active drug users, Hilsden et al randomized participants to immediate vs delayed HCV treatment [18]. They demonstrate that directly observed pegylated interferon and self-administrated ribavirin can lead to a high proportion of patients with SVR among active drug users, but suggest that delaying treatment may compromise subsequent engagement in HCV treatment [18]. Last, in the largest trial reported to date among people with chronic HCV infection receiving OST, Reimer et al demonstrate that an intervention based on psychoeducation may enhance adherence to HCV treatment and reduce dropouts, particularly among people with longer treatment durations (those with genotypes 1/4) or those with mental health comorbidities [19].

MANAGING HCV TREATMENT AMONG PWID

Until recently, HCV treatment guidelines (and many practitioners) excluded PWID from consideration, citing concerns about adherence, increased susceptibility to side effects and reinfection. Issues of HIV infection and management of multiple drug interactions (both prescribed and nonprescribed drug use) complicate HCV management in this population. However, until recently there have been no recommendations for the management of HCV among PWID.

Grady et al demonstrate that the rate of reinfection reported to date has been low (1%–5% per year), which does not support decisions to withhold HCV treatment in this group based on concerns of reinfection [20]. Schaefer et al focus on another common barrier to HCV treatment assessment, namely, mental health issues [21]. They review the available evidence in this area, providing practical information for practitioners interested in managing HCV among PWID. Taylor et al summarize the data to date on management of HCV/HIV coinfection, including recent data investigating new direct-acting antivirals and studies of PWID with HCV/HIV coinfection [22]. Mauss et al focus on the problem of drug–drug interactions, which are an issue among PWID, given the potential for HCV direct-acting antivirals to interact with drugs used to treat HIV coinfection, OST (eg, methadone and buprenorphine), and nonprescription drugs [23].

The supplement is concluded with recommendations for the management of HCV infection among PWID [24]. This is meant to supplement existing international guidelines for HCV treatment, focusing on specific issues encountered among PWID. These guidelines should serve as an evidence-based tool for practitioners managing HCV among PWID.

FUTURE PERSPECTIVES

High rates of HCV infection still occur among PWID. Research is needed to evaluate the efficacy of combined HCV prevention approaches (such as HCV treatment as prevention, OST, NSPs, and vaccines). In addition to primary prevention, efforts must be expanded to prevent advanced liver disease due to chronic HCV. HCV treatment can reduce morbidity and mortality, but HCV assessment and treatment remains low among PWID. The availability of simple, well-tolerated, and highly effective interferon-free direct-acting antivirals will facilitate engagement among PWID, but research on strategies to enhance HCV screening and assessment is still needed. The evaluation of strategies to enhance adherence and therapy outcomes (eg, directly observed therapy, medication reminders, adherence education, peer support) should also be a research priority.

Research in this area needs to move beyond small, single-center, retrospective studies demonstrating that HCV treatment among PWID is feasible. Larger, prospective clinical trials run through international clinical networks are required to more rapidly evaluate potential treatment strategies. One such trial, ACTIVATE (A Collaborative Trial in Injectors of Individualized Treatment for Genotype 2/3), is a phase 4, open-label, multicenter, international trial of response-guided treatment with directly observed pegylated interferon alfa 2b and self-administered ribavirin for patients with chronic HCV genotype 2 or 3 infection and ongoing injection drug use. It is the first attempt to establish a clinical network and may be a step in the right direction. Further evidence-based research focused on strategies for enhanced HCV prevention, screening, assessment, and treatment among PWID will be required to reduce the HCV-related burden that still exists globally.

Notes

Financial support. INHSU receives support from Merck, Janssen, Abbvie, Gilead, Roche, and Orasure. J. G. is supported through a National Health and Medical Research Council Career Development Fellowship. G. D. is supported through a National Health and Medical Research Council Practitioner Fellowship.

Supplement sponsorship. This article was published as part of a supplement entitled “Prevention and Management of Hepatitis C Virus Among People Who Inject Drugs: Moving the Agenda Forward,” sponsored by an unrestricted grant from the International Network on Hepatitis in Substance Users (INHSU), The Kirby Institute (University of New South Wales), Abbvie, Gilead Sciences, Janssen-Cilag, and Merck.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:

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