June 8, 2013

Low Vitamin D Linked to Hepatitis B

By Michael Smith, North American Correspondent, MedPage Today

Published: June 08, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Low 25(OH)D3 serum levels are associated with high levels of HBV replication in patients with chronic hepatitis B.
  • 25(OH)D3 and HBV DNA serum levels showed inverse seasonal fluctuations.

Vitamin D deficiency might be a key player in hepatitis B (HBV) replication, researchers reported.

Low levels of 25-hydroxyvitamin D predicted high levels of the virus and vice versa, said Christian Lange, MD, and colleagues at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany, in a retrospective case-control study.

Similarly the seasonal variation in 25-hydroxyvitamin D was reflected in an inverse variation of the virus, suggesting a "functional relationship" between the two, Lange and colleagues reported online in Hepatology.

Chronic HBV is difficult to cure although -- like HIV -- viral replication can be controlled by antiretroviral drugs. Nonetheless, better therapies are needed, Lange and colleagues noted.

"Vitamin D helps maintain a healthy immune system and there is evidence of its role in inflammatory and metabolic liver disease, including infection with hepatitis C virus," Lange said in a statement.

"However, the relationship between vitamin D metabolism and chronic HBV infection remains unknown and is the focus of our present study," he said.

Lange and colleagues looked back at samples taken from consecutive treatment-naïve HBV patients at their Frankfurt clinic from 2009 through 2012, excluding those with HIV, hepatitis C or D, excessive alcohol use, and liver or other cancers.

Aside from HIV viral load, the researchers also measured levels of 25-hydroxyvitamin D, where less than 10 nanograms per milliliter was defined as severe deficiency of the vitamin, 10 or more but less than 20 was deemed insufficient, and 20 or more was adequate.

Among the 203 patients, they found 34% had severe vitamin D deficiency, 47% had insufficient vitamin, and 19% had normal levels. The average concentration of 25-hydroxyvitamin D was 14.4 nanograms per milliliter.

Moreover, HBV viral load and 25-hydroxyvitamin D levels had an inverse relationship that was significant at P=0.0003, they reported.

In multivariate logistic regression analyses, they found:

  • 25-hydroxyvitamin D was significantly associated with HBV viral load (P=0.0013)
  • Conversely, HBV viral load was also associated significantly with 25-hydroxyvitamin D levels (P=0.000048)

In patients with low HBV DNA -- less than 2,000 IU per milliliter, a cutoff regarded as relevant for clinical decision-making -- levels of 25-hydroxyvitamin D averaged 17 nanograms per milliliter.

In contrast, among patients with higher viral loads of 2,000 IU per milliliter or more, 25-hydroxyvitamin D levels averaged 11 nanograms per milliliter, Lange and colleagues reported.

They also found that HBV DNA levels were significantly lower (P=0.01) when samples were taken in spring or summer compared with autumn or winter -- a "reciprocal seasonal variation" of both variables.

Interestingly, the findings contrast with research into the same issue in hepatitis C, "which found no connection between vitamin D levels and concentration of HCV in the blood," Lange said.

The researchers cautioned that associations do not prove causality and "the suggestive functional link between vitamin D metabolism and HBV replication therefore remains elusive."

They also noted that the cohort was composed of treatment-naïve patients and can't be extended to all HBV patients.

The researcher had support from the Deutsche Forschungsgemeinschaft, the Johann Wolfgang Goethe University, and the Deutsche Leberstifung. The journal said the authors reported they had no conflicts.

Primary source: Hepatology
Source reference:
Farnik H, et al. "Low vitamin D serum concentration is associated with high levels of hepatitis B virus (HBV) replication in chronically infected patients." Hepatology 2013.

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Comprehension a Barrier to Antiretroviral Adherence

8th International Conference on HIV Treatment and Prevention Adherence

This coverage is not sanctioned by, nor a part of, the International Association of Providers of AIDS Care.

Fran Lowry

Jun 07, 2013

Brief counseling sessions improve adherence to antiretroviral therapy for people with HIV who have limited health literacy, but they do nothing for those with especially poor understanding.

"Poor health literacy skills are a significant barrier to HIV medication adherence, and interventions are definitely needed to assist these folks," Seth Kalichman, PhD, from the University of Connecticut at Storrs told Medscape Medical News.

Health literacy is the degree to which individuals have the capacity to obtain, process, and understand basic health information. "For those with the lowest literacy, our take-home message is that interventions are going to have to be pretty intensive and likely for a longer duration than what we tried," he said at the 8th International Conference on HIV Treatment and Prevention Adherence in Miami, Florida.

Dr. Kalichman and his group have been studying health literacy as a barrier to medication adherence for several years. They began to notice that the research participants who had the most difficulty completing questionnaires and understanding the informed consent process were the same participants who were having a difficult time adhering to their medications.

In the current study, the researchers sought to determine the efficacy of a special antiretroviral adherence counseling program for 446 men and women with HIV and limited literacy.

All participants were older than age 18 years, were receiving antiretroviral therapy, and scored below 90% correct on a test of functional health literacy. They were divided into marginal- and lower-literacy groups and then randomly assigned to receive the adherence counseling or to general health improvement counseling.

Stick-to-It Program

The Stick-to-It program consisted of two 60-minute sessions and one 30-minute booster session, and it used a pictographic flip chart and personalized feedback customized for each participant.

"This was a counseling approach that was tailored to these people. They all had lower literacy skills, although some were much worse than others," Dr. Kalichman explained. "We tried to make the counseling as easy as possible, using pictographs and illustrations, and to make the concepts for the educational and skills training parts as basic as we could."

The participants were followed for 9 months, and their adherence to antiretrovirals was measured by unannounced pill counts and by reviewing their medical records for their HIV viral load.

The researchers found that 75% of the moderate-literacy group who were randomly assigned to receive the special counseling had undetectable viral loads at follow-up, compared with 57% of those with moderate literacy who were assigned to general health education counseling.

For patients who had the lowest literacy status, 65% of those randomly assigned to the special counseling achieved undetectable viral load, compared with 76% of those who were assigned to general health education counseling.

"The control condition participants actually did better, and we don't know why at this point," Dr. Kalichman said.

About 30% of the moderate- and low-health-literacy participants actually had very high adherence rates at study entry. But by the end of the 9 months, 50% of moderate-literacy participants who had been randomly assigned to the specialized counseling had very high adherence, compared with 40% of the low-literacy patients who did not get the specialized counseling.

"Just a few sessions of counseling really helped some of these patients with marginal literary skills, but we found no benefit in patients with the lowest literary skills," Dr. Kalichman reiterated.

His research team is now working on finding more effective ways to help low-literacy individuals improve their adherence to antiretrovirals.

"We want to work on an approach that might involve less counseling and more strategic use of tools, such as cell phone counseling. Some of our other studies show that these folks may really benefit from this. You can do a weekly counseling session over the phone, and it takes much less time," Dr. Kalichman said.

Text messaging is another promising option for low-health-literacy people with HIV, he suggested.

"It may seem counterintuitive to use text messaging in people with low literacy, but it is important to realize that the vast majority of these participants can read. They just don't read well."

Medscape Medical News asked Benjamin Young, MD, vice president and chief medical officer of the International Association of Providers of AIDS Care in Washington, DC, to comment on the study.

"Studies such as these highlight the importance of adherence to medications in HIV medicine. Part of the reason why this study is important is because there isn't much literature on what specific interventions work best to improve adherence," Dr. Young said.

The finding that people with very low health literacy have a different set of needs from those who have moderate health literacy educates us to be aware that one size does not fit all when it comes to behavioral interventions, added Dr. Young, who was not part of the study.

"The research from Dr. Kalichman and his group reminds us that individuals in the community are just that, they are individuals and we need to be aware that even if a person comes from the same community, he or she might benefit from a slightly different or entirely different intervention."

This study was funded by the National Institute of Mental Health and National Institute of Nursing Research. Dr. Kalichman has disclosed no relevant financial relationships. Dr. Young is an employee of the International Association of Providers of AIDS Care and reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co, and ViiV Healthcare.

8th International Conference on HIV Treatment and Prevention Adherence. Abstract 28. Presented June 3, 2013.

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Release Summary

New findings presented at APASL Liver Week in Singapore, highlighting the efficacy and safety of faldaprevir and PegIFN/RBV in treatment-naïve patients with genotype-1 hepatitis C virus (HCV) in Asia.

For media outside USA, UK and Canada only

  • In a new sub-analysis of the Phase III STARTVerso™1 and 2 trials entering patients with chronic genotype-1 HCV infection, 100% of patients in Taiwan, 86% in Korea and 85% in Japan achieved viral cure with faldaprevir+ (120mg) plus pegylated interferon alfa and ribavirin
  • Up to 95% of patients met the criteria to stop all treatment after 24 weeks and over 90% of these patients went on to achieve viral cure (SVR12)

June 08, 2013 05:50 AM Eastern Daylight Time 

INGELHEIM, Germany--(BUSINESS WIRE)--New findings presented today during the APASL Liver Week in Singapore, highlighted the efficacy and safety of faldaprevir+ plus pegylated interferon and ribavirin (PegIFN/RBV) in treatment-naïve patients with genotype-1 hepatitis C virus (HCV) in Asia.1 This post-hoc sub-analysis of the Phase III STARTVerso™1 and 2 trials showed that both doses of faldaprevir were associated with high viral cure rates and a shorter treatment duration in this particular patient group.1 The STARTVerso™1 and 2 trials are part of the global STARTVerso™ trial programme which includes four Phase III trials with more than 2,200 treatment-naïve, treatment-experienced and HIV co-infected patients with HCV.2,3,4,5

“Addressing the diversity of HCV patients worldwide is essential to drug development and individualised patient management in this field. We look forward to adding to our robust clinical data for faldaprevir with results from the STARTVerso™2, 3 and 4 studies.”

The prevalence of HCV infection is particularly high in Asia and there remains a significant unmet need for effective treatment options.6 This post-hoc sub-analysis included 243 patients with HCV from three Asian countries (Japan, Korea and Taiwan). The primary end point was viral cure 12 weeks after completion of treatment (SVR12). Key findings reveal that 88% (172/196) of patients treated with faldaprevir (FDV 120mg or 240mg) plus PegIFN/RBV achieved viral cure compared with 62% (29/47) treated with placebo plus PegIFN/RBV.1 Even at the lower dose, 100% of patients from Taiwan (18/18) achieved viral cure when treated with faldaprevir (120mg) plus PegIFN/RBV.1 Patients from Japan and Korea also achieved high viral cure rates of 85% (44/52) and 86% (25/29) respectively, with the 120mg dose. High efficacy was also seen with the higher 240mg dose of faldaprevir.1

“These data are very encouraging for physicians and patients in Asia as there is a large population of treatment-naïve patients in this region in need of more effective treatment options,” said Professor Masao Omata, Yamanashi Central and Kita Hospitals, Yamanashi, Japan and lead author of the STARTVerso™ sub-analysis in Asia. “The results are particularly relevant given that HCV presents a huge health burden in Asia. The viral cure rates of close to 90% in patients infected with the difficult-to-cure genotype-1 HCV highlight the potential of faldaprevir to address this unmet medical need.”

Findings also showed 95% and 93% of patients who received faldaprevir+120mg and 240mg respectively plus PegIFN/RBV achieved Early Treatment Success (ETS) and were eligible for shorter total treatment duration of only 24 weeks.1 ETS was determined by sufficiently low virus levels at week 4 and week 8 of treatment (as defined in the protocol*). Of those patients who achieved ETS, 91% (120mg) and 92% (240mg) of patients went on to achieve viral cure (SVR12).1

In addition, both faldaprevir+ doses were well tolerated and adverse events that led to discontinuation of all study medications was 5% for 240mg faldaprevir+-treated patients and 3% for 120mg versus 2% for placebo-treated patients.1 Rash (9%, 8%, 13%) and gastrointestinal side-effects (4%, 8%, 21%) were the most common Grade 2-4 adverse events in the placebo, faldaprevir+ 120mg and faldaprevir+ 240mg arms respectively.1 Elevations in unconjugated bilirubin were observed in all faldaprevir+ dose groups, but these were reversible and not accompanied by increases in liver enzymes. No incremental reduction in haemoglobin was observed compared with PegINF/RBV alone.1

“These data add to the growing body of evidence for faldaprevir and reinforce the comprehensive nature of the STARTVerso™ clinical trial programme,” said Professor Klaus Dugi, Senior Vice President Medicine at Boehringer Ingelheim. “Addressing the diversity of HCV patients worldwide is essential to drug development and individualised patient management in this field. We look forward to adding to our robust clinical data for faldaprevir with results from the STARTVerso™2, 3 and 4 studies.”

Overall results of the STARTVerso™1 study, which include patients from Europe and Japan, were presented at the International Liver Congress (ILC/EASL) in April 2013. Results show up to 80% of patients treated with faldaprevir+ and PegIFN/RBV achieved viral cure compared with 52% of patients treated with placebo plus PegIFN/RBV.7 At both doses (120mg and 240mg), 87% to 89% of patients met criteria to stop all treatment after 24 weeks and 86% to 89% of these patients went on to achieve SVR12.7 Faldaprevir+ was well tolerated at both doses; at the lower dose, side-effect related treatment discontinuation was similar to placebo.7

Additional results from the STARTVersoTM programme are expected to be presented at large international meetings in 2013 and 2014; data from STARTVerso™2, which include patients from USA, Canada, Taiwan and Korea, and data from STARTVerso™3 and 4, investigating treatment-experienced and HIV co-infected HCV patients.3,4,5

# # #

+faldaprevir is an investigational compound and not yet approved. Its safety and efficacy have not yet been fully established

*Criteria for shortened treatment duration is early treatment success = week 4 HCV below limit of quantification [BLQ] and week 8 HCV below limit of detection [BLD]

NOTES TO EDITORS

The Boehringer Ingelheim NewsHome: An innovative resource for journalists

The Boehringer Ingelheim hepatitis C www.NewsHome.com is available and is the one-stop-shop for clear, concise and easy to understand information about hepatitis C for media.

About STARTVerso™1 and 2

STARTVerso™1 and 2 are double-blind, placebo-controlled Phase III trials of faldaprevir+ in combination with PegIFN/RBV. The studies enroled and treated 1,310 (652 in STARTVerso™1 and 658 in STARTVerso™2) treatment-naïve patients who were infected with chronic genotype-1 hepatitis C. STARTVerso™1 included patients from Europe and Japan; STARTVerso™2 included patients from USA, Canada, Taiwan and Korea. Patients were randomised to receive a once-daily dose of 120mg faldaprevir+, 240mg faldaprevir+ or placebo in addition to PegIFN and RBV.

Treatment duration depended on whether patients met criteria for protocol-defined early treatment success (ETS) (week 4 below limit of quantification [BLQ] and week 8 below limit of detection [BLD]). All patients who met these criteria received 12 weeks of faldaprevir+ with 24 weeks of PegIFN/RBV. Patients who did not meet the criteria were re-randomised to receive 24 weeks of faldaprevir+ or 12 weeks of faldaprevir+ followed by 12 weeks of placebo in the 120mg dose group or 12 weeks of faldaprevir+ in the 240mg dose group; both groups received 48 weeks of PegIFN/RBV. Patients in the control arm received 24 weeks of placebo with 48 weeks of PegIFN/RBV.

About Hepatitis C

Hepatitis C is a blood-borne infectious disease caused by the hepatitis C virus which lives and replicates in the liver. Hepatitis C is a leading cause of chronic liver disease, liver cancer and transplantation.8 Chronic hepatitis C is a major public health issue and one of the most prevalent infectious diseases worldwide, affecting around 170 million people,9 with 3-4 million new cases occurring each year.10

It is common for hepatitis C patients to remain undiagnosed due to the initial unspecific symptoms of the disease. Consequently, a large number of patients first present to their physician when they experience symptoms or already have liver disease.11 Patients with advanced liver disease are challenging to cure, yet have the greatest need for more effective and better tolerated treatments.

Of patients with chronic hepatitis C, 20 percent will develop liver cirrhosis, of which 2-5 percent will die every year.12 Advanced liver disease due to hepatitis C currently represents the main cause for liver transplantation in the western world.12

About Boehringer Ingelheim in hepatitis C

Through pioneering science, Boehringer Ingelheim is striving to find answers to the pressing challenges still faced by the diverse population of hepatitis C patients. The company’s comprehensively designed hepatitis C clinical trial programme includes a broad range of patients, including the challenging to cure, that clinicians see every day in clinical practice.

Boehringer Ingelheim is developing faldaprevir+, an optimised second generation protease inhibitor, as the core component for both interferon-based and interferon-free treatment regimens.

Interferon-based therapy with faldaprevir+ has the potential to improve cure rates with the added convenience of once-daily dosing and no dietary requirements for intake. Faldaprevir+ has proven efficacy in a broad range of genotype-1a and 1b hepatitis C patients. The STARTVersoTM trial programme, which includes treatment-naïve, treatment-experienced and HIV co-infected patients with hepatitis C virus, is nearly complete.

Deleobuvir (BI 207127) is a potent investigational non-nucleoside NS5B polymerase inhibitor, specifically optimised to treat patients with genotype-1b hepatitis C virus. Phase III HCVersoTM trials, investigating the interferon-free regimen of deleobuvir in combination with faldaprevir+ and ribavirin, are well underway.

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

Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

For more information please visit www.boehringer-ingelheim.com

References

1. Omata, M. et al. Faldaprevir plus pegylated-interferon and ribavirin in chronic HCV genotype-1 treatment-naïve patients: subanalysis of patients from Japan, Taiwan and South Korea. Presented at APASL Liver Week, 6-10 June, 2013

2. ClinicalTrials.gov. Efficacy and Safety of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients. http://clinicaltrials.gov/ct2/show/NCT01343888?term=bi+201335&rank=4 [Last accessed 28/05/13]

3. ClinicalTrials.gov. BI 201335 Used in Treatment Naive Patients Infected With Genotype 1 Chronic Hepatitis C Infection. http://clinicaltrials.gov/ct2/show/NCT01297270?term=bi+201335&rank=5 [Last accessed 28/05/13]

4. ClinicalTrials.gov. Pivotal Trial Treatment Experienced Patient Infected With Hepatitis C Virus (HCV) Genotype 1 (GT1). http://clinicaltrials.gov/ct2/show/NCT01358864?term=bi+201335&rank=14 [Last accessed 28/05/13]

5. ClinicalTrials.gov. Phase III Trial of BI 201335 in Treatment Naive (TN) and Relapser Hepatitis C Virus (HCV)- Human Immunodeficiency Virus (HIV) Coinfected Patients. http://clinicaltrials.gov/ct2/show/NCT01399619?term=bi+201335+HIV&rank=1 [Last accessed 28/05/13]

6. Sievert W, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011; 31(Suppl. 2):61-80

7. Ferenci, P. et al. Faldaprevir plus pegylated interferon alfa-2A and ribavirin in chronic HCV genotype-1 treatment-naïve patients: final results from STARTVerso1, a randomised, double blind, placebo-controlled Phase III trial. Presented at the International Liver CongressTM (ILC), The 48th Annual Meeting of the European Association for the Study of the Liver (EASL), 24-28 April, 2013

8. World Health Organisation. Hepatitis C. 2002 http://www.who.int/csr/disease/hepatitis/Hepc.pdf [Last accessed on 28/05/13]

9. Centers for Disease Control and Prevention (2012) Hepatitis C available at: http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/hepatitis-c.htm [Last accessed on 28/05/13]

10. World Health Organisation. Hepatitis C Fact Sheet. Updated July 2012 http://www.who.int/mediacentre/factsheets/fs164/en/index.html [Last accessed on 28/05/13]

11. Chen S.L., Morgan T.R. The Natural History of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006; 3:47-52. Available from http://www.medsci.org/v03p0047.htm [Last accessed on 28/05/13]

12. Soriano, Vincent et al. New Therapies for Hepatitis C Virus Infection. Clinical Infectious Disease, February 2009

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