HCV Research and News: 06/24/13

June 24, 2013

Low fat intake tied to poor recovery from HCC therapy

Provided by Healio

Yamada K. Nutr J. 2013;doi:10.1186/1475-2891-12-79.

June 24, 2013

Patients treated for hepatocellular carcinoma who had a lower dietary fat intake experienced slower recovery from invasive therapies in a recent study.

Researchers assessed the dietary intake of 35 patients with hepatocellular carcinoma (HCC) before and after hospitalization. Nitrogen balance and nonprotein respiratory quotient (npRQ) were measured upon admission and four days later.

Patients’ mean dietary intake at admission was 1,977 ± 513 kcal/day, with a negative nitrogen balance (–2.1 ± 4.5 g/dL) and an npRQ of 0.83 ± 0.061. While at the hospital, mean intake was 1,834 ± 290 kcal/day (P=.061 for difference), with a similar nitrogen balance (–3.0 ± 2.8 g/dL; P=.31). The npRQ after 4 days in-hospital was 0.86 ± 0.075 (P=.0032).

Five patients experienced minimal hepatic encephalopathy (MHE), and investigators observed a trend toward lower npRQ among them compared with patients without MHE (0.78 ± 0.027 vs. 0.84 ± 0.062; P=.082). The MHE patients received significantly lower amounts of fat energy than those without MHE (18.9% ± 3.8% vs. 23.6% ± 4.2%; P=.024) and energy from fat intake trended positively with npRQ values (P=.11; r=0.28). A correlation was observed between change to npRQ after hospitalization and the difference between energy from fat intake through at-home and in-hospital diets (P=.014; r=.41).

In a further analysis of 20 cases, recovery speed after invasive HCC therapy as indicated by reduction rate of prothrombin time (PT) was negatively correlated with the post-admission change to npRQ (P=.0002; r=–0.73). Patient hospital stay after reaching peak PT-international normalized ratio was longer among five cases with low npRQ after admission compared with those who experienced npRQ improvement in-hospital (175 ± 76 days vs. 40 ± 59 days; P=.0006).

“These findings strongly suggest that nutritional intervention, especially for fat intake, should be involved in the HCC treatment scheme both at home and in the hospital,” the researchers concluded. “Because a hypermetabolic state and inappropriate nutritional usage may hamper the calculation of an exact energy requirement in cirrhotic patients, nutritional supports should be conducted based on a nutritional assessment, which includes nitrogen balance, npRQ and MHE.”

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Experts in sub-Sahara Africa join forces with MSD to battle Hepatitis C

By: SEM Contributor on June 25, 2013.

LAGOS, Nigeria, June 24, 2013/ – On June 18, the first of a series of meetings called “Hepatitis in Africa – Call for Action”, took place in Lagos, Nigeria to raise awareness on the burden of Hepatitis C in sub-Sahara Africa among stakeholders. Objectives of the program were engaging and building a relationship among scientific leaders, patient representatives and ministry of health officials from the participating countries to develop national and regional activity plans. During this event stakeholders for the combat against HCV ranging from clinicians, physician body representatives, patient groups and policy makers were converging to take a unified call for a plan of action towards hepatitis policy formation to battle Hepatitis C. Among the participating countries were Angola, Botswana, Burkina Faso, Cameroon, Cote d’Ivoire, Democratic Republic of Congo, Ethiopia, Gabon, Ghana, Kenya, Nigeria, Rwanda, Senegal, Tanzania and Uganda.

Overview of Initiative

The addition of World Hepatitis Day by the World Health Organization to the list of mandated health awareness days heralds the growing international awareness of hepatitis as a global health care issue. This realization is one that cannot come too soon, as several aspects of hepatitis characterize it as one of the most serious infectious disease challenges facing public health care today.

Amongst the viral hepatitis concerns, the hepatitis C virus (HCV) provides unique challenges like an acute phase that is generally asymptomatic and under-diagnosed; a chronic phase with a long latency period before development of life-threatening, difficult to treat complications; genetic polymorphism and the lack of a vaccine. Globally over 185 million people are believed to be afflicted with HCV. In Africa alone, the WHO estimates that the prevalence is 5.3% (1).

Focus Scientific Research Center (FSRC), a physician-led team of researchers, in association with the program sponsor MSD, a global healthcare leader, and a range of collaborators both regional and international are currently working on an initiative to create awareness about hepatitis with the main focus on HCV. The program – “Hepatitis in Africa – Call for Action”, intends to raise disease awareness among the relevant stakeholders in the region. Objectives of the program include but are not limited to engaging and building a relationship with scientific leaders, patient representatives and ministry of health officials from each country to form a regional expert group, and developing national and regional activity plans. The initiative intends to lay the foundation for the development of country-specific activity roadmaps with the involvement of local stakeholders for effective management of HCV.

Distributed by the African Press Organization on behalf of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

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Hepatitis C Test for Baby Boomers Urged by Health Panel

By ANDREW POLLACK

Published: June 24, 2013

An influential health advisory group has reversed itself and concluded that all baby boomers should be tested for hepatitis C, meaning that under the new health law many insurance plans will have to provide screening without charge to patients.

The group, the United States Preventive Services Task Force, announced its change of heart on Monday, saying there was likely to be some benefit from such screening.

An estimated 15,000 Americans a year die from the consequences of hepatitis C infection, which can cause liver scarring, liver failure and liver cancer, although such effects typically do not show up for decades, if at all.

About three-quarters of the more than three million Americans with hepatitis C are baby boomers, most of them infected decades ago. But most do not know it because they have no symptoms. Those at highest risk for the infection include users of injected drugs and recipients of blood transfusions before 1992, when screening of donated blood for the virus began.

The task force had said in a preliminary decision in November that screening all baby boomers would probably offer only a small benefit.

That finding put it at odds with the Centers for Disease Control and Prevention, which had said a few months earlier that all people born between 1945 and 1965 should be offered a one-time test to see if they are infected with the hepatitis C virus.

But the task force said on Monday that after reviewing some new studies and the public comments that it had received on its preliminary decision, it decided to recommend screening of baby boomers, saying there was a “moderate certainty” it would have a “moderate net benefit.”

The decision is good for drug companies selling or developing drugs to treat hepatitis C, like Merck, Vertex, Gilead and AbbVie, because it means more people who harbor the virus but do not know it will be discovered, making them candidates for treatment. The decision could also help companies that make hepatitis C tests, like OraSure Technologies.

New drugs introduced by Merck and Vertex Pharmaceuticals have increased the cure rates for hepatitis C when used along with existing drugs. Companies including Gilead Sciences and AbbVie are racing to bring drugs to market in the next two or three years that would do away with the need for weekly injections of a harsh drug, alpha interferon.

The task force, which is made up of independent experts appointed by the government, said in its preliminary decision that the C.D.C. might have overestimated how many infected people would develop liver problems or die, thus overstating the benefits of screening.

But in its final decision, the task force said new studies and the growing effectiveness of treatment buttressed the case for screening even those without any symptoms or risk factors.

Many of those who had submitted public comments after the preliminary decision had argued that screening all baby boomers would be more effective than testing only those thought to be at risk, like people who had used injected drugs. Many people either do not remember risky behavior from decades ago or do not want to tell their doctors about it.

The task force’s preliminary recommendation had a grade C, meaning testing could be offered to select patients and would probably have a small benefit. The final recommendation has a grade B, suggesting a moderate benefit.

Under the Affordable Care Act, preventive services that get a grade A or B from the task force are supposed to be provided without co-payments from patients, although some existing health plans are grandfathered in and would be exempt.

Although the task force is considered quasi-governmental — and its recommendations are meant for primary care physicians — it can be ignored. It encountered significant resistance from doctors and other medical experts when it recommended a reduction in mammography screening. It also got criticism over its recommendation against prostate screening, although the American Urological Association eventually reached a similar conclusion.

Legislators in New York State this month passed what advocates called the first state bill that would require hospitals and other health care providers to offer hepatitis C screening. The bill will now go to Gov. Andrew Cuomo for his signature.

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Adherence to, initiation of HBV therapy prove problematic in real-world settings

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June 24, 2013

ORLANDO, Fla. — Mindie H. Nguyen, MD, MAS, associate professor of medicine at Stanford University School of Medicine, discusses two of her studies presented at Digestive Disease Week.

In one study, “Effectiveness of Oral Antiviral Therapy for Treatment-Naive Chronic Hepatitis B (CHB) in Routine Clinical Practice,” Nguyen and colleagues evaluated the effectiveness of four oral therapies for HBV in a large, real world-cohort. They found that first-line agents tenofovir and entecavir were more effective than older medications lamivudine and adefovir. Nguyen said medical nonadherence can be a larger issue than antiviral resistance, and that many factors beyond patient noncompliance can contribute to this problem and lead to virologic breakthrough.

In a second study, “Antiviral Treatment Eligibility and Treatment Rates in Patients With Chronic Hepatitis B (CHB) At Primary Care, Community and University Referral Clinics: a Comparative Study,” the researchers evaluated treatment eligibility rates among HBV patients in various settings. Patients in tertiary clinics had greater HBV DNA and ALT levels and higher eligibility rates than those observed at other clinics. Nguyen points out, however, only 60% to 70% of patients meeting eligibility criteria at the evaluated community GI and tertiary clinics initiated therapy within 1 year of evaluation. Lower rates were observed among patients treated at primary care clinics.

Nguyen cites several factors, such as a patient’s unwillingness to start treatment while asymptomatic, can delay treatment initiation, and calls for improved education for patients and physicians.

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National HIV Testing Day: What You Need to Know

Learn why it’s important to get tested for HIV and discover ways to raise awareness on National HIV Testing Day, celebrated on June 27th.

By Amy Boulanger | Jun 24, 2013 12:14 PM EDT

According to the Centers for Disease Control and Prevention (CDC), nearly 1.1 million people are living with HIV (human immunodeficiency syndrome), and one in five are unaware that they are infected.

National HIV Testing Day (NHTD) was created to encourage people to get tested for HIV and seek medical care to live healthy lives and reduce the risk of spreading the infection to others. It was first observed on June 27, 1995. "Take the Test, Take Control."

Who Should Be Tested?

Many people with HIV don't present symptoms. They may not feel or look sick but are carrying the infection inside their body. That's why it's important to get tested so the infection is not passed to someone else.

Everyone between the ages of 15 to 65 should get tested for HIV at least once. All pregnant women should get tested.

HIV Testing

There is no cure for HIV. However, there have been great strides in the medications used to treat HIV. These medications can limit or slow the destruction of the immune system, improve health, and possibly reduce a person's ability to pass HIV to someone else.

Testing is quick and easy. The most common HIV tests use blood to detect an infection. Tests using saliva or urine are also available. Tests can take up to a few days for results. But rapid testing can show results in about 20 minutes.

All positive HIV tests must be followed up by another test to confirm the result.

Where To Get Tested

You can find an HIV testing location in various places:

HIV testing centers
health departments
hospitals
private doctors' offices
clinics

Find a testing site near you.

How is HIV spread?

The most common factors in the spread of HIV include:

Not using a condom. It is extremely risky to have unprotected sex with someone who has HIV.
Unprotected anal sex. This type of sex is riskier than unprotected vaginal sex.
Multiple sex partners.
Unprotected oral sex. Though it's a lower risk than anal or vaginal sex, this can also be a risk for HIV transmission.
Sharing drugs with needles.
Having another sexually transmitted infection (STI).
Being born to an infected mother. HIV can be passed from mother to child during pregnancy, birth, or breast-feeding.

Other less common factors may include:

Receiving blood transfusions, blood products, or organ/tissue transplants that are contaminated with HIV. This risk is extremely remote due to the rigorous testing of the U.S. blood supply and donated organs/tissue.
Unsafe or unsanitary injections. HIV may also be transmitted through unsanitary injections or other medical or dental practices. The risk, however, is extremely low thanks to current safety standards in the United States.
Eating food that has been pre-chewed by an infected person. This is a rare mode of HIV transmission, and has only been documented among infants whose caregiver gave them pre-chewed food.
Being bitten by a person with HIV. While very rare, there have been some documented cases of HIV transmission from a human bite, which involved severe trauma and blood. There is no risk of transmission if the skin is not broken.
Contact between broken skin, wounds, or mucous membranes and HIV-infected blood or blood-contaminated body fluids — an extremely rare method of transmission.
Tattooing or body piercing. While no cases of HIV transmission from tattooing or body piercing have been documented, it's still safe to use sterile equipment.
"French" or deep, open-mouth kissing. This is an extremely rare way of contracting HIV, but could potentially be passed from an HIV-infected person if the HIV-infected person's mouth or gums are bleeding.

How Can You Raise Awareness?

There are many ways that you can help spread HIV awareness.

Host a fundraising or community event, such as a run or walk, to raise money for a local HIV organization.

Send Twitter posts.

Sample Tweets:
- Today is National HIV Testing Day. Take the test, take control. Find HIV testing & services near you: http://1.usa.gov/9h37x0 #NHTD
- One in five people living with #HIV in the U.S. don't know they have it. Get tested: http://1.usa.gov/VqGcRW #NHTD

Make a website announcement to encourage people to get tested.

Learn more about the National HIV/AIDS strategy.

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Screen middle-aged adults for hepatitis C: panel

By Genevra Pittman

NEW YORK | Mon Jun 24, 2013 5:04pm EDT

NEW YORK (Reuters Health) - Adults born between 1945 and 1965 should be screened once for hepatitis C, a government-backed panel recommended today.

The statement, from the U.S. Preventive Services Task Force (USPSTF), is stronger than draft recommendations published in November, which advised doctors to "consider offering screening" to members of the Baby Boom generation (see Reuters Health story of Nov 26, 2012 here: reut.rs/WsjtVA).

The final recommendations - which also call for screening people at high risk of hepatitis C, such as injection drug users - were published Monday in the Annals of Internal Medicine.

The "moderate" net benefit of screening was supported by studies showing people with the chronic infection who take medicine and have a very low level of the virus in their blood - known as a sustained viral response - are at lower risk of liver cirrhosis, cancer and death.

"New evidence came out since the draft recommendation, which gave us greater confidence in the linkage between a sustained viral response and important outcomes," Dr. Albert Siu, co-vice chair of the task force, told Reuters Health.

The USPSTF also found that tools used to assess liver health and guide treatment are becoming safer, and that the harms of hepatitis C medication, including headaches and flu-like symptoms, are "small."

Hepatitis C is treated with a combination regimen of ribavirin and peginterferon alfa (also commonly known as Pegasys and Peg-Intron), to which newer drugs - known as boceprevir (Victrelis) and telaprevir (Incivek) - can be added.

Siu, from the Icahn School of Medicine at Mount Sinai in New York, said the rate of hepatitis C among people born in 1945 through 1965 is about 4 percent, compared to about 1 percent among other Americans.

That difference is likely due to "risky behavior that was engaged in during this time," he said.

Many people living with hepatitis C are not aware they have the condition, the task force said, and may go years without showing symptoms.

Stanford University's Jeremy Goldhaber-Fiebert, who worked on one of the studies that influenced the updated recommendation, told Reuters Health that screening middle-aged adults seems to be effective and cost-effective - but that there are other considerations as well.

"It's really important that when screening is rolled out, that we ensure that those people who screen positive have access to timely, high-quality treatment," he said.

SOURCE: bit.ly/bN9DEh Annals of Internal Medicine, online June 24, 2013.

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Improving quality of care in patients with cirrhosis†

Clinical Liver Disease

Special Issue: Cirrhosis and Kidney Function

Volume 2, Issue 3, pages 123–124, June 2013

Review

Fasiha Kanwal^*, Hashem El-Serag

Article first published online: 21 JUN 2013

DOI: 10.1002/cld.189

Abstract

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Abbreviations

EHR, electronic health records; SBP, spontaneous bacterial peritonitis.

Cirrhosis is a prevalent and expensive condition, affecting approximately 2.5 million individuals at a cost of over $4 billion annually in the United States.1–3 Cirrhosis is the second leading cause of digestive disease–related mortality, preceded only by colorectal cancer.3 The human and economic burden of cirrhosis is expected to increase substantially in the next 10 years as a result of an aging chronic hepatitis C population4 and the possible consequences of fatty liver disease.

Appropriate medical care for cirrhosis can delay complications, improve quality of life, and possibly extend survival.5–8 Experts commissioned by professional societies have published comprehensive evidence-based guidelines to help clinicians better manage these patients.9, 10 Existing data are sparse in the extent to which patients with cirrhosis receive guideline-recommended care, but few important studies indicate significant shortfalls.5, 11 In a cohort of 774 patients with cirrhosis and ascites seen at three Veterans Affairs Medical Centers between 2000 and 2007, we recently found that nearly all patients with documented spontaneous bacterial peritonitis (SBP) received antibiotics for treatment of SBP.12 However, only 30% of these patients received recommended antibiotics for secondary prophylaxis after their discharge from the hospital. In general, care targeted at diagnosis of acute events, especially with regard to hospitalized patients (e.g., paracentesis, ascitic fluid analysis) and treatment (e.g., antibiotics for documented SBP, diuretics), is more likely to meet guideline-recommended standards than preventive and more elective outpatient care (e.g., primary and secondary antibiotic prophylaxis for SBP), despite extensive data that preventive care improves outcomes in patients with cirrhosis.

The first step toward improving the quality of cirrhosis care is to try to measure it. Using a modified Delphi method, we developed a set of explicit quality indicators for patients with cirrhosis.13 These indicators can either be applied retrospectively (using preexisting data) or measured in real-time (at the time of clinical encounter). Regardless of the approach, the use of electronic health records (EHR)-based tools is likely to be important for efficient capture and reporting of quality measures. However, our studies show that the use of automated data that can be readily generated from EHR (such as diagnosis and procedure codes), while reasonably valid for some quality measures in cirrhosis, is fraught with errors for other indicators. For example, there are many reasons why patients do not receive recommended care, some of which are justifiable exceptions (e.g., presence of comorbidities, contraindications, and patient refusal).12 We found that for some of the cirrhosis quality indicators, preexisting data did not capture these exceptions to allow for accurate automated measurement.12 These results suggest that quality indicator measurement systems (such as EHR vendors) will need to incorporate ways of documenting justifiable exclusions. Clearly, more work is required to standardize and validate the methods of collecting cirrhosis quality indicators.

Quality measurement and reporting alone may not achieve higher quality care, and therefore efforts to improve care will need to target actionable drivers of timely cirrhosis care. Domains that can serve as potential targets for intervention at a practice level include providing better access to specialist care.12 Patient subgroups that may be important targets for future interventions include those with medical comorbidities.12 Our data also suggest that focused efforts on preventive care in ascites may improve quality of care delivered to patients with cirrhosis and ascites.12

Implementation of solutions and interventions will depend on the underlying problem as well as the structure and context of the clinical setting and practice needs (Table 1). Simpler interventions such as standardization (e.g., implementation of electronic order sets or care pathways) may be effective enough for situations that do not depend on the participation of many parties (such as ordering antibiotics in the setting of gastrointestinal bleeding and hepatocellular carcinoma screening). Designing a more expensive form of coordination may be necessary if the goal is to improve complex endpoints (such as hospital admission rates, morbidity, and mortality) that are dependent on many individuals, including patients, clinicians, caregivers, case managers, and so forth. We may also need to move toward new models of care in cirrhosis.14 These models include: (1) the application of elements of a chronic care model, in which active disease management continues in between clinic visits using home-based interventions such as home visits, scheduled telephone calls, and remote home monitoring systems; (2) multidisciplinary care, including gastroenterologists/hepatologists, primary care physicians, radiologists, infectious disease physicians and/or psychiatrists (who can either be colocated in a single clinic or actively engaged in cross-discipline collaboration via regular meetings [similar to tumor or transplant evaluation boards]); and (3) improving access to specialty care, particularly for patients with cirrhosis in underserved areas, via electronic consults and telemedicine. Although these models remain untested in patients with cirrhosis, their success in other areas of medicine suggest that they may improve outcomes in cirrhosis.

Table 1. Potential Interventions to Improve Quality of Care in Patients with Cirrhosis

Goal	Intervention

Administration of antibiotics in all patients with cirrhosis and gastrointestinal bleeding	Standardized electronic order sets
Screening for hepatocellular cancer	Established care pathways
Reducing preventable hospital readmissions; improving morbidity and mortality	Improving access to specialty care
	Multidisciplinary care, including gastroenterologists/hepatologists, primary care physicians, radiologists, and psychiatrists
	Case management, including home-based interventions such as home visits, scheduled telephone calls, and remote home monitoring systems

Implementation of interventions will depend on the underlying goals or problems as well as the structure and context of the clinical setting and practice needs.

In our setting (an academically affiliated Veterans Administration Medical Center with a mature EHR), we are increasingly relying on clinical templates that incorporate clinical guidelines and small registries to monitor timely and consistent delivery of recommended preventive care (such as variceal screening, liver cancer screening, and vaccinations). We are expanding our clinical staff to include midlevel providers who, in addition to sharing the physicians' workload, are playing a major role in the coordination of patient care. We are also streamlining electronic communication between primary care providers and gastroenterologists through explicit follow-up recommendations for patients seen in the specialty clinic and detailed justification in cases where consults are discontinued. These are some examples of steps we are taking to improve quality of care delivered to patients with cirrhosis while waiting for more concrete evidence regarding the effectiveness of alternative care models in this population.

References

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Baby Boomers Should Get Tested for Hepatitis C

ALEXANDRIA, Va., June 24, 2013 /PRNewswire/ -- The American Association for the Study of Liver Diseases (AASLD) applauds the US Preventive Services Task Force (USPSTF) decision of June 24, 2013 giving a "B" rating for testing baby boomers for hepatitis C virus. This seemingly small change -- from a "C" to a "B" -- in the USPSTF rating signals an incredible change in the lives of patients who have HCV and are unaware of it. A "B" rating allows for payment by Medicare and private insurers for testing with no copayment by patients.

More than 75 percent of the estimated 3 million US citizens with HCV are baby boomers. This new USPSTF "B" rating for HCV testing of baby boomers matches its rating for HCV testing among injection drug users and others at high risk.

Earlier this year, the Centers for Disease Control and Prevention (CDC) recommended an age-based screening strategy that required a one-time test for everyone born between 1945 and 1965. The USPSTF had initially recommended a "C" rating for this birth cohort in a draft proposal, conflicting with the CDC recommendation and creating confusion in the primary care community. The change from a "C" to a "B" rating gives primary care clinicians the absolute clarity of the hepatology community -- early detection of HCV allows for the drastically greater possibility of treatment success for patients.

HCV is usually an asymptomatic disease, and three out of four of those afflicted are unaware of their infection until their liver disease is far advanced. To allow the disease to progress to the point where a patient is showing symptoms greatly increases the danger of the disease, decreases our abilities to treat these patients, and often results in the development of liver cancer, frequently requiring liver transplantation -- at best. Liver cancer is one of the few cancers increasing in frequency and has one of the highest mortality rates. The ability of a patient to be tested and treated for HCV at the earliest possible date allows him or her to avoid the disease's progression to liver cancer.

Liver transplantation is an expensive procedure and testing for HCV with subsequent treatment is expected to decrease the number of patients who would otherwise require transplantation and provides a significant financial savings to the nation's healthcare system. It is worthy of note that these recommendations come at a time when the treatments for hepatitis C are becoming both more effective and easier to tolerate. The other savings is even greater -- decreasing the number of patients requiring and waiting for a liver transplantation equals saving lives. The number of livers available does not match the number of patients who currently require a transplantation, which means that patients die while on the waiting list. In 2012, there were 6,256 liver transplantations performed. As of June 7, 2013, there are 16,484 patients waiting for a suitable organ.

The CDC recommended one-time age-based screening allowing for early detection of HCV reduces the chance of progression to liver cancer, and decreases the number of patients requiring a liver transplantation. The new "B" rating by the USPSTF means that a large number of patients can be tested and successfully treated with new direct-acting antiviral drugs that have allowed the medical community to cure HCV. Ten years ago, we were not able to cure patients of HCV, but research in liver disease has led to these new drugs. Treatment is still difficult and expensive, but it is constantly improving, and we anticipate the FDA to approve numerous new drugs over the next three to five years. New drugs currently in the pipeline will allow us to increase the cure rate and decrease treatment side effects.

AASLD is a subspecialty society representing clinicians and researchers in liver disease. The work of our members has laid the foundation for the development of drugs used to treat patients with HCV. Our members are on the frontline of treating and curing these patients. This decision by the USPSTF helps us help patients.

AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD was founded in 1950 by a small group of leading liver specialists and has grown to an international society responsible for all aspects of hepatology.

Press releases and additional information about AASLD are available online at www.aasld.org.

Media Contact: Gregory Bologna
703/299-9766
gbologna@aasld.org

This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.XpressPress.com.

SOURCE American Association for the Study of Liver Diseases (AASLD)

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Expanded Hepatitis C Virus Screening Recommendations Promote Opportunities for Care and Cure

Annals of Internal; Medicine

Editorials | 25 June 2013

Quyen Ngo-Metzger, MD, MPH; John W. Ward, MD; and Ronald O. Valdiserri, MD, MPH

[+-] Article and Author Information

Ann Intern Med. Published online 25 June 2013 doi:10.7326/0003-4819-159-5-201309030-00675

Chronic hepatitis C virus (HCV) infection is a major health problem in the United States. An estimated 2.7 million to 3.9 million Americans are living with HCV, and transmission continues to occur (1). Hepatitis C is the leading cause of liver transplants in the United States, and without treatment, 15% to 40% of persons living with the virus will develop cirrhosis or cancer. Hepatitis C–related mortality has been steadily increasing, with a 50% rate increase from 1999 to 2007. An estimated 45% to 85% of persons with chronic HCV are unaware that they are infected and thus do not receive needed care and treatment (1). The Centers for Disease Control and Prevention (CDC) estimates that, in the absence of interventions, approximately 1 million HCV-infected persons will die of HCV-related disease. When accompanied by appropriate care and treatment, HCV testing can reduce risk by 70% for hepatocellular carcinoma and by 50% for all-cause mortality (1).

Viral hepatitis was recognized as an important public health problem by the Institute of Medicine in its groundbreaking 2010 report, “Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C” (2). In this report, the institute identified viral hepatitis as an “underappreciated health concern” and provided recommendations to improve hepatitis prevention and control. In response, the U.S. Department of Health and Human Services (HHS) convened a Viral Hepatitis Interagency Working Group to develop an action plan (3) that provides specific HHS agencies with explicit steps to achieve viral hepatitis prevention goals, including increasing the number of persons living with HCV who are aware of their infection status.

The U.S. Preventive Services Task Force (USPSTF) recommendations on HCV screening (4) represent a critical step toward achieving the prevention goals outlined in the HHS action plan. The USPSTF now recommends HCV screening in persons at increased risk and 1-time screening in adults born between 1945 and 1965. These recommendations, which are consistent with those issued by the CDC in 2012 (5), reflect the strength of evidence on the benefits of HCV testing linked to care, treatments, and improved health outcomes. The independently derived yet similar recommendations for HCV testing from the USPSTF and CDC send a clear signal to health care professionals, policymakers, and the public that screening for HCV is effective. We can now focus our efforts on ensuring capacity for the delivery of clinical preventive services that can reduce missed opportunities for HCV diagnosis and linkage to care and treatment.

Risk-based approaches (6) have been most effective in settings providing services for persons with ongoing risk behaviors or health issues indicative of those risks (for example, HIV-infected persons and those receiving dialysis or substance abuse treatment); however, these approaches have been less effective in identifying HCV infection in the general population, particularly in persons infected in the distant past. Among persons living with hepatitis C, approximately 76% were born between 1945 and 1965; persons in this birth cohort (“baby boomers”) accounted for more than 70% of all HCV-associated deaths in 2007 (5). This cohort may have received blood transfusions before the introduction of screening in 1992 or have a history of other risk factors. However, many in this cohort do not or cannot identify any risk factors for their infection. As such, a risk-based approach may miss a substantial proportion of HCV-infected individuals who may remain asymptomatic and unaware of their infection for years.

The expanded screening recommendations are especially important in light of highly effective treatment for HCV. Currently available antiviral agents can elicit a sustained virologic response (virologic clearance or cure) in up to 79% of patients when administered with pegylated interferon and ribavirin, and the benefits of HCV treatment are expected to increase. On the basis of clinical trial data for 2 agents submitted in new drug applications to the U.S. Food and Drug Administration, future treatment regimens will comprise 1 or more antiviral agents (given either with pegylated interferon and ribavirin or as all-oral combinations) and are expected to yield similar or improved rates of viral clearance. These new regimens require shorter durations of treatment (12 to 24 weeks rather than current 24- to 48-week regimens) and are associated with fewer serious adverse events (7).

The promise of improved health outcomes will be realized with successful implementation of both risk-based and birth cohort–based strategies for HCV testing and linkage to care and treatment. Given the USPSTF's grade B designation for HCV testing in baby boomers and others at risk for infection, the 2010 Patient Protection and Affordable Care Act (Affordable Care Act) will facilitate implementation because it requires nongrandfathered private health plans to cover clinical preventive services given an A or B grade by the USPSTF without cost sharing and provides incentives for Medicaid programs to cover these services. The law will also prohibit insurance companies from declining to sell or renew policies because of such preexisting conditions as viral hepatitis, thus increasing patient access to care and treatment called for in the HHS action plan.

The Affordable Care Act will improve health infrastructure by fostering the development of new health information technology and health information exchanges. Implementation of standards for electronic medical records can expedite the reporting of HCV-related laboratory and clinical information to public health surveillance systems and close current gaps in screening. As demonstrated by surveillance data, 50% of newly reported HCV cases lack a positive RNA test result (8); electronic medical records can facilitate implementation of recommended HCV testing policies. They also provide an opportunity to monitor the quality of viral hepatitis prevention, care, and treatment at the public health level.

The comprehensive screening strategies from the USPSTF and CDC create new opportunities for reaching the shared goals of reducing HCV transmission and identifying persons living with HCV and facilitate the receipt of care and treatment. Passage of the Affordable Care Act has created an environment conducive to implementation of risk-based and birth cohort–based strategies. Taken together, the law and newly expanded HCV screening recommendations will help generate the momentum needed to identify millions of Americans previously unaware of their infection status, thus preventing liver disease and deaths attributable to chronic HCV infection.

References

1 Ward JW. The epidemiology of chronic hepatitis C and one-time hepatitis C virus testing of persons born during 1945 to 1965 in the United States. Clin Liver Dis. 2013;17:1-11. [PMID: 23177279]

2 Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC: National Academies Pr; 2010.

3 U.S. Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care, and Treatment of Viral Hepatitis. Washington, DC: U.S. Department of Health and Human Services; 2011.

4 Moyer VA, on behalf of the U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013.

5 Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al; Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32. [PMID: 22895429]

6 Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-19):1-39. [PMID: 9790221]

7 Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med. 2013;368:1907-17. [PMID: 23675659]

8 Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;368:1859-61. [PMID: 23675657]

Source

Screening for Hepatitis C Virus Infection in Adults

U.S. Preventive Services Task Force

This topic page summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on screening for hepatitis C virus infection in adults.

Current Recommendation

Release Date: June 2013

The USPSTF recommends screening for hepatitis C virus (HCV) infection in persons at high risk for infection. The USPSTF also recommends offering one-time screening for HCV infection to adults born between 1945 and 1965.
Grade: B Recommendation.

Supporting Documents

Supporting Document	Related Items
Recommendation Statement (PDF File, 60 KB; PDF Help)	Clinical Summary (PDF File, 56 KB; PDF Help)
	Consumer Fact Sheet (PDF File, 119 KB; PDF Help)
	Editorial
Evidence Report, Screening (PDF File, 124 KB; PDF Help)	Comparative Effectiveness Report, Screening (PDF File, 618 KB; PDF Help)
Evidence Report, Mother-to-Infant Transmission (PDF File, 40 KB; PDF Help)
Evidence Report, Treatment (PDF File, 226 KB; PDF Help)	Comparative Effectiveness Report, Treatment (PDF File, 744 KB; PDF Help)

Current as of June 2013

Internet Citation:

Screening for Hepatitis C Virus Infection, Topic Page. U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm

Association of Vitamin D Serum Levels and Its Common Genetic Determinants, With Severity of Liver Fibrosis in Genotype 1 Chronic Hepatitis C Patients

S. Petta, S. Grimaudo, V. D. Marco, C. Scazzone, F. S. Macaluso, C. Cammà, D. Cabibi, R. Pipitone, A. Craxì

J Viral Hepat. 2013;20(7):486-493.

Abstract and Introduction

Abstract

Lower 25-hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome-wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D-binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy-proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.

Introduction

The key issue in patients with chronic hepatitis C (CHC) is the progression of liver fibrosis as a consequence of various mechanisms of tissue damage caused by viral infection,^[1] with the ultimate development of cirrhosis and its complications.

Other than well known risk factors for fibrosis severity, like liver necroinflammation, older age, consumption of alcohol, duration of infection and viral coinfections,^[2] metabolic alterations, namely steatosis,^[3] insulin resistance (IR)^[4] and menopause (in females)^[5] can affect the degree of liver fibrosis.

In this complex and interesting interplay between liver and metabolic factors, growing evidence also suggest a role of vitamin D status on liver disease severity in patients with chronic hepatitis C. In particular, we firstly reported that fully compensated genotype 1 (G1) CHC patients are characterized by a higher prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency compared to a control population, also showing in this clinical setting an independent inverse relationship between 25(OH)D serum levels and liver fibrosis severity.^[6] These clinical data not only were further confirmed by other groups,^[7,8] but also their strength was supported by experimental studies showing that vitamin D, acting via its nuclear vitamin D receptor, exerts its protective effect by inhibiting stellate cell proliferation and their profibrogenic activation.^[9]

Vitamin D has therefore a relevant role in patients with CHC, and its metabolism is regulated by several environmental factors, in particular sunlight and diet. In addition, a recent genome-wide association study (GWAS), in a large screening population of about 30 000 European descent individuals divided in a training and a validation set demonstrated that serum concentrations of 25(OH)-vitamin D are influenced by variants near genes involved in cholesterol synthesis (7-dehydrocholesterol reductase -DHCR7), vitamin D hydroxylation (CYP2R1) and vitamin D transport (vitamin D-binding protein–GC).^[10]

With this in mind, in a cohort of biopsy-proven G1 CHC patients, we aimed to assess the association between vitamin serum levels and its genetic determinants, with the severity of liver fibrosis.

Materials and Methods

Patients

Two hundred and sixty consecutive patients with G1 CHC, recruited at the Gastrointestinal and Liver Unit at the University Hospital in Palermo and fulfilling all inclusion and exclusion criteria detailed below, were assessed. Patients were included if they had a histological diagnosis of CHC (any degree of fibrosis, including cirrhosis) on a liver biopsy performed within 6 months prior to enrolment. G1 CHC patients were characterized by the presence of anti-HCV and HCV RNA, with persistently abnormal alanine aminotransferase (ALT) levels, and by alcohol consumption of <20 g/day in the last year or more, evaluated by a specific questionnaire. Exclusion criteria were (i) advanced cirrhosis (Child-Pugh B and C); (ii) hepatocellular carcinoma; (iii) other causes of liver disease of mixed aetiologies (excessive alcohol consumption, hepatitis B, autoimmune liver disease, Wilson's disease, hemochromatosis, α1-antitrypsin deficiency); (iv) HIV infection; (v) previous treatment with antiviral therapy, immunosuppressive drug and/or regular use of steatosis-inducing drugs (corticosteroids, valproic acid, tamoxifen, amiodarone); (vi) therapy with medications known to affect vitamin D3 metabolism, including vitamin/mineral supplements; and (vii) active IV drug addiction.

The study was performed in accordance with the principles of the Declaration of Helsinki and its appendices, and with local and national laws. Approval was obtained from the hospital's Institutional Review Board and Ethics Committee, and written informed consent was obtained from all patients.

Clinical and Laboratory Assessment

Clinical and anthropometric data were collected at the time of liver biopsy. BMI was calculated on the basis of weight in kilograms and height (in metres), and patients were classified as normal weight (BMI, 18.5–24.9 kg/m²), overweight (BMI, 25–29.9) or obese (BMI ≥ 30). The diagnosis of arterial hypertension was based on the following criteria: systolic blood pressure ≥135 mm Hg and/or diastolic blood pressure ≥85 mm Hg (measured three times within 30 min, in the sitting position and using a brachial sphygmomanometer) or use of blood pressure–lowering agents. The diagnosis of type 2 diabetes was based on the revised criteria of the American Diabetes Association, using a value of fasting blood glucose ≥126 mg/dL on at least two occasions.^[11] In patients with a previous diagnosis of type 2 diabetes, current therapy with insulin or oral hypoglycaemic agents was documented.

A 12-hour overnight fasting blood sample was drawn at the time of biopsy to determine serum levels of ALT, total cholesterol, HDL and LDL cholesterol, triglycerides, plasma glucose concentration, insulin and platelet count. Insulin resistance (IR) was determined with the homoeostasis model assessment (HOMA), using the following equation:^[12] insulin resistance (HOMA-IR) = fasting insulin (μU/mL) × fasting glucose (mm)/22.5. HOMA-IR has been validated in comparison with the euglycemic/hyperinsulinemic clamp technique in both diabetic and nondiabetic patients.^[13]

The analysis of serum 25(OH) D was performed using a Chromosystem reagent kit and a chromatographic system equipped with a Waters 1525 Binary high-pressure liquid chromatography pump connected to a photo diode array detector, and detection was carried out at 265 nm. 25(OH)D serum levels <10 μg/L, from 10 to 30 μg/L, and >30 μg/L, were considered the threshold values for identifying deficiency, insufficiency and normality of vitamin D levels, respectively.

All patients were tested at the time of biopsy for HCV RNA (RT-PCR homemade; limit of detection: 12 IU/mL). Genotyping was performed by INNO-LiPA, HCV II, Bayer.

Genetic Analyses. DNA was purified using the QIAmp blood Mini Kit (Qiagen, Mainz, Germany), and DNA samples were quantified using spectrophotometric determination.

Genotyping for IL28B (rs12979860), PNPLA3 (rs738409), CYP2R1 (rs 10741657), NADSYN1(rs 12785878) and GC (rs 2282679) was carried out using the TaqMan SNP genotyping allelic discrimination method (Applied Biosystems, Foster City, CA, USA). Commercial genotyping assays were available for the SNPs: rs738409 (cat. C_7241_10), rs 10741657 (cat. C_2958430_10); rs 12785878 (cat. C_32063037_10); rs 2282679 (cat. C_26407519_10). Instead, a custom assay has been created by AB for rs12979860.

The genotyping call was performed with SDS software v.1.3.0 (ABI Prism 7500, Foster City, CA, USA). Genotyping was conducted in a blinded fashion relative to patient characteristics.

Histology

Slides were coded and read by one pathologist (D.C.), who was unaware of the patient's identity and history. A minimum length of 15 mm of biopsy specimen or the presence of at least 10 complete portal tracts was required.^[14] Biopsies were classified according to the Scheuer numerical scoring system.^[15] The percentage of hepatocytes containing macrovescicular fat was determined for each 10× field. An average percentage of steatosis was then determined for the entire specimen. Steatosis was assessed as the percentage of hepatocytes containing fat droplets (minimum 5%) and evaluated as a continuous variable. Steatosis was classified as absent-mild at <20% or moderate–severe at ≥20%.

Statistics. Continuous variables were summarized as mean ± standard deviation and categorical variables as frequency and percentage. The Student's t-test and analysis of variance were used when appropriate. Multiple linear regression analysis was performed to identify independent predictors of 25(OH)D serum levels as a continuous dependent variable. As candidate risk factors for low serum levels of 25(OH)D, we selected age, sex, body mass index, baseline ALT, platelet count, total cholesterol, high-density lipoprotein cholesterol, triglycerides, blood glucose, insulin, HOMA score, diabetes, arterial hypertension, DHCR7,CYP2R1 and CG SNPs, HCV RNA levels, steatosis and activity score.

Multiple logistic regression models were used to assess the relationship of fibrosis to the demographic, metabolic, genetic and histological characteristics of patients. In the model, the dependent variable was severe fibrosis coded as 1 = F3–F4 in the fibrosis score versus 0 = F1–F2. As candidate risk factors, we selected the same independent variables included in the 25(OH)D model and added 25(OH)D serum levels as an additional independent variable.

In all analyses, DHCR7 SNP was evaluated as TT/TG vs GG, CYP2R1 as AA/AG vs GG, and CG as TT/TG vs GG, according to published data on genotypes associated with lower vitamin D levels.^[10]

Variables associated with the dependent variable at univariate analyses (probability threshold, P < 0.10) were included in the multivariate regression models. Regression analyses were performed by SAS.^[16]

Results

Patient Features and Histology

The baseline features of the 260 patients are shown in . Most of our patients were in the overweight to obesity range. One patient in four had fibrosis of at least three by Scheuer score, with a high prevalence of moderate/severe necroinflammation (grading 2–3). One patient in three had histological evidence of steatosis of moderate/severe grade.

Table 1. Demographic, laboratory, metabolic and histological features of 260 patients with genotype 1 chronic hepatitis C

Variable	Chronic hepatitis C genotype 1 (n = 260)
Mean age (yrs)	52.8 ± 11.9
Gender
Man	128 (49.2)
Woman	132 (50.8)
Mean body mass index (kg/m²)	26.8 ± 4.8
Body Mass Index (kg/m²)
<25	90 (34.6)
25–29.9	124 (47.6)
≥30	46 (17.8)
Arterial hypertension
Absent	203 (78.1)
Present	57 (21.9)
Type 2 diabetes
Absent	222 (85.4)
Present	38 (14.6)
Alanine aminotransferase (IU)	95.0 ± 78.9
Cholesterol (mg/dL)	174.0 ± 35.2
HDL Cholesterol (mg/dL)	54.7 ± 17.7
LDL Cholesterol (mg/dL)	100.8 ± 32.6
Triglycerides (mg/dL)	100.3 ± 51.1
Blood glucose (mg/dL)	97.7 ± 31.1
Insulin (μU/mL)	13.6 ± 7.6
HOMA score	3.37 ± 2.23
25(OH)D (μg/L)	24.5 ± 8.4
25(OH)D
Normality	64 (24.6)
Insufficiency	195 (75.0)
Deficiency	1 (0.4)
HCV RNA (UI/ml)	1,490,677 ± 2,542,912
DHCR7
TT	114 (43.8)
TG	133 (51.2)
GG	13 (5)
CYP2R1
AA	29 (11.1)
AG	109 (41.9)
GG	122 (46.9)
GC
TT	149 (57.3)
TG	94 (36.2)
GG	17 (6.5)
Histology at biopsy
Steatosis:	12.0 ± 16.6
-Continuous variable
-Categorical variable
<20%	180 (69.2)
≥20%	80 (30.0)
Stage of fibrosis
0	12 (4.6)
1	52 (20.0)
2	122 (46.9)
3	45 (17.3)
4	29 (11.2)
Grade of activity
1	44 (16.9)
2	144 (55.4)
3	72 (27.7)

yrs, years; IU, international units; HOMA, homoeostasis model assessment; HDL, high-density lipoprotein; LDL, low density lipoprotein; HCV RNA, hepatitis C virus ribonucleic acid; DHCR7, dehydrocholesterol reductase; GC, vitamin D-binding protein.

Mean serum values of 25(OH)D were 24.5 ± 8.4 μg/L. Accordingly, vitamin D deficiency, insufficiency and normality were observed in 0.4%, 75% and 24.6% of G1 CHC patients, respectively.

DHCR7 rs12785878 TT genotype was present in 114 (43.8%) patients, compared to 133 (51.2%) and 13 (5%) with TG and GG variants, respectively. The CYP2R1 rs10741657 AA genotype was observed in 29 patients (11.1%) compared with 109 (41.9%) and 122 (46.9%) with AG and GG variants, respectively. Finally, GC rs7041 TT genotype was present in 149 patients (57.3%) compared with 94 (36.2%) and 17 (6.5%) with TG and GG variants, respectively.

Serum 25(OH)D Levels

Older age (P = 0.002), female sex (P = 0.03), DHCR7 GG (P = 0.003), GC GG (P = 0.05) and the severity of fibrosis (P = 0.001) were associated with lower 25(OH)D levels in G1 CHC, although only DHCR7 GG (P = 0.003) (P = 0.008) and the severity of fibrosis (P = 0.03) were independent factors in multiple linear regression analysis (). Figure 1 shows the distribution of serum 25(OH)D levels in relation to DHCR7 genotype.

Table 2. Univariate and multivariate analysis of factors associated with vitamin D serum levels in 260 patients with genotype 1 chronic hepatitis C

Univariate analysis			Multivariate analysis
β	SE	P value	B	SE	P value
Mean age (yrs)	−0.192	0.043	0.002	−0.123	0.045	0.05
Male gender	−0.133	1.036	0.03	−0.107	1.031	0.08
Mean body mass index (kg/m²)	0.023	0.116	0.72	–
Alanine aminotransferase (IU)	0.058	0.007	0.35	–
Cholesterol (mg/dL)	0.045	0.015	0.46	–
HDL Cholesterol (mg/dL)	−0.096	0.032	0.15	–
LDL Cholesterol (mg/dL)	0.117	0.017	0.11	–
Triglycerides (mg/dL)	0.013	0.010	0.83	–
Blood glucose (mg/dL)	−0.102	0.017	0.10	–
Insulin (μU/mL)	−0.013	0.075	0.84	–
HOMA score	−0.049	0.023	0.43	–
Diabetes	−0.117	1.469	0.10	–
Arterial Hypertension	−0.097	1.257	0.11	–
HCV RNA	−0.038	0.001	0.64	–
DHCR7 TT/TG vs GG	−0.186	2.357	0.003	−0.161	2.317	0.008
CYP2R1 AA/AG vs GG	0.072	1.691	0.25	–
GC TT/TG vs GG	−0.118	2.100	0.05	−0.109	2.020	0.06
Histology at biopsy
Steatosis	0.036	0.031	0.56	–
Stage of fibrosis	−0.207	0.513	0.001	−0.135	0.532	0.03
Grade of activity	−0.099	0.779	0.11	–

Figure 1.

25(OH)D serum levels according to DHCR7 genotype, in 260 patients with genotype 1 chronic hepatitis C.

Accordingly, all patients with DHCR7 GG genotype had vitamin D insufficiency/deficiency, compared to 74% with DHCR7 TT/TG genotype (P = 0.03).

Variables Related to Severe Fibrosis

The univariate and multivariate comparison of variables between patients with and without severe fibrosis (F3–F4) are reported in . Older age, male sex, high baseline values of ALT, low cholesterol, high triglycerides, high blood glucose, high HOMA, diabetes, low 25(OH)D, vitamin D insufficiency/deficiency, DHCR7 GG genotype, moderate–severe steatosis and moderate–severe necroinflammatory activity were associated with severe fibrosis (P < 0.10). Multivariate logistic regression analysis showed that the following features were independently linked to severe fibrosis (Scheuer score ≥3): older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). The overall area under the curve (AUC) of this model was good (AUC, 0.870). Figure 2 showed the prevalence of severe fibrosis, according to DHCR7 genotype.

Table 3. Univariate and multivariate analysis of risk factors associated with severe fibrosis (F3–F4) in 260 patients with genotype 1 chronic hepatitis C

Variable	No severe Fibrosis (Scheuer score 0–2) n = 186	Severe Fibrosis (Scheuer score 3–4) n = 74	Univariate Analysis P value	Multivariate Analysis
Variable	No severe Fibrosis (Scheuer score 0–2) n = 186	Severe Fibrosis (Scheuer score 3–4) n = 74	Univariate Analysis P value	OR (95% CI)	P value
Age (yrs)	50.8 ± 12.4	58.0 ± 8.9	<0.001	1.056 (1.023–1.089)	0.001
Male gender
Male vs Female	89/97	39/35	0.48	–
Body mass index (kg/m²)	27.0 ± 5.2	26.1 ± 3.6	0.22	–
Alanine aminotransferase (IU)	78.1 ± 61.3	137.4 ± 100.1	<0.001	–
Cholesterol (mg/Dl)	178.1 ± 35.8	163.7 ± 31.5	0.003	0.984 (0.974–0.994)	0.002
HDL Cholesterol (mg/Dl)	57.0 ± 18.1	49.2 ± 15.6	0.004	–
LDL Cholesterol (mg/Dl)	104.9 ± 32.9	91.5 ± 29.9	0.005	–
Triglycerides (mg/Dl)	95.7 ± 43.6	112.0 ± 65.4	0.02	1.008 (1.002–1.015)	0.01
Blood glucose (mg/dL)	93.0 ± 28.9	109.5 ± 33.5	<0.001	1.008 (0.998–1.018)	0.11
Insulin (μU/mL)	13.3 ± 7.7	14.2 ± 7.5	0.41	–
HOMA score	3.18 ± 2.02	3.87 ± 2.64	0.02	–
Arterial Hypertension
Absent vs present	146/40	57/17	0.79	–
Type 2 diabetes
Absent vs present	169/17	53/21	<0.001	–
25(OH)D (μg/L)	25.5 ± 8.7	21.9 ± 7.0	0.002	0.958 (0.919–0.999)	0.04
25(OH)D insufficiency/deficiency
Absent vs present	51/135	13/61	0.09	–
HCV RNA (UI/mL)	1,501,661 ± 2,753,749	1,458,288 ± 1,812,436	0.92	–
DHCR7 TT/TG vs GG	180/6	67/7	0.03	4.222 (1.106–16.120)	0.03
CYP2R1 AA/AG vs GG	25/161	5/69	0.15
GC TT/TG vs GG	176/10	67/7	0.22
Histology at biopsy
Steatosis <20% vs ≥20%	139/47	41/33	0.002	2.588 (1.355–4.943)	0.004
Mild vs Moderate–Severe Grade of inflammation	39/147	5/69	0.006	2.437 (1.307–4.763)	0.001

Figure 2.

Prevalence of severe liver fibrosis according to DHCR7 genotype, in 260 patients with genotype 1 chronic hepatitis C.

Discussion

In this study, we have shown that, in a cohort of patients with biopsy-proven G1 CHC, DHCR7 GG genotype, other than being associated with lower vitamin D serum levels, was also independently linked to the severity of liver fibrosis, together with well known risk factors for fibrosis, including lower vitamin D serum levels.

Different lines of evidence showed a relevant role of vitamin D status in patients with CHC patients, and with neoplastic and cardiometabolic disorders,^[6,17] prompting genetic, clinical and experimental research on vitamin D metabolism and actions.

In our study we showed that, in G1 CHC patients, lower levels of serum 25(OH)D were independently linked to the DHCR7 GG genotype. Our data are in agreement with the GWAS study of Wong and colleagues on a cohort of about 30 000 subjects that identified the DHCR7 gene as able to affect vitamin D serum levels, with the lowest values in GG patients.^[10] In addition, the presence of lower vitamin D serum levels in patients with the DHCR7 GG genotype was also recently reported in a large cohort of Caucasian patients with chronic liver diseases due to different aetiologies.^[18] In our study, we did not identify a link between CYP2R1 and GC SNPs, also linked to vitamin D deficiency in the above quoted GWAS study,^[10] and vitamin D serum levels. This issue could be related to the demographic, clinical and biochemical characteristics of our studied population, like the very high prevalence of vitamin D deficiency, as well as to the relative low number of included patients.

This study offers the first evidence that the DHCR7 GG genotype, together with lower 25(OH)D serum levels, and with other known risk factors for fibrosis severity, such as older age, low cholesterol and high triglycerides levels, moderate–severe steatosis and high necroinflammatory activity, is independently associated with the presence of severe liver fibrosis in G1 CHC patients. Grünhage and colleagues,^[18] in a cohort of more than seven hundred patients with mostly clinically diagnosed chronic liver disease due to different aetiologies (60% HCV related), showed that, among subgroups of patients with liver stiffness measurement (LSM) lower than 7 kPa and lower than 9.5 kPa, the DHCR7 GG genotype was associated with higher LSM values. These data therefore suggested, with limits related to LSM use as surrogate marker of fibrosis, and to subgroups analyses, a potential association between severity of liver disease and the DHCR7 GG genotype. In this line, our study added further and relevant evidence about this issue, demonstrating the association between the DHCR7 GG genotype and severity of histological liver fibrosis, in a cohort of compensated, homogeneous and fully characterized biopsy-proven G1 CHC patients.

Another relevant finding of our study is that both the DHCR7 genotype and vitamin D levels were independently linked to the presence of severe liver fibrosis. This issue suggests that the association between the DHCR7 GG genotype and liver fibrosis is far complex. In fact, on the one hand, it is plausible that DHCR leads to fibrosis via lowering vitamin D serum levels.^[10] Experimental evidence in fact suggests that vitamin D, via interaction with VDR, is able to inhibit stellate cell proliferation and their profibrogenic activation.^[9] On the other hand, our results suggest that DHCR7 genotype could prompt fibrogenesis also via other direct/indirect mechanisms. However, literature data do not provide us with further help on this issue, and therefore, additional experimental work is needed.

The main limitation of this study lies in the low number of patients carrying the at-risk DHCR7 GG genotype. This issue could affect the interpretation of our results. However, the similar low prevalence of DHCR7 GG genotype reported in other studies,^[10,18] then our biologically plausible results^[9,10] and the presence in the literature of similar results^[10,18] makes us confident about the accuracy of our data, which obviously needs further validation in large cohort studies. Another limitation of our study is its cross-sectional nature and its inability to dissect the temporal relation between DHCR7 genotype, 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant.

In conclusion, this study showed that in a homogeneous cohort of compensated biopsy-proven G1 CHC patients, DHCR7 GG genotype, other than leading to lower vitamin D serum levels, is also associated with the severity of liver fibrosis, suggesting a complex interplay between liver damage, vitamin D and genetic determinants of vitamin D deficiency.

References

Herzer K, Sprinzl MF, Galle PR. Hepatitis viruses: live and let die. LiverInt 2007; 27: 293–301.
Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003; 362: 2095–2100.
Romero-G_omez M, Del Mar Viloria M, Andrade RJ et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005; 128: 636–641.
Petta S, Camm_a C, Di Marco V et al. Time course of insulin resistance during antiviral therapy in non-diabetic, non-cirrhotic patients with genotype 1 HCV infection. AntivirTher 2009; 14: 631–639.
Villa E, Vukotic R, Camm_a C et al. Reproductive Status Is Associated with the Severity of Fibrosis in Women with Hepatitis C. PLoS One 2012; 7:e44624.
Petta S, Camm_a C, Scazzone C et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 2010; 51: 1158–1167.
Baur K, Mertens JC, Schmitt J, et al. Combined effect of 25-OH vitamin D plasma levels and genetic vitamin D receptor (NR 1I1) variants on fibrosis progression rate in HCV patients. Liver Int 2012; 32: 635–643.
Lange CM, Bojunga J, Ramos-Lopez E et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011; 54: 887–893.
Abramovitch S, Dahan-Bachar L, Sharvit E et al. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. Gut 2011;60: 1728–1737.
Wang TJ, Zhang F, Richards JB et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 2010; 376: 180–188.
American Diabetes Association. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. American Diabetes Association: Clinical Practice Recommendations. 2000 Committee Report. Diabetes Care 2000; 2000 (23): S4–19.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.
Ikeda Y, Suehiro T, Nakamura T, Kumon Y, Hashimoto K. Clinical significance of the insulin resistance index as assessed by homeostasis model assessment. Endocr J 2001; 48: 81–86.
Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39: 239–244.
Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991; 13: 372–374.
SAS Technical Report. SAS/STAT Software: Changes and Enhancement, Release 6.07. Cary, NC: SAS Institute, Inc., 1992.
Holick MF, Vitamin D. importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79: 362–371.
Grünhage F, Hochrath K, Krawczyk M et al. Common genetic variation in vitamin D metabolism is associated with liver stiffness. Hepatology 2012; 56: 1883–1891.

Abbreviations
AUC, area under the curve; CHC, chronic hepatitis C; DHCR7, dehydrocholesterol reductase; G1, genotype 1; GC, vitamin Dbinding protein; GWAS, genome-wide association study; HCV, hepatitis C virus; HOMA, homoeostasis model assessment; IR, insulin resistance; LSM, liver stiffness measurement.

Contributors
S. Petta designed the study, contributed to data acquisition, was responsible for writing the manuscript and participated in statistical analysis. C. Camma', V. Di Marco and A. Craxì (Director of the GI and Liver Unit) were responsible for the project and writing of the manuscript. D. Cabibi, S. Grimaudo, F.S. Macaluso, R. Pipitone and C. Scazzone participated in patient management and data collection. All authors have seen and approved the final version of the manuscript.

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