November 28, 2013

16 million to 148m people infected with hepatitis viruses: experts

Provided by Business Recorder

November 29, 2013 MUHAMMAD SALEEM

Health professionals have expressed grave concern over the spread of Hepatitis-C virus in the country and said an estimated 16 to 148 million people are infected with various forms of hepatitis viruses. They were speaking at a public awareness seminar on Hepatitis C, held here at the University of Health Sciences (UHS) on Thursday.

While the use, reuse and misuse of syringes continue, health experts do not see the government winning the battle against the spread of Hepatitis-C virus in Pakistan.

Leading Liver and Gastroenterology Physician and Principal Gujranwala Medical College Gujranwala, Prof Aftab Moshin said that out of 200 million, an estimated 16 to 148 million are infected with various forms of hepatitis viruses. "Pakistan has the highest number of patients with chronic liver disease in the world", he added.

Prof Aftab Mohsin, who is also the former national programme manager of the Prime Minister's Programme for Prevention and Control of Hepatitis which has now been devolved to the provinces, said that all evidence for the spread of Hepatitis-C virus (HCV) points to the use of non-sterile syringes in Pakistan. "Annually, an estimated 16 billion therapeutic injections are administered the world over out of which 800 to 900 million are administered in Pakistan only," he said, adding: "Nine out of 10 injections administered in the country are unnecessary."

He said that doctors particularly those practising in small towns and rural areas do oblige patients when they demand infusion drips and injections. "It's not just quacks, I hold qualified dentists and medical practitioners responsible for unsafe practices of administering unnecessary injections, and using non-sterile syringes or needles", said Prof Mohsin.

He further said that unfortunately there is no legislation in place to ban reuse and misuse of syringes, as there is no law to date that prohibits quacks from practicing.

Pakistan Society of Gastroenterology President and professor of medicine at Allama Iqbal Medical College, Lahore, Prof Arif M. Siddiqui said that coupled with poverty and illiteracy, other reasons for the spread of what is known as a silent epidemic of hepatitis, as the symptoms do not show until 15 to 20 years later, are use of non-sterilised razors and dental instruments by roadside barbers and dentists and contaminated blood transfusions.

He added that the risk of infection could be reduced by taking precautionary measures and creating awareness among masses.

UHS acting vice chancellor Prof Mohammad Tahir said that around 66 per cent population of Pakistan is living in rural areas and they are ignorant about the transmission of viral infections.

UHS Director of Centre for Innovation in Learning and Teaching and noted liver surgeon Dr Arif Rashid Khawaja stressed the need of waging joint efforts to combat the menace of Hepatitis-C. He said that liver transplant is usually the only treatment option for patients with end-stage liver disease; however, there are only 3 to 4 qualified liver transplant surgeons available in the country who are making individual efforts.

Dr Shah Jahan of UHS Immunology Department spoke on the role of diagnostics in the treatment of patients with Hepatitis-C. He said that the response of conventional interferon provided by the government in public sector hospitals to treat HCV is only 40 per cent in 4-weeks.
It may be noted that Hepatitis is an inflammation of the liver commonly caused by a viral infection.

Hepatitis viruses are classified as types A, B, C, D, and E. Hepatitis A and E are generally caused by food or water contamination. Hepatitis B, C and D are acquired through contact with infected body fluids, particularly blood. For those infected with Hepatitis-B, 80pc of the patients recover naturally and may not suffer from liver damage and out of those infected with Hepatitis-C, 80pc may become chronic carriers.

Source

Hepatitis C virus: An overview for dental health care providers

J Am Dent Assoc. 2013 Dec;144(12):1340-7.

Klevens RM, Moorman AC.

Dr. Klevens is a medical epidemiologist, Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Mailstop G-37, 1600 Clifton Road, Atlanta, Ga. 30333, rmk2@cdc.gov.

Abstract

BACKGROUND: and Overview. Changes in the science of hepatitis C virus (HCV) infection and transmission in a private dental practice provide an opportunity to update dental health care providers about this pathogen. The authors' aims in this review were to create awareness of health care- associated transmission of hepatitis C and provide an update on the changes in testing and treatment. The authors include data from population-based epidemiologic surveys, clinical practice guidelines, surveillance reports and practice protocols.

RESULTS: In the United States, the elevated prevalence of chronic HCV infection among baby boomers-people born during the period from 1945 through 1965-led the Centers for Disease Control and Prevention to release new national screening guidelines. The authors summarize information about the natural history and epidemiology of hepatitis C and describe the new guidelines and novel treatment options. In addition, the authors provide an overview of how outbreaks of health care-associated HCV are detected and prevented. Practical Implications. Because dental health care professionals likely will treat people with current infection, education in the current science of HCV infection is useful.

KEYWORDS: Centers for Disease Control and Prevention, Hepatitis C, infections

Read full article here – PDF (Free) …..

Source

PUBLIC RELEASE DATE: 28-Nov-2013

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute

65204_rel

This is the new picture of hepatitis C's E2 protein, which the virus uses to infect liver cells, will aid in the design of a vaccine against the disease.

LA JOLLA, CA—November 28, 2013—Scientists at The Scripps Research Institute (TSRI) have determined the most detailed picture yet of a crucial part of the hepatitis C virus, which the virus uses to infect liver cells. The new data reveal unexpected structural features of this protein and should greatly speed efforts to make an effective hepatitis C vaccine.

The findings, which appear in the November 29, 2013 issue of the journal Science, focus on a protein known as E2 envelope glycoprotein.

"We're excited by this development," said Ian A. Wilson, the Hansen Professor of Structural Biology at TSRI and a senior author of the new research with TSRI Assistant Professors Mansun Law and Andrew B. Ward. "It has been very hard to get a high resolution structure of E2 and it took years of painstaking work to finally accomplish that."

Any successful hepatitis C vaccine is likely to target the E2 protein. Scientists already have isolated rare antibodies from patients that can bind E2 in ways that neutralize a broad range of viral strains.

"It took our team six years to crack this very difficult scientific problem, but we didn't give up," said Law. "Now that we can visualize the structural details of these binding sites, we can design vaccine molecules that mimic them."

A Silent Killer

There has long been an urgent need for an effective vaccine against hepatitis C virus. Once confined to isolated geographical regions, the virus spread globally during the 20th century, chiefly via blood transfusions, unsterilized medical instruments and re-used hypodermic needles. Although hospitals have screened blood products for hepatitis C virus (HCV) since the early 1990s, as many as 200 million people currently are thought to harbor the virus. These include more than 3 million people in the United States, where the virus is responsible for more deaths each year than HIV.

HCV was able to spread so widely because it typically causes few or no symptoms when it infects someone. In many cases it establishes a long-term infection of the liver, damaging it slowly for decades—until liver cirrhosis and/or cancer develop. "It's known as a 'silent killer'," said Law. Expensive and risky liver transplantation is often the only way to save a patient's life. Some antiviral drugs are useful in treating and even curing chronic HCV infection, but the more effective ones are extremely expensive—and most HCV-positive people don't even know that they're infected and need treatment.

An HCV vaccine could put an end to the global pandemic by preventing new infections. "It could be given to people when they're young and healthy, and they'd never have to worry about developing HCV-related liver diseases," said Ward.

However, like HIV and some other viruses, HCV uses several effective countermeasures to evade the immune system. These include fast-mutating regions on the E2 protein, which ensure that antibodies to one HCV strain typically are ineffective against other strains. The E2 protein also coats itself with relatively antibody-proof sugar molecules.

To defeat these viral countermeasures, scientists have wanted to "see" the high-resolution atomic structure of HCV, particularly E2 and its CD81 receptor binding site, which does not vary much from strain to strain. In recent years, Law's laboratory and others have isolated antibodies that manage to grab hold of this relatively conserved region of E2, thereby blocking the infectivity of a large fraction of HCV strains. In principle, a vaccine that prompts the body to make similar antibodies would effectively and cheaply immunize people against most of their risk of HCV infection.

Unruly E2

But precisely mimicking these antibody-binding sites in a vaccine means first determining their high-resolution structures, which has been difficult even to attempt. "Usually if you try to express the E2 protein in cultured cells, you either can't express it in useful quantities or you can but it aggregates and becomes a big mess," said Leopold Kong, a research associate in the Wilson laboratory who was the study's lead author.

Over the past several years, Kong and his colleagues have run dozens of experiments to find the right way to modify E2—enough that the protein doesn't aggregate so readily and also so that the antibody-binding sites are maintained. This would enable the protein to be soluble and pure enough to grow crystals to determine its structure by the technique known as X-ray crystallography. "It was a Herculean effort," said Ward. "This is one of the most difficult and unstable viral envelope proteins around."

In the end, the team succeeded, using a slightly altered version of E2—the E2 core—with some of its glycans (sugar molecules) and outer variable and stalk segments removed. The scientists were then able to obtain the high-resolution structure of the protein while it was bound to a known broadly neutralizing antibody developed at TSRI. The scientists then followed up by imaging a more complete version of E2 using electron microscopy to extend the structural model.

When finally revealed, E2's structure surprised the researchers. "It had been thought that HCV's E2 belongs to a family of viral fusion proteins called class 2 fusion proteins, which includes envelope proteins for West Nile and dengue viruses, for example," said Kong. "But we showed that E2 is structurally distinct and probably works differently than what had been widely assumed."

Based on the new structural data, Law and colleagues at TSRI are already designing and testing novel antibody-stimulating components of a future HCV vaccine. "Having the E2 structure has certainly helped us," said Law.

###

Other co-authors of the study, "Hepatitis C virus E2 envelope glycoprotein core structure," were Erick Giang and Kristin E. Cogburn of the Law lab at TSRI; Robyn L. Stanfield, Rameshwar U. Kadam, Yuanzi Hua and Xiaoping Dai of the Wilson lab; Travis Nieusma of the Ward lab; and Professor Dennis Burton of TSRI's Department of Immunology and Microbial Science.

The study was funded in part by the National Institutes of Health (AI079031, AI080916, AI071084, AI084817, U54 GM094586 and RR017573) and the Skaggs Institute of Chemical Biology at TSRI.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www.scripps.edu.

Source

AASLD 2013: War with difficult HCV genotypes

Translation from Russian

November 25, 2013

20132711202217

In November, the sixty-fourth Annual Conference of the American Association for the Study of Liver Diseases AASLD 2013 (Washington, DC, USA) Science and Life Science literally vying to report on progress in the fight against viral hepatitis C. Particular attention was drawn to a number of reports on research in the field of treatment of the most difficult first genotype of hepatitis C virus (HCV) - relevance of progress in this area for co-infected with HIV and HCV is particularly high. A year ago we wrote about the success of therapy difficult HCV genotypes, the past year has also proved eventful in this area.

Mark S. Sulkowski (Johns Hopkins Medical Center, Baltimore, USA) talked about bezinterferonovom mode sofosbuvir inhibitor (NS5B) plus ribavirin, is being developed by Gilead. The study PHOTON-1 studied the effectiveness of the regime in relation to different genotypes of HCV in co-infection with HIV. Effectiveness of a relatively modest - week 24 sustained virologic response (SVR) in genotype 1 achieved in 76% of cases, however, has not sofosbuvir significant interactions with ART and has a good safety profile. For the second and third genotype of HCV in co-infected patients demonstrates the effectiveness of this mode is 88 and 67%, but by week 12.

Eric Lawitz (The Texas Liver Institute, San Antonio, Texas) submitted test data PEARL -1 second phase mode without interferon and ribavirin. Preparations of AbbVie ABT-450 / r (HCV protease inhibitor) + ABT-267 in combination with ABT-333 are in Phase III, which will be completed later this year, and the approval of these modes can be expected in the U.S. in the middle of next year. Genotype 1b genotype 1a generates less resistance to antiviral therapy, and therefore for the treatment of a given genotype was tested double rather than triple therapy. Participants were given during the 12 weeks of treatment, ABT-450 (150 mg once daily) amplified 100 mg ritonavir and ABT-267, and (25 mg once a day). Sustained virological response at week 12 was achieved in 95.2% of naive patients (40 of 42 patients) and 90% (36 of 40) of patients who previously failed the victims in some antiviral modes.

Another report Eric Lawitz was devoted to research LONESTAR, which examined modes without interferon promising nucleotide polymerase inhibitor HCV sofosbuvirom (SOF, sofosbuvir, formerly GS-7977) in combination NS5A inhibitor new ledipasvirom (ledipasvir, LDV, formerly GS-5885) with ribavirin or without it. The same treatment was investigated in the study ELECTRON (see below). Included in the study, patients were divided into two cohorts: 60 naive patients and 40 patients (50% with cirrhosis), formerly of failed standard therapy. In the first cohort, 95% achieved sustained response virusologichesokgo to week 12 in the group without ribavirin and 100% in the group with ribavirin. In the second cohort of patients demonstrated identical parameters to achieve SVR12 with and without ribavirin.

Edward Gane (Auckland Clinical Studies, Auckland, New Zealand) presented the results of the second phase of the study ELECTON. The study investigated the ELECTRON company Gilead modes based sofosbuvira (SOF) in conjunction with ledipasvirom (ledipasvir, LDV, formerly GS-5885), and in one (n = 25) had a triple combination with non-nucleoside inhibitor of NS5B GS-9669, and the other , ribavirin (n = 25). This study examines the same preparations as in the aforementioned study LONESTAR. The primary endpoint was SVRustoychivy virological response at 12 weeks (SVR12). Dual therapy SOF + LDV demonstrated SVR12 only 70% of cases, whereas the combination of SOF + LDV + RBV or SOF + LDV + GS-9669 showed 100% SVR at week 12 as naïve and in previously treated patients with HCV genotype 1a or 1b.Moreover, the likelihood of sustained virologic response to therapy naïve patients SOF + LDV + RBV significant (68%) at 6 weeks and up to 100% by the 8 week. Regimens based SOF + LDV (400 mg + 90 mg once a day) demonstrated a good safety and tolerability.

Ira Jacobson (Weill Cornell Medical College, New York, USA) presented his presentation phase IIa study COSMOS - 12 and 24 weeks of therapy simeprevirom (simeprevir, SMV, formerly TMC435, a drug already approved in the U.S. and is available under the tradename Olysio, company Janssen ) in conjunction with sofosbuvirom modes with or without ribavirin. Regimes were studied in two cohorts: the first - not responding to standard therapy in the past, patients without significant fibrosis (METAVIR F0-F2), the second - naive and nonresponders with pronounced symptoms of fibrosis or compensated cirrhosis (F3-F4). The first cohort SVR12 achieved in 93% of the mode without ribavirin and for 96% in the regime with ribavirin. In the second cohort mode without ribavirin in 100% of the participants had neopredelyamuyu load at week 12. In both groups, 100% of patients with HCV subtype 1a or 1b, but no mutations achieved SVR12 or SVR4. Recorded three relapse in the first cohort and the second one probably associated with subtype 1a mutation Q80K (SVR12 89% and 91%, respectively SVR4). The study demonstrated approximately equal to the high efficiency mode SMV + SOF (± RBV - combination with ribavirin regime bore no significant increase in efficiency).

Kazuaki Chayama (Hiroshima University, Hiroshima, Japan) reported on trials of a dual mode of HCV therapy without interferon and ribavirin on the basis of two new direct-acting drugs company Bristol-Myers Squibb - NS5A replication complex inhibitor daklatasvira (daclatasvir, DCV, BMS-790052) inhibitor NS3 protease asunaprevira (asunaprevir, ASV, BMS-650032). In research conducted in Japan, which is dominated by genotype 1b, included 222 patients with chronic hepatitis C subtype. Feature of the study was that two-thirds were women, and the median age of the participants exceeded 63. Patients received 60 mg daklatasvira once daily and 100 mg twice daily asunaprevira for 24 weeks. Overall sustained virological response at week 24 was 85% in the subgroup who had contraindications or intolerance to interferon - 87%, and in the subgroup not previously responding to standard therapy - 81%. The answer does not depend significantly on the presence or absence of IL28B CC gene predictor of a favorable response to therapy.Company Bristol-Myers Squibb announced at the conference that the drug fixed-dose combination daklatasvira asunaprevira and will soon be submitted to regulatory authorities for approval in Japan medical applications.

Gregory Everson (University of Colorado Denver, Aurora, Colorado, USA) presented interim data from phase IIb study triple mode without interferon and ribavirin, developed by Bristol-Myers Squibb, where the effective mode DCV + ASV enhanced third component. In the 12-week study, HCV genotype studied first combination regimen comprising the above-mentioned daklatasvir (daclatasvir), asunaprevir (asunaprevir) and non-nucleoside polymerase inhibitor NS5B BMS-791325. The study involved two groups of naive patients (n = 80 and 85) receiving DCV (30 mg) + ASV (200 mg) was combined with 75 or 150 mg of BMS-791325. 82% of participants had found the first genotype and expressed liver (F3 or F4 METAVIR according fibroskanirovaniya). Modes with doses of 75 and 150 mg of BMS-791325 were equally effective, and in the subsequent phase III trials will use a smaller dosage. By 12 weeks of therapy, more than 90% of participants had sustained virologic response to treatment (92.2% in the 75 mg BMS-791325, and 91.7% in the 150 mg group). Regimen was well tolerated, the most common pobochnymie effects were headache (24.7%), diarrhea (15.1%), fatigue (11.4%) and nausea (10.2%), in all cases, the severity was mild or moderate.

  • Sulkowski MS, etc. «All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1)», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, # 212, 2013.
  • Lawitz E, etc «Interferon-and ribavirin-free regimen of ABT-450 / r + ABT-267 in HCV genotype 1b-infected treatment-naive patients and prior null responders», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, # 75, 2013.
  • Lawitz E, etc «Once daily sofosbuvir / ledipasvir fixed dose combination with or without ribavirin resulted in ≥ 95% sustained virologic response in patients with HCV genotype 1, including patients with cirrhosis: the LONESTAR trial», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, # 215, 2013.
  • Gane EJ, etc. "Once Daily sofosbuvir / ledipasvir Fixed Dose combination with ribavirin or Without: the ELECTRON Trial", 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, # 73, 2013.
  • Jacobson IM, Ghalib RM, Rodriguez-Torres M et al «SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive Prior null and Responder Patients: the COSMOS Study ", 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington DC, LB-3, 2013.
  • Chayama K, etc. «All-oral combination of daclatasvir plus asunaprevir in interferon ineligible naive / intolerant and nonresponder Japanese patients chronically infected with HCV genotype 1b: results from a phase 3 trial», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, # 211, 2013.
  • Everson G, etc. «Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naive patients with chronic HCV genotype 1 infection», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington DC, LB-1, 2013.

Original Translation

AASLD 2013: война с трудными генотипами ВГС

В ноябре на шестьдесят четвертой ежегодной Конференции американской ассоциации изучения заболеваний печени AASLD 2013 (Вашингтон, Округ Колумбия, США) наука и фарминдустрия буквально наперебой отчитывались об успехах в области борьбы с вирусным гепатитом С. Особое внимание привлек ряд докладов по исследованиям в области терапии наиболее трудного первого генотипа вируса гепатита С (ВГС) — актуальность подвижек в этой области для ко-инфицированных ВИЧ и ВГС особенно высока. Год назад мы писали об успехах терапии трудных генотипов ВГС, прошедший год оказался также богат на события в данной области.

Mark S. Sulkowski (Johns Hopkins Medical Center, Балтимор, США) рассказывал о безинтерфероновом режиме софосбувир (ингибитор NS5B) плюс рибавирин, разрабатываемом компанией Gilead. В исследовании PHOTON-1 изучалась эффективность данного режима в отношении различных генотипов ВГС при ко-инфекции с ВИЧ. Эффективность относительно скромная — к 24 неделе устойчивый вирусологический ответ (SVR) при 1 генотипе достигнут в 76% случаев, однако, софосбувир не имеет значимых взаимодействий с АРВТ и имеет хороший профиль безопасности. Для второго и третьего генотипа ВГС у ко-инфицированных пациентов данный режим демонстрирует эффективность 88 и 67%, но уже к 12 неделе.

Eric Lawitz (The Texas Liver Institute, Сан-Антонио, Техас) представил данные испытаний PEARL -1 второй фазы режима без интерферона и рибавирина. Препараты компании AbbVie ABT-450/r (ингибитор протеазы ВГС) + ABT-267 в сочетании с ABT- 333 находятся в III фазе, которая будет закончена уже в этом году, а одобрение данных режимов можно ожидать в США в середине следующего года. Генотип 1b реже генотипа 1а формирует устойчивость к противовирусной терапии, и поэтому для лечения данного генотипа была опробована двойная, а не тройная терапия. Участники получили в течение 12 недель лечения ABT-450 (150 мг один раз в день) усиленный 100 мг ритонавир,а и ABT- 267 ( 25 мг один раз в день). Устойчивый вирусологический ответ к 12 неделе был достигнут у 95,2% наивных пациентов (40 из 42 пациентов) и у 90% (36 из 40) пациентов, ранее потерпевших неудачу в иных противовирусных режимах.

Другой доклад Eric Lawitz был посвящен исследованию LONESTAR, в котором изучались режимы без интерферона с перспективным нуклеотидным ингибитором полимеразы ВГС софосбувиром (SOF, sofosbuvir, ранее GS-7977) в сочетании новым ингибитором NS5A ледипасвиром (ledipasvir , LDV, ранее GS-5885) с рибавирином или без него. Тот же режим изучался в исследовании ELECTRON (см. далее). Включенные в исследование пациенты были разбиты на две когорты: 60 наивных пациентов и 40 пациентов (50% с циррозом печени), ранее потерпевших неудачу со стандартной терапией. В первой когорте 95% достигли устойчивого вирусологичесокго ответа к 12 неделе терапии в группе без рибавирина и 100% в группе с рибавирином. Во второй когорте пациенты продемонстрировали идентичные параметры достижения SVR12 с рибавирином и без него.

Edward Gane (Auckland Clinical Studies, Окленд, Новая Зеландия) рассказал о результатах второй фазы исследования ELECTON. В исследовании ELECTRON компания Gilead изучало режимы на базе софосбувира (SOF) в сочетании с ледипасвиром (ledipasvir , LDV, ранее GS-5885), также в одной (n=25) была тройная комбинация с ненуклеозидным ингибитором NS5B GS-9669, а в другой, с рибавирином (n=25). В этом исследовании изучаются те же препараты, что и в упомянутом выше исследовании LONESTAR. Первичной конечной точкой исследования был SVRустойчивый вирусологический ответ на 12 неделе (SVR12). Двойная терапия SOF+LDV продемонстрировала SVR12 лишь в 70% случаев, тогда как комбинация SOF+LDV+RBV или SOF+LDV+ GS-9669 показала 100% SVR к 12 неделе как у наивных, так и у ранее получавших терапию пациентов с ВГС с генотипом 1а или 1b. Более того, вероятность устойчивого вирусологического ответа наивных пациентов на терапию SOF+LDV+RBV существенна (68%) на 6 неделе и достигает 100% уже к 8 неделе. Режимы терапии на основе SOF+LDV (400 мг + 90 мг один раз в день) продемонстрировали хорошую безопасность и переносимость.

Ira Jacobson (Weill Cornell Medical College, Нью Йорк, США) представил в своей презентации фазы IIa исследования COSMOS — 12 и 24 недельная терапия симепревиром (simeprevir, SMV, ранее TMC435, препарат уже одобрен в США и доступен под торговым наименованием Olysio, компания Janssen) в сочетании с софосбувиром в режимах с рибавирином или без него. Режимы исследовались в двух когортах: первая — не ответившие на стандартную терапию в прошлом пациенты без выраженного фиброза (METAVIR F0-F2), вторая — наивные и нонреспондеры с выраженными явлениями фиброза или компенсированного цирроза печени (F3-F4). В первой когорте SVR12 достигнут в 93% случаев для режима без рибавирина, и в 96% для режима с рибавирином. Во второй когорте при режиме без рибавирина 100% участников имели неопределямую нагрузку к 12 неделе. В обеих группах 100 % пациентов с ВГС подтипа 1b или с 1а , но не имеющих мутаций, достигли SVR12 или SVR4 . Зафиксированные три рецидива в первой когорте и один во второй видимо связаны с подтипом 1а с мутацией Q80K (SVR12 89% и SVR4 91% соответственно). Исследование продемонстрировало примерно равную высокую эффективность режима SMV + SOF (± RBV — комбинация режима с рибавирином не несло значимого увеличения эффективности).

Kazuaki Chayama (Hiroshima University, Хиросима, Япония) докладывал об испытаниях двойного режима терапии ВГС без интерферона и рибавирина на базе двух новых препаратов прямого действия компании Bristol-Myers Squibb — ингибитора комплекса репликации NS5A даклатасвира (daclatasvir, DCV, BMS-790052) и ингибитор протеазы NS3 асунапревира (asunaprevir, ASV, BMS-650032). В исследование, проводившееся в Японии, где доминирует генотип 1b, были включены 222 пациента с хроническим гепатитом С данного подтипа. Особенностью исследования было то, что две трети были женщины, а медиана возраста участников превышала 63 года. Пациенты получали 60 мг даклатасвира один раз в день и 100 мг асунапревира дважды в день в течение 24 недель. Общий устойчивый вирусологический ответ к 24 неделе составил 85%, в подгруппе имевших непереносимость или противопоказания к интерферону — 87%, а в подгруппе ранее не отвечавших на стандартную терапию — 81%. Ответ не зависел значимо от наличия или отсутствия IL28B СС— гена предиктора благоприятного ответа на терапию. Компания Bristol-Myers Squibb объявила на конференции о том, что препарат с фиксированной комбинацией доз даклатасвира и асунапревира в ближайшее время будет представлен регулирующим органам Японии для одобрения медицинского применения.

Gregory Everson (University of Colorado Denver, Аврора, Колорадо, США) представил промежуточные данные фазы IIb исследования тройного режима без интерферона и рибавирина, разработанного компанией Bristol-Myers Squibb, где эффективный режим DCV+ASV усилен третьим компонентом. В 12-недельном исследовании лечения ВГС первого генотипа изучался комбинированный режим, включающий упомянутые выше даклатасвир (daclatasvir), асунапревир (asunaprevir) и ненуклеозидный ингибитор полимеразы NS5B BMS-791325. В исследовании участвовало две группы наивных пациентов (n=80 и 85), получавших DCV (30 мг)+ASV (200 мг) в сочетании с 75 или 150 мг BMS-791325. 82% участников имели первый генотип и обнаруживали выраженные поражения печени (F3 или F4 METAVIR по данным фибросканирования). Режимы с дозами 75 и 150 мг BMS-791325 оказались одинаково эффективны, и в дальнейших исследованиях III фазы будет использоваться меньшая дозировка. К 12 неделе терапии более 90% участников имели устойчивый вирусологический ответ на терапию (92,2% в группе 75 мг BMS-791325 и 91,7% в группе 150 мг). Режим хорошо переносился, наиболее частыми побочнымие эффектами были: головная боль (24,7% ) , диарея ( 15,1%) , утомляемость (11,4%) и тошнота (10,2%) , во всех случаях выраженность была легкая или умеренная.

  • Sulkowski MS и др. «All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1) », 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC,#212, 2013.
  • Lawitz E и др «Interferon- and ribavirin-free regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected treatment-naive patients and prior null responders», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC,#75, 2013.
  • Lawitz E и др «Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin resulted in ≥95% sustained virologic response in patients with HCV genotype 1, including patients with cirrhosis: the LONESTAR trial», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, #215, 2013.
  • Gane EJ и др. «Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON trial», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, #73, 2013.
  • Jacobson IM, Ghalib RM, Rodriguez-Torres M и др. «SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington DC, LB-3, 2013.
  • Chayama K и др. «All-oral combination of daclatasvir plus asunaprevir in interferon ineligible naive/intolerant and nonresponder Japanese patients chronically infected with HCV genotype 1b: results from a phase 3 trial», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, #211, 2013.
  • Everson G и др. «Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naive patients with chronic HCV genotype 1 infection», 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington DC, LB-1, 2013.

Source

Young people are given hepatitis C option with NICE guidance

Thu, 28/11/2013 - 13:08

By News team

180_Liver_ShubhangiKene_dreams_0

Peginterferon alfa with ribavirin is the only licensed treatment for young people with chronic hepatitis C

Treatment for children and young people with chronic hepatitis C should include the option of peginterferon alfa in combination with ribavirin, recommends the National Institute for Health and Care Excellence in its 300th technology appraisal, issued today (27 November).

"Treatment with peginterferon alfa and ribavirin can decrease the hepatitis C virus to undetectable levels, effectively providing a cure for the disease. Early successful treatment is also likely to lessen the social stigma that can be associated with hepatitis C infection later in life," said Carole Longson, director of the NICE health technology evaluation centre.

Peginterferon alfa with ribavirin is currently the only licensed treatment in the UK for children and young people with chronic hepatitis C.

Source

Journal of Hepatology

Article in Press

Vincent Donckier, Valerio Lucidi, Thierry Gustot, Christophe Moreno

Received 11 June 2013; received in revised form 15 November 2013; accepted 19 November 2013. published online 27 November 2013.
Accepted Manuscript

Summary

A recent study proposed that liver transplantation may represent life-saving treatment in patients with severe alcoholic hepatitis not responding to medical therapy. In this pilot experience, stringent patient selection resulted in major improvement of short-term survival with low rates of post-transplant alcohol relapse. In the context of organ shortage, which imposes a need for strict selection of transplant candidates, these results raise major ethical questions. Reluctance to perform liver transplantation in alcoholics is based on the fact that alcoholism is frequently considered to be self-inflicted and on fears of harmful post-transplant alcoholism recurrence. A minimal interval of sobriety lasting at least 6-months is a widely adopted criterion for the selection of patients with alcoholic liver disease for liver transplantation. In severe alcoholic hepatitis, the disastrous short-term prognosis in patients not responding to medical therapy does not allow one to reasonably impose an arbitrary period of 6-months of abstinence. This means that these patients must be either systematically excluded from transplantation or selected according to other criteria. Without significant pre-transplant abstinence, it might be argued that these patients do not merit a graft as they have not demonstrated their ability to gain control over their disease through durable modification of their behaviour. Consequently, this procedure could have a negative impact in the public, affecting organ donation and confidence in the fairness of transplant programs. In contrast, ethical principles recommend active treatment of patients, without discrimination, according to the best scientific knowledge. At this stage, we propose that there are no major ethical barriers for further evaluation of this new therapeutic option. The next steps should include transparent communication with the public and further studies to reproduce these results and identify the selection criteria that provide the best long-term outcomes.

Keywords: Alcohol, Hepatitis, Severe, Early, Transplantation, Ethic

No full text is available. To read the body of this article, please view the PDF online (Free).

Source

Journal of Hepatology

Article in Press

Thierry Poynard, Julien Vergniol, Yen Ngo, Juliette Foucher, Mona Munteanu, Wassil Merrouche, Massimo Colombo, Vincent Thibault, Eugene Schiff, Clifford A. Brass, Janice K. Albrecht Marika Rudler,Olivier Deckmyn, Pascal Lebray, Dominique Thabut, Vlad Ratziu,Victor de Ledinghen, on behalf of FibroFrance Study Group, the Epic3 Study Group and the Bordeaux HCV Study Group.

Received 8 October 2013; received in revised form 15 November 2013; accepted 19 November 2013. published online 27 November 2013.
Accepted Manuscript

Abstract

Background and Aims

FibroTest (FT) and Transient Elastography (TE) have been validated as noninvasive markers of METAVIR fibrosis stages from F0 to F4 using biopsy, and as prognostic markers of liver related mortality in patients with chronic hepatitis C. The aim was to extend the validation of FT and TE as markers of critical steps defined by occurrence of cirrhosis without complications (F4.1), esophageal varices (F4.2), and severe complications (F4.3): primary liver cancer, variceal bleeding, or decompensation (ascites, encephalopathy, or jaundice).

Methods

The updated individual data of 3927 patients (1046 cirrhotics) without complications at baseline were pooled from three prospective cohorts called “EPIC”, “Paris” and “Bordeaux” cohorts.

Results

At 5 years among 501 patients without varices at baseline (F4.1), varices occurred in 19 patients F4.2 incidence of 4.0% (95%CI 2.2-5.8). The predictive performance (AUROC) of FT was 0.77 (0.66-0.84; P<0.001).

At 10 years severe complications occurred in 203 patients, F4.3 incidence of 13.4% (9.6-17.1), including primary liver cancer in 84 patients 6.4%(3.5-9.3). FT was predictive (Cox adjusted on treatment) of severe complications AUROC 0.79(76-82); P<0.0001, including primary liver cancer AUROC 0.84(80-87); P<0.0001. Similarly TE was predictive of severe complications AUROC 0.77(72-81); P<0.0001, including primary liver cancer AUROC 0.86(81-90); P<0.0001.

Conclusion

FibroTest and TE increase were associated with the occurrence of all severe complications including hepatocellular carcinoma, hepatic insufficiency and variceal bleeding. FibroTest increase was also associated with the occurrence of esophageal varices.

Keywords: FibroTest, Elastography, Fibrosis stages, Cirrhosis complications, Prognostic factors, Hepatocellular carcinoma, Surrogate markers

No full text is available. To read the body of this article, please view the PDF online.

Source

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Review Article

You have free access to this content

V. Carreño*

Article first published online: 26 NOV 2013

DOI: 10.1111/apt.12562

© 2013 John Wiley & Sons Ltd

Summary

Background

There are patients with chronic hepatitis C who are not eligible for the current interferon-based therapies or refuse to be treated due to secondary effects.

Aim

To provide information on alternative treatments for the management of these patients.

Methods

A PubMed search was performed to identify relevant literature. Search terms included hepatitis C virus, anti-inflammatory treatment, antioxidant, natural products and alternative treatment, alone or in combination. Additional publications were identified using the references cited by primary and review articles.

Results

Several approaches, such as iron depletion (phlebotomy), treatment with ursodeoxycholic acid or glycyrrhizin, have anti-inflammatory and/or anti-fibrotic effects. Life interventions like weight loss, exercise and coffee consumption are associated with a biochemical improvement. Other alternatives (ribavirin monotherapy, amantadine, silibinin, vitamin supplementation, etc.) do not have any beneficial effect or need to be tested in larger clinical studies.

Conclusions

There are therapeutic strategies and lifestyle interventions that can be used to improve liver damage in patients with chronic hepatitis C who cannot receive or refuse interferon-based treatments.

Introduction

Treatment of chronic hepatitis C virus (HCV) is aimed to eradicate HCV and to prevent liver disease progression. All currently approved anti-viral therapies against HCV are pegylated-interferon (PEG-IFN)-based. Response rates in patients with genotype 1 have increased with the implementation of the triple therapy of PEG-IFN plus ribavirin (RBV) plus protease inhibitors. However, around 25% of naïve patients with HCV genotype 1 infection and about 70% of null responders to previous anti-viral treatment do not respond to triple therapy.[1] In addition, there are patients in whom current therapies are contraindicated (low platelet count, advanced liver disease, coronary artery disease, autoimmunity, seizure disorders, pregnancy), or who are intolerant to IFN-based therapies or who refuse to be treated due to the side effects.[2, 3] IFN-free regimens are near approval for many patients but, while awaiting these new therapies, measures to slow liver disease progression (that could make future therapy difficult and less beneficial) should be adopted. Furthermore, there will be still some patients who could not be treated with these upcoming therapies. In the present review, other options for the treatment and clinical management of chronic hepatitis C are summarised.

Iron depletion and drug interventions

Phlebotomy

Iron overload is a common finding in patients with chronic hepatitis C and elevated iron indices are correlated with the progression of liver disease.[4, 5] An excess of iron induces formation of reactive oxygen species that activate hepatic stellate cells, which contribute to hepatic fibrogenesis.[6] Iron depletion via phlebotomy has been used as a collateral treatment of chronic hepatitis C. In the first report by Baconet al.,[7] eight patients who failed to respond to IFN were treated by weekly phlebotomy (500 mL) until iron deficiency was achieved (after 5–10 units of blood were removed). After phlebotomy, serum alanine amino transferase (ALT) fell in all but one patient, but serum HCV-RNA levels did not change. Following this report, several studies on iron depletion by phlebotomy in these patients have been published and the finding of that first report was confirmed.[8-16] Generally, phlebotomies (between 200 and 400 mL) have been applied in different studies (Table 1) with a weekly or monthly frequency to reach a decrease in ferritin up to 10 ng/mL,[8, 9, 20] although in some studies the limit of reduction was 50–60 ng/mL.[10, 11] The limit of reduction in haemoglobin was 11 g/dL.[13] In these studies, patients underwent repeated phlebotomies to maintain the iron deficiency state. Usually, the total amount of blood removed to achieve an iron deficiency state oscillated between 2.5 and 3.5 L and men needed around 0.5 L more blood removed than women.[8-11, 14, 17, 18, 21] In all these studies, a significant reduction in ALT and ferritin levels (the majority of the included patients had increased basal values of ferritin) was achieved. Time required to obtain this iron depletion was 5 ± 2 months.[9] The percentage of ALT normalisation oscillated between 10% and 69%.[8, 18] This percentage of normalisation increased with prolongation of therapy to maintain iron deficiency over time. These studies included patients who were nonresponders to anti-viral therapy or naïve patients with a similar response between them.[8-10, 18]Serum HCV-RNA levels did not change during or after treatment. No important secondary effects were observed during treatment. It has been reported ascitis development has been reported in two patients treated with phlebotomy who had a serum albumin <3.6 g/dL. Hence, in these type of patients, phlebotomy should be used with caution.[17]

Table 1. Summary of some studies on the effects of phlebotomy in chronic hepatitis C

Author (Ref.) Number of patients Phlebotomy Results
  1. ALT, alanine aminotransferase; AST, aspartate aminotransferase; gamma-GTP, gamma-glutamyl transpeptidase; HCC, hepatocellular carcinoma; Hb, haemoglobin.

Hayashiet al.[8] 10 200 or 400 mL weekly or monthly to reduce ferritin ≤10 ng/mL Significant reduction in ALT; 50% of patients normalised ALT; disappearance of iron deposits from liver (79% of patients)
Katoet al.[13] 34 200 mL weekly to reduce ferritin ≤10 ng/mL and/or Hb = 11 g/dL. Additional phlebotomies if Hb >11 g/dL 6 years) and low-iron diet Significant reduction in ALT; 65% of patients normalised ALT; significant improvements in liver necrosis, inflammation and fibrosis scores
Tanakaet al.[17] 19 200 or 400 mL biweekly for 6 months Significant reduction in ALT, AST and alpha-fetoprotein levels
Katoet al.[18] 35 200 g weekly to reduce ferritin ≤10 ng/mL. Monthly phlebotomies (44–144 months) and low-iron diet Significant reduction in ALT; 69% of patients normalised ALT; significant lower risk of HCC
Sartoriet al.[19] 28 250 mL bimonthly or monthly to reduce ferritin ≤35 ng/mL. Phlebotomies every 1–3 months (minimum 2 years) to maintain ferritin at ≤70 ng/mL Significant decrease in ALT, AST and gamma-GTP; 25% of patients normalised ALT; histological improvement in 43% of patients

The effect of phlebotomy on the liver histology of patients with chronic hepatitis C has been demonstrated in several reports. Thus, Yanoet al.[20] treated 25 patients with maintained phlebotomies (5 years) and included a control group (n = 13) who were nonresponders to interferon. A second liver biopsy was obtained more than 3 years after the beginning of phlebotomies. They observed a significant reduction in the fibrosis score from 2.3 to 1.7 in the phlebotomy group, while this score increased from 1.7 to 2.0 in the controls. Moreover, the severity of inflammation increased significantly in the control group (from 2.0 to 2.9), but remained unchanged in the phlebotomy group. Similar results were obtained by other authors.[19, 22] A high hepatic iron concentration before treatment has been reported associated with histological improvement.[19] Thus, up to 70% of patients with hepatic iron concentration greater than 20 μmol/g of dry tissue in the basal liver biopsy achieved histological improvement following mild iron depletion.

Some authors reported a high correlation between the baseline levels of ALT and their reduction after treatment and a trend towards a greater ALT reduction in patients with the highest baseline serum ferritin values.[9, 11] The possible effect of a low-iron diet (5–7 mg of iron per day) without phlebotomy in chronic hepatitis C has also been studied. Sumida et al.[21] demonstrated that, in patients under a low-iron diet for 6 months, a significant decrease in ALT levels was achieved, although to a lesser extent than that achieved by phlebotomies.

As it is known that iron absorption is significantly increased in an iron-deficient state,[23] several studies combined phlebotomies with a low-iron diet.[17, 18, 24] It has been demonstrated that this combination induces an additional effect in iron reduction therapy for chronic hepatitis C. Furthermore, a high percentage of ALT normalisation (69%) was obtained with this combination.[18] In one study, it was reported that, in patients with chronic hepatitis C and a partial response to phlebotomy, the addition of ursodeoxycholic acid (UDCA) might improve the biochemical parameters.[25] A decrease in ALT levels by phlebotomy was observed from 137 ± 72 to 75 ± 23 IU/L and a further significant reduction to 42 ± 16 IU/L after combination with UDCA.

Also, phlebotomy may lower risk of development of hepatocellular carcinoma (HCC). Kato et al.[18] treated 35 patients with chronic hepatitis C with weekly phlebotomy (200 mL), followed by maintenance phlebotomy for 44–144 months and a low-iron diet and they also studied a control group of 40 untreated chronic hepatitis C. They observed development of HCC in 8.6% of patients of the phlebotomy group and in 39% of the control group after 10 years of follow-up (P < 0.05).

In summary, all these data suggest that treatment with phlebotomy and low-iron diet during a prolonged time (3 years or more) may be useful for patients with chronic hepatitis C who are not eligible for PEG-IFN-based anti-viral therapy.

Ursodeoxycholic acid

Ursodeoxycholic acid has a direct protective effect on hepatocytes against apoptosis induced by endogenous bile acids and stimulates bile acid secretion hence reducing retention of toxic bile acids and therefore, cell injury.[26] Regarding HCV infection, Takano et al.[27]reported a randomised, controlled-dose trial in naïve patients with chronic hepatitis C who received 150 (n = 20), 600 (n = 18) or 900 (n = 19) mg/day of UDCA for 16 weeks. A significant decrease in ALT and gamma-glutamyl transpeptidase (gamma-GTP) levels was observed with doses of 600 and 900 mg compared to 150 mg, but serum HCV-RNA remained unchanged. The adverse effects of UDCA were not serious and the doses used were well tolerated. In another controlled study, 18 patients were treated with 600 mg/day of UDCA for 12 months and a significant reduction in serum aminotransferases and gamma-GTP values during UDCA treatment was found compared with the placebo group.[28] However, liver biopsies performed after 12 months of therapy did not demonstrate an improvement in the histological activity index scores with respect to the basal liver sample. Probably, the interval between both paired liver biopsies was too short to prove the effects of UDCA treatment on liver histology.

The majority of the posterior studies have confirmed that UDCA treatment in chronic hepatitis C decreases serum ALT and gamma-GTP levels, although with no anti-viral effect, 600 mg/day being the preferred UDCA dose.[29-36] However, in a large double-blind trial, 596 patients with chronic hepatitis C (including nonresponders to IFN treatment) were treated with UDCA at 150, 600 or 900 mg/day for 24 weeks and it was found that, although changes in ALT and aspartate amino transferase (AST) were similar between doses of 600 and 900 mg/day, gamma-GTP decreased significantly more in the group receiving 900 mg/day.[34] This suggests that increasing UDCA dose up to 900 mg/day may have additional benefits without compromising safety of therapy. Sato et al.[35] performed a dose-up trial from 600 mg to 900 mg/day of UDCA in patients with chronic hepatitis C (n = 25) or compensated liver cirrhosis (n = 7) for 24 weeks and reported that administration of 900 mg/day was more effective than 600 mg/day of UDCA for reducing aminotransferases and gamma-GTP levels.

In most of the published trials, UDCA was administered for 24 weeks, but longer treatment periods (12 and 24 months) are well tolerated and safe.[28, 32, 33] Omata et al.[34] prolonged UDCA therapy up to 104 weeks in 247 patients. In this extended period, an initial dose of 600 mg/day was adopted that could be increased to 900 mg/day. The authors observed a maintained decrease in ALT, AST and gamma-GTP over that period. Unfortunately, it was not reported in how many of those patients the UDCA dose was increased to 900 mg/day and neither whether adverse events were more severe or not. In our clinical experience, treatment of patients with chronic hepatitis C with higher UDCA doses (up to 20 mg/kg/day) and for longer periods (more than 5 years) is well tolerated and safe, and may induce a persistent decrease in the biochemical parameters.

Only few articles have studied the predictive factors of response to UDCA in chronic hepatitis C, but results should be taken with caution because of the different UDCA schedules used and the heterogeneity of the patients (naïve patients, nonresponders to previous IFN therapy and patients with liver cirrhosis.). Thus, a better response to treatment has been associated with low basal ALT levels, high basal values of gamma-GTP, low histological activity index scores or even with the presence of liver cirrhosis.[32-34] Also it was found that the response was independent of HCV genotypes or HCV-RNA levels.[32, 33]

As levels of aminotransferases have been associated with progression of liver fibrosis,[37] the decrease in ALT levels with UDCA treatment could reduce the risk of development of HCC. Tarao et al.[38] showed that, in 56 patients with early-stage liver cirrhosis due to HCV infection who received UDCA for 37.3 ± 15.9 months, the cumulative incidence of HCC over 5 years was significantly lower (10/56: 17.9%) than in the group of 46 patients who did not received UDCA (18/46: 38%). The results suggest that UDCA treatment may prevent HCC development in patients with chronic hepatitis C. Thus, UDCA treatment may be a possible alternative for patients with chronic hepatitis C who are not candidates for currently approved anti-viral treatments.

Other agents

Several studies have assessed the possible role of RBV monotherapy in patients with chronic hepatitis C, either naïve or nonresponders to anti-viral therapy. These studies administered RBV twice daily, most of them using a dose of 1000–1200 mg.[39-49] The treatment duration oscillated between 12 weeks up to 24 months.[39, 46] A significant decrease in ALT levels was observed in these studies, ranging from 30% (only 2 or 4 weeks of treatment) to 75%.[47, 48] The frequency of ALT normalisation during treatment usually was around 40–60%,[44, 45, 48] reaching 66% after 24 months of treatment.[46] The mean time to ALT normalisation was approximately 8 weeks[40, 43, 44], but in the majority of the studies, ALT levels returned to pre-treatment values in all patients within 2–3 months after discontinuation of therapy.[40, 43-46] During treatment, no effect of RBV on HCV-RNA was observed in most of the trials.[42-46, 48, 49] It has also been reported that patients with basal lower levels of ALT and of serum HCV-RNA responded more frequently.[44, 45] Regarding liver histology, several studies demonstrated an improvement in hepatic inflammation and necrosis when comparing basal and final liver biopsies,[42, 44-46] especially among those patients who normalised ALT values, although no changes in fibrosis were noted.[46, 49] It should be remarked that an increase in hepatic iron has been documented in patients under RBV therapy.[46, 49] The most frequent secondary effects of RBV treatment were haemolysis, anaemia, skin disorders (pruritus, rash, dry skin), nervous system disorders (depression, insomnia, somnolence, vertigo), increases in bilirubin concentration, uric acid and platelets.[43, 45, 49] All these effects disappeared when treatment was stopped.

In summary, RBV may decrease ALT levels and may improve liver histology in a proportion of patients with chronic hepatitis C. However, taking into account the relatively small number of patients included, the short administration period and the potentially harmful of hepatic iron accumulation with RBV treatment, the general use of this drug as monotherapy cannot be recommended for chronic hepatitis C.

Colchicine was found to be an anti-fibrotic agent in animal models. However, a meta-analysis of 15 randomised clinical trials concluded that colchicine should not be used, as it has no beneficial effect on liver fibrosis.[50]

Amantadine is a symmetric tricyclic amine that inhibits replication of influenza A virus. This drug has been administered as monotherapy to naïve patients with chronic hepatitis C or nonresponders to IFN or IFN/RBV treatment, at doses of 200 mg/day for 6 or 12 months.[51-54]In all these studies, although no anti-viral effect was found, a significant decrease in ALT levels was observed with respect to basal values. However, the total number of patients treated with amantadine alone is low and hence its use cannot be recommended.

The metabolic syndrome, which includes hepatic steatosis, hypercholesterolaemia, hypertriglyceridaemia and insulin resistance/diabetes, is a common feature in patients with chronic hepatitis C.[55] As the metabolic syndrome is associated with hepatic inflammation and fibrosis,[56] it is important to assess and lower increased cholesterol, triglycerides and glucose concentrations. Statins are potent drugs for reducing circulating low-density lipoprotein cholesterol levels. Statins also have anti-inflammatory, antioxidant and anti-thrombotic effects.[57] Clinical studies have reported controversial results on the activity of statins against HCV.[58-67] However, statins must be prescribed for high cholesterol levels to HCV-infected patients, as hypercholesterolaemia is associated with steatosis and potential progression of liver disease.

Pioglitazone and metformin are used to improve glycaemic control in patients with type-2 diabetes. Chojkier et al.[68] studied whether pioglitazone has an anti-viral effect in chronic HCV infection. They included 20 overweight patients with genotype 4 chronic hepatitis C who received 30 mg daily of pioglitazone for 14 days. Serum HCV-RNA and ALT values were significantly decreased at the end of therapy with respect to basal levels. Metformin has been proven to be effective in reducing the incidence of HCC in patients with HCV-related cirrhosis and with type 2 diabetes.[69] Both drugs seem to have a beneficial effect on liver disease progression in patients with chronic hepatitis C and type-2 diabetes, although further evidences are needed to confirm these findings.

Antioxidants

Oxidative stress is thought to play a role in the pathogenesis of chronic hepatitis C because oxidative stress occurs early during HCV infection and increases with disease progression and severity.[70] Vitamin deficiencies are common among patients with chronic hepatitis C and thus vitamin supplementation provides a basis for their therapeutic use.[71] Vitamins C, D and E are the most investigated as antioxidant therapy in chronic liver diseases. However, there are no studies on the efficacy of vitamin C as monotherapy, while vitamin D did not show beneficial effect when administered to patients with chronic hepatitis C.[72] Vitamin E (1200 IU/day) administration for 8 weeks to nonresponder patients to IFN significantly decreased the index of oxidative stress in liver biopsy, but did not significantly affect ALT levels, HCV-RNA titres or the histological degree of hepatocellular inflammation or fibrosis.[73] However, in another study, vitamin E at doses of 800 IU/day for 12 weeks reduced serum ALT values by 46% (and AST by 35%) at the end of treatment, although ALT and AST returned to baseline levels 1 month after therapy discontinuation.[74] Oral vitamin E supplementation (500 mg/day) given for 3 months resulted in modest reduction in serum ALT levels and improved oxidative stress in those patients with initial ALT levels >70 IU/L.[75] In patients with HCV-related cirrhosis, bedtime administration of 900 IU/day vitamin E for 6 months almost normalised ALT values, but only in the vitamin E-deficient individuals.[76]

The preventive effect of vitamin E on hepatocarcinogenesis has been investigated in patients with HCV-related liver cirrhosis. ALT levels, platelet counts, serum albumin and total cholesterol were not different compared with controls, untreated patients during the 5-year survey. The administration of vitamin E did not improve liver function, suppress hepatocarcinogenesis or improve cumulative survival.[77]Vitamin E is nontoxic even at elevated doses (≥500 mg/day) over extended periods of time (from 6 months up to 5 years).[73-77] On the other hand, the efficacy of vitamin E is more evident among patients with vitamin E deficiency and in those with moderately elevated ALT values.[75]

When combined, daily supplementation with vitamin C (500 mg) and vitamin E (800 mg) plus zinc (40 mg) for 6 months reduced ALT values in previously untreated HCV patients.[78] In contrast, daily doses of ascorbic acid (500 mg), D-alpha-tocopherol (945 IU) plus selenium (200 μg) for 6 months had no significant effects on ALT values or the viral load.[79] The hepatoprotective and anti-inflammatory effects of silybin-phospholipids and vitamin E complex (SPV complex) have been investigated in patients with chronic HCV infection. SPV complex administered for 3 months had a significant and persistent reduction in ALT and AST serum levels.[80]

Multi antioxidant (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, l-glutathione and alpha-tocopherol) oral daily treatment for 20 weeks may decrease viral load and ameliorate necro-inflammation in some patients.[81] Combined oral and intravenous antioxidant therapy was associated with a decline in ALT levels and mild anti-inflammatory effects in chronic hepatitis C patients who were nonresponders to IFN.[82] Other antioxidants, such as resveratrol and astaxanthin, are not suitable as an antioxidant therapy for chronic hepatitis C.[83]

In conclusion, the data available suggest some benefits of vitamin E in reducing serum ALT concentrations, most likely in cases with vitamin E deficiency. Most studies involving antioxidant therapy (including vitamin supplementation other than vitamin E) failed to show any beneficial effect on HCV-RNA levels or liver histology in chronic hepatitis C.[71, 84] The results of the clinical studies are difficult to interpret because of the small sample sizes, short follow-up duration, inadequate end points and, finally, failure to demonstrate tissue delivery and antioxidant efficacy.[85]

Other compounds like S-adenosyl-methionine or acetylcysteine when administered alone do not show significant effect on ALT levels,[86, 87] and hence their use is not recommended.

Immune modulators and cytokines

Viusid, a nutritional supplement, may improve oxidative stress and immunological parameters in patients with chronic hepatitis C. In patients with HCV-related decompensated cirrhosis, it seems to improve survival, disease progression and prevent HCC development. However, low numbers of patients have been analysed and the studies did not show effects on HCV-RNA levels.[88, 89]

Interleukin (IL)-10 is a cytokine that down-regulates the pro-inflammatory immune response and has a modulatory effect on liver fibrogenesis. IL-10 treatment induced ALT normalisation in 86% of patients and improved liver histology, but an increase in HCV-RNA was observed.[90, 91] Hence, IL-10 treatment is discouraged for patients with chronic hepatitis C.

Interleukin-12 and Thymosin alpha 1 have also been administered to patients with chronic hepatitis C, with no effects on ALT values or HCV-RNA levels.[92-94] Other molecules with immunomodulatory properties, such as the glycoconjugate AM3, have been investigated in vitro,[95] but not administered therapeutically to patients with chronic hepatitis C.

Natural products

Glycyrrhizin

Glycyrrhizin is a natural component extracted from the roots of Glycyrrhiza glabra that inhibits in vitro the release of infectious HCV particles.[96] Different studies have been published using glycyrrhizin as therapy in patients with chronic hepatitis C.[97-101] The pharmacological composition of the treatment with glycyrrhizin is a solution of 0.2% glycyrrhizin, 0.1% cysteine and 2% glycine in physiological solution.[97] Glycyrrhizin has been administered directly into a peripheral vein in a 3- to 5-min period,[100] but patients may be treated as out-patients. Several reports have demonstrated that glycyrrhizin significantly reduces ALT levels in patients with chronic hepatitis C.[97-103] However, different doses and schedules of administration have been used. Thus, van Rossum et al.[98] performed a double-blind randomised placebo-controlled trial giving 80, 160 or 240 mg of glycyrrhizin or placebo to 57 chronic hepatitis C patients (nonresponders to interferon or unlikely to respond). The medication was administered intravenously thrice weekly for 4 weeks. The mean ALT decrease at the end of the active treatment was 26%, which was significantly higher than that of the placebo group (6%), but after the end of therapy, a rebound in ALT levels was observed. The eficacy of the treatment was similar among doses of 80, 160 and 240 mg, but glycyrrhizin had no effect on HCV-RNA concentration. This finding has been confirmed in other studies.[99-101, 103] The time elapsed since the beginning of the treatment until ALT decrease varied between 2 days to 2 weeks,[98, 101] while the percentage of ALT normalisation oscillated between 10% and 35.7%.[97-99] It seems that the frequency of ALT normalisation depends on the duration of treatment. Thus, the highest frequency (35.7%) was achieved with a continuous administration of glycyrrhizin for a period of 2–16 years (median 10.1 years).[97]

Glycyrrhizin treatment schedules of six, five, three times per week or one time per week for 26–52 weeks have been evaluated. [100, 101]From both studies, it is concluded that the optimal schedule of glycyrrhizin administration is five to six times per week for a minimum of 26 weeks.

In relation to the response to glycyrrhizin, sex, age, HCV genotype, viral load, presence of liver cirrhosis, height, weight, body mass index, baseline ALT levels, inflammation or fibrosis were nonpredictive for ALT response.[100] Regarding the effect of glycyrrhizin on liver histology, an improvement in the necrosis score was found after 52 weeks of treatment in 45–46% of the patients when comparing basal and final liver biopsies.[101] ALT responders presented a tendency towards improvement of the inflammation score, while nonresponders had a deterioration.[100]

The possible efficacy of glycyrrhizin therapy to prevent the development of HCC in patients with chronic hepatitis C has been evaluated in several studies.[97, 104-107] Arase et al.[97] treated 84 patients with 100 mL of glycyrrhizin for 2–16 years (median 10.1 years) and compared the results with a control group of 104 patients of similar characteristics. They found a cumulative HCC incidence rate significantly lower in the treated group than in the controls (12% vs. 25%) after 15 years. In a similar study, Ikeda et al.[106] treated 244 patients with chronic hepatitis C and nonresponders to IFN therapy with intravenous glycyrrhizin for 6 years or longer and they also included an untreated group of 102 patients. They found that glycyrrhizin therapy significantly decreased the hepatocarcinogenesis rate. These results have also been reported by other authors,[104, 105] especially among those patients treated with glycyrrhizin who normalised ALT levels.[105] Also, the liver cirrhosis occurred less frequently in 178 patients than in 100 control patients after 15 years of glycyrrhizin treatment (28% vs. 40% respectively, P < 0.002).[104] With respect to the secondary effects of the treatment, it has been proven that it can induce pseudo-aldoteronism.[108] Thus, aggravated hypertension (8.7%), hypertension (5.1%) and hypokalaemia (3.6%) have been reported with a schedule of administration of five times per week of glycyrrhizin.[101] Other described side effects were arrhythmia and thrombophlebitis related to daily intravenous administration, although glycyrrhizin was generally well tolerated.[100]

Tsubota et al.[102] performed a randomised controlled study to determine whether the combination of glycyrrhizin plus UDCA may improve the efficacy of glycyrrhizin administration alone in chronic hepatitis C. Patients (n = 170) were treated with intravenous glycyrrhizin three times per week for 24 weeks alone or in combination with a daily oral dose of 600 mg of UDCA. Overall, AST and ALT decrease during treatment was significantly greater in the group receiving combined therapy than in the group receiving glycyrrhizin alone. Platelet count, serum total protein, albumin and bilirubin did not change in either group. Unfortunately, no further studies have been published using this combined treatment.

Finally, Tanaka et al.[109] conducted a randomised study to evaluate if addition of minor phlebotomy to glycyrrhizin treatment further reduced ALT values in chronic hepatitis C. A total of 36 patients were assigned to the group of glycyrrhizin plus phlebotomy and another 36 patients to glycyrrhizin alone. Phlebotomy was performed before every glycyrrhizin injection to a total 60 mL of blood per week until reaching a ferritin level of 20 ng/mL. If so, phlebotomy was suspended, but was resumed as needed to maintain that ferritin level. The volume of glycyrrhizin varied between 111 and 127 mL per week. Patients treated with phlebotomy and glycyrrhizin presented a significant decrease in ALT values, while no changes were seen in patients treated with glycyrrhizin alone. The tolerance was good. However, these results have not been confirmed.

Glycyrrhizin has also been administered as suppository (300 mg) for 12 weeks to 13 patients with chronic hepatitis C in comparison to another 13 patients who received it intravenously with a similar efficacy in both groups.[110] Xianshi et al.[111] showed that oral administration of glycyrrhizin (7.5 mg) twice a day can significantly improve liver tests in chronic hepatitis B, but its effect on chronic hepatitis C has not been documented.

In summary, glycyrrhizin may be useful to decrease ALT levels, to improve liver histology and to reduce the risk of HCC. However, the route of administration (intravenous) limits its possible application and there is a need to study its efficacy when administered by other routes (suppository, oral).

Silymarin/Silibinin

Silymarin, an extract of the milk thistle (Silybum marianum), and its components have anti-viral activity against HCV in vitro.[112-117] Apart from its anti-viral capacity, silymarin has antioxidant, anti-inflammatory, anti-proliferative, anti-fibrotic and immunomodulatory activities[112, 114] that may have hepatoprotective effects.

Oral silymarin has been used in the treatment of patients with chronic hepatitis C, either naïve or nonresponders to previous anti-viral therapy[118-122] at total daily doses ranging from 149 to 2.1 g for 1 week to 1 year. All these studies showed that silymarin was safe and well tolerated, but it had no effect on ALT or serum HCV-RNA levels. The lack of efficacy of oral silymarin in the treatment of chronic hepatitis C is probably due to the low bioavailability of this compound.[121]

The main component of silymarin is silibinin, which is a mixture of the flavonolignans silybin A and silybin B. To circumvent its rapid metabolisation after oral administration,[123] silibinin has been administered intravenously in the form of a water-soluble succinate conjugate. Some studies have reported the administration of intravenous silibinin at doses ranging from 5 to 20 mg/kg/day to nonresponder patients to PEG-IFN/RBV or to PEG-IFN + RBV + protease inhibitor therapy.[124-126] Silibinin had an important anti-viral activity, with clearance of serum HCV-RNA in up to 87% of the patients.

Regarding secondary effects, increase in serum bilirubin levels is observed during silibinin treatment, returning to basal values when the therapy is stopped. Other side effects are mild gastrointestinal symptoms (nausea, abdominal pain and diarrhoea) during the first day of administration.

Taking together, all these studies have shown that silibinin has anti-viral activity against HCV, but the total number of patients included in these studies (n = 88) is small and the effect of silibinin on ALT levels has not been reported. Moreover, predictive factor of response to silibinin and its impact on liver histology are unknown. An important drawback of silibinin is that it must be administered intravenously due to its rapid metabolisation after oral administration. Very recently, new methylated analogues of silybin B with higher bioactivity and anti-viral properties in vitro have been developed.[127] Whether these analogues have also a higher bioactivity in vivo has not been tested. In summary, although silibinin is a promising agent for the treatment of patients who cannot receive standard anti-viral therapy, it cannot be recommended, as the optimal dose of silibinin, duration of treatment and its effect on liver disease progression remain to be determined.

Other natural products

Several compounds extracted from plants and fruits, such as Epigallocatechin-3-gallate (green tea extracts), naringenin (a flavonone present in grapefruit), proanthocyanidin (isolated from blueberry leaves) or curcumin (a polyphenol isolated from the curry spice turmeric), have been shown to have anti-viral properties against HCV in vitro, but no clinical studies have been reported on their real efficacy and safety in patients with chronic hepatitis C.[128-136] Extracts of Spirulina platensis (a blue-green algae) and artichoke leaves have been shown to be ineffective when administered to patients with chronic hepatitis C in pilot studies.[137, 138]

Other herbal preparations have been tested in clinical trials,[139-141] and, although some of them seem to have anti-inflammatory or anti-viral activities, there are no convincing data to suggest a definite histological and/or virological improvement due to nonstandardised formulations and lack of information about the potential active compounds. In addition, the hepatotoxicity of herbal remedies is still a major concern.

Lifestyle interventions

Diet and exercise

Obesity is becoming a major health problem in Western countries. In patients with chronic HCV infection, obesity is associated with steatosis and progression of liver fibrosis.[142] Caloric restriction diet and/or physical activity induce an improvement in biochemical parameters and liver histology in individuals with non-alcoholic steatohepatitis.[143-145] Therefore, weight reduction could be a useful management strategy for overweight patients with chronic hepatitis C. In this regard, Hickman et al.[146] included 19 patients with chronic HCV infection and steatosis demonstrated by a liver biopsy in a 3-month weight reduction programme. The programme consisted of individualised energy restriction (from a mean of 2740 calories per day to a mean of 1620 calories per day) and exercise regimen for 12 weeks. In 10 of the patients, a second liver biopsy was obtained 3–6 months after completion of the programme. At the end of the intervention, weight loss was associated with a significant decrease in ALT levels. In the second liver biopsy, a significant reduction in steatosis was observed in 9/10 patients and fibrosis improved in 5 of them. In another study,[147] 35 overweight patients with chronic hepatitis C and steatosis were included in a 15-month lifestyle intervention: 3 months of an energy restriction diet with 150 min of aerobic exercise per week followed by 12 months of weight maintenance. It was found that weight loss correlated with a decrease in ALT levels. In those patients who maintained the weight loss after 15 months, ALT values remained significantly lower than the basal levels.

Regarding exercise alone, a study with 17 patients proved that exercise consisting of walking, synchronised breathing and focused attention (breathwalk) for an hour, three times a week for 6 months induced a significant decrease in ALT and bilirubin levels, even in patients who did not lose weight.[148] Also it has been shown that aerobic exercise (walking at least 8000 steps per day) for 6 months significantly reduces ALT values.[149] Lifestyle intervention aimed at weight loss could be of benefit in patients with chronic hepatic C as it reduces liver damage. Aerobic exercise may be recommended due to its effect on ALT levels.

Nutritional recommendations

An appropriate dietary intake is important not only to avoid development of liver steatosis but also because there are dietary nutrients that may have hepatoprotective effects or may cause hepatic injury.

Consumption of soft drinks with high fructose corn syrup must be moderate, as an excessive fructose intake is associated with development of non-alcoholic fatty liver disease[150] Resveratrol, a component of red wine, is a popular nutritional supplement due to its antioxidant effect.[151] In vitro studies have shown that resveratrol enhances HCV replication, but prevents HCV-induced steatosis.[83, 152] These contradictory results, and the lack of studies in patients with HCV, discourage recommendation of resveratrol in these patients. Foods rich in polyunsaturated fatty acids (olive oil, corn oil, oily fish etc.) are advisable, as these fatty acids improve lipid profile and may have anti-HCV activity.[153]

The effect of zinc supplementation in patients with chronic hepatitis C has also been assessed. In a first study,[154] 14 patients received 50 mg/day of zinc for 6 months and the authors found a significant decrease in ALT values with no anti-viral effect. In another study,[155] 32 patients with chronic hepatitis C or HCV-related liver cirrhosis were treated with 33.9 mg of zinc daily for 3 years and the patients experienced a significant reduction in AST and ALT levels, but not in HCV-RNA titres. These patients continued with zinc supplementation for a mean time of 7 years and it was found that the incidence of HCC was significantly lower in patients receiving zinc when compared with a control group.[156] No side effects were reported. However, the results of the studies have to be interpreted with caution as patients, both in the zinc supplementation group and control, were receiving other treatments such as UDCA, and hence it is not possible to determine if the observed effect is attributable only to zinc or to its combination with another drug.

As mentioned before, iron overload is common in chronic hepatitis C and it can accelerate liver damage. Some authors have reported that haemochromatosis gene (HFE) mutations in chronic HCV infection are independently associated with iron loading and the severity of liver disease,[157, 158] and hence a low-iron diet could be recommendable in these patients. However, other studies have not found such association.[159, 160] In any case, HCV-infected patients should avoid dietary compounds that may increase iron absorption, like citrate or ascorbate. By contrast, intake of compounds containing tannins, like tea, is advisable as they inhibit iron absorption.

Coffee consumption is beneficial in chronic hepatitis C. Thus, Freedman et al.[161] analysed the baseline characteristics of 766 patients with chronic hepatitis C and found that higher coffee consumption was associated with a lower AST/ALT ratio, less steatosis and lower levels of alpha-foetoprotein. After 4 years of follow-up, the authors showed that patients who drank three or more cups of coffee per day had a 53% lower risk of liver disease progression than those who took less than three cups. In another study in which 121 patients with chronic HCV infection were studied, Modi et al.[162] reported that coffee consumption was associated with a reduced hepatic fibrosis. The effect of coffee was not linear and the threshold below which no protective effect was observed was established in 308 mg of caffeine (two to three cups of coffee) per day. This protective effect was not observed in patients who consumed caffeine from other sources, such as tea or caffeine-containing sodas.[162] Finally, Costentin et al.[163] studied 218 patients with chronic hepatitis C and observed that coffee consumption was inversely correlated with the activity grade on the liver biopsy. In this study, the threshold for a beneficial effect on liver inflammation was 408 mg of caffeine (three to four cups of coffee) per day.

In the light of these results, consumption of two to four cups of regular coffee per day should be recommended to patients with chronic hepatitis C, as it may help slow liver disease progression.

Alcohol/smoking

Alcohol consumption, even moderate, and smoking must be forbidden in patients with chronic hepatitis C, as these habits increase the risk of histological progression of liver damage.[164-166]

A summary of the clinical management of patients with chronic HCV infection not suitable for current anti-viral therapies is shown in Figure 1.

apt12562-fig-0001

Figure 1. Management of patients with chronic hepatitis C who are not suitable for current interferon-based therapies.

Conclusions

Several approaches may be used to treat patients with chronic hepatitis C who are not candidates for PEG-IFN based therapy. Phlebotomies in combination with a low-iron diet may induce a beneficial effect. If a favourable response is achieved, a deficiency iron status should be maintained over a prolonged period. UDCA, at dose of 900 mg, may be useful in the management of these patients. Glycyrrhizin may be considered, but the intravenous administration route implies a limitation for its general use. Metabolic disorders, if present (increased levels of cholesterol, triglycerides, glucose), must be treated. In overweight patients with chronic hepatitis C, a diet to reduce weight is desirable. Physical exercise, even if no weight is lost, may be recommended in these patients. Finally, coffee consumption is helpful, while alcohol intake and smoking are strictly forbidden.

Authorship

Guarantor of the article: Vicente Carreño.

Author contribution: Vicente Carreño performed the literature review, analysed the data, wrote the paper and approved the final version of the manuscript.

Acknowledgement

Declaration of personal and funding interests: None.

References

Source