August 21, 2013

Hepatitis C virus: Antiviral therapy in wait-listed patients

Clinical Liver Disease

Volume 2, Issue 4, pages 173–176, August 2013

Review

Asmeen Bhatt M.D., Ph.D.*, Gregory T. Everson M.D.

Article first published online: 19 AUG 2013

DOI: 10.1002/cld.225

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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Recurrent infection with hepatitis C virus (HCV) after liver transplantation (LT) is universal in patients who are viremic at the time of transplantation. Recurrent HCV is associated with reduced graft survival and increased patient mortality.1, 2 Current antiviral treatments for established posttransplant recurrence are characterized by low rates of virological clearance, poor tolerability, cytopenias, infections, drug interactions with immunosuppressants, and a risk of allograft rejection. In addition, allografts are often significantly damaged by HCV by the time of the initiation of antiviral treatment.3 Preventing the recurrence of HCV infection is desirable.

Pretransplant antiviral therapy for wait-listed patients is one strategy for preventing allograft reinfection by HCV. In some cases, achieving a sustained virological response (SVR) might stabilize or reverse the liver disease and potentially prevent the need for LT. However, for most wait-listed patients, the primary goal is rendering the blood free of HCV at the time of transplantation to achieve posttransplant viral clearance, which is defined as HCV RNA being undetectable 12 weeks or more after transplantation [posttransplant viral response (pTVR)]. Achieving pTVR eliminates the risk of recurrence and should preserve graft function, increase graft survival, and improve patient outcomes and survival.4, 5, 6, 7 Despite the potential benefits, the effectiveness of pretransplant treatment is dependent on the potency and tolerability of the antiviral regimen and the severity of the underlying liver disease.

Interferon-Based Treatment

Current treatment options are limited. The standard of care for HCV genotype 1 (GT1) is peginterferon (PEG)/ribavirin (RBV) plus either telaprevir or boceprevir (triple therapy).8, 9, 10, 11, 12 For non-1 genotypes, the standard of care is PEG/RBV alone.13, 14, 15 These treatments are less effective in patients with cirrhosis because of reduced virological responses and poor tolerability.

Patients with HCV on the waiting list exhibit a wide range of disease severity, which affects selection for treatment. Interferon-related side effects, adverse reactions, and serious adverse events occur with greater frequency and severity in patients with decompensated cirrhosis. Patients with high Model for End-Stage Liver Disease (MELD) scores or clinical complications such as ascites, variceal hemorrhage, and encephalopathy are poor candidates because they are at increased risk for serious infections, hepatic decompensation, and even death. Thus, interferon-based treatment is limited to patients with MELD scores < 18 and lesser hepatic impairment, such as potential recipients of living donor grafts and potential recipients of deceased donor grafts with MELD upgrades for hepatocellular carcinoma.

The Low Accelerating Dose Regimen-Adult-to-Adult Living Donor Liver Transplantation Study (LADR-A2ALL) was a randomized controlled trial of PEG/RBV treatment.16 Candidates included HCV patients with either potential living donors or MELD upgrades for hepatocellular carcinoma. Among the treated GT1/genotype 4 (GT4)/genotype 6 (GT6) patients, 23 of 30 received a transplant, and 22% of these patients achieved pTVR. Among the treated genotype 2 (GT2)/genotype 3 (GT3) patients, 21 of 29 received a transplant, and 29% of these patients achieved pTVR. The likelihood of achieving pTVR was related to the duration of treatment: 50% of the patients who received the treatment for >16 weeks achieved pTVR (P = 0.01; Fig. 1). The overall pTVR rate reported in this study (25%) was similar to the rates reported by Everson et al.17 (26%), Forns et al.18 (23%), and Carrión et al.19 (23%). In all of these studies, some treated patients experienced serious, even life-threatening adverse events (mainly infections). Antibiotic prophylaxis to prevent spontaneous bacterial peritonitis is recommended. Patients with cirrhosis frequently have baseline cytopenias that worsen during treatment. In LADR-A2ALL, 75% of the treated patients required an erythropoietin analogue or granulocyte colony-stimulating factor, alone or in combination.16 Eltrombopag can raise platelet counts and potentially improve the chances for SVR, but it carries a risk for portal vein thrombosis and hepatic decompensation.20

nfig001

Figure 1. Results of pretransplant treatment with the low accelerating dose regimen in LADR-A2ALL.16 The likelihood of pTVR was related to the duration of treatment: the pTVR rate was 50% for patients receiving greater than 16 weeks of PEG/RBV. At LTx refers to the HCV RNA status at the time of LT; pTVR indicates undetectable HCV RNA 12 weeks or more after transplantation.

Patients infected with HCV GT1 currently have the option to be treated with triple therapy. The A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir (ADVANCE),9 Illustrating the Effects of Combination Therapy with Telaprevir (ILLUMINATE),11 and Serine Protease Inhibitor Therapy-2 (SPRINT-2) studies10 showed that patients with cirrhosis have much higher rates of SVR when they are treated with triple therapy versus PEG/RBV. SVR with triple therapy is also predicted by the responsiveness to interferon. Patients who have interleukin-28b polymorphism CC (versus CT or TT), a greater than 1 log10 drop in HCV RNA during the lead-in with PEG/RBV, or a relapse response to prior PEG/RBV are more likely to achieve SVR when they are treated with triple therapy.8, 9, 10, 11, 12

There is limited information regarding the use of triple therapy in wait-listed patients. Verna et al.21 presented results for 28 HCV GT1 patients awaiting LT. Nine (32%) discontinued treatment because of adverse events, a null response, relapse, hepatic decompensation, or death. Rates for achieving undetectable HCV RNA were 50%, 71%, and 80% at weeks 4, 8, and 12, respectively. Eight patients (28%) underwent LT, and six of them had undetectable HCV RNA after transplantation (pTVR rate = 75%). One patient with pTVR received only 3 weeks of triple therapy. Among the transplant patients, 75% were treatment-experienced, and 88% had hepatocellular carcinoma. There were two deaths: one before transplantation (due to an unknown cause) and one after transplantation (due to sepsis).

This early experience suggests that pretransplant treatment using triple therapy may be more effective than PEG/RBV alone in achieving pTVR in patients with an HCV GT1 infection. However, the treatment is complicated by serious side effects, adverse events, and potentially life-threatening complications. Anemia is a major problem requiring RBV dose reduction, the use of erythropoietin analogues, and blood transfusions.

Abbreviations

1st first-generation drug, 2nd later generation drug, 5aI inhibitor of nonstructural 5A protein, DAA direct-acting antiviral, GT1 genotype 1, GT2 genotype 2, GT3 genotype 3, GT4 genotype 4, GT5 genotype 5, GT6 genotype 6 ,HCV hepatitis C virus, LADR-A2ALL Low Accelerating Dose Regimen-Adult-to-Adult Living Donor Liver Transplantation Study, LT liver transplantation, MELD Model for End-Stage Liver Disease, NI nucleos(t)ide-based inhibitor of nonstructural 5B polymerase, PEG peginterferon, PI inhibitor of nonstructural 3/4A protease, pTVR posttransplant viral response, RBV ribavirin, SOF sofosbuvir, SVR sustained virological response

Emerging Drugs and Interferon-Free Treatment

The next wave of antiviral drugs for HCV may include sofosbuvir (SOF; nonstructural 5b polymerase inhibitor), simeprevir (nonstructural 3/4a protease inhibitor), faldaprevir (nonstructural 3/4a protease inhibitor), and daclatasvir (nonstructural 5a protein inhibitor). These drugs have greater potency, a lower potential for drug-drug interactions, once daily dosing, a shorter duration of therapy, and fewer side effects. The increased tolerability should expand the pool of pretransplant patients who could be candidates for treatment22 (Table 1).

Table 1. Speculations Regarding Future Drug Regimens for Pretransplant Treatment, Timelines, and Potential or Expected SVR or pTVR Rates, Treatment Durations, and Severity of Side Effects

Genotype Year Treatment Options SVR or pTVR Rate (%) Optimum Duration of Treatment (%) Severity of Side Effects
<8 Weeks 8-16 Weeks >16 Weeks
  1. This table was adapted with permission from Clinics in Liver Disease.22 Copyright 2013, Elsevier.

  2. Abbreviations: 1st, first-generation drug; 2nd, later generation drug; 5aI, inhibitor of nonstructural 5A protein; NI, nucleos(t)ide-based inhibitor of nonstructural 5B polymerase; PI, inhibitor of nonstructural 3/4A protease. + shows severity of side effects, where + is minimum and +++++ is maximum side effects.

GT2 or GT3 2013 PEG/RBV 29-50 100 ++++
≥2013 RBV-NI >65 20 80 +
GT1a or GT1b 2013 PEG/RBV 20-25 100  
2013 PEG/RBV + PI-1st 40 80 20 +++++
≥2013 PEG/RBV + PI-2nd 55 80 20 +++
≥2014 PEG/RBV-5aI 55 80 20 +++
≥2014 PEG/RBV-NI >60 100 ++
≥2014 RBV-NI >55 100 +
≥2014 Multi-DAA >60 20 80 ++
GT1b ≥2014 5aI + PI-2nd >60 20 80 +
GT1a >2014 PEG/RBV + 5aI + PI-2nd >60 20 80 ++

GT1 [and GT4, Genotype 5 (GT5), and GT6]

The initial use of SOF, simeprevir, faldaprevir, or daclatasvir in patients infected with HCV GT1, GT4, GT5, or GT6 is likely to be in combination with PEG/RBV. In a trial of treatment-naive patients, 17% of whom had cirrhosis, 12 weeks of SOF/PEG/RBV achieved an SVR rate of 92% in patients without cirrhosis and an SVR rate of 80% in patients with cirrhosis23 (Fig. 2). In studies of simeprevir/PEG/RBV, 85% to 93% of patients had a rapid virological response and qualified for a reduced treatment duration of 24 weeks. Overall, 79% to 81% of patients achieved SVR despite F3/F4 fibrosis in 22% to 31% of the cases (Medivir press releases, December 2012). Clearly, the new drugs offer advantages over both telaprevir and boceprevir: higher potency, ease of dosing, and fewer side effects. However, virological responses may be further impaired in sicker wait-listed patients who have more advanced liver disease.

nfig002

Figure 2. Impact of cirrhosis on SVR with SOF-based treatment.23, 27 Cirrhosis reduces the likelihood of achieving SVR during SOF treatment. This effect of cirrhosis is true whether patients are treatment-naive (GT1 and GT3); interferon-ineligible, intolerant, or unwilling (GT3); or treatment-experienced (GT2 and GT3). The negative impact of cirrhosis on SVR can be at least partially reversed by an extension of the duration of SOF/RBV treatment (GT2 and GT3). P stands for PEG/RBV, % SVR 12 stands for sustained viral response at 12 weeks post treatment. Weeks indicated in the X-axis are duration of total treatment.

Preliminary results with multi direct-acting antivirals (DAAs), interferon-free regimens in HCV GT1 patients without cirrhosis are very encouraging.24, 25, 26 SVR rates approach 100% with few, if any, side effects or adverse reactions. Promising combinations, with or without RBV, include SOF/ledipasvir, SOF/daclatasvir, SOF/simeprevir, daclatasvir/asunaprevir, daclatasvir/asunaprevir/BMS-791325, and ABT-450/r/ABT-333/ABT-267. We must emphasize that none of these regimens has been adequately tested in patients with cirrhosis (particularly decompensated cirrhosis) or in patients on the waiting list for LT.

GT2 and GT3

Three phase 3 trials have examined the efficacy of SOF/RBV in patients infected with HCV GT2 or GT323, 27 (Fig. 2). HCV RNA declines rapidly and is undetectable by week 4 in nearly all patients. Treatment failures are primarily due to relapse without evidence of viral resistance. The reported side effects have been those associated with RBV. Treatment-naive patients with HCV GT2 (even those with cirrhosis) achieved an SVR rate > 90% with 12 weeks of treatment. Treatment-experienced HCV GT2 patients with cirrhosis benefited from an extension of the treatment from 12 to 16 weeks (the SVR rate improved from 60% to 78%). Treatment-experienced HCV GT3 patients with cirrhosis demonstrated the greatest improvement in SVR when the treatment duration was increased from 12 to 16 weeks (the SVR rate increased from 19% to 61%).

This simple all-oral regimen would seem to be ideal as a pretransplant treatment for preventing recurrent infection of the allograft. However, the metabolic derangements and portosystemic shunting of cirrhosis could alter the pharmacokinetics and bioavailability of these drugs and impair efficacy. We anxiously await results from studies of interferon-free combinations of DAAs in cirrhosis and advanced liver disease.

In summary, the era of DAAs for HCV has expanded treatment options for the wait-listed patient. Rates of pTVR after pretransplant treatment have improved with current triple therapy, but the management of side effects and complications remains challenging. Future regimens incorporating interferon-free, multi-DAA treatments should improve the effectiveness and tolerability of pretransplant treatment.

References

Source

The American Journal of Gastroenterology , (23 July 2013) | doi:10.1038/ajg.2013.219

Barjesh Chander Sharma, Praveen Sharma, Manish Kumar Lunia, Siddharth Srivastava, Rohit Goyal and S K Sarin

Abstract

OBJECTIVES:

Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.

METHODS:

In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.

RESULTS:

A total of 120 patients (mean age 39.4±9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child–Turcotte–Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7±2.8 and the MELD (model for end-stage liver disease) score was 24.6±4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, P=0.001).

CONCLUSION:

Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.

Source

20/08/2013

83 organizations from Russia, Ukraine, Moldova, Georgia, Kyrgyzstan, Uzbekistan, Belarus, Lithuania, Estonia, Kazakhstan, Azerbaijan and Armenia signed an open letter addressed to manufacturers of Hepatitis C treatment with a request to reduce the price for a 48-week regimen to 2000 US dollars.

In the letter, the activists state that the current price in the countries of the region is around 15,000 US dollars which is a lot more than the average annual income, making the treatment unaffordable for patients who urgently need it. According to the activists, if the price is reduced, it will enable governments to provide more patients with life-saving treatment within national programmes; moreover, more patients will be able to afford the treatment themselves.

Gregory Vergus, coordinator of the International Treatment Preparedness Coalition in Eastern Europe and Central Asia, says, "The experience of such countries as Egypt shows that the price indeed can be reduced to 2000 US dollars; moreover, it is a necessary precondition for an effective response to the epidemic. Also, in our region with a high prevalence of drug use, accessible Hep C treatment is not a luxury – it is a necessity. A necessity must not cost 15,000 US dollars”.

Eastern Europe and Central Asia remains one of the most difficult regions in terms of Hep C prevalence. The estimated number of people living with Hepatitis C in the region is 7 million. On the eve of the World Hepatitis Day, several organizations in Russia, Ukraine, Latvia, Moldova, Georgia, Armenia and Kyrgyzstan held street actions aimed at reducing prices for Hep C treatment.

This is not the first time activists in EECA demand price reduction from the producers of Hep C drugs. Last year, at the meeting of EECA Community Advisory Board, the activists issued a similar statement asking Roche and Merck to take measures to reduce prices.

The full text of the letter can be found here.

Source: EECA CAB

Source

What you eat can affect your liver

Aaliver3

Written by  Thursday, 22 August 2013 00:00

Once upon a time, poor liver health and failure almost always occur as a result of alcohol abuse. But experts say that in few people, their unhealthy livers can be traced to poor eating habits, reports Sade Oguntola.

It is possible that you are damaging your liver on a daily basis, and you don’t even realise it— down too many alcoholic drinks at weekends, pop too many pain killers or two or three carbonated soft drink on a daily basis. But being healthy is also about eating right, choosing the right foods from all food groups such as grains, meat, dairy, fruits, vegetables, and fats in the amounts that the body needs.

Studies after studies have shown that good food choices have a positive impact on health, including maintaining functionality of organs in the body such as the liver. Unfortunately, the consequences of an improper diet, in combination with sedentary lifestyle, high stress and obesity are much more extensive than simply being fat.

Fat builds up in the liver cells when the liver fails to break down, transfer and store fat effectively, causing a type of liver disease that is medically termed “fatty liver disease”. Overtime, less and less healthy liver tissue remains. This disease can lead to more serious problems such as liver scarring (known as cirrhosis), cancer, heart disease, and other degenerative diseases. This means normal, healthy liver tissue becomes partly replaced with fatty tissue.

The liver is the body’s most important organ after the heart, performing many important functions including metabolism, detoxification, and formation of important compounds including blood clotting factors.  It also filters, regulates, and stores blood.  But if the liver is full of fat, it cannot do these important jobs and this could be dangerous.

Indeed eating unhealthy food, especially junk food which contains a lot of fat, affects the liver. “The deposited fat in the liver can cause hepatitis on its own, but this is not due to viruses. Overtime, this progresses to form liver cirrhosis and also to liver cancer,” said Professor Abiodun Otegbayo, a consultant gastroenterologist, University College Hospital (UCH), Ibadan, Oyo State.

“But when you take healthy foods that contain a lot of fruits and vegetables, it gives the liver less work to do. It also prevents accumulation of fat.  Also, such healthy foods contain some chemical substances called antioxidants. These are substances that mop up injurious substances that are generated as a result of the activities of the liver and other cells in the body that cause damages to the liver and any other organ in the body.”

Professor Otegbayo, who stated that eating healthy foods can reduce the possibility of developing liver diseases since liver diseases can also be caused by excessive intake of alcohol and germs, cautioned on excessive eating because it predisposes to fatty liver disease, a precursor of liver cirrhosis and cancer.

Nonetheless, he said that what constitutes a healthy and adequate diet varies from one age group to another. Although young people need more calories than older people, excess weight in men is stored in the tummy and hips for women. Moreover, other organs of the body will also have fat stored in them, including the liver and all the blood vessels.

Are livers of Nigerians also being destroyed unknowingly due to inappropriate diet? “Fatty liver disease is a well known disease all over the world, Nigeria inclusive.

It is common but Nigeria lacks data on its prevalence because people do not have regular liver tests to ascertain its functionality until something fatal happens to them and then they are rushed to the hospital on emergency,” said Mr Tunde Ajobo, a dietician, UCH, Ibadan.

Mr Ajobo, warning that individuals should be careful of foods they eat, including intake of alcoholic drinks because this could have implications for body organs, also stressed the need for adequate intake of water to help the liver in its function.

“Water helps in lubrication. Also liver contains a lot of water itself and as such adequate intake of water is important to ensure its functionality,” he said.

Moreover, Mr Ajobo suggested consumption of walnuts to help ensure healthy liver being a rich source of antioxidants.

Use of medicines indiscriminately and herbs, he urged people to dissuade from given that they could also destroy the liver. He said: “The liver does a lot of work in the body and so it is important that people be mindful of what they put into their mouths.”

Fatty liver is diagnosed with a blood test and liver ultrasound scan. Many people with a fatty liver are unaware that they even have a liver problem, as the symptoms can be vague and non-specific, especially in the early stages. Most people with fatty liver feel generally unwell, and find they are becoming increasingly fatigued and overweight for no apparent reason.

Fatty liver disease is a called silent disease whose symptoms — including fatigue, weight loss, excessive sweating and weakness — doesn’t show up until the disease is advanced. Even though there is no formal treatment for fatty liver disease, medical experts’ advice is to lose weight, eat right, exercise, and get enough sleep.

On the other hand, good nutrition - a balanced diet with adequate calories, proteins, fats, and carbohydrates - can actually help the damaged liver to regenerate new liver cells. In fact, in some liver diseases, nutrition becomes an essential form of treatment.

Source

PRESS RELEASE August 21, 2013, 7:05 a.m. ET

This is the first patent granted for company's method of evaluating the liver condition of patients utilizing its breath test device

JERSEY CITY, N.J.--(BUSINESS WIRE)--August 21, 2013--

Exalenz Bioscience (TASE: EXEN), developer of advanced diagnostic systems that use the patient's breath to assess gastrointestinal and liver conditions, announced today that the company was granted its first patent for a liver application of its technology. The patent was granted by the United States Patent and Trademark Office. Patent number 8,512,258 was granted to Exalenz for the BreathID Platform Technology's method of evaluating the liver condition of a patient.

Exalenz's breath test liver application is designed to evaluate the liver condition of a patient by computing and comparing breath test parameters, before and after ingestion of a test substrate in real-time, while collecting a continuous flow of the patient's breath, as described in the patent announced today. The technology has multiple diagnostic applications. For example: Exalenz conducted an extensive market survey which showed that there is a clear need for a simple, non-invasive test for detecting the onset of Clinically Significant Portal Hypertension (CSPH), an increase in blood pressure in the veins of the portal system caused by obstruction in the liver. Chronic high blood pressure is prevalent in advanced stages of chronic liver disease and affects liver function. Today, direct measurement of portal pressure is invasive, costly, inconvenient, and requires highly-skilled and experienced physicians to perform the procedure accurately.

"We are enthusiastic about today's patent. Exalenz intends to develop an impressive product pipeline based on the BreathID Technology Platform. Today's achievement marks the latest progress in this ongoing initiative, " said Exalenz CEO Mr. Lawrence Cohen. "It has been a busy summer. In July, we launched the BreathID Hp for the detection and management of the H. pylori bacteria. We also established a new direct US sales team purposed to better service our valued customers. We are looking forward to continuing the momentum and to more exciting developments in the fall."

About Exalenz Bioscience

Exalenz Bioscience develops advanced diagnostic systems that use the real-time, continuous flow of a patient's breath to diagnose and help manage digestive system and liver conditions. The company's flagship BreathID Hp product detects the presence of the H. pylori bacteria, the cause of various illnesses. The BreathID Hp system is FDA cleared and has a CE mark.

For more information: www.breathid.com

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This news release may contain "forward-looking statements." Statements in this press release, which are not purely historical, are forward-looking statements including statements concerning the Company's business outlook or future economic performance, anticipated revenues, expenses or other financial items, plans and objectives related thereto, and assumptions or expectations relating to any future events, conditions, performance or other matters. Forward-looking statements are subject to risks, uncertainties and factors including, but not limited to, changing customer demands, changing regulatory requirements, customer acceptance of the Company's products, the impact of competitive products and pricing, dependence on existing management, that technology may not function as expected and general economic conditions. The Company assumes no obligation to update the information in this release.

CONTACT: Exalenz Bioscience

Marjie Hadad, +972-54-536-5220

Media Liaison

marjie@netvision.net.il

SOURCE: Exalenz Bioscience

Source

[Date: 2013-08-21]

The Third International Symposium on Hepatitis Care in Substance Users (INHSU) will be held from 5 to 6 September 2013 in Munich, Germany.

Hepatitis C is caused by the virus (HCV) which is most prevalent among injecting drug users. This high-risk group acts as a virus reservoir and threatens to be responsible for the future burden of HCV-induced disease.

This event will bring together experts from various disciplines in health and social care. It will promote novel intervention strategies for hepatitis in substance users by taking a cross-sectional approach to pathogenic, diagnostic and therapeutic research.

For further information, please visit:
http://www.inhsu.com/about-inhsu.html

Category: Events
Data Source Provider: Arud Centres for Addiction Medicine
Document Reference: Based on an event announcement
Subject Index: Healthcare delivery/services; Medicine, Health

RCN: 35995

Source

Liver International

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

Viral Hepatitis

Mattias Mandorfer1,3, Berit A. Payer1,3, Bernhard Scheiner1,3, Florian Breitenecker2,3, Maximilian C. Aichelburg2,3, Katharina Grabmeier-Pfistershammer2,3, Armin Rieger2,3, Michael Trauner1,3, Markus Peck-Radosavljevic1,3, Thomas Reiberger1,3,*

Article first published online: 29 JUL 2013

DOI: 10.1111/liv.12253

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords: Antiviral therapy; pegylated interferon; ribavirin; FSS ; hepatitis C; HIV ; quality of life; SF36

Abstract

The aim of this study was to prospectively assess health-related quality of life (HRQL) and severity of fatigue before, during and after antiviral therapy in HIV/HCV co-infected patients.

Design

59 HIV/HCV co-infected patients receiving pegylated interferon plus ribavirin (PEGIFN+RBV) in the HIVCOPEG study were included in this substudy evaluating the secondary endpoints HRQL and severity of fatigue.

Methods

HRQL and severity of fatigue were assessed using SF36 and FSS, respectively. Advanced liver fibrosis was defined as METAVIR F3/F4 or liver stiffness >9.5 kPa.

Results

At baseline, advanced liver fibrosis was associated with worse physical health. Mental health was impaired in female patients and in patients with a history of intravenous drug abuse, while a history of depression was associated with higher severity of fatigue. Female gender was associated with a more pronounced relative decrease in mental health during therapy. At follow-up, 24 weeks after the end of therapy, both physical health and fatigue symptoms had improved. Virological response was associated with better physical and mental health, as well as with reduced severity of fatigue. A correlation between anemia grade and the relative impairments in physical health, mental health and fatigue was observed.

Conclusions

Antiviral therapy with PEGIFN+RBV impairs physical and mental health and increases severity of fatigue, while virological response is associated with improvements in physical health and fatigue symptoms. The optimization of anemia management is essential for reducing the burden of impaired HRQL and fatigue in HIV/HCV co-infected patients receiving antiviral therapy with PEGIFN+RBV.

Source

From Medscape Education Gastroenterology

Andrew J. Muir, MD

CME Released: 07/31/2013; Valid for credit through 07/31/2014

In May 2011, the US Food and Drug Administration (FDA) approved the use of direct-acting antiviral agents telaprevir and boceprevir for treatment of chronic hepatitis C (HCV) genotype 1 infection in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV). This represented a new paradigm in the management of HCV. On May 29, 2013, Medscape spoke to Andrew J Muir, MD, Associate Professor of Medicine and Director of GI/Hepatology Research at Duke Clinical Research Institute in Durham, North Carolina, to discuss the current HCV treatment approaches and provide a case-based illustration of the decision whether a patient is a candidate for treatment with the current standard of care.

Medscape: To start, please briefly describe the current standard of care for HCV genotype 1 infection in the United States. According to the guidelines, what patients are considered appropriate candidates for treatment with the current standard of care?

Andrew J. Muir, MD: The current standard of care for treatment of chronic HCV genotype 1 infection in the United States is the combination of PEG-IFN-alfa, RBV, and one of the HCV NS3/4A protease inhibitors boceprevir or telaprevir.[1] In clinical studies, the addition of boceprevir or telaprevir to the previous standard of care for these patients (ie, PEG-IFN plus RBV) was associated with a significantly increased rate of sustained virologic response (SVR) in both treatment-naïve and previously treated patients.[2-5]

Medscape: How are patients evaluated with regard to their eligibility for HCV therapy?

Dr Muir: The key to treatment eligibility right now is a patient’s ability to tolerate PEG-IFN. Many of the adverse effects and risks associated with the currently available treatment are driven by PEG-IFN. For example, patients need to have no significant mental illness, including active depression, because it can be exacerbated by PEG-IFN.[6,7] Presence of other comorbidities -- such as advanced heart failure or lung disease -- should also be considered. Liver disease stage is important. In order to be eligible for treatment, patients should not have decompensated cirrhosis, and no complications of cirrhosis such as ascites, variceal bleeding, or hepatic encephalopathy. Finally, as there is a significant risk of anemia, thrombocytopenia, and neutropenia, it is important for patients to have appropriate blood counts prior to the start of treatment.

The guidelines recommend that treatment should be considered in all patients who qualify; we take that approach on a case-by-case basis to determine whether treatment is appropriate for an individual patient at this time. A number of the new HCV agents are expected to become available in the next few years, and we expect that there will be an IFN-free regimen available for HCV genotype 2 and 3 by late 2013, and hopefully for genotype 1 by 2015 or so. The question, then, is this: Should you treat the patient now, or wait until these new therapies are available?

I think that patients should weigh this decision and discuss it carefully with their provider. As we just discussed, the IFN adverse effects are real and significant, and it’s very reasonable for many of these patients to delay treatment for now. However, I do not think that providers should make that decision for their patients. We should tell them about the chances of cure and the risks associated with the current therapies. Patients with advanced fibrosis have the most concern about progression of their liver disease, and therefore might be more motivated to get treatment right away. These are also patients with a lower chance of cure and potentially at increased risk for adverse events, such as prior nonresponders and those with advanced liver disease. We need to work through that with them. Finally, some patients may be highly motivated to begin treatment right away because they want to be cured or for other reasons (eg, fear of losing health insurance coverage while they await newer therapies). Understanding the patients’ concerns and motivations helps guide our clinical decisions. On the other hand, we need to ensure that the patients understand what is involved in HCV treatment right now: length of time on treatment, regimen complexity, likelihood of treatment success, and so on.

Medscape: Please describe a case scenario in which the patient is a candidate for therapy with the current standard of care.

Dr Muir: I saw a patient recently for whom it was quite reasonable to consider moving forward with treatment (Table). This was a 30-year-old woman recently diagnosed with HCV genotype 1a infection, which is the most difficult-to-treat genotype, yet the most common in the United States. She was treatment-naïve, and had mild liver disease. Her laboratory test results were all within normal range, and her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were mildly elevated. Her HCV RNA was 1,100,000 IU/mL, which is a somewhat high viral load. Finally, her IL28B genotype, which is associated with treatment response, was CC. This is the most favorable IL28B haplotype in terms of likelihood of treatment response.

Table. A Patient With Recently Diagnosed Hepatitis C Infection Considering Therapy

30-year-old woman

HCV diagnosis in 2013

  • Genotype 1a
  • HCV RNA 1,100,000 IU/mL
  • Liver enzymes slightly elevated
  • Platelets, albumin, bilirubin, prothrombin within normal range
  • IL28B CC haplotype

Medscape: What makes this patient an appropriate candidate for treatment now?

Dr Muir: She was very motivated to initiate treatment right away because she wanted to put HCV infection behind her. Clinically, she has a number of favorable prognostic factors that would suggest she has a great chance to be cured: young age, female gender, and a favorable IL28B haplotype (IL28B CC).[8] Although she would also do well on therapies that are currently in development, she and similar patients also have good response rates to the first-generation protease inhibitors boceprevir and telaprevir. She may also be a candidate for a shortened treatment course, what is called a response-guided therapy approach (Figures 1 and 2).[9]

808485-fig1

Figure 1. Response-guided therapy algorithm for boceprevir. Adapted from Shiffman ML, et al. Liver Int. 2012;32:54-60. [9]

808485-fig2

Figure 2. Response-guided therapy algorithm for telaprevir. Adapted from Shiffman ML, et al. Liver Int. 2012;32:54-60.[9]

Medscape: What are some of the issues that you would want to discuss with this patient?

Dr Muir: First, I would want her to know the data, particularly as it relates to patients with her disease characteristics. We just talked about response-guided therapy. Could she be a candidate for an even shorter treatment course? In the PROVE-2 study of telaprevir given in combination with PEG-IFN and RBV, the overall SVR rates were only 60% in patients who received a total of 12 weeks of triple therapy.[10] This was a disappointing result and this treatment approach was discontinued moving forward. However, a retrospective subanalysis of 12 patients with IL28B CC genotype revealed that 100% of those patients achieved SVR with just 12 weeks of triple therapy.[11]

Subsequently, a randomized study called CONCISE was initiated to examine two durations of therapy with telaprevir, PEG-IFN, and RBV. In CONCISE, patients who had undetectable HCV RNA at week 4 of triple therapy were randomly assigned at 12 weeks to either stop all treatment (T12PR12 arm) or continue for 12 more weeks with PEG-IFN plus RBV only (T12PR24 arm).[12] At the European Association for the Study of the Liver (EASL) conference in 2013, interim results of CONCISE showed an SVR12 rate of 87% for patients in the T12PR12 arm compared with 97% in the T12PR24 arm,[12] which is encouraging. It should be noted that boceprevir is also administered in a response-guided approach. For treatment-naive patients whose HCV RNA is undetectable at weeks 8 and 24 of treatment, all treatment can be stopped at 28 weeks, whereas if HCV RNA is detectable at week 8 but undetectable at week 24 of treatment, the total duration of triple therapy with boceprevir, PEG-IFN, and RBV is 32 weeks, followed by 12 weeks of PEG-IFN plus RBV only for a 48-week total treatment course (Figure 1).[9]

Although 12 weeks of total therapy is not presently an FDA-approved approach, it does give some indication of these agents’ potency. Also, if a patient is having significant adverse effects after 12 weeks of therapy and is trying to decide whether it is worthwhile to continue, I think I am going to be much more comfortable if this patient stops treatment at week 12 provided he or she had undetectable HCV RNA at week 4. This is something we should discuss with our patients.

Medscape: The currently available therapies are fairly complex. What should providers keep in mind with regard to patients’ treatment readiness and willingness to adhere to a complex regimen?

Dr Muir: Yes, this is a challenging treatment course. We need to provide patients with much education upfront, and to support them as much as possible while on treatment. Administration schedules are different for the 3 regimen components. The IFN injection is given once a week; patients inject themselves at home on a day of the week that they choose. Ribavirin is dosed twice daily and boceprevir and telaprevir are dosed 3 times daily. Boceprevir should be taken with food, and telaprevir should be taken with food that includes 20 g of fat with each dose. Patients have to be very organized, not only to remember which medicine is taken at which time, but also to make sure that they’ve worked out their meals for the day. It takes planning.

A variety of strategies can be used to address treatment adherence. Patients can use pill boxes or set alarms or mobile phone reminders to help them remember, but all of these take some planning. This is why the patient needs to be motivated to receive therapy and to understand what impact treatment is going to have on his or her life. I think that it’s our job as providers to let them know what is involved and how to ensure the highest likelihood of success.

Patients also need to adhere to their scheduled appointments. Their lab values require close monitoring, especially in the first few weeks after treatment initiation, to ensure that they are tolerating the regimen. We sometimes have to make adjustments in the dose of RBV based on their blood counts.[13,14] Additionally, the patient’s HCV viral load has to be obtained at specific times in order to evaluate his or her candidacy for response-guided therapy, so appointments need to be scheduled and attended in the appropriate time frame.

Medscape: Do you evaluate the patient to assess whether he or she is at risk for treatment nonadherence before you recommend treatment?

Dr Muir: We try to address this issue with our patients in a couple of different ways. For instance, we look at the notes from the referring providers to see whether there have been any concerns raised about medication and/or visit adherence in the past. Have they had other medical conditions -- such as diabetes -- for which they didn’t take their medications regularly? We also need to see how the patients interact with us. At our clinic, we would never start treatment the first time we see a patient. We want to see that they keep their appointments and that they follow our advice as far as educating themselves about what they will need to do. We really like to see them have somebody else with them at teaching visits, for example, because there is much information to absorb. Do they comply with those recommendations so that we are doing all that we can to educate them and their support team as they get ready for this therapy? These are just some of the ways to address patient readiness to adhere to the treatment plan.

Medscape: Let’s return to the patient case you described earlier. What is her status at this point in time?

Dr Muir: The patient is currently on treatment and we are waiting to see how her HCV infection will respond.

Medscape: To conclude, what are some key messages that providers should take away with regard to selecting the appropriate patient to start HCV therapy at this time?

Dr Muir: Realistically, most patients are going to want to delay starting HCV therapy until the newer agents come along. However, I think it would be inappropriate to suggest that no one will be treated until IFN-free regimens are available. There will be some patients who will want to move forward with the current treatment options. Some of them will have advanced disease and are concerned about disease progression. Some may consider it the most appropriate time for them to move forward with treatment; they may have favorable prognostic characteristics to suggest a high probability of treatment success. Therefore, the decision to treat now or wait should be made by each patient with the help of his or her provider on an individual basis that takes all of these factors into account.

Return to Medscape to earn CME Credit …..

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By: BRUCE JANCIN, Family Practice News Digital Network

ESTES PARK, COLO. – Treatment of hepatitis C infection is likely to shift from gastroenterology and hepatology clinics to primary care physicians’ offices, perhaps as early as next year.

That’s the prediction of Dr. Gregory T. Everson, who cited rapid progress in developing interferon-free treatment regimens as the driving force behind what is anticipated to be a huge change in clinical practice, given that there are an estimated 5 million or more patients with hepatitis C virus (HCV) infection in the United States

Five major pharmaceutical companies are developing oral, interferon-free HCV treatment regimens based upon still-investigational direct-acting antiviral agents (DAAs) that target HCV proteins and their functions. The clinical trials experience to date indicates these DAA-based regimens have substantially higher cure rates, far better tolerability and safety, and a much lower pill burden. Also, they are vastly simpler to administer than are current standard therapies. And all this is being achieved with a 12-week treatment duration instead of the 24 weeks required with standard therapy in 2013, Dr. Everson said at a conference on internal medicine sponsored by the University of Colorado.

"In the past I could say we really had pretty [intolerable] therapy, and it was pretty difficult for patients to take it. Interferon-free therapy is evolving rapidly, and I hope that it will be in primary care physicians’ backyards in the near future. I think this is probably going to be a treatment that you all provide," added Dr. Everson, professor of medicine and director of hepatology at the university.

Indeed, at hepatology clinics around the country, patients with early-stage HCV and their physicians are taking a "wait until next year" attitude toward starting treatment in anticipation that the Food and Drug Administration could approve the first of these new DAAs, sofosbuvir, before the year’s end.

The number of prescriptions for HCV therapy for treatment-naive patients at the University of Colorado clinic has plummeted in 2013 compared with 2012. The only patients starting treatment now are those with advanced HCV liver disease, to halt further disease progression and reduce the risk of developing hepatocellular carcinoma, according to Dr. Everson.

The FDA has granted Gilead Sciences priority review status for sofosbuvir, an oral inhibitor of nucleotide N55b polymerase, with a target decision date in early December. The application for marketing approval is for two indications. One involves sofosbuvir as part of a 12-week, triple-therapy regimen including pegylated interferon and ribavirin in treatment-naive patients with HCV genotypes 1, 4, 5, and 6, based in large part upon the highly favorable results of the phase III NEUTRINO trial (N. Engl. J. Med. 2013;368:1878-87).

The other proposed indication is sofosbuvir in combination with ribavirin as an interferon-free, 12-week regimen in patients with HCV genotypes 2 or 3, based upon the results of the FISSION and POSITRON trials (N. Engl. J. Med. 2013;368:1867-77).

In the NEUTRINO trial, 12 weeks of triple-therapy with sofosbuvir/interferon/ribavirin resulted in a 90% cure rate in patients with HCV genotype 1, which accounts for three-quarters of all HCV infections in the United States. The dropout rate due to side effects was a mere 2%. In contrast, today’s standard therapy, consisting of either of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis) combined with pegylated interferon and ribavirin, has a 70%-75% cure rate. And many patients can’t tolerate or are ineligible for interferon.

"When I started treating hepatitis C patients 25 years ago, I was happy because the ALT would normalize in half the patients with genotype 1, but I wasn’t curing anybody. And now triple therapy with sofosbuvir, with a 90% cure rate, could be approved by the end of the year," Dr. Everson marveled.

In the FISSION trial, treatment-naive patients with HCV genotype 2 had a 97% cure rate with 12 weeks of sofosbuvir/ribavirin compared with 78% in those assigned to today’s standard regimen of 24 weeks of pegylated interferon/ribavirin. And sofosbuvir is just one pill per day, coupled with ribavirin at two or three pills twice daily.

In POSITRON, conducted in patients who had relapsed or were nonresponders to the standard 24 weeks of pegylated interferon/ribavirin, 12 weeks of sofosbuvir/ribavirin had an 86% response rate in patients with HCV genotype 2. With an additional 4 weeks of the interferon-free regimen, the cure rate climbed to 94%. Cure rates were lower in genotype 3 patients, but of note, the cure rate in treatment-experienced genotype 3 patients with cirrhosis more than tripled from 19% with 12 weeks of sofosbuvir/ribavirin to 61% with 16 weeks.

Other oral DAAs in the developmental pipeline include simeprevir, daclatasvir, and asunaprevir. The clinical trials experience to date demonstrate that combination therapy with more than one DAA boosts the cure rate even higher than with sofosbuvir/ribavirin. For example, in the phase II, open-label AVIATOR study, 12 weeks of a cocktail comprising three DAAs plus ribavirin brought a 96% cure rate in treatment-naive patients with HCV genotype 1 and a 93% cure rate in those who had previously failed on standard interferon-containing therapy. The AVIATOR cocktail is being formulated as a two-pills-per-day regimen.

Further, Dr. Everson was principal investigator in a Bristol-Myers Squibb–sponsored study of a totally interferon- and ribavirin-free regimen consisting of triple-DAA therapy. Each of the DAAs has a different mechanism of action: Daclatasvir is an inhibitor of the HCV NS5a protein; asunaprevir is an NS3 protease inhibitor; and the agent known for now as BMS-791325 is a nonnucleoside polymerase NS5b inhibitor. The cure rate with 12 weeks of triple-DAA therapy in treatment-naive, noncirrhotic patients with HCV genotype 1 was 94%.

Hepatologists define cure of HCV as an SVR12, or a sustained virologic response featuring no detectable HCV RNA in the blood for 12 weeks after the conclusion of therapy. The likelihood that a patient who achieves an SVR12 will remain HCV free through 10 years is 99%-100% (Gastroenterology 2010;139:1593-1601).

"The future looks pretty good for hepatitis C patients," Dr. Everson observed.

Moreover, curing HCV is going to have major downstream benefits for the health care system, he added. Today, 36% of all patients on the liver transplantation waiting list have HCV; that proportion will drop substantially. There will be fewer cases of hepatocellular carcinoma, B-cell lymphoma, and adult-onset diabetes, a drop in HCV-related autoimmune disorders, and reduced costs of care for patients with chronic HCV.

Dr. Everson reported that he receives research grants from and/or serves as a consultant to or advisory board member for roughly two dozen pharmaceutical companies.

bjancin@frontlinemedcom.com

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