November 21, 2013

Posted by Justin Snow
November 21, 2013 4:51 PM

President Barack Obama signs H.R. 2751, the “FDA Food Safety Modernization Act,” in the Oval Office, Jan. 4, 2011.  (Official White House Photo by Pete Souza)
This official White House photograph is being made available only for publication by news organizations and/or for personal use printing by the subject(s) of the photograph. The photograph may not be manipulated in any way and may not be used in commercial or political materials, advertisements, emails, products, promotions that in any way suggests approval or endorsement of the President, the First Family, or the White House.

President Barack Obama signed into law Thursday a bill lifting the ban on organ transplants between people who are HIV-positive.

The HIV Organ Policy Equity Act, also known as the HOPE Act, ends a decades-long federal ban on allowing donated HIV-positive organs from being translated into HIV-positive patients.

"For decades, these organ transplants have been illegal. It was even illegal to study whether they could be safe and effective," Obama said in a statement after signing the bill. "But as our understanding of HIV and effective treatments have grown, that policy has become outdated. The potential for successful organ transplants between people living with HIV has become more of a possibility."

By lifting the research ban, Obama said a door has been opened that could "lead to life-saving organ donations for people living with HIV while ensuring the safety of the organ transplant process and strengthening the national supply of organs for all who need them."

The HOPE Act received bipartisan approval in both houses of Congress earlier this year. Introduced by Sens. Barbara Boxer (D-Calif.), Tammy Baldwin (D-Wis.), Tom Coburn (R-Okla.) and Rand Paul (R-Ky.), the Senate approved the bill in June with no opposition. The House of Representatives passed the Senate version of the bill earlier this month, with Reps. Lois Capps (D-Calif.) and Andy Harris (R-Md.) leading the fight in the House.

"The bipartisan passage of the HOPE Act will fundamentally improve the quality of healthcare available for people living with HIV and AIDS," said Allison Herwitt, vice president for government affairs for the Human Rights Campaign, in a statement. "By removing these antiquated barriers to transplants, the lives of hundreds of people living with HIV and AIDS can be saved each year."

The HOPE Act directs the Department of Health and Human Services and the Organ Procurement Transplant Network (OPTN) to develop and institute standards for research on HIV-positive organ transplants, opening the door for the HHS secretary to permit HIV-positive transplants in HIV-positive patients when that research is complete.

According to HRC, more than 100,000 patients are currently waiting for organ transplants, with about 50,000 added each year. Permitting HIV-positive organ transplants in HIV-positive patients with liver or kidney failure could save up to 1,000 people per year.

"Improving care for people living with HIV is critical to fighting the epidemic, and it’s a key goal of my National HIV/AIDS Strategy," Obama said. "The HOPE Act marks an important step in the right direction, and I thank Congress for their action."

[Photo: Barack Obama. Credit: Official White House Photo by Pete Souza.]

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The Next Wave of Agents for Treatment of Hepatitis C

Medscape Gastroenterology

William F. Balistreri, MD

November 21, 2013

The Next Wave of Hepatitis C Treatment

For several years, the recommended standard of care for patients with chronic hepatitis C virus (HCV) infection consisted of a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). On the basis of understanding of the biology of the virus and identification of proteins involved in HCV replication came the development of agents that inhibited the HCV protease and polymerase enzymes.

A few years ago, the US Food and Drug Administration (FDA) approved 2 direct-acting antiviral agents for the treatment of HCV genotype 1: the NS3 protease inhibitors telaprevir and boceprevir. The American Association for the Study of Liver Diseases guidelines[1] were updated to recommend triple therapy consisting of one of these protease inhibitors given in combination with PEG-IFN and RBV. This recommendation was based on results of clinical trials of this combination, which showed significantly improved sustained virologic response (SVR) rates. Although this triple therapy is generally well tolerated, troublesome side effects occur in many patients. The good news is that the guidelines may once again be revised thanks to the emergence of the next wave of direct-acting antivirals.

Simeprevir and Sofosbuvir

Simeprevir is a potent, once-daily oral investigational NS3/4A protease inhibitor that was shown to be effective when coadministered with standard therapy (PEG-IFN and RBV) for treatment of HCV genotype 1 infection both in treatment-naive patients and in patients who did not respond to standard therapy.[2-10]

Primary efficacy and safety data from clinical trials of simeprevir in patients with genotype 1 chronic HCV infection were in part responsible for the recommended FDA approval of this agent on October 24, 2013. The FDA's Antiviral Drugs Advisory Committee recommendation was unanimous, commenting that the available data overwhelmingly supported approval of the simeprevir, PEG-IFN, and RBV combination for HCV genotype 1 infection in treatment-naive patients and in those who had relapse after previous therapy. The committee reviewed safety and efficacy data from a series of double-blind, placebo-controlled trials -- phase 3 studies of treatment-naive patients and patients with previous relapse, and a phase 2b study involving patients with previous relapse and nonresponders.

For example, simeprevir (TMC435) administered once daily in combination with PEG-IFN and RBV was associated with SVR 12 weeks after the end of treatment (SVR12) in approximately 80% of treatment-experienced (relapsed) genotype 1 chronic hepatitis C patients. The SVR12 rate was less than 40% in patients receiving placebo plus PEG-IFN and RBV. Treatment failure rates and relapse rates were lower in simeprevir recipients than placebo recipients.

Simeprevir was shown to be generally safe and well tolerated, even among patients with advanced liver fibrosis. The most common adverse events were fatigue, headache, and influenza-like illness.

The FDA Advisory Committee did, however, further recommend that patients be screened for the commonly occurring Q80K mutation because simeprevir was found to be less effective in the presence of this mutation. They also recommended that the label should indicate that sunburn is a common side effect. More information about the simeprevir clinical trials can be found at ClinicalTrials.gov.

Soon to follow was the recommended FDA approval of sofosbuvir, a nucleotide analog that inhibits NS5B-directed HCV replication; this agent has also been shown to be highly effective. Sofosbuvir in combination with standard therapy was associated with SVR12 rates of 90% compared with 58% in placebo-treated patients.[11,12]

Both agents will be indicated for treatment of patients with HCV genotype 1, but only in combination with PEG-IFN and RBV. These drugs represent an advance in management -- they promise to be capable of inducing high SVR rates with 1 pill per day, shorter duration of therapy, better tolerability, and no resistance development. The 1-pill-daily regimen simplifies the treatment strategy; however, the cost and side effects are likely to remain high.

A Glimpse of the Future in HCV Treatment

There is an even higher degree of optimism, however, because recent studies may usher in the next wave of treatment strategies for HCV infection. In my opinion, the goal for treatment in terms of efficacy, safety, and tolerability is an IFN-free regimen. Simeprevir is being studied in phase 2 IFN-free trials with and without RBV and in combination with a host of other agents that act synergistically to inhibit HCV replication, and which include all oral regimens. For example, studies in progress suggest that high SVRs can be achieved in patients treated with simeprevir and sofosbuvir together, with and without RBV.

I will end by offering a glimpse of the future. Currently under evaluation in clinical studies are second-generation protease inhibitors and small-molecule drugs that inhibit other viral enzymes. Drug cocktails that target multiple HCV enzymes simultaneously may ultimately become the standard of treatment, as in the current strategy for the management of infection with HIV.

The bottom line is that these exciting advances in antiviral therapy will lead to significant improvements in response rates with reduced adverse effects. These advantages may lower the threshold for HCV treatment for both patients and physicians.

It is important to note, though, that at present only a minority of HCV-infected patients may benefit because of multiple barriers that have been identified and that impede delivery of therapy. A major issue is inadequate case-finding, an obstacle that could be overcome by widespread screening. The Centers for Disease Control and Prevention recently advised enhanced testing; their guidelines state that many persons who test positive for hepatitis C do not receive the necessary follow-up to determine whether they require medical care. Therefore, enhanced efforts to improve awareness, education, and specialist availability are needed.

The high prevalence of HCV infection worldwide should also stimulate expanded efforts in primary prevention, including vaccine development. Perhaps we can soon wave good-bye to HCV!

References

1. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-444. Abstract

2. Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013 Aug 2. [Epub ahead of print]

3. Lenz O, Vijgen L, Berke JM, et al. Virologic response and characterisation of HCV genotype 2-6 in patients receiving TMC435 monotherapy (study TMC435-C202). J Hepatol. 2013;58:445-451. Abstract

4. Lenz O, de Bruijne J, Vijgen L, et al. Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy. Gastroenterology. 2012;143:1176-1178. Abstract

5. Tanwar S, Trembling PM, Dusheiko GM. TMC435 for the treatment of chronic hepatitis C. Expert Opin Investig Drugs. 2012;21:1193-1209. Abstract

6. Moreno C, Berg T, Tanwandee T, et al. Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study. J Hepatol. 2012;56:1247-1253. Abstract

7. Manns M, Reesink H, Berg T, et al. Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther. 2011;16:1021-1033. Abstract

8. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once-daily simeprevir (TMC435) with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1-infected patients in Japan: the DRAGON study. J Gastroenterol. 2013 Sep 5. [Epub ahead of print]

9. Poordad F, Khungar V. Emerging therapeutic options in hepatitis C virus infection. Am J Manag Care. 2011;17 Suppl 4:S123-130. Abstract

10. Reesink HW, Fanning GC, Farha KA, et al. Rapid HCV-RNA decline with once daily TMC435: a phase I study in healthy volunteers and hepatitis C patients. Gastroenterology. 2010;138:913-921. Abstract

11. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887. Abstract

J12. acobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877. Abstract

Medscape Gastroenterology © 2013  WebMD, LLC

Cite this article: William F. Balistreri. The Next Wave of Agents for Treatment of Hepatitis C. Medscape. Nov 21, 2013.

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Progress towards a hepatitis C virus vaccine

Journal home > Current issue > November 20 2013 > Full text

Review

Subject Category: Vaccines

Citation: Emerging Microbes & Infections (2013) 2, e79; doi:10.1038/emi.2013.79
Published online 20 November 2013

OPEN

Lok Man John Law, Abdolamir Landi, Wendy C Magee, D Lorne Tyrrell and Michael Houghton

Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton T6G 2E1, Canada

Correspondence: M Houghton, E-mail: mhoughton@ualberta.ca

Received 7 August 2013; Revised 1 October 2013; Accepted 9 October 2013

ABSTRACT

New drugs to treat hepatitis C are expected to be approved over the next few years which promise to cure nearly all patients. However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world’s HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections. For these reasons, there is an urgent need to develop a prophylactic HCV vaccine and also to determine if therapeutic vaccines can aid in the treatment of chronically infected patients. After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism. This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.

Keywords: HCV; hepatitis; infection; prophylactic; therapeutic; vaccine

\HEPATITIS C AND THE NEED FOR A VACCINE

Hepatitis C is a major global health concern and the leading cause of liver transplantation in North America. The etiology of this blood borne disease is infection with the hepatitis C virus (HCV).1 Acute HCV infection causes mild disease and is usually asymptomatic. Most of the disease symptoms, including liver cirrhosis, are manifested during the chronic phase of infection which is life-long unless successfully treated. In some cases, infection with HCV can lead to the development of hepatocellular carcinoma. Currently, it is estimated that around 170 million people worldwide (~2% of the population) are persistently infected with the virus and some of the chronic carriers are not aware of their infection.

The current standard of care therapy includes treatment with a combination of pegylated interferon (IFN) and ribavirin plus inhibitors of a viral-encoded serine protease. This therapy is about 70% effective in patients infected with genotype 1 virus, the most common genotype of HCV in the world. Infections with HCV genotypes 2 and 3 are currently treated with only interferon and ribavirin, and the overall treatment efficacy is about 80%. The regulatory approval of the protease inhibitors Telaprevir and Boceprevir marked the beginning of the clinical use of HCV-specific direct acting antivirals (DAAs).2 Many more DAAs are being developed against various virus-specific genes and proteins and will soon reach the clinic.3 A combination of these antiviral agents could present a possible treatment to overcome this infection in the future.

Despite this progress, many challenges remain. The current therapy is associated with many side effects. This leads to early termination of therapy in some cases resulting in suboptimal treatment. Further, genetic determinants in both the host and the virus can prevent 100% efficacy.4,5 Although the DAAs represent a step forward in the treatment of HCV, other problems occur with this therapy as well. Viral resistance against Telaprevir and Boceprevir has been observed clinically and has been associated with treatment failure.6,7 Importantly, the high costs of these new therapies and the large numbers of HCV-infected individuals means the health-care system, even in developed countries, cannot afford to treat all patients; this limitation is even more pronounced in developing countries. Therefore, development of a vaccine to prevent acute or chronic infection is essential. In this review, we summarize the strategies and progress on HCV vaccine development.

VIROLOGY AND NATURAL IMMUNITY

HCV is an enveloped positive strand RNA virus of the family Flaviviridae.8 The virus genome encodes a large, single open reading frame that is subsequently processed into 10 major viral proteins. The first three are structural proteins: the nucleocapsid forming protein core, and the two envelope glycoproteins E1 and E2. The latter seven proteins are viroporin p7 and six non-structural (NS) proteins: NS2, NS3, NS4a, NS4b, NS5a and NS5b. HCV is a heterogeneous virus and is divided into seven major genotypes found worldwide. There is up to a 30%difference between these genotypes at the nucleotide level,9 especially in the region of the genome encoding structural proteins. Ideally, treatment for hepatitis C should be effective against all genotypes of the virus in order to confer global protection. However, the diversity of HCV translates into various sensitivities to treatment,10,11 none of which are 100% effective. The basic mechanism behind virus diversity lies with the viral RNA-dependent RNA polymerase (NS5b) which replicates the HCV genome. NS5b is an error-prone enzyme lacking proof-reading activity which results in HCV genome populations existing as a fluid RNA swarm termed quasispecies. This poses a problem for HCV treatment and vaccine development because resistance mutations within the virus population can potentially emerge and dominate under any therapeutic or vaccine selection pressure.

HCV has adapted exquisitely to escape host immune control with most cases progressing into a chronic or persistent infection. Nonetheless, 20% of acute HCV infections can be spontaneously cleared.12 Identifying the correlates of immune protection among these spontaneous resolvers is a central question for vaccine design and therapy. During primary HCV infection, the viral RNA accumulates in serum during the first 1–2 weeks. This is followed by induction of serum transaminase levels reflective of liver injury, which can be asymptomatic. At the peak serum transaminase level, adaptive T-cell responses to HCV can be detected.13 In the case of spontaneous virus clearance, this T-cell response is followed by a reduction of viremia to an undetectable level. Studies following individuals in this group of spontaneous resolvers showed that a broad virus-specific CD4+ and CD8+ T-cell response correlates with protection.14,15 In contrast, where infection progresses into a chronic state, adaptive immunity is weaker and ineffective in controlling the virus, HCV RNA remains high in serum and T cells show limited reactivity to HCV.16,17,18 The role of humoral immunity in HCV clearance is not well understood. It is thought that neutralizing antibodies are detected only in the chronic phase of infection.19,20,21,22 Although these antibodies cannot clear the infection, they do exert a selective pressure, driving virus evolution and suggesting immune regulation of the virus.22,23 Indeed, there is evidence that during the chronic phase of infection, HCV virions exist as immune complexes in sera bound to HCV-specific antibodies.24 With the recent development of a tissue culture system to study virus entry,25,26,27,28 the role of neutralizing antibodies is being better defined, particularly during the acute phase of infection.29,30 The role of antibodies in the control of HCV infection will be discussed in more detail below. Re-infection of individuals who spontaneously cleared their first HCV infection show reduced levels and duration of viremia compared to the primary infection. The rate of spontaneous clearance also rises from 20% to 80%.29 This increase in spontaneous clearance rate is suggestive of immune memory to HCV infection, which provides great encouragement for the effectiveness of a prophylactic vaccine.

emi201379f1

Figure 1. Summary of selected potential HCV vaccines in clinical development. These vaccines were grouped based on either prophylactic or therapeutic usage. They are currently either in phase I, phase I/II or phase II development (no HCV-specific vaccine has reached phase III development yet). The biological component(s) of the vaccine is listed on top of the arrow. Sponsor or company conducting the trial is listed at the end of arrow along with clinical ID number (http://www.clinicaltrials.gov). Selected examples of vaccines will be further discussed in the text. NIAID, National Institute of Allergy and Infectious Diseases.

Most, if not all of the current successful vaccines in the market today are dependent on the induction of neutralizing antibodies to prevent or limit infection/disease.32 Even for another diverse virus such as HIV-1, the recent RV 144 human vaccine trial showed that modest reduction of infection risk is correlated with antibody response to the envelope spike of HIV-1.33,34 This approach to HCV vaccine development is strengthened by recent studies of HCV infection showing that neutralizing antibodies correlate with HCV clearance.29,30,35 In a single-source outbreak of HCV, Pestka et al.30 showed that patients who resolve HCV infection have a higher level of neutralizing antibodies during the acute phase infection (Figure 2). Response to interferon therapy has also been correlated with antibody titers to virion proteins.36 One vaccine designed to induce a humoral response against HCV used recombinant glycoprotein (gp) E1/gpE2 adjuvanted with MF59. In the chimpanzee model, this vaccine showed efficacy in reducing the rate of chronicity following both homologous and heterologous 1a virus challenge.37 In a few cases, it also completely prevented infection against homologous challenge.37 Importantly, if vaccination can reduce the incidence of chronic infection, it will be very effective since HCV-associated disease is manifested mostly during this chronic phase. The safety and immunogenicity of this recombinant glycoprotein-based vaccine has been tested in humans in a phase I clinical trial. The results of this trial indicated that the vaccine induced strong humoral and CD4+ T-cell responses and the vaccinated volunteers presented with minimal side effects.38

emi201379f2

Figure 2. Neutralizing antibodies in patients with resolved or chronic hepatitis C. Anti-HCVpp neutralizing titers were determined by end point dilution of sera. HCVpp or control pp were pre-incubated for 1 h with serial serum dilutions before infection of Huh7 target cells. The end point titers of the early phase (1–6 months after infection) and late-phase (10–17 years after infection) serum samples are shown as scatter plots. The median titer is marked by a line. Data are expressed as means of two independent experiments performed in duplicate. Samples showing a titer of <1/20 were considered negative. The cutoff titer 1/20 is indicated by a dashed line. The data are reproduced with permission from Pestka et al.30 HCVpp, HCV pseudo-particles.

The major drawback of this vaccine approach is the heterogeneity of HCV as described earlier. Historically, neutralizing antibodies were presumed to be genotype-specific rendering it very difficult to confer global protection.21,39,40,41However, other studies describing broadly cross-neutralizing antibodies that prevent infection have been reported in the literature.42 Most of these antibodies recognize conserved regions mainly within the glycoprotein E2, although some recognizing E1 have also been described.43 Some of these cross-neutralizing antibodies target discontinuous epitopes suggesting conformation-dependent recognition. It is possible that the virion envelope glycoproteins from the various genotypes maintain a conserved globular structure in order to interact with the conserved entry pathway, despite substantial genomic diversity at the primary sequence level.44 Glycoprotein based vaccination has been shown to induce cross-genotype neutralizing activity in chimpanzees and humans.45,46 Recently, our group showed this same vaccine induced broad neutralizing antibodies against representatives of all seven major HCV clades from around the world, although with varying efficacy.47 Whether this vaccine induces similar cross-neutralizing B-cell epitopes as those previously reported is currently being investigated. Furthermore, it has been reported that HCV can spread from cell to cell in order to avoid neutralizing antibodies.48 Whether vaccine-induced antibodies can prevent this mode of transmission is an open question although certain antibodies capable of preventing this mode of transmission have been reported.49,50

An alternative method to produce vaccines designed to elicit neutralizing antibodies is the use of whole, killed virus. This method is used in many licensed vaccines such as influenza A, hepatitis A, polio, rabies, Japanese encephalitis and papilloma virus vaccines.51 This approach was recently tested for HCV by Akazawa et al.52 Inactivated cell culture-derived HCV virions are capable of inducing cross-genotype neutralizing antibodies and confer protection against HCV infection in a mouse model by passive immunization with vaccinees’ serum. This work opens up an important new avenue for HCV vaccine development. However, regulatory approval of a prophylactic vaccine produced in the transformed hepatocyte Huh7 cell line may be difficult. Another approved cell line for virus propagation may be required and these cell lines would need to be modified in order to support HCV particle production so that they express virus entry receptors, microRNA 122 and the apolipoproteins essential for virus assembly.53,54In addition, the low yield of HCV particle production in cell culture could limit its widespread use. The recent demonstration of much higher viral yields by culturing HCV-producing cells in the presence of human serum (rather than calf serum) could overcome this latter obstacle.55 Virus-like particles presenting HCV envelope proteins to induce neutralizing antibody is an alternate approach aiming to improve safety and low yield. Garrone et al.56 has reported HCV virus-like particles capable of inducing cross-neutralizing antibodies in an animal model. This result provides an encouraging result for further clinical testing. However, since HCV glycoproteins are arranged differently on virus-like particles than on the native HCV virion, the breadth of the subsequently induced antibodies should be compared.

Another HCV vaccine approach aims at induction of broad cellular immunity using the delivery of HCV genomic regions encoding the non-structural proteins. Spontaneous resolvers of acute HCV infection have been shown to elicit strong, broad HCV-specific cellular immune responses, whereas individuals progressing to chronic, persistent infection exhibit much weaker and narrowly-targeted cellular immune responses (Figure 3).57 Further, immunodepletion of either CD4+ or CD8+ T cells in the chimpanzee HCV infection model leads to a progression to chronic infection confirming the importance of T cell-mediated immunity in preventing chronicity.14,15 Furthermore, eradication of HCV in chimpanzees can still occur in the absence of antibodies against gpE1/gpE2.58,59,60 Since the region encoding the non-structural proteins is less diverse than the structural protein-encoding region, this approach provides an attractive advantage compared to the glycoprotein approach. Okarios Inc. has tested the delivery of the HCV NS3, NS4a, NS4b, NS5a and NS5b genes of genotype 1b using a combination of replication-defective modified vaccinia Ankara and chimpanzee-derived adenovirus 3 vectors.61 Efficacy has been demonstrated by showing suppression of acute viremia and acute hepatitis after heterologous genotype 1a virus challenge in chimpanzees vaccinated with the prototype vaccine.62 However, no significant reduction in the chronic carrier rates was observed, possibly due to the small numbers of animals tested. Currently, this vaccine is being tested for efficacy in intravenous drug users in the United States and this trial is expected to be completed by 2015/2016.63

emi201379f3

Figure 3. Proliferative CD4+ T-cell response of the first sample in the acute phase of disease to recombinant HCV proteins (HCV-NS3, -NS4, -NS5 and -core) of PBMCs from 38 patients with acute hepatitis C. Patients are grouped according to the final outcome of disease in self-limited hepatitis C (SL, n=20) and patients with chronic evolution (C, n=18). Results are shown as SI=3H-thymidine incorporation of antigen-stimulated PBMCs (counts per minute)/unstimulated control. All patients with self-limited disease displayed a significant proliferative T-cell response against at least one of the viral proteins, while patients with chronic evolution mounted no or only transient antiviral T-cell responses. NS3 and NS4 revealed the most frequent and most vigorous responses. In four patients, the proliferative response against NS5 was not tested in the first sample. The data are reproduced with permission from Gerlach et al.57 PBMC, peripheral blood mononucleated cell; SI, simulation index.

It would be pertinent in future to test the combination of envelope glycoprotein-based and T cell-based vaccines for potential additive or synergistic effects to boost efficacy. A recent study that followed spontaneous clearance of chronic HCV infection highlighted the role of both the humoral response as well as T-cell immunity.35 Mechanistically, it is probable the cross-neutralizing antibodies could limit the acute infection, which then allows effective T-cell immunity to efficiently clear the infection.

THERAPEUTIC VACCINE

There are many mechanisms leading to the dysfunction of HCV-specific T cells, thus rendering them ineffective in the control of infection.13 Reactivation of these HCV-specific T cells is critical for a therapeutic vaccine to induce recruitment to the liver where they can exert their antiviral activity by secreting cytokines such as IFN-γ and tumor necrosis factor-alpha (TNF-α) and by direct killing of infected hepatocytes. The efficacy of these vaccines may possibly be improved by prior treatment with DAAs to first suppress HCV viremia (Figure 1).

One therapeutic vaccine candidate was codeveloped by CSL Limited and Chiron Corporation based on recombinant HCV core formulated with the T-cell adjuvant IMX. This vaccine demonstrated encouraging animal data64 and favorable phase I trial data in healthy human volunteers.65 Preliminary results also showed modest reduction in the viral load in a subset of chronic HCV patients.37 Transgene Inc. has used a modified vaccinia Ankara vector expressing the HCV NS3, NS4a, NS5a and NS5b genes to boost CD4+ T helper and CD8+ cytolytic T cells against these antigens. In a phase I clinical trial, 6 of 15 treated patients showed a reduction (0.5–1.4 log) in viral load following vaccination. The two patients with the highest reduction in virus titers also showed a concomitant increase in vaccine-specific T-cell responses.66 Recently, Transgene’s report of a phase II clinical trial showed that pre-treatment of HCV-infected patients with the vaccine prior to treatment with INF-α and ribavirin increased the early virological response (64% versus 30%in the control group).67 However, significant side effects of this combined therapy have been reported rendering this regimen potentially problematic. Okarios is conducting a phase Ib trial using the prime/boost method with replication defective adenovirus 6 and modified vaccinia Ankara expressing the HCV NS3, NS4a, NS4b, NS5a and NS5b genes in concert with standard-of-care drug therapy.68 Another approach was used by the Swedish company ChronTech to directly deliver a DNA plasmid encoding the HCV proteins 3/4a by electroporation. This vaccine has currently moved into phase II clinical testing.69

It will be of interest to determine the efficacy of these therapeutic vaccines in combination with interferon-free DAA therapy. However, the probability of future combinations of DAAs being able to cure all HCV patients is so high that developing therapeutic vaccination strategies for HCV may be unnecessary.

PERSPECTIVE

Combinations of new HCV DAAs to effectively treat chronic HCV infections are expected to become available over the next 1–2 years. However, it is very unlikely that these very costly drug combinations can be made accessible to most HCV carriers around the globe since treatment of all of these individuals will cost in the region of US$10 trillion! Therefore, we consider the development of a global prophylactic vaccine to be of high priority.

The rate of liver cancer is rapidly climbing70 and one of the major risk factors is HCV infection. Many individuals were unknowingly infected with HCV prior to the identification of the virus about 25 years ago. Since many of these infections are only now manifesting as late stage liver disease, the incidence of HCV-related morbidity and mortality will continue to climb in the future.71,72,73 Therapeutic vaccines could provide a needed boost to complement the success of HCV DAAs to combat chronic infection. However, these vaccines are aimed at boosting HCV-specific T cells targeting infected liver cells. As such, there is a risk that these could potentially increase liver injury and exacerbate inflammation within the liver of these chronic HCV carriers. Continual monitoring of the safety of these therapeutic vaccines will be critical. Their use is also likely to be limited unless they can be provided at much lower cost than HCV DAAs.

Recently, some genetic factors have been identified that favor the outcome of HCV therapy.4,5,74,75,76 In particular, IL28B polymorphisms have been linked to spontaneous clearance as well as to a favorable response to IFN-α based therapy.4,5,74,75 It is not yet known if vaccine efficacy will be similarly tied to host genetics. Expansion of the population tested with promising vaccine candidates will help to answer these questions. Further exploration of the immune correlates of HCV clearance will also aid in improving vaccine design and regulatory approval. Additional cohorts of patients are currently being followed during acute HCV infection in order to answer these questions.

With the arrival of many more HCV-specific DAAs and promising candidates for HCV vaccine antigens and delivery on the prophylactic and therapeutic fronts, HCV therapy options are rapidly expanding. The obstacle to HCV prevention and treatment will soon be an economic and political issue in terms of how to effectively divide health-care resources for HCV therapy and prophylactic vaccine implementation.

REFERENCES

Source

U.S. Food & Drug Administration (FDA)

During cold and flu season, people turn to medicines that can help relieve their symptoms, but many of these contain acetaminophen, which can cause liver damage if too much is taken. Acetaminophen is a fever reducer and pain reliever, and FDA has developed resources to help consumers recognize this commonly used ingredient in medicines and how to use it safely. Check out FDA’s fact sheet “Careful: Acetaminophen in pain relief medicines can cause liver damage” to avoid taking too much acetaminophen and learn about the dangers of taking more than directed.

Acetaminophen is the active ingredient found in more than 600 prescription and over-the-counter (OTC) medications, including cough suppressants and cold remedies. When taken correctly, acetaminophen can be safe and effective. However, taking more than one medication containing acetaminophen per day may lead to liver damage.

In addition to the fact sheet, consumers also can read the Drug Facts labels on OTC medications to see if they contain acetaminophen. On the labels of prescription medicines, acetaminophen may be spelled out, or it may be abbreviated such as APAP, Acet, Acetaminoph, Acetaminop, Acetamin, or Acetam. FDA’s Web site has brochures, tutorials and articles to help identify acetaminophen on labels and how to take the drug safely.

For more information about acetaminophen, visit www.fda.gov/otcpaininfo and always check with your healthcare professional if you have questions. Stay safe and healthy this cold and flu season by knowing the active ingredients in your medicines and following the directions carefully

Source FDA

Eur J Gastroenterol Hepatol. 2013 Dec;25(12):1377-84. doi: 10.1097/MEG.0b013e3283624a28.

Sockalingam S, Blank D, Banga CA, Mason K, Dodd Z, Powis J.

aMedical Psychiatry Program, University Health Network, Toronto General Hospital Departments of bPsychiatry cPsychology dMedicine, University of Toronto eSouth Riverdale Community Health Centre fToronto East General Hospital, Toronto, Ontario, Canada.

Abstract

BACKGROUND: Advances in hepatitis C virus (HCV) treatment have yielded improved virological response rates, and yet, many individuals with psychiatric illness still fail to receive HCV therapy. Concerns about safety, adherence, and efficacy of HCV treatment are compounded and treatment is further deferred when substance use is also present. This is especially problematic given the disproportionately high rates of both mental health issues and substance use among individuals living with HCV.

OBJECTIVE: This study sought to examine HCV treatment outcomes in clients with serious mental illness (SMI) and with high rates of active substance use who were participating in a community-based HCV treatment program.

PATIENTS AND METHODS: A retrospective chart review of 129 clients was carried out. Patients were classified as having an SMI if they had a history of bipolar disorder, psychotic disorder, past suicide attempt or mental health related hospitalization.

RESULTS: Fifty-one patients were defined as having an SMI. Among the 46 patients with SMI and a detectable HCV viral load, HCV antiviral therapy was initiated in nine (19.6%). A relapse or an increase in substance use was common (77.8% or n=7), as was the requirement for adjustment or initiation of psychotropic medications (66.7% or n=6) during HCV antiviral therapy. Despite these barriers, rates of adherence to antiviral therapy were high and overall sustained virological response rates were comparable with published trials.

CONCLUSION: This study is the first to report HCV treatment outcomes in a population in which SMI and active polysubstance use was prevalent and suggests that with appropriate models of care, clients with trimorbidity can be treated safely and effectively.

PMID: 23680911 [PubMed - in process]

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Patient Prefer Adherence. 2013 Oct 17;7:1067-1075.

Mravčík V, Strada L, Stolfa J, Bencko V, Groshkova T, Reimer J, Schulte B.

National Monitoring Centre for Drugs and Drug Addiction, Prague, Czech Republic ; Department of Addictology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.

Abstract

INTRODUCTION AND METHODS: Hepatitis C virus (HCV) infections are highly prevalent amongst people who inject drugs (PWID). Despite well documented evidence of its effectiveness, suggested cost-effectiveness, and potential to reduce HCV prevalence rates, the uptake of antiviral HCV treatment by PWID is low. This nonsystematic literature review describes factors associated with the uptake, adherence, and efficacy of HCV treatment among PWID and discusses strategies to increase their uptake of treatment.

RESULTS: Low HCV treatment uptake among PWID is associated with a number of patient-related and provider-related barriers. Beliefs and fears about low efficacy and adverse effects on the patient's part are common. A substantial number of factors are associated with the chaotic lifestyle and altered social functioning of PWID, which are often associated with decompensation or relapsing into drug addiction. This may lead to perceived low adherence with treatment and low efficacy on the provider's part too, where lack of support, inadequate management of addiction, and other drug-related problems and poor treatment of side effects have been described. Practical issues such as the accessibility of treatment and finances also play a role. Strategies to improve the HCV treatment rate among PWID involve pretreatment management and assessment, a multidisciplinary approach, management of side effects, and enhanced education and counseling.

CONCLUSION: Specific factors are associated with poorer treatment outcomes in PWID on the side of both the patient and the treatment system. However, given that PWID can achieve treatment adherence and sustained virologic response rates comparable with those in nondrug users, drug use per se should not be considered a criterion for exclusion from treatment. Further development of measures leading to higher uptake of treatment and adherence in PWID and appropriate adaptation of HCV treatment guidelines represent important tools in this regard.

KEYWORDS: adherence, efficacy, hepatitis C virus, people who inject drugs, treatment uptake

PMID: 24204126 [PubMed - as supplied by publisher] PMCID: PMC3804540

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Aliment Pharmacol Ther. 2013 Nov 10. doi: 10.1111/apt.12544. [Epub ahead of print]

Maasoumy B, Cobb B, Bremer B, Luk K, Halfon P, Aslam S, Manns MP, Cornberg M, Wedemeyer H.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Abstract

BACKGROUND: Early on-treatment virological response is one of the most important predictors for sustained virological response (SVR) to treatment of chronic hepatitis C virus (HCV) genotype 1 infection with triple therapy including HCV protease inhibitors (PI). Treatment duration (24 vs. 48 weeks) is based on HCV RNA results at weeks 4 and 12 of PI therapy when HCV RNA must be 'undetectable' to allow shorter therapy.

AIM: To analyse the reliability of HCV RNA measurements at key decision time points (weeks 4 and 12) and the predictive value of concordant or discordant assay results for SVR.

METHODS: Weeks 4 and 12 samples of patients receiving telaprevir-containing triple therapy were initially tested with the AmpliPrep/COBAS-TaqMan_HCV-Test-v1.0 (limit of detection; LOD = 15IU/mL) and retested with the AmpliPrep/COBAS-TaqMan_HCV-Test-v2.0 (LOD = 15IU/mL) and the High_Pure/COBAS-TaqMan_HCV-Test-v2.0 (LOD = 20IU/mL).

RESULTS: Concordance among the three test results in classifying samples as HCV RNA 'undetectable' or 'detectable' was only 55% at week 4, but 85% at week 12. Retesting of 'undetectable' week 4 samples with the respective other assays revealed positive HCV RNA results in 32-50%. In 30%, HCV RNA was 'undetectable' by all three tests at week 4 and all of these patients achieved SVR. In contrast, treatment failure occurred in 62% of patients with at least one 'detectable' result, including cases with one or two other 'undetectable' tests at week 4.

CONCLUSIONS: A single 'undetectable' HCV RNA result at week 4 is not always associated with achieving SVR. Repeated testing in difficult-to-treat patients may identify those at risk for treatment failure.

© 2013 John Wiley & Sons Ltd.

PMID: 24206524 [PubMed - as supplied by publisher]

Source

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Abbas Mourad1,2, Sylvie Deuffic-Burban1,2,*, Nathalie Ganne-Carrié3, Thibaud Renaut-Vantroys4, Isabelle Rosa5, Anne-Marie Bouvier6, Guy Launoy7, Stephane Cattan4, Alexandre Louvet1,4, Sébastien Dharancy1,4, Jean-Claude Trinchet3,  Yazdan Yazdanpanah2,8, Philippe Mathurin1,4,*

DOI: 10.1002/hep.26944

Copyright © 2013 American Association for the Study of Liver Diseases

Publication History
Accepted manuscript online: 21 NOV 2013 02:20AM EST
Manuscript Accepted: 18 NOV 2013
Manuscript Revised: 31 OCT 2013
Manuscript Received: 9 JUN 2013

Keywords: Lead-time bias;  Life expectancy;  Liver cancer;  Markov model

Abstract

Because of the ongoing debate on the benefit of ultrasound (US) screening for HCC, we assessed the impact of screening on HCV-related compensated cirrhosis aware of their HCV status. A Markov model simulated progression from HCC diagnosis to death in 700 patients with HCV-related compensated cirrhosis aware of their HCV status to estimate life expectancy (LE) and cumulative death at 5 years. Five scenarios were compared: S1, no screening; S2, screening by currently existing practices (57% access and effectiveness leading to the diagnosis of 42% at stage BCLC-0/A); S3, S2 with increased access (97%); S4, S2 with an efficacy of screening close to that achieved in a randomized controlled trial leading to the diagnosis of 87% of patients at stage BCLC-0/A; S5, S3+S4. The analysis was corrected for lead-time bias. Currently existing practices of HCC screening increased LE by 11 months and reduced HCC mortality at 5 years by 6% compared to no screening (P=0.0013). Compared to current screening practices we found that: a) increasing the rate of access to screening would increase the LE by 7 months and reduced HCC mortality at 5 years by 5% (P= 0.045); b) optimal screening would increase the LE by 14 months and reduced HCC mortality at 5 years by 9% (P=0.0002); c) combination of an increased rate of access and optimal effectiveness of HCC screening would increase the LE by 31 months and decreased HCC mortality at 5 years by 20% (P<0.001). Conclusion: The present study shows that US screening for HCC in patients with compensated HCV-related cirrhosis aware of their HCV status improves survival and emphasizes the crucial role of screening effectiveness. (Hepatology 2013;)

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Over 21,000 'unaware' of HIV infection

Provided by Nursing in Practice

21 NOVEMBER, 2013 09:36 AM

mi-34378

More than 21,000 people living with HIV in the UK are unaware of their infection, according to a new Public Health England (PHE) report.

Close to half (47%) of the 6,360 people newly diagnosed with HIV in 2012 were identified late, the report shows.

And new HIV diagnoses among men who have sex with men (MSM) have reached an all time high, with 3,250 cases in 2012.

There was a small decline in the number of people living with HIV who were unaware of the condition, the report shows. But PHE believes improvements must be made, as early diagnosis and timely treatment can mean a near-normal lifespan with current treatments.

Professor Kevin Fenton, PHE’s Health and Wellbeing Director, said “National HIV Testing Week is a great opportunity to alert people to the benefits of testing – for individuals and for the UK’s public health. PHE is urging members of the public, clinicians, commissioners and community leaders to support and engage with the campaign.”

Professor Noel Gill, head of PHE’s HIV and STI department, “In the UK, people who are unaware of their infection are likely to be those most at risk of transmitting HIV to others. We must increase the speed at which we’re reducing the number of undiagnosed HIV infections by encouraging earlier and more frequent HIV testing, especially by those most at-risk. Earlier diagnosis will help reduce new HIV infections across the UK.

“Around half of men who have sex with men recently diagnosed with HIV received their diagnosis the first time they tested, which is a strong indication that many men who should be testing are not. National HIV Testing Week gives people a great opportunity to get tested.”

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Excess Sugar Not Directly Tied to Liver Disease

Published: Nov 5, 2013 | Updated: Nov 6, 2013

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By Cole Petrochko, Staff Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

  • On an isocaloric diet, overweight men who were on a high-fructose or a high-glucose diet did not develop any significant changes in hepatic triacylglycerol concentration or serum levels of liver enzymes.
  • Note that on a hypercaloric diet, both high-fructose and high-glucose diets produced significant increases in these parameters without any significant difference between the two groups.

Sugar intake was not associated with nonalcoholic fatty liver disease (NAFLD) in a population of overweight men who were otherwise healthy, researchers found.

Overweight men who consumed high-fructose or high-glucose diets did not see significant increases in insulin resistance (increase of 0.8 in a homeostasis model assessment versus 0.1), serum concentration of uric acid (22 mu-mol/L versus 23 mu-mol/L), concentration of hepatic triacylglycerol, or body weight, according to Ian MacDonald, PhD, of the University of Nottingham in England, and colleagues.

However, significant increases in weight and concentration of hepatic and serum triacylglycerol occurred when the patients were transitioned to a high-calorie diet with high glucose or high fructose, they wrote online in the journal Gastroenterology.

"Based on the results of our study, recommending a low-fructose or low-glycemic diet to prevent nonalcoholic fatty liver disease is unjustified," MacDonald said in an accompanying statement. "The best advice to give a patient is to maintain a healthy lifestyle with diet and exercise."

Past research in the association between fructose consumption and fatty liver disease has shown a significant association between daily consumption with increased hepatic fibrosis.

A mouse study showed that those whose diet contained 10% glucose, but was otherwise the same, had an increase in energy intake, body weight, visceral obesity, fatty liver, elevated insulin, and hyperlipidemia.

Researchers have shown a link between liver fat and worse metabolic profiles in twin studies.

The authors looked at hepatic outcomes in 32 overweight but healthy men ingesting a high- fructose diet compared with those receiving a high-glucose diet.

Participants were randomized to receive either high glucose or high fructose in their diets over 2 weeks, which was followed by a 6-week washout period, a second baseline assessment, and a second 2-week period where their calorie intake was also increased.

Those enrolled were ages 18 to 50, had a body mass index of 25 to 32 kg/m2, and had a waist circumference greater than 94 cm (around 37 inches).

Participants were excluded if they drank more than 21 units of alcohol weekly, had weight change of more than 3 kg (about 6.6 lbs) in the last 3 months, had regular high-intensity physical activity, were vegetarian, or drank more than 25 g/day of fructose (500 mL), which is roughly the same as a 16 oz bottle (480 mL) of soda daily.

Roughly a quarter of participants' energy intake was given through monosaccharides mixed into four times daily doses of 500 mL of water in the initial 2-week study period. During the second study period, participants were subject to habitual food consumption with the same quantities of monosaccharides.

Sweetened drinks were forbidden during both study periods, while exercise was encouraged.

The primary outcome was hepatic steatosis, while secondary endpoints were hepatic adenosine triphosphate content, insulin resistance, and enzymes. Also collected were weight, satiety, insulin resistance, nonhepatic triglycerides, inflammatory cytokines, and adipokines.

Between-group differences were significant for measures of insulin resistance (P=0.03) and uric acid concentration (P<0.01).

During the hypercaloric period, participants in both groups had similar increases in:

  • Weight: 1.0 versus 0.6 kg (P=0.29)
  • Absolute concentration of hepatic triacylglycerol in the liver: 1.70% versus 2.05% (P=0.73)
  • Serum: 0.36 versus 0.33 mmol/L (P=0.91)

"The outcomes were less influenced by the type of monosaccharides than by energy status," they wrote.

There was an increase in abdominal and diarrheal symptoms among participants in the fructose group.

They noted that the study was limited by the large quantity of each monosaccharide in participants' diets relative to the average sugar consumption in England (25% versus 14.6%), lack of crossover between groups, short-term of the study, lack of regulation in food intake during the hypercaloric period, and lack of liver biopsy data.

Nonetheless, "our study serves as a warning that even short changes in lifestyle can have profound impacts on your liver," MacDonald said.

The study was supported by a grant from Core charity, the National Institute for Health Research Biomedical Research Unit in Gastrointestinal and Liver Diseases, the Nottingham University Hospitals NHS Trust, and the University of Nottingham.

MacDonald reported serving on scientific advisory boards for Mars and Coca Cola.

Primary source: Gastroenterology
Source reference: MacDonald IA, et al "No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men" Gastroenterology2013; 145: 1016-1025.

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Excess bile acids can signal beginning of liver cancer

Baylor College of Medicine > Baylor College of Medicine News > Cancer

Dipali Pathak
(713) 798-4710
Houston, TX - Nov 21, 2013

The road to liver cancer can start with the toxic and chronic pile-up of bile acids that act as tumor promoters. This begins a deadly cascade that leads to overexpression of a protein called IQGAP1, which activates the Yes-associated protein (YAP), said researchers from Baylor College of Medicine in a report that appears online in the journal Cell Reports.

Normally, levels of bile acids ­ components of bile, which is essential to digestion ­ are tightly controlled because they are potentially toxic to the liver, said Dr. David Moore, professor of molecular and cellular biology at BCM and the corresponding author of the report. In studies with a mouse model that lacks two key components (nuclear receptors FXR and SHP) of this regulatory pathway, he and his colleagues found that the animals have enlarged livers, proliferation of liver progenitor cells and YAP activation and eventually develop spontaneous liver tumors.

"In this case, toxic levels of bile acids activate YAP, and the mice develop cancer spontaneously," said Moore.

In cultures of liver cells, treatment with bile acids resulted in YAP activation. Feeding normal mice a diet that increases bile acid levels also activates YAP in the liver.

The mechanism begins with increased levels of bile acids, said Moore, and requires a membrane protein called IQGAP1.

"IQGAP1 is not originally present in the liver. It only appears in the presence of toxic levels of bile acids," he said.

In fact, he said overexpression or higher levels of IQGAP1 are enough to induce YAP, indicating that decreasing levels of this protein or of the bile acids that induce it may be protective against liver cancer.

"Activation of YAP is associated with human liver cancer and a form of that disease that is associated with particularly poor prognosis," he said.

Others who took part in this work include: Sayeepriyadarshini Anakk and Milton J. Finegold, both of BCM; Manoj Bhosale of University of Illinois at Urbana-Champaign; Valentina A. Schmidt of Stony Brook University in New York; and Randy L. Johnson of the University of Texas MD Anderson Cancer Center in Houston. Anakk is now at the University of Illinois at Urbana-Champaign. Moore holds the The R. P. Doherty, Jr. Welch Chair in Science.

Funding for this work came from the National Institute Diabetes and Digestive and Kidney Diseases, Digestive Disease Center Morphology Core (Grant DK56338, DK068804, DK62434), the National Cancer Institute MD Anderson Cancer Center proteomics core (Grant CA16672) and Cancer Prevention and Research Institute of Texas (Grant RP120138), the R.P.Doherty, Jr. Welch Chair in Science , National Institutes of Health (Grant R01HD060579 , American Cancer Society Research Scholar (Grant RSG-09-033-01-CSM ) and start-up funds from the University of Illinois at Urbana-Champaign.

Source

Journal of Hepatology
Volume 59, Issue 6 , Pages 1184-1192, December 2013

Macarena Simón-Talero, Rita García-Martínez, Maria Torrens, Salvador Augustin, Susana Gómez, Gustavo Pereira, Mónica Guevara, Pere GinésGermán Soriano, Eva Román, Jordi Sánchez-Delgado, Roser Ferrer, Juan C. Nieto, Pilar Sunyé, Inma Fuentes, Rafael Esteban,Juan Córdoba

Received 17 April 2013; received in revised form 4 July 2013; accepted 7 July 2013. published online 22 July 2013.

Abstract

Background & Aims

Episodic hepatic encephalopathy is frequently precipitated by factors that induce circulatory dysfunction, cause oxidative stress-mediated damage or enhance astrocyte swelling. The administration of albumin could modify these factors and improve the outcome of hepatic encephalopathy. The aim of this study is to assess the efficacy of albumin in a multicenter, prospective, double-blind, controlled trial (ClinicalTrials.gov number, NCT00886925).

Methods

Cirrhotic patients with an acute episode of hepatic encephalopathy (grade II–IV) were randomized to receive albumin (1.5g/kg on day 1 and 1.0g/kg on day 3) or isotonic saline, in addition to the usual treatment (laxatives, rifaximin 1200mg per day). The primary end point was the proportion of patients in which encephalopathy was resolved on day 4. The secondary end points included survival, length of hospital stay, and biochemical parameters.

Results

Fifty-six patients were randomly assigned to albumin (n=26) or saline (n=30) stratified by the severity of HE. Both groups were comparable regarding to demographic data, liver function, and precipitating factors. The percentage of patients without hepatic encephalopathy at day 4 did not differ between both groups (albumin: 57.7% vs. saline: 53.3%; p>0.05). However, significant differences in survival were found at day 90 (albumin: 69.2% vs. saline: 40.0%; p=0.02).

Conclusions

Albumin does not improve the resolution of hepatic encephalopathy during hospitalization. However, differences in survival after hospitalization suggest that the development of encephalopathy may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.

Abbreviations: HE, hepatic encephalopathy, ACLF, acute-on-chronic liver failure, ALB, albumin group, SAL, saline group, CHESS, clinical hepatic encephalopathy staging scale, HESA, hepatic encephalopathy scoring algorithm, TNF-α, tumor necrosis factor alpha, IL, interleukin,MDA, malondialdehyde, MELD, Model for End-Stage Liver Disease

Keywords: Albumin, Hepatic encephalopathy, Treatment, Cirrhosis, Human

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Surveyed Physicians Expect Nearly 20 Percent of Their Actively Treated HCV Patients to Be On a Newly Approved Regimen, According to a New Report from BioTrends Research Group

EXTON, Pa., Nov. 21, 2013 /PRNewswire/ -- BioTrends Research Group, one of the world's leading research and advisory firms for specialized biopharmaceutical issues, finds that, following the launches of Gilead's sofosbuvir and Janssen/Medivir's simeprevir in the United States, currently marketed triple (Vertex's Incivek- and Merck's Victrelis-containing regimens) and dual therapy hepatitis C virus (HCV) regimens will lose market share to sofosbuvir-and simeprevir-based regimens. When asked about treatment practices in the next six months, surveyed physicians plan to treat 17 percent of their genotype 1 and 21 percent of their actively treated genotype 2/3 HCV patients with a sofosbuvir- and/or simeprevir-containing regimen.

(Logo: http://photos.prnewswire.com/prnh/20130103/MM36805LOGO)

The report entitled TreatmentTrends®: Hepatitis C Virus (US), Wave 2 also finds that the majority of surveyed physicians reported, unaided, that they are currently warehousing HCV patients in anticipation of new therapies, with nearly 30 percent of this warehousing specifically attributed to waiting for access to sofosbuvir/polymerase inhibitors. While most surveyed physicians are warehousing treatment-naive and treatment-experienced patients as they wait for the approval of simeprevir, sofosbuvir and/or other interferon-free therapy options, only 12 percent of surveyed physicians indicated they are satisfied with currently approved therapies.

"In anticipation of availability of new directly-acting antivirals, the shift in the HCV treatment paradigm is already apparent," said BioTrends Research Group Analyst Sandra Renz. "With the imminent approval of simeprevir and sofosbuvir – agents offering potentially shorter treatment duration, possible interferon-free regimens, improved safety and tolerability profiles and higher cure rates – physicians are eagerly awaiting these new regimens and holding off on prescribing treatment until they are part of the arsenal."

The study also finds that at least one-third of surveyed physicians have received a patient request for one of the currently available HCV brands in the past month. Further, a subset of surveyed physicians has already received patient requests for sofosbuvir and simeprevir, suggesting that awareness of these products exists among patients even ahead of their anticipated U.S. launch later this year.

TreatmentTrends®: Hepatitis C Virus (US), Wave 2 is a report that covers the use of agents for the treatment of HCV infections. This biannual study focuses on current and future use of leading HCV treatment regimens, patient market share, perceived strengths and weaknesses of the key brands, barriers to broader usage, sales force performance and perceived value of manufacturers' patient assistance programs. In addition, this report assesses potential impact of regimens in development, including AbbVie's ABT-267, ABT-333 and ABT-450/r, Boehringer Ingelheim's faldaprevir and deleobuvir, Bristol-Myers Squibb's asunaprevir and daclatasvir, Gilead's ledipasivr and sofosbuvir and simeprevir. In the current wave of research, BioTrends surveyed 98 U.S. gastroenterologists, hepatologists and infectious disease specialists in September 2013.

About BioTrends Research Group
BioTrends Research Group provides syndicated and custom primary market research to pharmaceutical manufacturers competing in clinically evolving, specialty pharmaceutical markets. For information on BioTrends publications and research capabilities, please visit www.bio-trends.com. BioTrends is a Decision Resources Group company.

About Decision Resources Group
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ccomfort@dresources.com

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