January 6, 2014

Egypt battling hepatitis C epidemic

January 06, 2014

By Leyla Doss/Cairo

After being unemployed for three years, 26-year-old Emad Hassan was offered a job at a local bank on the condition that he take a blood test. It was then that he discovered that he had been infected with the hepatitis C virus (HCV), which can cause liver disease and eventually hepatocellular carcinoma - better known as liver cancer.

The bank consequently withdrew its offer, and Hassan fell victim to the social stigma associated with hepatitis C and other chronic diseases.

In fact, Egypt has the highest prevalence of HCV in the world with 10-14% (8mn to 10mn  people) infected with HCV, and an approximate 1.5mn in need of treatment. Of these, Gamal Esmat, a professor of liver disease in Cairo, notes that the vast majority are in the Nile Delta region.

HCV’s high prevalence in Egypt is in part due to a mass state campaign in the 1960s and 1970s to treat schistosomiasis using improperly sterilised glass syringes and needles.

But a new treatment for HCV could radically change the situation. In collaboration with the ministry of health and other global organisations, the National Hepatology and Tropical Medicine Research Institute (NHTMRI) plans to introduce a new HCV treatment in 2014.

Unlike previous treatments - antiviral drugs that treat HCV by boosting the immune system - the new treatment cures the virus within 12 weeks at a 97% effectiveness rate and with no side effects.

Known as “direct acting antiviral agents,” the new HCV treatment combats the disease by targeting the infected liver cells and destroying the virus’ replication machinery.

Raymond Schinazi, an American research scientist of Italian-Egyptian descent at Atlanta’s Emory University, was the founder of Pharmasset Inc., the company that originally developed the drug. Schinazi’s team of researchers worked for over six years, finding what they consider to be the cure: the PSI-7977 molecule, now named “sofosbuvir,” which the US Food and Drug Administration (FDA) approved on December 8.

Born and raised in Alexandria, Schinazi and his family left Egypt during the large-scale Jewish exodus that took place in the 1950s and 1960s. Schinazi says he still has a close relationship with Egypt and hopes his collaborative research will eventually help cure those infected in his country of birth.

“When I first heard of HCV, I thought to myself: This is my next target,” he says. “My dream was to one day find a cure for it and help my mother country,” says Schinazi, who sold his company and the drug patent to the US-based Gilead Sciences for $11.4bn.

There are currently over six drug companies competing for the production of a HCV cure. But unlike the other drugs in the market, sofosbuvir is also pan-genotypic, which means that it can be used to treat infected people with all genotypes worldwide - including genotype 4, which is most common in Egypt.

Dubbed the “silent epidemic”, hepatitis C has infected approximately 170mn people worldwide and has caused about 350,000 deaths per year from HCV-related diseases.

“Our aim is to provide a treatment for HCV which is safe, effective and with minimal side effects,” says Manal al-Sayed, professor of paediatrics at Ain Shams University and a member of the National Committee for the Control of Viral Hepatitis. “Our challenge will be to have it at affordable prices for all,” she adds.

With prospects of the cure costing as much as $100,000 in the US, many are concerned it would be unaffordable for most Egyptians. Egyptian authorities, doctors, ministry of health members and others are currently negotiating with major pharmaceutical companies producing this and other treatments to reduce costs.

Nevertheless, Egyptian authorities and doctors remain hopeful of bringing HCV treatment to Egypt at 5% of the global price, with the rest subsidized by government authorities.

Hepatitis C is blood-borne, and symptoms are often not visible until 20 years after infection. It can range in severity from a mild illness lasting for a few weeks to a serious, lifelong condition that can lead to cirrhosis of the liver or liver cancer.

Despite treatment and the likelihood of a total cure looking promising in the near future, authorities and researchers admit that more attention should be focused on preventing the infection stage of hepatitis C.

Dina Iskander, a researcher for the Right to Health Programme, applauds the prospects for new treatment, but believes that more attention and expenditure should be directed at the inefficiency of the Egyptian health care system.

According to the US Centers for Disease Control and Prevention (CDC), almost 20% of the Health Ministry’s budget has been allocated to care and treatment and just 1% toward infection control.

In Egypt, there are approximately 165,000 new cases of infection each year, and a staggering 70% of them are related to the health care system. Equipment is often not sterilized according to acceptable standards, and infection is very often transmitted through improperly screened blood transfusions of infected patients.

Other modes of infection include the sharing of unsterilized needles and unsterilized tools for pedicures, manicures and tattoos. In rare cases, HCV can also be transmitted from mother to fetus or through sexual intercourse.

There are, therefore, plans to implement a comprehensive national registry system and screening programs for the disease, al-Sayed says. Over the past six years, there have also been extensive campaigns to raise awareness about infection and treat large numbers of patients for free.

The World Health Organisation says Egypt is one of only two developing countries that provide free universal treatment for HCV. With over 23 centres in Egypt developed over the past six years for treating patients, approximately 300,000 infected individuals have received free care.

Al-Sayed hopes eventually to get more assistance for training and research in the field in order to produce new safe and effective products in Egypt. “This would make it markedly cheaper and easily accessible for all,” she says. “It would be a huge turning point in our history.”- Worldcrunch/Mada Masr


Transplant benefit for patients with hepatocellular carcinoma

World J Gastroenterol. 2013 December 28; 19(48): 9183-9188.

Published online 2013 December 28. doi: 10.3748/wjg.v19.i48.9183.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Alessandro Vitale, Michael Volk and Umberto Cillo.

Alessandro Vitale, Umberto Cillo, Unità di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera-Università di Padova, 35128 Padova, Italy

Michael Volk, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, United States

Author contributions: Vitale A, Volk M and Cillo U wrote, edited and revised the manuscript.

Correspondence to: Alessandro Vitale, MD, PhD, Unità di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera-Università di Padova, Via Giustiniani 2, 35128 Padova, Italy. alessandro.vitale@unipd.it

Telephone: +39-49-8212211 Fax: +39-49-8211816

Received October 1, 2013; Revised November 13, 2013; Accepted November 28, 2013;


Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma (HCC), it is limited by the realities of perioperative complications, and the shortage of donor organs. Furthermore, in many cases there are available alternative treatments such as resection or locoregional therapy. Deciding upon the best option for a patient with HCC is complicated, involving numerous ethical principles including: urgency, utility, intention-to-treat survival, transplant benefit, harm to candidates on waiting list, and harm to living donors. The potential contrast between different principles is particularly relevant for patients with HCC for several reasons: (1) HCC candidates to liver transplantation are increasing; (2) the great prognostic heterogeneity within the HCC population; (3) in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome; and (4) effective alternative therapies are often available for HCC candidates to liver transplantation. In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles, and also introduce equity between patients with HCC and nonmalignant liver disease. We also propose a triangular equipoise model to help decide between deceased donor liver transplantation, living donor liver transplantation, or alternative therapies.

Keywords: Hepatocellular carcinoma, Deceased donor liver transplantation, Living donor liver transplantation, Transplant benefit, Utility, Urgency, Intention-to-treat survival, Harm

Core tip: Deciding upon the best option for a patient with hepatocellular carcinoma is complicated, involving numerous ethical principles including: urgency, utility, intention-to-treat survival, transplant benefit, harm to candidates on waiting list, and harm to living donors. In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles, and also introduce equity between patients with hepatocellular carcinoma and those with nonmalignant liver disease. We also propose a triangular equipoise model to help decide between deceased donor liver transplantation, living donor liver transplantation, or alternative therapies.


Urgency, utility, and equity

Liver transplantation (LT) is theoretically the best treatment for patients with end-stage liver disease but its effectiveness is limited by intrinsic characteristics with important ethical implications: (1) LT remains a technical demanding procedure with a well-established short-term mortality and morbidity[1]; (2) a persistent shortage of deceased donors corresponds to an increasing demand of deceased donor liver transplantation (DDLT)[2]; and (3) the application of living donor liver transplantation (LDLT) is limited by ethical and legal issues related to the risk of harming the living donor[3]. Specific selection policies have consequently been developed over the last two decades to identify good candidates for this complex therapeutic option[4,5].

For patients with non-malignant (NM) liver cirrhosis, scores have been developed to measure disease severity, such as the Child Pugh and the model for end-stage liver disease (MELD) scores[4], which support a selection policy based on the urgency principle. Under a medical urgency-based selection system, patients with worse outcomes while on the waiting list (WL) are given higher priority for transplantation[6]. Use of the MELD score, for example, has significantly reduced waiting list times and in the United States system in recent years[4,7]. If we consider the development of hepatocellular carcinoma (HCC) as a complication of liver cirrhosis, and therefore as a sign of disease severity, assigning a high priority to HCC patients would also comply with this principle of urgency. This viewpoint is reflected in the United Network for Organ Sharing (UNOS) allocation system, where an arbitrary high MELD score is assigned to patients with T2-HCC[7].

The limit of this approach is that it fails to consider the extremely relevant prognostic heterogeneity of patients with HCC and the potential effectiveness of alternative therapies[8]. It is also only reasonable to consider HCC as a complication of liver cirrhosis if this condition is maintained within certain proportions of candidates on the WL (e.g., < 20%), as in the US[9]. In some geographical LT settings, however, there has been a significant increase in the proportion of LT candidates on the WL with liver tumors in recent years and this has given rise to similar proportions of liver transplants for HCC and NM disease[10]. In these modern LT realities, it is probably more reasonable to consider HCC patients as a separate LT population and analyze the prognostic heterogeneity of this particular medical condition more deeply[11].

If we observe the issues of patient selection and organ allocation from the HCC population point of view, therefore, current LT selection policies for HCC patients (e.g., the UNOS allocation system) appear to be based mainly on a utility principle for two main reasons. First, a utility-based system is one that gives priority according to expected post-transplant outcomes[6]. For patients with HCC, the poor results achieved in early experiences with patients transplanted for advanced tumors have favored the introduction of strict selection criteria focusing mainly on post-LT outcome[5]. Therefore, patients beyond Milan criteria have limited probability of receiving a transplant.

Second, in the current system all T2 HCC patients receive the same priority regardless of their likelihood of death on the waiting list.

If we consider LT candidates with and without cancer as two separate populations, therefore, apparently opposite allocation principles are currently used at the majority of LT centers around the world. This diversity in patient selection policy intrinsically creates an ethical paradox, in that donated organs are allocated to the “sickest patient first” among the candidates with NM hepatic disease, but to the “earliest patient first” among candidates for LT who have HCC, irrespective of their survival prospects with therapies other than transplantation.

Aristotle defined justice as “treating equal cases equally, and unequal cases unequally”. One of the fundamental challenges of organ allocation science is maintaining equity among the heterogeneous groups of patients on the waiting list. In the specific organ allocation context, equity means treating all patients according to a common endpoint. From this perspective, the principle of equity is hierarchically more important than all others, whether we decide to favour urgency, or utility or benefit as endpoints for our allocation system.

Based on these considerations (i.e., the increasing proportion of HCC patients enlisted, and an excess of priority for HCC patients with a low urgency for LT), recent proposals have tried to resolve the unbalance in the access to transplantation between HCC and non-HCC patients. One attempt involved developing risk models within the HCC population for 3-mo drop-out risk as common urgency endpoint[12,13]. However, this approach (i.e., to equate the drop-out risk of different patients) carries the risk of prioritizing HCC patients with higher biological aggressiveness in terms of nodule size and AFP levels, and consequently dramatically increasing the risk of post-LT tumour recurrence or death[14]. Thus, methods are needed which balance the principles of urgency and utility when attempting to reach equity between HCC and non-HCC patients.

Intention-to-treat survival

To describe the effect of long waiting times on the effectiveness of LT as curative therapy for HCC[15], some years ago the concept of intention-to-treat (ITT) survival was introduced. Interestingly, analyzing the survival figures of HCC patients from the day of enlisting and not from that of transplant, the overall results of LT for HCC became worse than resection[16] due to the high dropout rate of HCC patients from the WL for tumor progression.

However, ITT survival is strongly related to the specific local/regional WL characteristics and in particular to the patient median waiting time: assuming as a constant the post-LT outcome, the lower the pre- LT mortality, the higher the intention-to-treat survival. For this reason, in a clinical scenario where HCC patients receive high priority for LT (i.e., low waiting time and low risk of dropout) the intention-to-treat survival of LT for HCC patients may exceed that of liver resection[17].

For these reasons, survival analysis in LT should use the ITT principle because it accounts for all the complex LT processes from the day that LT is first considered.

Transplant benefit

The concept of transplant benefit expresses the survival gain offered by LT by comparison with the best alternative therapy. Transplant benefit can be calculated from the time of transplant, or from the time a patient is first evaluated for transplant-the latter would make it an ITT endpoint. On an individual basis, the main advantage of this principle is that it covers the overall LT process, simultaneously considering post- and pre-LT outcome. The transplant benefit principle applied to the individual LT candidate thus has the potential to create an ideal balance between the concepts of urgency and utility. As suggested by Schaubel et al[6], moreover, by prioritizing patients based on life-years gained thanks to transplantation, the transplant benefit principle performs better than urgency and utility schemes from a population perspective too. This is because an urgency-based system would assign donor organs to patients who are most likely to die while on the WL, but this approach may be to the detriment of utility because patients at the greatest risk of death while on the WL may also be patients with the highest post-LT mortality risk. A utility-based allocation system would ensure that transplanted organs go to patients with the lowest post-LT mortality risk, but patients with the best post-LT outcomes may also have the best outcomes while on the WL. The transplant benefit principle is consequently the one best able to maximize the total life-years gained by the patient population.

In recent years, the transplant benefit principle has been proposed for LT candidates based on studies using data from the Scientific Registry of Transplant Recipients (SRTR)[2,6,18], but these studies did not consider the transplant benefit for the HCC population of LT candidates, because they either focused only on NM candidates[2,11] or they considered HCC as a complication[6] and not as a separate, prognostically heterogeneous medical condition.

The concept of transplant benefit has the intrinsic potential for being especially useful for HCC patients since a particular feature of the approach lies in that it is calculated by subtracting the area under the survival curve after alternative therapies from the area under the survival curve after transplantation[9], a definition that coincides with the gain in life expectancy (LE). This gives a relevant weight not only to the crude post-LT outcome, but also to the alternative therapies available and to the patient’s age, which are extremely important prognostic variables for HCC patients[19]. Figure 1 shows two different clinical scenarios. The first (Figure 1A) concerns the case of a young patient (40 years old) with a tumor beyond the Milan criteria (calculated 5-year post-transplant survival = 60%). The lack of any effective alternative therapies makes the benefit of LT extremely high (8 years). The second scenario (Figure 1B) considers an older patient (65-year-old) within the accepted indications for LT (5-year post-transplant survival = 70%), but with an effective alternative treatment option, i.e., liver resection, which makes the benefit of LT much lower (4 years) than in the first case, although the post-LT outcome would be better.


Figure 1 Clinical examples of the transplant benefit principle applied to hepatocellular carcinoma patients. A: Man 40-year-old, HBV with 2 HCC nodules, the largest of 6 cm, Child B (Milan out, University of California San Francisco out); B: Man 65-year-old, HCV, with 1 HCC (diameter = 4 cm), Child A. HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus.

The recent publication of important studies on the survival prospects of patients with more advanced tumors after LT[20] and other therapies[21,22] makes it potentially feasible now to evaluate transplant benefit across different stages of HCC disease. This could be extremely important because, from a utility perspective, adopting extended criteria for HCC patients would mean allocating more donated organs to HCC patients than to NM patients[16]; taking a transplant benefit perspective, on the other hand, would mean reallocating the same number of organs to different groups of patients with a greater benefit. In other words, the transplant benefit principle would be able to maximize the total life-years of both the HCC and NM population.

These concepts have been recently incorporated in three papers[23-25] evaluating the transplant benefit principle in the HCC population. These studies underline three main points: (1) Liver transplantation results in the highest survival benefit for HCC patients with advanced liver cirrhosis (BCLC stage D); (2) Patients with intermediate tumours (BCLC stages B-C) without effective alternative therapies receive a relevant benefit from LT, regardless of the nodule number-size criteria (i.e., Milan criteria), provided that macroscopic vascular invasion and extra-hepatic disease are absent; and (3) Patients with early tumors and compensated cirrhosis have the lowest benefit from LT when effective alternative therapies are available[23-25].

Harm-benefit to other patients on the waiting list

When patients on a given WL receive an organ, they harm the rest of the candidates on the WL because it is as if they were taking that organ away from other potential candidates. The entity of this harm depends on the extra time the other patients on the WL have to wait for another organ. We can also see this concept from the opposite point of view: if we find an alternative treatment for a patient on a WL for LT (e.g., if we perform a LDLT or a liver resection), we create a benefit for the people on said WL that can be calculated from the further waiting time they spare. Knowing the characteristics of a WL in detail (death probabilities according to disease severity, median waiting time for LT, mean number of organs per year, patient stratification according to MELD score and HCC stage), we can calculate this harm/benefit to candidates on the WL[9,26,27]. This is very important because it is the only allocation principle that takes the characteristics of a specific WL into account (WL size, donor resources and proportions of patients with severe disease).

Harm to the living donor

The crucial element limiting the general applicability of LDLT is the risk of harming a healthy living donor. In the literature, the overall mortality attributed to living donor procedures is lower than 1%, but the risk of morbidity is significant, being around 38% in some experiences as a whole, and < 10% when severe complications are considered alone[28].

A recent worldwide survey[29] has brought more evidence about this field. Overall donor morbidity rate was 24%, but only 0.2% of them died, and 0.04% required transplantation. If harm to donors is only considered in terms of mortality, its impact on the therapeutic decision (between LDLT, DDLT, or no LT) would be minimal compared to the recipient’s risk of death on the WL[30]. Quantifying morbidity could be done by determining the impact of complications on quality of life, but limited data is currently available to derive such estimates.

Furthermore, it is controversial whether donor morbidity and mortality should be weighted equally to that of the recipient[31]. Currently the transplant community takes a protective approach (paternalist principle) to the living donor, and tends to assign greater ethical weight to the donor’s risk of death than to the recipient’s risk of death. This approach, however, comes at the expense of donor autonomy. Further thought is needed on this subject, including input from donors themselves.

One interesting proposal is to define a cut-off for acceptable morbidity and mortality from the perspective of the donor[32,33].


An ideal selection/allocation process for patients with HCC should consider all aspects of the benefits and harms of LT, and the aim of allocation systems should be to reach a balance between the different principles involved in the selection process.

We have represented this equipoise using a triangle containing vectors (Figure 2): the transplant benefit (life expectancy with LT minus life expectancy without LT) is at the top vertex and the potential harm to the rest of the WL and to the living donor at the bottom vertices. According to this model, transplantation is generally indicated when the transplant benefit exceeds the harm. Then, according to the relative weights of the harm to the WL and donor, the decision will be oriented towards LDLT or DDLT.


Figure 2 Ethical equipoise between benefit and harm of deceased-donor liver transplantation and living donor liver transplantation. WL: Waiting list; DDLT: Deceased donor liver transplantation; LDLT: Living donor liver transplantation.

The first advantage of this conceptual model is that it includes all ethical principles involved in the LT decision process. The use of transplant benefit satisfies both utility and urgency principles, while the relationship between benefit and harm to the waiting list satisfies equity-the first principle aims to maximize the need of the single patient, while the second maximizes population total life years[26].

The second advantage of this model is that it considers as different therapeutic procedures DDLT and LDLT. Whenever we used urgency, utility or benefit, these principles taken alone do not distinguish between LDLT and DDLT, so they cannot be used to decide between these different strategies. The indication for LDLT is therefore inevitably the same as for DDLT[32,33], so choosing between the two is difficult. This may partially explain why LDLT has had a limited development in Western countries, especially since the introduction of the MELD[33].

Some authors[32] have recently stressed the possibility to consider different indications between LDLT and DDLT based on the consideration that living donor recipients don’t compete with other patients on the WL. The same authors proposed a sort of double equipoise model specific for LDLT to balance the donor risk and the recipient benefit[32]. Our model has the advantage to be used for both DDLT and LDLT. LDLT has a potentially relevant advantage over DDLT because it only minimally harms the other candidates on the WL: this harm is limited to the risk of the patient needing re-LT after LDLT, which is estimated to be approximately 7%[34], while the risk of liver failure requiring transplantation of the donor is estimated to be 0.04%[29].

This model helps the selection of HCC patients for LT and the choice of the more appropriate transplant procedure (DDLT vs LDLT). However, it can not consider some crucial aspects. First of all, in some countries religiosity or cultural aspects are barriers to DDLT[31]. As second point, in some recipients of a partial liver from a living donor insufficient liver volume can not be avoided to maintain an adequate donor safety. A small-for-size graft easily causes perioperative complications and results in poor outcomes[31]. In summary, although LT is theoretically the best treatment for HCC, it is limited by the realities of perioperative complications, and the shortage of donor organs. Furthermore, the benefit of transplantation is not uniform among patients with HCC; rather, it depends upon the severity of liver disease and the available alternative treatment options. Current systems allocate organs to HCC patients primarily based upon the utility principle, as opposed to the urgency principle which governs allocation to patients with nonmalignant liver disease. Allocating organs by transplant benefit could introduce equity between these patient groups. We propose a triangular equipoise model to help decide between DDLT, LDLT, or alternative therapies.


P- Reviewers: Boin I, Koike H, Tomohide H S- Editor: Qi Y L- Editor: A E- Editor: Zhang DN


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Coffee Consumption and Chronic Liver Disease: The New Best Prescription?

Medscape Gastroenterology > Viewpoints

David A. Johnson, MD

January 06, 2014

Review Article: Coffee Consumption, the Metabolic Syndrome and Non-alcoholic Fatty Liver Disease

Yesil A, Yilmaz Y
Aliment Pharmacol Ther. 2013;38:1038-1044

Study Summary

Coffee consumption is a part of daily life in most areas of the world. As such, a number of studies have evaluated the chemical composition and related effects that this enjoyable beverage may have on health and disease.

For many years, healthcare providers have advised patients to avoid excessive consumption because of a concern about caffeine dependence. Several recent studies, however, suggest that regular coffee consumption may modulate the risk for fibrosis in chronic liver disease.

Yesil and Yilmaz analyzed the experimental, epidemiologic, and clinical studies and the modulation of the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Animal studies showed a reduction in the metabolic syndrome with improvements in glycemic and lipid regulation, as well as reductions in transaminases and proinflammatory cytokine hepatic gene expression. Other studies showed reductions in hepatic fat and collagen proinflammatory tumor necrosis factor, as well as increases in anti-inflammatory interleukins. Epidemiologic and clinical studies demonstrated a significant inverse association between coffee consumption and prevalence of metabolic syndrome, as well as a reduced risk for NAFLD.

View This Abstract Online

Review article: coffee consumption, the metabolic syndrome and non-alcoholic fatty liver disease.

Aliment Pharmacol Ther.  2013; 38(9):1038-44 (ISSN: 1365-2036)

Yesil A; Yilmaz Y

BACKGROUND: Coffee consumption may modulate the risk of the metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD).

AIM: To review the experimental, epidemiological and clinical studies investigating the association between coffee consumption and the risk of MetS and NAFLD.

METHODS: A literature search was conducted with the aim of finding original experimental, epidemiological and clinical articles on the association between coffee consumption, MetS and NAFLD. The following databases were used: PubMed, Embase, Scopus and Science Direct. We included articles written in English and published up to July 2013.

RESULTS: Three experimental animal studies investigated the effects of coffee in the MetS, whereas five examined whether experimental coffee intake may modulate the risk of fatty liver infiltration. All of the animal studies showed a protective effect of coffee towards the development of MetS and NAFLD. Moreover, we identified eleven epidemiological and clinical studies that met the inclusion criteria. Of them, six were carried out on the risk of the MetS and five on the risk of NAFLD. Four of the six studies reported an inverse association between coffee consumption and the risk of MetS. The two studies showing negative results were from the same study cohort consisting of young persons with a low prevalence of the MetS. All of the epidemiological and clinical studies on NAFLD reported a protective effect of coffee intake.

CONCLUSIONS: Coffee intake can reduce the risk of NAFLD. Whether this effect may be mediated by certain components of the MetS deserves further investigation.


Bhoo-Pathy N, Uiterwaal CS, Dik VK, et al. Intake of coffee, decaffeinated coffee, or tea does not affect risk for pancreatic cancer: results from the European Prospective Investigation into Nutrition and Cancer Study. Clin Gastroenterol Hepatol. 2013;11:1486-1492.


Postoperative recurrence pattern and prognosis of patients with hepatocellular carcinoma related with hepatitis B and C Viral infection

Liver Int. 2013 Dec 18. doi: 10.1111/liv.12447. [Epub ahead of print]

Naito S, Imamura H, Tsuakada A, Matsuyama Y, Yoshimoto J, Sugo H, Ishizaki Y, Kawasaki S.


BACKGROUND: Various modalities have been employed effectively according to the tumor recurrence status in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. Therefore, their overall prognosis depends largely on the pattern of recurrence/treatment.

AIM: We investigated the patterns of recurrence and prognosis in HCC patients, especially in relation to the hepatitis virus infection status.

METHODS: The study population comprised 244 patients with HCC undergoing hepatectomy. Curative treatments, including repeated hepatectomies, were performed for recurrences, whenever possible. Detailed information on recurrences was collected until the recurrences exceeded Milan's criteria.

RESULTS: The 5-year disease-free survival, survival within the Milan criteria, and overall survival were 38.4 %, 56.3 %, and 74.5 %, respectively. In the comparison between patients with hepatitis C and B virus-related HCC (HC-HCC: n = 111; and HB-HCC: n = 45, respectively), the former showed lower disease-free (30.2 % vs. 40.7 % at 5 years, P = 0.061) and overall (65.7 % vs. 89.7 % at 5 years, P = 0.011) survivals; they also showed a higher incidence of multinodular (≥4) intrahepatic recurrences (19.4 % vs. 5.3 % at 3 years, P = 0.010). Whereas, the incidences of recurrences exceeding the Milan criteria because of other components were comparable. Patients with HC-HCC showed a higher incidence of intrahepatic recurrences characterized by multiple lesions and the difference became increasingly more pronounced with time.

CONCLUSIONS: Patients with HC-HCC was associated with a higher carcinogenesis in the background liver than those with HB-HCC, and this difference was aggravated with time after hepatic resection. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS: Hepatitis B, Hepatitis C, Hepatocellular Carcinoma, Milan criteria, Prognosis

PMID: 24350618 [PubMed - as supplied by publisher]


Telaprevir in the Treatment of Acute Hepatitis C Virus Infection in HIV-Infected Men

Clin Infect Dis. 2014 Jan 2. [Epub ahead of print]

Fierer DS, Dieterich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, van Seggelen WO, Hijdra RM, Cassagnol DG; and the New York Acute Hepatitis CSurveillance Network.


Background. There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal. Methods. We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV viral load <5 IU/mL at least 12 weeks after completing treatment. Results. In the telaprevir group, 84% (16/19) of men achieved SVR12 vs 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens. Conclusions. Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.

KEYWORDS: HIV infection, acute HCV, men who have sex with men, telaprevir, treatment

PMID: 24336914 [PubMed - as supplied by publisher]


Management of Hepatitis B: Our Practice and How It Relates to the Guidelines

Clinical Gastroenterology and Hepatology
Volume 12, Issue 1 , Pages 16-26, January 2014

Suna Yapali, Nizar Talaat, Anna S. Lok

published online 08 May 2013.

Seven drugs have been approved for the treatment of chronic hepatitis B. Antiviral treatment has been shown to be effective in suppressing hepatitis B virus replication, decreasing inflammation and fibrosis in the liver, and preventing progression of liver disease. However, current medications do not eradicate hepatitis B virus; therefore, a key question is which patients need to start treatment and which patients can be monitored. Professional societies have developed guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with chronic hepatitis B. These guidelines suggest preferred approaches, and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations, and we discuss what we do in our practice to illustrate factors that may influence decisions regarding hepatitis B management.

Keywords: Chronic Hepatitis B, Management, Antiviral Therapy, Hepatitis B Guidelines

Abbreviations used in this paper: AASLD, American Association for the Study of Liver Diseases, AFP, α-fetoprotein, ALT, alanine aminotransferase, anti-HBc, hepatitis B core antibody, anti-HBe, hepatitis B e antibody, APASL, Asian Pacific Association for the Study of the Liver, CHB, chronic hepatitis B, EASL, European Association for the Study of the Liver, HBV, hepatitis B virus, HBeAg, hepatitis B e antigen, HBsAg, hepatitis B surface antigen, HCC, hepatocellular carcinoma, IFN, interferon, NUC, nucleos(t)ide analogue, PEG-IFN,pegylated-interferon, ULN, upper limit of normal

The advent of sensitive assays for the detection of hepatitis B virus (HBV) and the availability of potent antiviral agents have improved the management of patients with chronic hepatitis B (CHB); however, current treatment cannot eradicate the virus. Because of the high cost and risk of adverse events, as well as drug resistance with long-term treatment, the most important question regarding the management of hepatitis B is which patients need to be treated now and which patients can be monitored and have treatment deferred. The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) have developed clinical practice guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with CHB.1,2, 3 These guidelines suggest preferred approaches and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient. Recommendations of the 3 guidelines vary slightly because of differences in timing when the guidelines were issued and also differences in available resources. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations and we discuss what we do in our practice to illustrate factors that may influence the management of CHB.

Natural History of Chronic Hepatitis B Virus Infection 

The natural course of chronic HBV infection consists of 4 phases; however, patients may not experience all phases (Figure 1).4


Figure 1  The natural course of chronic HBV infection consists of 4 phases. The immune tolerance phase is characterized by the presence of HBeAg, high HBV DNA levels, and persistently normal ALT levels, but no evidence of active liver disease. The immune clearance phase is characterized by the presence of HBeAg and high/fluctuating HBV DNA and ALT levels. An outcome of the immune clearance phase is HBeAg seroconversion. Most patients then enter the inactive HBV carrier phase, which is characterized by the absence of HBeAg and the presence of anti-HBe, low or undetectable HBV DNA levels (<2000 IU/mL), normal ALT levels, and no/minimal inflammation on liver biopsy. The reactivation phase is characterized by the absence of HBeAg, intermittent/persistently increased ALT and HBV DNA levels, and inflammation on liver biopsy.

Reprinted with permission from Lok.4

Host, viral, and environmental factors influence progression of HBV-related liver disease. Recent studies have focused on the importance of HBV replication as an independent predictor of cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths.5, 6 However, other factors including sex, age, HBV genotype, co-infection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus, increased alanine aminotransferase (ALT) level, and alcohol and tobacco use also contribute to cirrhosis and HCC.

Indications for Treatment 

Practice guidelines recommend that the treatment decision be made based on clinical status, serum HBV DNA and ALT levels, hepatitis B e antigen (HBeAg) status, and liver histology if available.1, 2, 3

Who Should Be Treated? 

All guidelines recommend starting treatment as soon as possible in patients with life-threatening liver disease: acute liver failure, decompensated cirrhosis, or severe exacerbation of CHB regardless of HBV DNA and ALT levels. Although data from randomized controlled trials in these settings are lacking, in case series antiviral treatment has been shown to be beneficial with little or no adverse effects. In addition, for patients requiring liver transplantation, viral suppression decreases the risk of HBV recurrence after transplant.7

The AASLD and APASL guidelines recommend antiviral therapy in patients with compensated cirrhosis and serum HBV DNA level greater than 2000 IU/mL regardless of ALT level.1, 2, 3 For patients with increased ALT levels, the AASLD guidelines recommend treatment regardless of HBV DNA level.1 The EASL guideline recommends treatment of patients with any detectable level of serum HBV DNA.2 There is growing evidence that long-term treatment with nucleos(t)ide analogues (NUCs) not only prevents disease progression but also reverses fibrosis and cirrhosis. In a double-blind, randomized, placebo-controlled study of 651 patients with advanced fibrosis or cirrhosis, who were HBeAg-positive or had high levels of HBV DNA (>150,000 IU/mL), lamivudine therapy was shown to decrease progression of liver disease.8 A follow-up report of the phase 3 tenofovir vs adefovir trial including 348 patients who had paired biopsies at baseline and year 5 showed that 51% of patients had a decrease in fibrosis stage by 1 or more and 71 of 96 (74%) patients with cirrhosis on initial biopsy had regression of cirrhosis.9

All guidelines agree that treatment should be initiated in noncirrhotic patients with serum HBV DNA levels greater than 20,000 IU/mL and persistently increased ALT levels and/or histologic evidence of moderate/severe inflammation or fibrosis. However, cut-off values of HBV DNA and ALT levels and the need for liver biopsy in determining treatment indications vary slightly among the guidelines (Table 1). The AASLD guideline suggests an arbitrary HBV DNA level of 20,000 IU/mL for initiating treatment.1 The APASL guideline recommends an HBV DNA threshold of 20,000 IU/mL for HBeAg-positive patients and 2000 IU/mL for HBeAg-negative patients, whereas the EASL guideline recommends a cut-off value of 2000 IU/mL irrespective of HBeAg status.2, 3 All guidelines agree that serial HBV DNA and ALT level is more important than a single value in making treatment decisions. For patients who fulfill the criteria for HBV DNA, the EASL recommends treating patients with ALT levels greater than the upper limit of normal (ULN) if the liver biopsy (or noninvasive markers validated in HBV-infected patients) shows moderate-severe inflammation and/or at least moderate fibrosis, whereas the APASL and AASLD recommend treatment for patients with an ALT level greater than 2 times the ULN. The AASLD guideline suggested lower values be used to define the ULN for an ALT level of 30 U/L for men and 19 U/L for women, and a liver biopsy should be performed in patients with mildly increased ALT levels, particularly in patients older than age 40.1 Besides HBV replication status, ALT levels, and liver histology, all guidelines recommend that patient age, HBeAg status, family history of HCC, occupational requirements, family planning, and patient preference should be considered in making treatment decisions.

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Living-donor liver transplantation associated with higher incidence of hepatocellular carcinoma recurrence than deceased-donor liver transplantation

Transplantation. 2014 Jan 15;97(1):71-7. doi: 10.1097/TP.0b013e3182a68953.

Park MS, Lee KW, Suh SW, You T, Choi Y, Kim H, Hong G, Yi NJ, Kwon CH, Joh JW, Lee SK, Suh KS.


BACKGROUND: Living-donor liver transplantation (LDLT) is becoming an important tool in hepatocellular carcinoma (HCC) treatment. However, the oncologic outcome between LDLT and deceased-donor LT (DDLT) for HCC remains controversial. This study aims to compare the HCC recurrence rates after LDLT versus DDLT.

METHODS: Two hundred sixteen patients (166 LDLTs and 50 DDLTs) who underwent LT for HCC within University of California-San Francisco criteria were retrospectively reviewed. LDLT patients were divided into two groups: small living-donor graft (LDG; graft-to-recipient body weight ratio<1.0, n=59) and nonsmall LDG (graft-to-recipient body weight ratio≥1.0, n=107). Patients were further stratified into low- and high-risk settings by the number of risk factors for recurrence.

RESULTS: The recurrence-free survival was lower in LDLT compared with DDLT (88.6% and 80.7% vs. 96.0% and 94.0% at 1 and 5 years; P=0.045). There was no significant difference between two groups regarding the majority of clinical and tumor characteristics, with the exception of a higher proportion of microvascular invasion presence in LDLT. After the adjustment for microvascular invasion, LDLT was identified as an independent risk factor for recurrence. Moreover, recurrence-free survival between small and nonsmall LDG was not statistically significant. In low-risk setting (≤1 risk factor), LDLT showed comparable outcome with DDLT. However, the risk of recurrence was higher in LDLT than DDLT in high-risk patients.

CONCLUSION: In conclusion, LDLT showed poorer outcome than DDLT. This should be considered to select optimal strategy for HCC.

PMID: 24056623 [PubMed - in process]


Galectin Therapeutics Receives US Patent for Combination Treatment for Liver Fibrosis

PRESS RELEASE January 6, 2014, 8:06 a.m. ET


NORCROSS, Ga., Jan. 6, 2014 (GLOBE NEWSWIRE) -- Galectin Therapeutics (Nasdaq:GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today announced that it has received a notice of allowance from the U.S. Patent and Trademark Office for patent application number 13/550,962 titled "Galactose-Pronged Polysaccharides in a Formulation for Anti-fibrotic Therapies." The patent covers both composition claim for and uses of the Company's carbohydrate-based galectin inhibitor compound GR-MD-02 for use in patients with liver fibrosis in combination with other potential therapeutic agents. The patent covers use of GR-MD-02 with agents directed at multiple targets, some of which are currently in clinical development for fibrotic disorders including monoclonal antibodies to connective tissue growth factor, integrins, and TGF-1.

"This patent provides additional coverage in the U.S. for the use of GR-MD-02 in combination with other potential anti-fibrotic agents in the treatment of liver fibrosis," said Peter G. Traber, MD, President, CEO and CMO of Galectin Therapeutics. "In the future, liver fibrosis could be treated with a combination of agents, and this patent provides important intellectual property for this possibility. We are hopeful that our development program for GR-MD-02 will lead to the first therapy for the large unmet medical need of liver fibrosis."

Galectin Therapeutics is currently conducting a Phase 1 clinical trial to evaluate the safety, tolerability and exploratory biomarkers for efficacy for single and multiple doses of GR-MD-02 over four weekly doses of GR-MD-02 treatment in patients with fatty liver disease with advanced fibrosis. In March 2013, the U.S. Food and Drug Administration (FDA) granted GR-MD-02 Fast Track designation for non-alcoholic steatohepatitis (NASH) with hepatic fibrosis, commonly known as fatty liver disease with advanced fibrosis.

About Fatty Liver Disease with Advanced Fibrosis

Non-alcoholic steatohepatitis (NASH), also known as fatty liver disease, has become a common disease of the liver with the rise in obesity rates, estimated to affect nine to 15 million people, including children, in the U.S. Fatty liver disease is characterized by the presence of fat in the liver along with inflammation and damage in people who drink little or no alcohol. Over time, patients with fatty liver disease can develop fibrosis, or scarring of the liver, and it is estimated that as many as three million individuals will develop cirrhosis, a severe liver disease where liver transplantation is the only current treatment available. Approximately 6,300 liver transplants are done on an annual basis in the U.S. There are no drug therapies approved for the treatment of liver fibrosis. FDA and AASLD (American Association for the Study of Liver Disease) recently held a 2-day workshop with leading scientific experts in NASH and key FDA officials to discuss acceptable regulatory endpoints for approval of drugs to treat NASH (http://www.aasld.org/additionalmeetings/Pages/aasldfdanash.aspx).

About Galectin Therapeutics

Galectin Therapeutics (Nasdaq:GALT) is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com.

Forward Looking Statements

This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate, " "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. These statements include those regarding any statements regarding patents received by the Company and hopes that our development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with fibrosis. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others, that we may not be successful in developing effective treatments and/or obtaining the requisite approvals for the use of GR-MD-02 or any of our other drugs in development. Our current clinical trial and any future clinical studies may not produce positive results in a timely fashion, if at all, and could prove time consuming and costly. Plans regarding development, approval and marketing of any of our drugs are subject to change at any time based on the changing needs of our company as determined by management and regulatory agencies. Regardless of the results of any of our development programs, we may be unsuccessful in developing partnerships with other companies that would allow us to further develop and/or fund any studies or trials. To date, we have incurred operating losses since our inception, and our ability to successfully develop and market drugs may be impacted by our ability to manage costs and finance our continuing operations For a discussion of additional factors impacting our business, see our Annual Report on Form 10-K for the year ended December 31, 2012, and our subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.


Impact of Rural Residence and Health System Structure on Quality of Liver Care

PLoS One. 2013 Dec 26;8(12):e84826.

Rongey C1, Shen H2, Hamilton N2, Backus LI3, Asch SM4, Knight S5.


BACKGROUND: Specialist physician concentration in urban areas can affect access and quality of care for rural patients. As effective drug treatment for hepatitis C (HCV) becomes increasingly available, the extent to which rural patients needing HCV specialists face access or quality deficits is unknown. We sought to determine the influence of rural residency on access to HCV specialists and quality of liver care.

METHODS: The study used a national cohort of 151,965 Veterans Health Administration (VHA) patients with HCV starting in 2005 and followed to 2009. The VHA's constant national benefit structure reduces the impact of insurance as an explanation for observed disparities. Multivariate cox proportion regression models for each quality indicator were performed.

RESULTS: Thirty percent of VHA patients with HCV reside in rural and highly rural areas. Compared to urban residents, highly rural (HR 0.70, CI 0.65-0.75) and rural (HR 0.96, CI 0.94-0.97) residents were significantly less likely to access HCV specialty care. The quality indicators were more mixed. While rural residents were less likely to receive HIV screening, there were no significant differences in hepatitis vaccinations, endoscopic variceal and hepatocellular carcinoma screening between the geographic subgroups. Of note, highly rural (HR 1.31, CI 1.14-1.50) and rural residents (HR 1.06, CI 1.02-1.10) were more likely to receive HCV therapy. Of those treated for HCV, a third received therapy from a non-specialist provider.

CONCLUSION: Rural patients have less access to HCV specialists, but this does not necessarily translate to quality deficits. The VHA's efforts to improve specialty care access, rural patient behavior and decentralization of HCV therapy beyond specialty providers may explain this contradiction. Lessons learned within the VHA are critical for US healthcare systems restructuring into accountable care organizations that acquire features of integrated systems.

PMID: 24386420 [PubMed - as supplied by publisher]