Treatment of Recurrent Genotype 1 Hepatitis C Post-Liver Transplantation: Single Center Experience with Telaprevir-Based Triple Therapy

Z Gastroenterol. 2014 Jan;52(1):27-34. Epub 2014 Jan 13.

Werner CR¹, Egetemeyr DP¹, Nadalin S², Königsrainer A², Malek NP¹, Lauer UM¹, Berg CP¹.

Abstract

Recurrent HCV infection post-liver transplantation (post-LT) is still a major challenge in the treatment of hepatitis C virus (HCV) infection. In this retrospective analysis we gathered data about treatment response and safety of all 14 post-LT patients who were treated between 2011 and 2013 at our centre with a telaprevir (TVR)-based triple therapy. Seven out of 14 patients completed the full treatment course of 48 weeks. Five patients achieved a SVR 24, while 3 additional HCV RNA-negative patients are still in follow-up (end of treatment, SVR 12 and 22). Four patients discontinued treatment prematurely due to side effects. A virological non-response at TW 4 was seen in 1 patient. Virological breakthrough was observed in 2 patients at TW 16 and 28, respectively; 1 patient displayed a virological relapse after the end of treatment (EOT). Patients with a complicated course post-LT accumulated most of the severe side effects, largely infections. One patient with cholestatic hepatitis died 11 weeks after discontinuation of treatment due to progressive graft failure. In conclusion, TVR-based triple therapy in post-LT patients reveals an acceptable antiviral efficacy. Unfortunately, severe side effects are frequent and often require therapeutic interventions. Therefore, with the approval of less straining DAA like sofosbuvir in sight, TVR-based triple therapy in post-LT patients should be, if possible avoided.

© Georg Thieme Verlag KG Stuttgart · New York.

PMID: 24420796 [PubMed - as supplied by publisher]

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A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma

J Hepatol. 2014 Feb;60(2):319-24. doi: 10.1016/j.jhep.2013.09.008. Epub 2013 Sep 14.

Abou-Alfa GK¹, Capanu M², O'Reilly EM³, Ma J⁴, Chou JF², Gansukh B⁴, Shia J⁵, Kalin M⁴, Katz S⁶, Abad L⁷, Reidy-Lagunes DL³, Kelsen DP³, Chen HX⁸, Saltz LB³.

BACKGROUND & AIMS: IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study.

METHODS: Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS.

RESULTS: As a result of pre-specified futility criteria, only stage 1 was accrued: N=24: median age 67.5years (range 49-83), KPS 80% (70-90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%)/10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1-140). Grade 3/4 toxicities >10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13-48), and there were no objective responses. Median overall survival was 8months (95% CI 5.8-14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95% CI 1-1.4]; p 0.009) and OS (1.2 [95% CI 1.1-1.4]; p 0.003).

CONCLUSIONS: Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3-4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS.

Copyright © 2013 European Association for the Study of the Liver. All rights reserved.

KEYWORDS: ADCC, AJCC, ALT, AST, Alanine aminotransferase, American Joint Committee on Cancer, Antibody-dependent complement-mediated cytotoxicity, Aspartate aminotransferase, CALGB, CC1, CDC, CTCAE, CTEP/NCI, Cancer Leukemia Group B, Cancer Therapy Evaluation Program (CTEP)/National Cancer Institute, Cell conditioning 1, Cells per microliter, Cixutumumab (IMC-A12, NSC742460), Common terminology criteria for adverse events, Complement-dependent cytotoxicity, Diabetes, ELISA, Enzyme-linked immunosorbent assay, Free IGF1, HCC, HIV, HR, Hazard ratio, Hepatocellular Carcinoma, Hepatocellular carcinoma, Human immunodeficiency virus, IGF-1, IGF-1R, IGF-2, IGF-2R, IGF-IR, IGF2, IGFBP 1, IGFBP 3, IRB, IgG1, Immunoglobulin 1, Institutional Review Board, Insulin growth factor 1, Insulin growth factor 1 receptor, Insulin growth factor 2, Insulin growth factor 2 receptor, Insulin-like growth factor binding protein 1, Insulin-like growth factor binding protein 3, KPS, Karnofsky performance status, LOH, Loss of heterozygosity, MAP, Milligram/deciliter, Milliliter per minute, Mitogen activated protein, NASH, Non-alcoholic steatohepatitis, OS, Overall urvival, PFS, PT/INR, Prothrombin time/International normalized ratio, RECIST, Response evaluation criteria in solid tumors, Units/Liter, mcl, mg/dl, mg/kg, milligram/kilogram, ml/min, progression free survival, units/L

PMID: 24045151 [PubMed - in process]

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New study reveals links between alcoholic liver disease and the circadian clock

William G. Gilroy    Published: January 16, 2014

Researchers from the University of Notre Dame and the Indiana University School of Medicine have revealed a putative role for the circadian clock in the liver in the development of alcohol-induced hepatic steatosis, or fatty liver disease.

Hepatic steatosis is the abnormal accumulation of fats in the cells of the liver, and is linked to disturbed control of fat metabolism. Alcohol-induced liver steatosis is produced by excessive alcohol consumption and is linked to hepatitis, or inflammation of the liver. It can be a precursor to an even more serious illness, liver cirrhosis, which includes scarring of the liver. Ten percent to 35 percent of chronic heavy drinkers develop alcoholic hepatitis, and it is the main cause of liver disease in Western countries.

The team, led by associate professors Giles Duffield, from Notre Dame’s Department of Biological Sciences and Eck Institute for Global Health, and Suthat Liangpunsakul from the Indiana University School of Medicine’s Department of Medicine, Division of Gastroenterology and Hepatology, is interested in the molecular genetic basis for the molecular clock and liver steatosis.

The study, using molecular biological approaches and long-term alcohol feeding of experimental mice, reveals that the development of liver steatosis produced by alcohol abuse is intertwined with disturbances of the normal operation of the 24-hour clock system located in the cells of the liver. Importantly, this change in the liver clock seems to occur independently from the master clock system located in the brain.

The circadian clock regulates 24-hour rhythms in biochemistry, physiology and behavior, and its normal operation and appropriate synchronization to the external world, especially the alternating cycle of day and night, is critical to maintaining a normal healthy state. Disturbances of the clock have been linked to mental health disorders, to metabolic disease including obesity and diabetes, and to the development of cancer.

The liver plays many roles in the body, and includes control of metabolism, storage and release of energy molecules, and detoxification.

“Liver function changes daily in a rhythmic manner and is coordinated with cycles of feeding-fasting and to the energy demands of the body, such as activity and rest,” Duffield said. “These daily rhythms are regulated by the circadian clock within those liver cells, and disturbances to the molecular clock mechanism or poor temporal coordination of the clock with the timing of eating, or the sleep-wake and rest-activity cycle, can lead to illness.”

The study suggests that either the circadian clock is important in the actual development of the liver disease or that the development of steatosis disrupts the normal pattern of the clock mechanism. The researchers’ findings also offer novel insights into how the disease might be manipulated for clinical purposes.

Interestingly, the mechanism by which chronic alcohol intake is thought to alter the control of fat metabolism in the liver is also a shared signal to the circadian clock mechanism, this being the ratio of production of reduced nicotinamide adenine dinucleotide, or NADH, to NAD+. The authors suggest that this may be a key to the shared disturbance to the two biological mechanisms of lipid metabolism and the circadian clock.

The study, Zhou et al., was published this week in the journal Nature: Scientific Reports.

The work was a collaborative effort between the Duffield and Liangpunsakul laboratories, involving lead author and doctoral candidate Peng Zhou, undergraduate student Cameron Pywell and research technician Roth Ross. The work was supported from grants from the National Institutes of Health National Institute of General Medical Sciences and National Institute on Alcohol Abuse and Alcoholism, the American Heart Association, the Veterans Association and the U.S. Department of Defense.

Contact: Giles Duffield, 574-631-1834, Giles.E.Duffield.2@nd.edu

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Better allocation of donated livers in transplants

Provided by MedicalXpress

January 20, 2014

Volume rendering image created with multi detector computed tomography (MDCT) source image./ Credit: I-Chen Tsai-Wikipedia

Researchers at the University of Cordoba (Spain) have developed a system that measures compatibility between donors and the most serious receivers in liver transplants. This is a mathematical method that includes the experience of almost 1,500 donations registered in transplant units in Spain and the United Kingdom.

The allocation criteria for organs in Spain, the worldwide transplant leader and example, are set according to territorial and clinical aspects that guarantee altruism in donations and equality of access. Nevertheless, there are still some aspects of the allocation of organs that could be improved, according to a study by researchers in the University of Cordoba.

In the case of liver transplants, the properties of the owner such as the blood group -which must match that of the receiver- as well as the seriousness of the patient, measured with the so-called Model for End Stage Liver Disease (MELD), are taken into account. The result is a number obtained from the patient's bilirubin, creatinine and prothrombin time figures that serve to prioritise the waiting list according to the risk of mortality in the following three months.

"In this donor/receiver assessment, other variables that would optimise the compatibility between them and that could be a decisive factor in the results of the transplant are not assessed," explained María Pérez Ortiz, one of the authors. "We therefore propose an improvement that favours the principles of justice for the receiver and of utility of the transplant, matches the waiting times to the mortality risk on the active list and improves survival."

Specifically, the team, comprising researchers in the University and Reina Sofía Hospital in Cordoba, has developed an allocation model that would allocate each organ to each of the most serious receivers from whom the one with the maximum survival probability is chosen. The details are published in the journal Applied Soft Computing.

"This system respects the principle of urgency required by the MELD model and discriminates between receivers on a waiting list who theoretically would have a better prognosis but who, transplanted with a specific liver, would benefit from a better survival," explain the researchers, adding, "The interactions set up in the transplant procedure are more complex than those arising simply from matching a good donor with a very serious receiver."

Automated learning techniques have been used to create the model, an area of computing that imitates the brain when it comes to learning from experience and from known data. In fact, the application is based on 38 variables (age, gender, body mass index, existence of diabetes, arterial hypertension, etc.) taken from almost 1,500 donor/receiver pairs in seven Spanish transplant units and one in King's College Hospital, London.

Together with the survival time of the transplanted liver, these variables serve to train the model which is then used to match donor/receiver pairs with a given survival time, specifically, whether the transplant survives for 15 days after the operation, for three months, for a year or more, so that it is very useful to assess the suitability of the allocations made.

According to data published this week by the Ministry of Health, Social Services and Equality, 1,093 liver transplants were carried out in 2013 in Spain, where the historic series adds up to almost 22,000.

Explore further: Spain transplants hit record despite crisis

More information: M. Pérez-Ortiz, M. Cruz-Ramírez, M.D. Ayllón-Terán, N. Heaton, R. Ciria, C. Hervás-Martínez. "An organ allocation system for liver transplantation based on ordinal regression". Applied Soft Computing 14: 88-98, 2014.

Provided by Plataforma SINC

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