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DECEMBER-,)9<(9@ 20140::<, ISSUE A review of new data on the treatment of chronic presented at The Liver 7KMeetingH,QWHUQDW 2014LRQDO /LYHU&RQJUHVV WK Alessio Aghemo M.D. PhD Fondazione $SULO IRCCS/RQG Ca’ GrandaRQ Ospedale Maggiore Policlinico I`7YVMLZZVY4HYR\Z7LJR9HKVZH]SQL]PJ di Milano, Milan, Italy and EASL:LJYL[ GoverningHY`.LULYHSVM[ OL,Board\YVWLHU(ZZVJP Member.H[PVU MVY[OL:[\K`VM[OL3P]LY,(:3 Treatment of chronic hepatitis C was in 2330 patients recruited in the US and recommends a 24-week treatment course ;OL0U[LYUH[PVUHS3P]LY*VUNYLZZ03* PU[LYUH[PVUHSH[[LU[PVUMYVT^P[OPUV\Y IL`VUK^OH[PZZ[HUKHYK[YLH[TLU[PU the mainstay,(:3»ZÅ atHNZOPWTLL[PUN the recent AASLDPZ Liver V^Germany.UJVTT\UP[ The combination`HZ^LSSHZ[O of LWsofosbuvirYLZZ >Lof sofosbuvirZ[LYU,\YVW plusLV ledipasvirY[OL<:H in Utreatment-KP[^PSSIL HMeetingWWYVHJOPUNMHZ[HUK^PSSVWLUVU(WYPS in Boston. Although most phase HUplusKT simeprevirLKPH^VYSK^PKL was extremely safe, as PUexperienced[LYLZ[PUN[VZL patientsLOV^[O with L`Lcirrhosis,U]PZHN L 3[O; dataO L.on V]theLYUPU IFN-freeN)VHYKV combinationsM,(:3^HZ of  only 2% of patients discontinued due [YLalthoughH[TLU [VMJthis mightOYVUP beJO optimalLWH[P[PZ*P in termsU ]LsofosbuvirY`Z\JJLZZM\ plusSP ledipasvirUW\[[PUN[ andVNL[OL paritaprevirYH ;OtoLO sidePNOSPNO effects,[VM[O an LLespeciallyK\JH[PVUHS remarkable YLofZV\Y efficacyJLSPTP[ at theLKZL[ individual[PUNZ; patientOL> level,/6 OPNOWplus ombitasvirYVÄSLZJPLU[PÄJHUKLK\JH[PVUHS and dasabuvir were  WYfeatVNYH if oneT[OP considersZ`LHY^ thatPSSIL[OL, 48% of(:3 patients N\PKLSPULat the populationZ^PSSILKPZJ\ZZLKK\YPUN[OL level this strategy might  WYpresentedVNYHT^ inOPJO^PSSH April at EASL’s[[YHJ[HSV International[VM 7VhadZ[ NYHK\H[cirrhosisL* withV\YZL an episode^OPJO^PSSM of previousVJ\Z  W\ISPJOLHS[OZLZZPVUHZ^limit access to treatment as drugLSSHZK pricing\YPUN Liver Congress, several compelling VdecompensationU[OL[YLH[TLU[VM] reportedPYHSOLWH[P[PZ in 40% of0U HZmayLWHY beH[ prohibitiveLZ`TWVZP\ for TKmostLKPJ healthcareH[LK[V[ OL 1HZVOHreal-lifeWWHU&RQWHQW data or clinical trials presentedV HKKP[PVU[them. SofosbuvirV[OL7VZ plus[NYHK\H[ simeprevirL*V\YZ was Lalso >/6OLWH[P[PZ*N\PKLSPULsystems. By analyzing PhaseZ II-III studies in Boston are likely to further advance [OLWYVNYHhighly effectiveT^ PSSILZ\WWSLTLUas sustained virological[LK and looking at treatment duration (12 treatment of HCV in the near future. The ^P[responseO1VPU[> (SVR)VYRZOVW ratesZI wereL[^L 89%LU, overall(:3 0HvsTZ 24 \Yweeks)L[OH[[O andLW ribavirinYVNYH TKneedL] inPZL 513KI` HUKHU\TILYVMPU[LYUH[PVUHSTLKPJHS [OL,(:3NV]LYUPUNIVHYK^PSSILHISL :KQO  data can be divided into three broad with only a minimal impact of , cirrhotic patients, Bourlière and colleagues HZZVJPH[PVUZPU[OLÄLSKVMSP]LYKPZLHZL [VZH[PZM`[OLULLKZVMWYVMLZZPVUHS +XXY_XMOWOX^categories:$ >RO 3X^ Real-lifeO\XK^SYXKV 6S`O\ data of approved subtype 1a and previous treatment failure were able to suggest that the addition JV]LYPUNH^PKLZLSLJ[PVUVMPTWVY[HU[ OLWH[VSVNPZ[ZHZ^LSSHZWYV]PKLH -YXQ\O]] #regimens,^R + fine-tuningZ\SV 6YXNYX of approved to a protease inhibitor on the efficacy of ribavirin increased the efficacy of the LK\JH[PVUHS[VWPJZPU[OLLHYS`TVYUPUN Z[PT\SH[PUNSLHYUPUNH[TVZWOLYL[OH[^PSS Lc :\YPO]]Yregimens\ 7K\U_] :OM and RCTsU

Several new compounds were presented genotype 1 patients with advanced companies, which should translate into at the Liver Meeting including the fibrosis or with a previous treatment a rapid decrease in costs of drugs for second-generation NS5A inhibitor failure with pegylated interferon-based healthcare systems. A key factor if broad GS-5816 which managed to achieve regimens. Both interferon-free regimens and equal access to these drugs across high SVR rates in combination with were extremely safe with less than Europe is to be achieved. sofosbuvir. Still the most compelling data 3% of patients discontinuing due to came from the Phase III studies of the side effects and without any significant Alessio Aghemo, M.D. PhD. combination of grazoprevir (protease safety signal in these two large Phase III Division of Gastroenterology and inhibitor) plus elbasvir (NS5A inhibitor) studies. These efficacy and safety rates Hepatology, Fondazione IRCCS Ca’ and the combination of daclatasvir are not surprising nowadays. Given the Granda Ospedale Maggiore Policlinico (NS5A) plus asunaprevir (protesase fact that in the past limited access to di Milano and Università degli Studi di inhibitor) and beclabuvir (NS5b Non- treatment hampered the effectiveness Milano, Italy nucleoside inhibitor). These 2 different of anti-hepatitis C therapy hence, any Email: [email protected] interferon strategies managed to reach new player in the therapeutic field should 90-100% and 93-98% SVR rates, be viewed positively as this will likely respectively in difficult-to-cure HCV lead to competition between pharma

The Gilead Sciences Research Scholars Program: An interview with Professor Michael Manns, Chairman of the The Gilead Sciences Research Scholars Committee.

Q1. Could you kindly explain the Gilead Sciences The applicant should also be able to obtain/secure a faculty Research Scholars Program for our readership? position within the next 3 years and should devote his academic career to research in liver diseases. The Gilead Sciences Research Scholars Program is a very attractive program for junior researchers to obtain funding to the Q2: As the Chairman of the Committee, what are the value of US$ 130,000, which is paid in two annual installments features you are looking for when evaluating a research of up to US$ 65,000 each. The Gilead Sciences Research project proposal? Scholars Program is active in various fields of medicine including cardiovascular disease, primary pulmonary hypertension, cystic The package of the research proposal consists of the applicant, fibrosis, haematology and oncology as well as liver diseases. the mentor, the institution, and the project. We evaluate The Liver Disease Research Scholars Program has a North the applicant concerning his past and present research American as well as an International Program. I have the performance. We also evaluate the originality of the research privilege to chair the committee evaluating the applications for proposal whether it addresses significant unmet needs in the International Gilead Sciences Research Scholars Program. hepatology. We evaluate the mentor as well as the institution The closing date for applications is 19th January 2015. Detailed where the work is supposed to take part. And finally, we information can be obtained at http://researchscholars. evaluate whether the proposed project can be realistically gilead.com. completed within a 2-year time frame.

For this program, non-US researchers are eligible to apply. Q3: Do you see a shift in research areas now that viral Scholarship awards are awarded annually. The international hepatitis will be effectively treated in more than 90% liver disease program grants up to three awards each year. of cases? Applicants who are working and have permanent residency in Europe, Australia, Hong Kong, Japan, Middle East, New If I interpret this question correctly 90% relate to chronic hepatitis Zealand, Singapore, South Korea and Taiwan can apply. The C? ! In chronic hepatitis B currently, we can only suppress viral application must contain a description of a research project replication. A cure is not yet possible and HBsAg loss in serum that should be original and should also be completed within is just evolving as the next optimum end-point of treatment - the 2-year funding period. In addition to the description of the the gold standard, which is as close as we can get to a cure. research project, the applicant’s CV and bibliography should be For chronic hepatitis D we have no specific therapies in place accompanied by a letter of support from the scientific mentor as although pegylated interferon has some benefits. We are just well as by the department or division head who has to guarantee learning to understand the role of chronic hepatitis E in the a protected time to perform the research project. Proposed immunosuppressed patient in the Western world. research projects should be innovative and should address significant unmet needs in all areas of liver diseases. Continued

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Liver cancer, non-alcoholic fatty liver disease (NAFLD) and Michael P. Manns, MD liver fibrogenesis are further areas where future research Professor and Chairman efforts have to focussed. And then there is Primary Sclerosing Department of Gastroenterology, Hepatology and Endocrinology Cholangitis (PSC) the big “black box” in hepatology affecting Medical School of Hannover young people, associated with malignancy, unknown etiology, Carl-Neuberg-Str. 1 with no medical therapy..... So as you can see, there is still a lot 30625 Hannover, Germany to do in liver disease research. It will be interesting to see the E-Mail: [email protected] future applications for the Gilead Sciences Research Scholars’ Program for 2015 and beyond.

How a reduced price for Sofosbuvir was obtained for Egypt Gamal Esmat M.D. Director of the Viral Hepatitis Treatment Centers and Ministry of Health, Cairo, Egypt.

It is generally acknowledged that of pegylated interferon and ribavirin NCCVH, negotiated an agreement for Egypt has the highest prevalence of therapy. The cost of this treatment the introduction of Sofosbuvir in Egypt the hepatitis C virus (HCV) worldwide, regimen was extremely high for a with a 99% discount on the U.S. price. with a rate of seropositivity as high as resource-limited country like Egypt. However, the drug will still cost $900 for 15%. Thus, combating such a disease Negotiations with the manufacturing a 12-week course of treatment; which represents a primary objective on the companies of pegylated interferon, and is a fraction of the $84,000 charged national agenda. In 2006, in response the market competition represented for a course of treatment in the United to this huge burden of HCV infection, by the presence of a locally produced States. The reduced price will apply a National Treatment Program as part bio-similar of pegylated interferon have to Sofosbuvir supplies used in official of the National Control Strategy for gradually driven down the price reaching treatment centers only, and the access Viral Hepatitis was launched. This 15 percent of its international price. programmes start in late 2014, following programme aims to provide access to Reducing the cost of therapy has been completion of registration procedures in treatment for HCV-infected individuals critical to the success of the Egyptian Egypt. A standardized protocol, tailored by offering low-price and even cost- programme and has improved access to adapt to the Egyptian situation as well free antiviral medicines. A nationwide to care for individuals with chronic as priority for treatment protocol have treatment network comprising 25 HCV infection that has enabled the been issued. Furthermore, precautions centers was established. They are programme to treat more than 350,000 to ensure proper and strict utilization located all over the country to allow patients over the past 7 years. of the drug within the official treatment access to patients residing in all centers will be applied. We hope that Egyptian regions. Training programs This maximized Egyptian experience in Sofosbuvir will have a major impact on were organized to qualify physicians providing mass treatment for patients public health in Egypt, by significantly working in these centers, and a with chronic disease, in which the increasing the number of people who standardized protocol was issued by the treatment duration lasts up to one year, can be cured of HCV. National Committee for the Control of along with the international publications, Viral Hepatitis (NCCVH). This protocol is as well as the presentations of Egyptian Prof. Gamal Esmat, M.D. responsible for overseeing the centers to hepatologists at international meetings, Vice-President for Graduate Studies and ensure provision of high standard care have all led to global awareness of the Research, Cairo University. and treatment. A specialized network, HCV problem in Egypt. Discussing the Professor of Tropical Medicine and at the National Committee for Control Egyptian situation with international Hepatology, Faculty of Medicine, Cairo of Viral Hepatitis was established to organizations (WHO, UNICEF, etc.) and University. Director of the Viral Hepatitis interconnect these centers. stakeholders paved the way to seeking Treatment Centers the up to date standard of care for those and Ministry of Health, The programme started with the patients according to the most updated Egypt standard care treatment for HCV at international guidelines. As a result, the http://www.gamalesmat.com/ that time, which was a combination Egyptian Government represented by

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Chronic hepatitis E virus infection Professor Stanislas Pol MD, PhD and Prof. Vincent Mallet M.D, PhD, Université Paris Descartes ; APHP, Unité d’Hépatologie, Hôpital Cochin; INSERM U-1016, Institut Cochin, Paris, France.

Over the last few years, interest in achieved to avoid progression of liver Finally, an unsolved issue is the cause of HEV infection, endemic in developing fibrosis and occurrence of extra-hepatic the high prevalence of HEV 3 infection countries, has increased in the developed manifestations. in STO, in addition to the food-related world 1. Indeed, the genotype-3 hepatitis route of transmission. HEV 3 infection E virus (HEV 3) has been shown to be To date, there is no established may be transmitted by transfusion of responsible for self-limiting infection in therapy for HEV infection. Reducing red blood cells and platelets and the non-compromised patients 1 2; however, immunosuppression, mainly prevalence of anti-HEV antibodies ranges it can lead to chronic hepatitis in all immunosuppressants that target T-cells, from 10-50% in blood donors and 10% situations of immune deficiency: solid- has achieved HEV clearance in nearly of plasma fractionated pools (1000 organ transplant (SOT) patients 3, HIV 30% of SOT patients with chronic donors) test positive for HEV-RNA but patients with low CD4-cell counts 4, hepatitis 10. Small case series and case are pathogen-inactivated with solvent- and hematological patients receiving reports in this setting have also shown the detergent incubation or Amotosalen. chemotherapy 5. efficacy of peg-interferon (peg-INF) alone We recently performed a retrospective or ribavirin as a monotherapy 13-14 with study in 347 kidney-transplants (from Chronic genotype HEV 3 infection has promising results provided with a short October 2010 to December 2012), been suspected or clearly shown to be course. We have recently reported data including 48 (14%) treated with TPE. The responsible for several extra-hepatic 6, 7, 8 collected from several transplant centers prevalence of anti-HEV IgG antibodies and hepatic manifestations. Neurological in France including the largest number of was 31% (83/267)(works in progress symptoms, mainly peripheral nerve solid-organ-transplant patients infected submitted to AASLD 2013). Ten per involvement, have been observed in by HEV and treated by ribavirin alone (n cent of patients had evidence of post- immunocompetent and SOT patients = 51) 15. Our study clearly assessed the transplant HEV infections (25 anti-HEV infected by HEV 3 6, 7 and, interestingly, efficacy and safety of ribavirin for three IgG seroconversions and 1 chronic HEV HEV clearance induces complete (1–18) months as a monotherapy to infection without seroconversion): 19 and or partial resolution of neurological treat chronic HEV infection. A sustained 8% of patients treated with TPE or not, symptoms 6. Very recently, cases of HEV virological response (SVR) was observed respectively (P=0.035). Only two patients 3-induced glomerulonephritis have been in 82% of patients and the SVR rate did treated with TPE developed chronic HEV reported in kidney-transplant patients 9 not differ significantly between patients infection and all patients who developed yet cryoglobulinemia disappeared after who had received ribavirin therapy HEV infection without TPE had all HEV clearance 9. We also observed for ≤3 months (67% of patients) and received red blood cells. In summary, a clear case of HEV 3-associated those who had received ribavirin for >3 TPE, like blood transfusion, is a route of lymphoma with detection of the virus in months. The end of treatment virological transmission of HEV. Since pathogen- the cutaneous tumor, its remission under response was 98%: only one patient was inactivated plasma pools, including those ribavirin and its clinical recurrence with a non-responder who remained viremic using the last generation inactivating virologic relapse (work in progress, when he was retreated after a washout products, may transmit HEV, plasma June 2014). period, suggesting the presence of a pools should be tested for HEV, especially ribavirin-associated resistant variant. those destined to SOT recipients and The main issue with HEV 3 chronic The only independent predictive factor other susceptible recipients. infection remains the risk of chronic active of SVR was a high lymphocyte count hepatitis with rapidly evolving cirrhosis at the initiation of ribavirin therapy (OR Prof. Stanislas Pol, MD, PhD which may require liver transplantation 1.002, CI95% 1–1.004, p=0.03) and Unité d’Hépatologie 10 and re-transplantation in viremic-liver this is in line with recent evidence that Hôpital Cochin patients may re-induce chronic HEV the use of tacrolimus, a more potent 27 rue du Faubourg Saint Jacques infection 11. immunosuppressant than cyclosporine 75679 Paris Cedex 14 A, was found to be an independent Email : [email protected] In a large cohort of SOT patients, HEV predictive factor for chronic HEV infection infection occurring after transplantation after SOT 11. In relapsers (12%), most evolved to chronic infection in two-thirds of those who completed a second and of patients 10; nearly 10% developed prolonged course of ribavirin achieved cirrhosis within a short time period 10. SVR. In contrast, no HEV reactivation was observed after kidney re-transplantation A few reports also suggest that ribavirin in patients who have been cleared of the has a beneficial effect in patients with virus 12. Hence, in patients chronically severe acute HEV infection and in infected by HEV, clearance should be patients with acute chronic hepatitis.

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References 9. Kamar N, Abravanel F, Selves J, et al. Influence of immunosuppressive therapy on the natural history 1. Kamar N, Bendall R, Legrand-Abravanel F, et al. Hepatitis E. of genotype 3 hepatitis-E virus infection after organ Lancet 2012;379:2477-88. transplantation. Transplantation 2010;89:353-60.

2. Hoofnagle JH, Nelson K, Purcell RH. Hepatitis E. N Engl J 10. Kamar N, Garrouste C, Haagsma EB, et al. Factors Med 2012;367:1237-44. associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. 3. Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and Gastroenterology 2011;140:1481-9. chronic hepatitis in organ-transplant recipients. N Engl J Med 2008;358:811-7. 11. Haagsma EB, van den Berg AP, Porte RJ, et al. Chronic hepatitis E virus infection in liver transplant recipients. Liver 4. Dalton HR, Bendall R, Keane F, Tedder R, Ijaz S. Persistent Transpl 2008;14:547-53. carriage of hepatitis E virus in patients with HIV infection. N Engl J Med 2009;361:1025-27. 12. Kamar N, Izopet J, Rostaing L. No reactivation of hepatitis E virus after kidney retransplantation. Am J Transplant 5. Ollier L, Tieulie N, Sanderson F, et al. Chronic Hepatitis 2012;12:507-8. After Hepatitis E Virus Infection in a Patient With Non- Hodgkin Lymphoma Taking Rituximab. AnnIntern Med 13. Kamar N, Rostaing L, Abravanel F, et al. Pegylated 2009;150:430-1. interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation. Clin Infect Dis 6. Kamar N, Bendall RP, Peron JM, et al. Hepatitis E virus 2010;50:e30-3. and neurologic disorders. Emerging infectious diseases 2011;17:173-9. 14. Haagsma EB, Riezebos-Brilman A, van den Berg AP, Porte RJ, Niesters HG. Treatment of chronic hepatitis E in 7. Cheung MC, Maguire J, Carey I, Wendon J, Agarwal K. liver transplant recipients with pegylated interferon alpha-2b. Review of the neurological manifestations of hepatitis E Liver Transpl 2010;16:474-7. infection. Ann Hepatol 2012;11:618-22. 15. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, 8. Kamar N, Weclawiack H, Guilbeaud-Frugier C, et al. Hepatitis Dumortier J, et al. Ribavirin for chronic hepatitis E virus E virus and the kidney in solid-organ-transplant patients. infection in transplant recipients New England Journal of Transplantation 2012;93:617-23. Medicine 2014; Mar 20;370(12):1111-20.

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