A. Aghemo

Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.

Restrictions for reimbursement of interferon-free direct-acting antiviral therapies for HCV infection in Europe

[Marshall, A. D.; Cunningham, E. B.; Dore, G. J.; Grebely, J.] UNSW Sydney, Kirby Inst, Sydney, NSW, Australia. [Nielsen, S.] Freelance Epidemiologist, Madrid, Spain. [Aghemo, A.] Univ Milan, Fdn IRCCS CA Granda Osped Maggiore Policlin, Div Gastroenterol & Hepatol, Milan, Italy. [Alho, H.] Helsinki Univ Hosp, Abdominal Ctr, Helsinki, Finland. [Alho, H.] Univ Helsinki, Helsinki, Finland. [Backmund, M.] Univ Hosp Munich, Dept Med 2, Munich, Germany. [Bruggmann, P.] Arud Ctr Addict Med, Zurich, Switzerland. [Dalgard, O.] Univ Oslo, Akershus Univ Hosp, Dept Infect Dis, Oslo, Norway. [Dalgard, O.] Univ Oslo, Fac Med, Oslo, Norway. [Flisiak, R.] Med Univ Bialystok, Dept Infect Dis & Hepatol, Bialystok, Poland. [Foster, G.] Queen Mary Univ London, London, England. [Gheorghe, L.] Fundeni Clin Inst, Gastroenterol & Hepatol, Bucharest, Romania. [Goldberg, D.] Hlth Protect Scotland, Glasgow, Lanark, Scotland. [Goulis, I.] Dept Internal Med, Thessaloniki, Greece. [Hickman, M.] Univ Bristol, Social Med, Bristol, Avon, England. [Hoffmann, P.] Minist Hlth Luxembourg, Luxembourg, Luxembourg. [Jancoriene, L.] Vilnius Univ Hosp, Santariskiu Klin, Ctr Infect Dis, Vilnius, Lithuania. [Jarcuska, P.] Univ Hosp, Dept Internal Med 1, Kosice, Slovakia. [Jarcuska, P.] Univ Pavol Jozef Safarik, Kosice, Slovakia. [Kaberg, M.] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Makara, M.] St Istvan & St Laszlo Hosp, Hepatol Ctr, Budapest, Hungary. [Maimets, M.] Univ Tartu, Dept Internal Med, Tartu, Estonia. [Marinho, R.] Hosp Santa Maria, Med Sch Lisbon, Dept Gastroenterol & Hepatol, Lisbon, Portugal. [Maticic, M.] Univ Med Ctr, Clin Infect Dis & Febrile Illnesses, Ljubljana, Slovenia. [Norris, S.; Tait, M.] Dr Steevens Hosp, Natl Hepatitis Treatment Programme C, Hlth Serv Execut, Dublin, Ireland. [Olafsson, S.] Landspitali Univ Hosp, Dept Med, Div Gastroenterol, Reykjavik, Iceland. [Ovrehus, A.] Univ Southern Denmark, Odense Univ Hosp, Dept Infect Dis, Odense, Denmark. [Pawlotsky, J. -M.] Univ Paris Est, Hop Henri Mondor, Creteil, France. [Pocock, J.] Mater Hosp, Gastroenterol Dept, Msida, Malta. [Robaeys, G.] Ziekenhuis Oost Limburg, Dept Gastroenterol & Hepatol, Genk, Belgium. [Robaeys, G.] UHasselt, Dept Med & Life Sci, Hasselt, Belgium. [Robaeys, G.] UZLeuven, Dept Hepatol, Leuven, Belgium. [Roncero, C.] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Psychiat Serv, Addict & Dual Diag Unit, Barcelona, Spain. [Simonova, M.] Mil Med Acad, Dept Gastroenterol HPB Surg & Transplantol, Sofia, Bulgaria. [Sperl, J.] Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic. [Tolmane, I.] Infectol Ctr Latvia, Dept Hepatol, Riga, Latvia. [Tomaselli, S.] Off Publ Hlth, Vaduz, Liechtenstein. [van der Valk, M.] Acad Med Ctr, Dept Infect Dis, Amsterdam, Netherlands. [Vince, A.] Univ Zagreb, Sch Med, Univ Hosp Infect Dis, Zagreb, Croatia. [Lazarus, J. V.] Univ Copenhagen, Rigshosp, CHIP, Copenhagen, Denmark. [Lazarus, J. V.] Hosp Clin Barcelona, Barcelona Inst Global Hlth ISGlobal, Barcelona, Spain.

Persistence of hepatocellular carcinoma risk in hepatitis C patients with a response to IFN and cirrhosis regression

In patients with HCV‐related cirrhosis, a sustained virological response may lead to cirrhosis regression. Whether histological changes translate into prevention of long‐term complications, particularly hepatocellular carcinoma is still unknown. This was investigated in a cohort of histological cirrhotics who had been prospectively followed‐up for 10 years after the achievement of a sustained virological response to IFN.

What do clinicians need to watch for with direct‐acting antiviral therapy?

The introduction of drugs targeting the virus replication cycle has revolutionized treatment of chronic hepatitis C virus. These drugs, called direct‐acting antivirals, have brought about extremely high rates of virological cure and have increased the number of patients who can receive treatment due to the lack of absolute contraindications. A combination of different classes of direct‐acting antivirals is the current standard of care. Although treatment administration and monitoring has been simplified in recent years, it is still relatively complex and mostly in the hands of specialists. Several factors must be assessed before starting treatment to maximize efficacy and minimize side effects of treatment. In this review, we describe the factors that impact on the efficacy and safety of antiviral treatment for hepatitis C and provide clear recommendations for clinicians prescribing direct‐acting antivirals.

The removal of DAA restrictions in Europe – One step closer to eliminating HCV as a major public health threat

Of ∼10.2 million people with chronic HCV infection in Europe, 6.7 million live in Eastern Europe, 2.3 million in Western Europe and 1.2 million in Central Europe. HCV transmission continues to occur in parallel with an increasing HCV-related liver disease burden, the result of an ageing population infected during peak HCV epidemics decades earlier. In 2016, the World Health Organization set targets to eliminate HCV infection as a major public health threat by 2030. Across Europe, an estimated 36% of those living with chronic HCV infection have been diagnosed and ∼5% have been treated. A major barrier to enhancing HCV treatment uptake has been restrictions set by payers, including national governments and others, in response to the initially high list prices of direct-acting antiviral (DAA) therapies. The aims of this article are to discuss DAA restrictions in Europe, why DAA restrictions are still in place, what has facilitated the removal of DAA restrictions, and what challenges remain as we attempt to eliminate HCV as a major public health threat in the region by 2030.

Autoimmune Hepatitis During Ledipasvir/Sofosbuvir Treatment of Hepatitis C: A Case Report

We report the case of a woman with chronic hepatitis C and idiopathic thrombocytopenic purpura (ITP) who developed autoimmune hepatitis (AIH) during antiviral therapy with ledipasvir (LDV)/sofosbuvir (SOF). The onset of acute hepatitis rose two weeks after starting treatment with LDV/SOF when HCV‐RNA tested negative, suggesting a link between rapid HCV clearance and de novo autoimmune diseases. Conclusion: This case report proposes new immunologic scenarios in patients with hepatitis C virus (HCV) with laboratory or clinical signs of autoimmunity during direct‐acting antiviral (DAA) therapy.

12 weeks ombitasvir/paritaprevir–ritonavir + ribavirin achieve high SVR rates in HCV-4 patients with advanced fibrosis

BACKGROUNDnOmbitasvir/paritaprevir-ritonavir (OBT/PTV-r) plus ribavirin (RBV) for 12 weeks in hepatitis C virus (HCV) genotype 4 patients with advanced fibrosis has been only investigated in clinical trials.nnnAIMSnTo assess safety and efficacy of OBT/PTV-ru202f+u202fRBV for 12 weeks in real-life HCV-4 patients with advanced fibrosis.nnnMETHODSnHCV-4 patients with advanced fibrosis consecutively receiving OBT/PTV-ru202f+u202fRBV for 12 weeks in a single center were enrolled. Fibrosis was staged by transient elastography (TE) (F3: ≥10u202fkPa; F4 ≥11.9u202fkPa) or histologically. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks post-treatment.nnnRESULTSnBetween January 2016 and February 2017, 49 HCV-4 patients were included: median age 54 (39-72) years, 84% males, 59% Egyptians, 35% fibrosis F3 and 65% F4, all Child Pugh class A. Median RBV dose was 1200 (200-1200) mg/day. At ITT analysis, 47 (96%) patients achieved an SVR (100% at PP analysis). SVR was not affected by ancestry (Egyptian vs. Italian 97% vs. 95%, pu202f=u202f1.0), fibrosis stage (F3 vs. F4 100% vs. 94%, pu202f=u202f.53), presence of baseline resistance associated substitutions (RASs) or RBV reduction.nnnCONCLUSIONSnWe report 100% SVR with 12-weeks of OBT/PTV-ru202f+u202fRBV in HCV-4 patients with advanced liver disease, including compensated cirrhotics.

Factors Associated with Increased Risk of de Novo or Recurrent Hepatocellular Carcinoma in Patients with Cirrhosis Treated with Direct-Acting Antivirals for HCV Infection

BACKGROUND & AIMS Patients with cirrhosis and hepatitis C virus (HCV) infection treated with direct‐acting antivirals (DAAs) are still at risk for developing hepatocellular carcinoma (HCC). We aimed to identify features of de novo or recurrent HCCs in these patients, and factors associated with HCC development, in a large cohort of patients with cirrhosis who received treatment with DAAs. METHODS In a retrospective study, we collected data from 565 patients with cirrhosis (median age, 64 years; range, 28–87 years; 60% male, 49% infected with HCV genotype 1; median liver stiffness measurement [LSM], 19.1 kPa; 87% Child‐Pugh‐Turcotte score A) treated with DAAs at a single center in Italy, from December 2014 through 2016. Cirrhosis was defined based on clinical features, histologic factors (METAVIR F4), or LSM >11.9 kPa. Patients were assessed (complete blood analysis and HCV‐RNA quantification) every 4 weeks during treatment; at weeks 4, 12, and 24 afterward; and at 6‐month intervals thereafter. HCC surveillance was performed by ultrasound or CT scans every 3–6 months, based on history of HCC. Non‐invasive markers of fibrosis, such as ratio of aspartate aminotransferase to platelets, fibrosis‐4 (FIB‐4) score, and LSMs were assessed. RESULTS During a median 25 months of follow up (range, 3–39 months), HCC developed in 28/505 patients without a history of HCC (de novo HCC); the 3‐year estimated cumulative probability for HCC was 6% (95% CI, 4%–9%). Of patients with de novo HCC, 75% had a single tumor and 82% of these were Barcelona liver cancer stage 0–A; the median level of alpha‐fetoprotein was 6 ng/mL (range, 1.0–9240 ng/mL). Male sex (hazard ratio [HR], 6.17; 95% CI, 1.44–26.47; P = .01), diabetes (HR, 2.52; 95% CI, 1.08–5.87; P = .03), LSM (HR, 1.03; 95% CI, 1.01–1.06; P = .01), and FIB‐4 score (HR, 1.08; 95% CI, 1.01–1.14; P = .01) were independently associated with de novo HCC. HCC developed in 20/60 patients with a history of HCC (HCC recurrence); the 3‐year cumulative probability for recurrence was 43% (95% CI, 20%–61%). In the 20 patients with HCC recurrence, 11 had a single tumor and 90% were Child‐Pugh‐Turcotte score A. Diabetes was independently associated with HCC recurrence (HR, 4.12; 95% CI, 1.55–10.93; P = .004). CONCLUSIONS In a large, single‐center cohort of consecutive patients with cirrhosis and who received DAA treatment for HCV infection, most liver tumors were identified at early stages. Male sex, diabetes, and non‐invasive markers of liver fibrosis can be used to identify patients at increased risk for HCC following DAAs therapy.

LBP-505 – Restrictions for reimbursement of interferon-free direct-acting antiviral therapies for HCV infection in Europe

[Marshall, A. D.; Cunningham, E. B.; Dore, G. J.; Grebely, J.] UNSW Sydney, Kirby Inst, Sydney, NSW, Australia. [Nielsen, S.] Freelance Epidemiologist, Madrid, Spain. [Aghemo, A.] Univ Milan, Fdn IRCCS CA Granda Osped Maggiore Policlin, Div Gastroenterol & Hepatol, Milan, Italy. [Alho, H.] Helsinki Univ Hosp, Abdominal Ctr, Helsinki, Finland. [Alho, H.] Univ Helsinki, Helsinki, Finland. [Backmund, M.] Univ Hosp Munich, Dept Med 2, Munich, Germany. [Bruggmann, P.] Arud Ctr Addict Med, Zurich, Switzerland. [Dalgard, O.] Univ Oslo, Akershus Univ Hosp, Dept Infect Dis, Oslo, Norway. [Dalgard, O.] Univ Oslo, Fac Med, Oslo, Norway. [Flisiak, R.] Med Univ Bialystok, Dept Infect Dis & Hepatol, Bialystok, Poland. [Foster, G.] Queen Mary Univ London, London, England. [Gheorghe, L.] Fundeni Clin Inst, Gastroenterol & Hepatol, Bucharest, Romania. [Goldberg, D.] Hlth Protect Scotland, Glasgow, Lanark, Scotland. [Goulis, I.] Dept Internal Med, Thessaloniki, Greece. [Hickman, M.] Univ Bristol, Social Med, Bristol, Avon, England. [Hoffmann, P.] Minist Hlth Luxembourg, Luxembourg, Luxembourg. [Jancoriene, L.] Vilnius Univ Hosp, Santariskiu Klin, Ctr Infect Dis, Vilnius, Lithuania. [Jarcuska, P.] Univ Hosp, Dept Internal Med 1, Kosice, Slovakia. [Jarcuska, P.] Univ Pavol Jozef Safarik, Kosice, Slovakia. [Kaberg, M.] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Makara, M.] St Istvan & St Laszlo Hosp, Hepatol Ctr, Budapest, Hungary. [Maimets, M.] Univ Tartu, Dept Internal Med, Tartu, Estonia. [Marinho, R.] Hosp Santa Maria, Med Sch Lisbon, Dept Gastroenterol & Hepatol, Lisbon, Portugal. [Maticic, M.] Univ Med Ctr, Clin Infect Dis & Febrile Illnesses, Ljubljana, Slovenia. [Norris, S.; Tait, M.] Dr Steevens Hosp, Natl Hepatitis Treatment Programme C, Hlth Serv Execut, Dublin, Ireland. [Olafsson, S.] Landspitali Univ Hosp, Dept Med, Div Gastroenterol, Reykjavik, Iceland. [Ovrehus, A.] Univ Southern Denmark, Odense Univ Hosp, Dept Infect Dis, Odense, Denmark. [Pawlotsky, J. -M.] Univ Paris Est, Hop Henri Mondor, Creteil, France. [Pocock, J.] Mater Hosp, Gastroenterol Dept, Msida, Malta. [Robaeys, G.] Ziekenhuis Oost Limburg, Dept Gastroenterol & Hepatol, Genk, Belgium. [Robaeys, G.] UHasselt, Dept Med & Life Sci, Hasselt, Belgium. [Robaeys, G.] UZLeuven, Dept Hepatol, Leuven, Belgium. [Roncero, C.] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Psychiat Serv, Addict & Dual Diag Unit, Barcelona, Spain. [Simonova, M.] Mil Med Acad, Dept Gastroenterol HPB Surg & Transplantol, Sofia, Bulgaria. [Sperl, J.] Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic. [Tolmane, I.] Infectol Ctr Latvia, Dept Hepatol, Riga, Latvia. [Tomaselli, S.] Off Publ Hlth, Vaduz, Liechtenstein. [van der Valk, M.] Acad Med Ctr, Dept Infect Dis, Amsterdam, Netherlands. [Vince, A.] Univ Zagreb, Sch Med, Univ Hosp Infect Dis, Zagreb, Croatia. [Lazarus, J. V.] Univ Copenhagen, Rigshosp, CHIP, Copenhagen, Denmark. [Lazarus, J. V.] Hosp Clin Barcelona, Barcelona Inst Global Hlth ISGlobal, Barcelona, Spain.

POSTER PRESENTATIONS: Posters Thursday, 20 April 2017: Late breakers: PostersLBP-505 - Restrictions for reimbursement of interferon-free direct-acting antiviral therapies for HCV infection in Europe

[Marshall, A. D.; Cunningham, E. B.; Dore, G. J.; Grebely, J.] UNSW Sydney, Kirby Inst, Sydney, NSW, Australia. [Nielsen, S.] Freelance Epidemiologist, Madrid, Spain. [Aghemo, A.] Univ Milan, Fdn IRCCS CA Granda Osped Maggiore Policlin, Div Gastroenterol & Hepatol, Milan, Italy. [Alho, H.] Helsinki Univ Hosp, Abdominal Ctr, Helsinki, Finland. [Alho, H.] Univ Helsinki, Helsinki, Finland. [Backmund, M.] Univ Hosp Munich, Dept Med 2, Munich, Germany. [Bruggmann, P.] Arud Ctr Addict Med, Zurich, Switzerland. [Dalgard, O.] Univ Oslo, Akershus Univ Hosp, Dept Infect Dis, Oslo, Norway. [Dalgard, O.] Univ Oslo, Fac Med, Oslo, Norway. [Flisiak, R.] Med Univ Bialystok, Dept Infect Dis & Hepatol, Bialystok, Poland. [Foster, G.] Queen Mary Univ London, London, England. [Gheorghe, L.] Fundeni Clin Inst, Gastroenterol & Hepatol, Bucharest, Romania. [Goldberg, D.] Hlth Protect Scotland, Glasgow, Lanark, Scotland. [Goulis, I.] Dept Internal Med, Thessaloniki, Greece. [Hickman, M.] Univ Bristol, Social Med, Bristol, Avon, England. [Hoffmann, P.] Minist Hlth Luxembourg, Luxembourg, Luxembourg. [Jancoriene, L.] Vilnius Univ Hosp, Santariskiu Klin, Ctr Infect Dis, Vilnius, Lithuania. [Jarcuska, P.] Univ Hosp, Dept Internal Med 1, Kosice, Slovakia. [Jarcuska, P.] Univ Pavol Jozef Safarik, Kosice, Slovakia. [Kaberg, M.] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Makara, M.] St Istvan & St Laszlo Hosp, Hepatol Ctr, Budapest, Hungary. [Maimets, M.] Univ Tartu, Dept Internal Med, Tartu, Estonia. [Marinho, R.] Hosp Santa Maria, Med Sch Lisbon, Dept Gastroenterol & Hepatol, Lisbon, Portugal. [Maticic, M.] Univ Med Ctr, Clin Infect Dis & Febrile Illnesses, Ljubljana, Slovenia. [Norris, S.; Tait, M.] Dr Steevens Hosp, Natl Hepatitis Treatment Programme C, Hlth Serv Execut, Dublin, Ireland. [Olafsson, S.] Landspitali Univ Hosp, Dept Med, Div Gastroenterol, Reykjavik, Iceland. [Ovrehus, A.] Univ Southern Denmark, Odense Univ Hosp, Dept Infect Dis, Odense, Denmark. [Pawlotsky, J. -M.] Univ Paris Est, Hop Henri Mondor, Creteil, France. [Pocock, J.] Mater Hosp, Gastroenterol Dept, Msida, Malta. [Robaeys, G.] Ziekenhuis Oost Limburg, Dept Gastroenterol & Hepatol, Genk, Belgium. [Robaeys, G.] UHasselt, Dept Med & Life Sci, Hasselt, Belgium. [Robaeys, G.] UZLeuven, Dept Hepatol, Leuven, Belgium. [Roncero, C.] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Psychiat Serv, Addict & Dual Diag Unit, Barcelona, Spain. [Simonova, M.] Mil Med Acad, Dept Gastroenterol HPB Surg & Transplantol, Sofia, Bulgaria. [Sperl, J.] Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic. [Tolmane, I.] Infectol Ctr Latvia, Dept Hepatol, Riga, Latvia. [Tomaselli, S.] Off Publ Hlth, Vaduz, Liechtenstein. [van der Valk, M.] Acad Med Ctr, Dept Infect Dis, Amsterdam, Netherlands. [Vince, A.] Univ Zagreb, Sch Med, Univ Hosp Infect Dis, Zagreb, Croatia. [Lazarus, J. V.] Univ Copenhagen, Rigshosp, CHIP, Copenhagen, Denmark. [Lazarus, J. V.] Hosp Clin Barcelona, Barcelona Inst Global Hlth ISGlobal, Barcelona, Spain.