Keynote sessions and Symposia / International Journal of Antimicrobial Agents 42S2 (2013) S1–S40 S3

individuals in risk groups who are below 65 years and in whomthe disease has high morbidity and mortality, strategies needto be considered for their indirect protection from reduction oftransmission. This could be achieved by vaccination of young andschool-age children reducing the risk of transmission and whoalso benefit from direct protection. Examples will be shown of theingredients that are necessary for analysis of a performance basedapproach to programme management that are necessary for such astrategy.As a corollary to the concept of the need for more rational use ofinfluenza vaccine, it will be proposed that the present vaccines areinadequate for successful interventions against influenza either be-cause of their probability for mismatch against strains that circulate,their low efficacy even when they do match strains, their limitedeffectiveness formore than one season and their lack of suitability foruse in young children.After such prolongeduse of such flawed tools, itis clearly time for investment in better vaccines to prevent influenzaand better strategies for the use of influenza vaccination. This mayinclude the use of adjuvanted vaccines, quadrivalent vaccines andLAIVs in the short term, and universal long-lasting vaccines in thelong term.

Symposium 3. Hepatitis B and C

SP3-1Hepatitis B and C in Japan. Past and future

J. Hayashi1 *, N. Furusyo2, M. Murata2. 1 Haradoi Hospital, Japan,2Department of General Internal Medicine, Kyushu University Hospital,JapanE-mail address : hayashij@gim.med.kyushu-u.ac.jp

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infectionsare important, because patients with these infections tended todevelop hepatocellular carcinoma (HCC).In the past, HBV was endemic in Japan. Our early studies showedmaternal and horizontal transmission. We found HBV infectionamongnursery school children,Sumo-wrestlers,and institutionalizedmentally retarded patients. At present, HBV infection has beenremarkably decreased in the younger age cohorts by the strategyof giving HBV vaccine and HB globulin to the newborn babiesof HBV carrier mothers. Unfortunately, HBV infection has recentlyre-emerged. HBV genotype A, along with human deficiency virus,was introduced to Japan from Europe and the USA by sexualtransmission. The native HBV genotypes in Japan are B and C. Wheninfants are infected with these genotypes of HBV, they may becomehepatitis B surface antigen (HBsAg) carriers, but adults do not. Incontrast, when even adults are infected with genotype A of HBV,10% become HBsAg carriers and a source of HBV infection. De novohepatitis B occurs among HBsAg-negative patients but antibody tohepatitis B core antigen (anti-HBc)-positive while chemotherapy.Patients with de novo hepatitis B not only develop severe illness, butalso become a source of HBV infection. Although nucleoside analogdrugs(lamivudine, adefovir, entecavir) are effective for 80% of patientswith chronic HBV infection, side effects and the appearance of drug-resistant HBV by long-term treatment are problems.

HCV became endemic in Japan through the commercial blood donorsystem and medical procedures.We found that patients with chronicHCV infection had often been injected with insufficiently sterilizedsyringes and needles. Currently, we seldom find new HCV infection,but we have many chronic hepatitis C patients. The developmentof HCC occurs often in HCV infected patients with persistent liverdamage. The interferon (IFN) monotherapy used from 1992 producedsustained viral response (SVR) rates of 15% for genotype 1 and 50% forgenotype 2. The combination therapy of pegylated IFN (PEG-IFN)-a +ribavirin used from 2004 produced SVR rates of 40% for genotype 1and 80% for genotype 2. IFN therapy was not so effective in patientsinfected with HCV genotype 1. Fortunately, the combination therapyof PEG-IFN-a + ribavirin + telaprevir used from 2011 is very effectivefor patients with genotype1, andwe have achieved an SVR rate of 80%.Importantly, IFN therapy for patients with chronic HCV infection hasdecreased the development of HCC.In Japan, HBV andHCV infections are generallywell controlled and therate of mortality from HCC has gradually decreased among patientswith chronic HBV or HCV infection.

SP3-2New direct-active antiviral agents for hepatitis C virus infectionin previous treatment failureA.I.M. Hoepelman*. Department of Internal Medicine & InfectiousDiseases, University Medical Centre, The NetherlandsE-mail address : i.m.hoepelman@umcutrecht.nl

A significant proportion of patients will not achieve an SVR with theprevious SoC treatment consisting of pegylated interferon + ribavirindue to virological failure. These patients can broadly be divided intothree groups:i. Virological relapse: Patients who have undetectable HCVRNA at

the end of treatment, but do not achieve an SVR (i.e. detectableHCVRNA during follow-up period).

ii. Virological partial response: Patients who have a �2 log10 IU/mLdrop in HCVRNA by 12 weeks of treatment, but never achieveundetectable HCVRNA.

iii. Virological null response: Patients who have a <2 log10 IU/mL dropin HCVRNA by 12 weeks of treatment.

Studies have now been conducted using boceprevir and telaprevirin these patients who have not achieved an SVR despite priortreatment. In the RESPOND-2 study using boceprevir, patients withprevious relapse and partial response were recruited. All patientsreceived treatment for 4weeks with SoC Peg IFN-a2b 1.5mg/kg weeklyand ribavirin 600–1400mg daily. Patients were then randomized:Group 1 [control (total 48 weeks)] and Group 2 [response-guidedtherapy for 32 additional weeks (up to week 36); Group 3 (SoCpeginterferon-ribavirin and boceprevir for an additional 44 weeks).Overall SVR rates were Group 1 (control) = 21%, Group 2 (response-guided therapy) = 59% andGroup3 = 66%. Subgroup analysis indicatedSVR rates among patients with previous relapse of 29% vs. 69% vs. 75%and among patients with previous partial response of 7% vs. 40% vs.52% in favour of treatment with three agents.In the REALISE study using telaprevir, patients with previous relapse,partial response and null response were randomized to three

Table (abstract SP3-2): Summary of the SVR and relapse rates, where quoted, from the stated clinical trials for the addition of boceprevir or telaprevir to SoC therapy for Genotype

1 HCV-infected patients who have had prior virological failure with treatmenta

Drug [trial] Boceprevir [RESPOND-2] Telaprevir [REALISE]

Previous response Relapse Partial response Relapse Partial response Null response

Group 1 Group 2

(RGT)

Group 3

(48 wks)

Group 1 Group 2

(RGT)

Group 3

(48 wks) PR48

T12

PR48

Lead-in

T12PR48 PR48

T12

PR48

Lead-in

T12PR48 PR48

T12

PR48

Lead-in

T12PR48

SVR 29% 69%* 75%* 7% 40%* 52%* 24% 83%* 88%* 15% 59%* 54%* 5% 29%* 33%*

Relapse NR NR NR NR NR NR 65% 7%† 7%† N/A 21% 25% 60% 27%† 25%†

aPatients are divided into thosewith prior relapse (undetectableHCVRNA at the end of treatmentbut do not achieve an SVR), prior partial response (�2 log10 UI/mL drop inHCVRNA

by 12 weeks of treatment but never achieve undetectable HCVRNA) or prior null response (�2 log10 IU/mL drop in HCVRNA by 12 weeks of treatment). Shaded columns indicate

control groups receiving SoC treatment alone. Relapse is defined as undetectable HCVRNA at end of treatment but detectable within 24 weeks of follow-up. Study design and

treatment groups are summarised in the text. Statistical analyses are comparedwith SoC treatment alone.

HCV, hepatitis C infection; NR, No data reported; RGT, response-guided treatment; SVR, sustained virological response.

*P < 0.001. †No P -value reported.

S4 Keynote sessions and Symposia / International Journal of Antimicrobial Agents 42S2 (2013) S1–S40

groups: PR48 (control group receiving SoC PR daily for 48 weeks),T12PR48 (receiving SoC for 48 weeks with telaprevir treatment forthe first 12 weeks) and lead-in T12PR48 (4 weeks lead-in with SoCfollowed by 12 weeks triple therapy, then continuation on SoC for atotal of 48 weeks). Overall SVR rates were PR48 = 17%, T12PR48 = 64%and lead-in T12PR48 = 66%. Subgroup analysis indicated SVR rates(PR48 vs. T12PR48 vs. lead-in T12PR48) among patients with priorrelapse of 24% vs. 83% vs. 88%; among patients with prior partialresponse of 15% vs. 59% vs. 54%; and among patients with prior nullresponse of 5% vs. 29% vs. 33% (Table).In summary, there is a significant benefit to re-treating patientswho have previously had virological failure using triple therapy witha protease inhibitor. Overall, this can improve SVR rates in thesepatients by over 40%. The benefits of protease inhibitor regimensover SoC treatment seem to hold for patients with prior relapse,partial response and null response, although the SVR rate is lower inprior partial responders and null responders. The regimens used forboceprevir and telaprevir differed between the studies, but showedsimilar SVR rates. Of note, boceprevir has not been used in patientswith a prior null response.

SP3-3Immune therapy of HCVF.A. Amer*. Department of Medical Microbiology and Immunology,Zagazig Faculty of Medicine, Zagazig, EgyptE-mail address : egyamer@yahoo.com

Nearly 3% of the people, worldwide, are suffering from hepatitis Cvirus (HCV) infection. Although there is a long fight aiming at theprevention and treatment of that disease, HCV infection remainsa serious problem, due to the late complications of liver cirrhosisand carcinoma. The gold-standard therapy for HCV infection isweekly subcutaneous injection of pegylated interferon combinedwith daily oral ribavirin for a period of 24–48 weeks according to theHCV genotype. In addition to being expensive, this therapy is fraughtwith significant side effects and with low to moderate sustainedvirological response (SVR). Moreover, a large number of HCV patientsrelapse after completion of treatment. Therefore, exploration of newtherapeutic strategies is of paramount importance.Emerging and future therapeutic options for HCV infection includetreatment with direct acting antivirals (DAAs), and immune-basedtherapy. DAAs target HCV-RNA or HCV-specific enzymes, or influencehost–virus interactions. Two selective inhibitors of the HCV protease,boceprevir and telaprevir, have been approved in 2011. During 2012,the drug development pipeline has contained at least 30 additionalDAAs in various stages of clinical development. They act in concertin combination therapy with peginterferon alfa and ribavirin and/ortogether. However,many questions are stillwaiting for answers. Theseinclude, which combination is the most effective, well-tolerated,and cost effective in all patients and on different genotypes. Thisis of particular concern in low-resource settings, where problemsrelated to inadequate infrastructure for medical supervision anddistribution may interfere with achieving the required outcomes.Perhaps, immune-based therapy can provide such answers. Strategiesof the immune-based therapy are directed towards augmenting theindividuals’ immune responses against HCV infection. Such strategiesare bases upon understanding the natural history of HCV infection.It is well established that nearly 20–40% of HCV patients recoverspontaneously, which could be due to enhancing specific T cellresponses, and/or antiviral innate immunity. At present, varioustypes of immune-based therapies are under development. The mostintensively studied are: (1) dendritic cell immunotherapy, involvingvaccination with autologous DCs loaded with HCV-specific cytotoxicT cell epitopes, (2) antagonists of T cell inhibitory factors: e.g.,blocking IL-10 and combined blockade of programmed death-1/cytotoxic T lymphocyte-associated antigen-4, (3) anti-HCV neutraliz-ing antibodies, like anti-E2 human monoclonal Ab, (4) cytokines: asIFN-g, IFN-l and IL-12, (5) agonists for TLRs: either synthetic versionsof natural TLR ligands with optimized pharmacologic properties,or small molecule agonists derived from drug screening effort,(6) caspase inhibitors: e.g., the pancaspase inhibitors IDN-6556, and(7) vaccines: either therapeutic or prophylactic vaccines.

Symposium 4. Parasitic zoonoses in the changing world

SP4-1Lethal cestode zoonoses, cysticercosis and echinococcoses inAsia and the World

A. Ito1 *, Y. Sako1, T. Yanagida1, M. Nakao1 , M. Okamoto2. 1 Departmentof Parasitology, Asahikawa Medical University, Asahikawa, Japan,2 Primate Research Institute, Kyoto University, Inuyama, JapanE-mail address : akiraito@asahikawa-med.ac.jp

Both cysticercosis (CC) caused by eggs of Taenia solium , andechinococcoses caused by eggs of Echinococcus granulosus (cysticechinococcosis, CE) and E. multilocularis (alveolar echinococcosis, AE)are included in the Neglected Tropical Diseases (NTDs) spreadingworldwide. CC, especially neurocysticercosis (NCC) is one of the mostpotentially lethal parasitic zoonoses. All of these all diseases arecaused by eggs released from tapeworm carriers (humans for CC,dogs and wolves for CE, and foxes and dogs for AE). CC is basicallymeat-borne parasitic zoonosis, whereas both CE and AE are vector-borne zoonoses. Therefore, the strategies for control or interventionof these cestode zoonoses are critically different. As the wave ofglobalization in the 21st century including the increase in worldwidebusiness, tourism especially to visit ethnic minorities, immigrantsand refugees easily contaminate everywhere including so-calleddeveloped countries. Additional problem for control of CC is thatT. solium adult tapeworm is not the sole species which maturesin the human intestine. There are two other species: cosmopolitantapeworm T. saginata (the beef tapeworm) and T. asiatica througheating uncooked viscera of pigs in Asia which do not cause CC inhumans but cause CC in domestic animals exclusively. Human CC,especially NCC caused by eggs of T. solium , is often lethal. Therefore,we have to differentiate eggs from two other species. By contrast,echinococcoses are affected by the living environment includingcompanion animals, dogs and often wild animals, foxes or wolves.Therefore, it is rationally easy (but practically difficult) to preventechinococcoses by “keeping distance from dogs and foxes”. So,the strategy for control or intervention of echinococcoses is moredifficult. The essential basic research on these cestode zoonosesand any other infectious diseases is how to establish highly reliabletools for detection or identification of the patients and animalscontaminated with the pathogenic parasites and how to obtainthe sound evidence of the infection itself. Recent advances indevelopment of immunological and molecular tools for identificationof patients infected with T. solium and Echinococcus spp. and animalsinfected with T. solium are overviewed. These tools for identificationof tapeworm carriers and pigs and humans infected with cysticerci ofT. solium are overviewed through our international joint projects. Thestudies are through international joint projects mainly in Indonesia,Thailand and China with international experts from UK and France.The studies were supported by Grant-in-Aid for Scientific Researchfrom JSPS (21256003, 24256002 to AI; 21406009, 24406011 to MO),by JSPS Asia-Africa Scientific Platform Funds to AI (2006–2008, 2009–2011), the Hokkaido Translational Research Fund (2007–2011) and theSpecial Coordination Fund for Promoting Science and Technology toAI (2003–2005, 2010–2012) from the Ministry of Education, Japan(MEXT).

SP4-2Current situation of food-borne parasitic helminthiases in JapanH. Yamasaki*, H. Sugiyama, M. Yasuyuki. Department of Parasitology,National Institute of Infectious Diseases, Tokyo, JapanE-mail address : hyamasak@nih.go.jp

Food-borne parasitic diseases such as diphyllobothriasis and anisaki-asis have frequently occurred in Japan and the occurrence is closelyassociated to Japanese food habits of eating raw or undercookedfish. Some food-borne parasitic diseases are also becoming importantglobally as the international transport systems for fresh foods haveadvanced.In Japan, a variety of food-borne parasitic helminthiases includingthe two above-mentioned diseases, sparganosis, toxocariasis, para-gonimiasis, metagonimiasis, fascioliasis and taeniasis/cysticercosis