Seminarie > 22 november 2012 Séminaire > 22 novembre 2012 · Page 1 Medewerking en financiële steun Collaboration et appui financier QISP : DO Santé publique et Surveillance│

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Centre Culturel et de Congrès de Woluwé-St-Pierre

Diagnose en surveillance van infectieuze aanDoeningen

Diagnostic et surveillance Des malaDies infectieuses

28Ste Seminarie > 22 november 201228e Séminaire > 22 novembre 2012

Cultureel en Congrescentrum van St.-Pieters-

Woluwe

Programme | ProgrammaDiagnosis Hiv

infection control antimicrobial resistance microbiome N. meningitidis

risk & Prevention HPv

surveillance CPe measles Syndromic surveillance

Page 1

Medewerking en financiële steunCollaboration et appui financier

ISP : DO Santé publique et Surveillance│WIV : OD Volksgezondheid en SurveillanceOrganiserend Comité │Comité OrganisateurStandsPublicités │Advertenties

Dr J. Bots (GGC)Dr P. Butaye (CODA)Dr B. Catry (WIV-ISP)Dr G. Daube (ULg)Dr K. De Schrijver (Vl. Gem.)Mrs G. Ducoffre (WIV-ISP)Dr G. Ieven (UZA)Dr S. Jacquinet (FWB)Dr P. Melin (ULg)

Dr E. Padalko (UGent)Dr D. Pierard (UZ Brussels)Dr C. Potvliege (CH Tivoli)Dr H. Rodriguez-Villalobos (UCLouvain)Dr Y. Van Laethem (CHU St-Pierre)Dr H. Van Oyen (WIV-ISP)Dr J. Verhaegen (UZ Leuven)Dr K. Vernelen (WIV-ISP)

Voorzitter │Président : Dr. S. Quoilin (WIV-ISP)

Comité OrganisateurOrganiserend Comité

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Write in your agendaNext seminar

21/11/2013

Evolutionary changes in antimicrobial resistance of invasive Neisseria meningitidis isolates : recent trends

Evolutionary changes in antimicrobial resistance of

invasive Neisseria meningitidis isolates

Recent trends

Dr. Bertrand Sophie, Dr. Mattheus Wesley, Ig. Carion Françoise and Dr. Vanhoof Raymond.

Bacterial Diseases Division

Rue Juliette Wytsmanstraat 14 | 1050 Brussels | BelgiumT +32 2 642 51 11 | F +32 2 642 50 01 | email: [email protected] | www.iph.fgov.be

1


Neisseria meningitidis

• Gram-negative organism (diplococcal form)

• Asymptomatic carriers (colonises the nasopharynx)

• Exclusive human pathogen

• Transmission via droplet secretion and close contact

• Invasive meningococcal diseases : meningitis, septicaemia


Neisseria meningitidisInvasive meningococcal diseases

• Fulminant septicaemia (coma, purpura fulminans)

• Case-fatality rate (10%)

• Sequelae (neurological, amputations)

• High incidence among infants

Net societal costs per case (estimations 2002) :

UK = 12.513€ /case BMJ 2002;324:1-6Québec = 14.070 € /case Vaccine 2002;20:2840-2844

2


• Exists since 1971

• Officially recognised by INAMI/RISIV in 2010

• Surveillance and detection of outbreak(s) :detection of new serogroups (vaccine pressure)

detection of new phenotypes (capsule switching)

detection of antibiotic resistances

Neisseria meningitidisBelgium : The National Reference Centre


Neisseria meningitidisTyping Methods

• « classical » typing

3


• Molecular typing

Neisseria meningitidisTyping Methods


Neisseria meningitidisDistribution of serogroups B and C in Belgium (1991-2011)

0

50

100

150

200

250

300

350

400

90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11

Cas

es

Total B C

4


Neisseria meningitidisDistribution of serogroups B and C in Belgium (1991-2011)

0

50

100

150

200

250

300

350

40090 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11

Cas

es

Total B C

Serogroup Cvaccination


• Prompt treatment• Prevention: rifampicin or ciprofloxacin• Penicillin G : drug of choice for IMD

Neisseria meningitidisTreatment of IMD

5


Antimicrobial susceptibility testing for 1,933 strainsCtx, Chl and CipAll susceptible

Rif-R1,932 strains susceptible

Penicillin1,637 are PenS(Susceptible)273 are PenI(Intermediate)23 are PenR(Resistant)

296 / 1,933 PenNS= 15,3 %

Neisseria meningitidisSurveillance 2000 to 2010 in Belgium


Neisseria meningitidisDistribution of the MIC for penicillin G, 2000

6


Neisseria meningitidisDistribution of the MIC for penicillin G, 2000 and 2006


Neisseria meningitidisDistribution of the MIC for penicillin G, 2000, 2006 and 2010

7


Neisseria meningitidisEvolution of MIC50 (expressed in µg/ml) in PenS and PenNS isolates

0.012 0.016 0.023 0.032 0.047 0.064 0.094 0.125 0.19 0.25 0.38 0.520002001200220032004200520062007200820092010

1 MIC50: Minimal Inhibitory Concentration for 50% of the isolates; values are shaded

YearMIC501 values and number of isolates at indicated concentration

PENS PENI PENR

PENNS


Neisseria meningitidisPenicillin G susceptibility linked to penA alleles

8


Neisseria meningitidisDistribution of the penA allele among the Non Susceptible population and relation between the penA allele and the average MIC value.


Neisseria meningitidisDistribution of the most frequent penA alleles in the PenNSisolates, between 2000 and 2010

0%

20%

40%

60%

80%

100%

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

penA1

penA12

penA14

penA9

penA13

others

9


Neisseria meningitidisDistribution of penA alleles in the different serogroups

penA1penA12penA14penA9penA13

B C Others




Neisseria meningitidisDistribution of the most frequent penA alleles in the PenNSisolates, between 2000 and 2010

0%

20%

40%

60%

80%

100%

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

penA1

penA12

penA14

penA9

penA13

others

Serogroup Cvaccination

10


• N. meningitidis remains susceptible to antibiotics

• Susceptibility to penicillin decreases

• Pen S population is less sensitive

• Decreased susceptibility to penicillin G is linked

to alterations of the penA gene

• The penA allele is predictive

Neisseria meningitidisConclusions


Neisseria meningitidisTo read more ...

11


Thank you for your attention!

Treatment and new vaccines formeningococcusI. De SchutterUZ Brussel, Pediatric Pulmonology, CF-Clinic and PediatricInfectious Diseases

1

2

Meningococcal disease: Clinical syndromes

43%

48%

meningitis bacteremia pneumoniaarthritis otitis media epiglottitis

http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf

3

Meningococcal disease: outcome

Case fatality rate:Invasive menigococcal disease: 9-12%Menigococcemia: up to 40%

sequelae: 20% of survivorsHearing lossNeurological damageLoss of a limb

http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf

1

4

Meningococcal disease: treatment

Bacterial meningitis (pathogen unidentified)3rd generation cephalosporine ± ampicillin*Dexamethasone (controversial)

N. meningitidis identified – susceptibility pending1st choice: 3rd generation cephalosporineAlternative: Aztreonam or FQ2

N. meningitidis identified – susceptibility proven1st choice: Penicilline G

* In case of: child <3months or risk factor (alcoholism, debilitatingilness, impaired cellular immunity,…)

Sanford guide Belgian/Luxembourg Ed 2010-2011

5

Prophylaxis

Rationale: prevention through elimination of carriership in close contacts

Risk secundary case in household members: 2-4/1000 (= 500-800x risk in general population)1,2

Who should get chemoprophylaxis?2

Patient: at discharge from the hospital (unless he was treated with an agent that eliminates carriership, i.e; ceftriaxone or ciprofloxacine)Close contacts:

Close contacts (contact period 7d prior to disease in index patient)- Household members- Persons that shared a room (overnight) with the index patient- Intensive face to face contact during >4h (indoors)Anyone directly exposed to the patient’s oral secretions (healthcareworkers)Indiv. seated next to index case on a long travel (>4h) (to beconsidered for chemoprophylaxis)

1http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/mening.pdf2 Handboek Richtlijnen Infectieziektenbestrijding Vlaanderen Ed. 20113 Sanford guide Belgian/Luxembourg Ed 2010-2011

1

6

Prophylaxis: which antibiotic?

500mg 1x10mg/kg

1x

10mg/kg

1xazithromycin

250mg IM 1xceftriaxone

1g 2x/d5 daysspiramycin

15 mg/kg(max 500mg)

1x

Children> 5y

FQ2ciprofloxacin

rifampicin

500mg 1x

600mg 2x/d

2 days

10mg/kg 2x/d

2 days

5mg/kg 2x/d

2 days

PregnancyAdo’s & adults

Children< 5y

neonates

Sanford guide Belgian/Luxembourg Ed 2010-2011

7

Meningococcal infections: evolution1991-2011

Vaccination Men C

- 88%

WIV annual report 2011

1

8

Current vaccination schedule (Flanders)

X14 jaar

XXXXX(X)12 jaar

X10 jaar

X6 jaar

XX15 maand

XX12 maand

(X)XX4 maand

XX3 maand

XXX2 maand

TdpaHPVHBVIPV-DTPa

MenCMBRRota**Pnc-13IPV-

DTPa-Hib-HBV

leeftijd

9

Meningococcal vaccines- timelines

MenA CV- Africa

MenCCVMenPSV4

2001 20101970-80’s

MenBV

?

MenCV4

1

10

Characteristics of the immune response evoked bydifferent vaccine types

√xHerd immunity

√xReduction of carriage

√xBooster effect

√xImmune memory / long term protection

√xT-cell dependent

√√B-cell dependent

√xImmunogenicity in <2y olds

Protein conjugatevaccines

Polysaccharidevaccines

Property

Adapted from Nohynek et al. PIDJ 2009;28(10):S127-S132

11

1 x>11j(<12m) β

CRM 197Men A PS 10 μgMen C PS 5 μg

Men W135 PS 5 μg Men Y PS 5 μg

CVMenveo®

1 x>12mTetanus toxoidMen A PS 5 μgMen C PS 5 μg


CVNimenrix®

3-18m: 3x >18m: 1x

All ages **/Men A PS 50 μgMen C PS 50 μg


PSVMencevax®*

<12m: 3 x >12m: 1 x

> 2mCRM 197 (AL-hydroxide)

Men C PS 10 μgCVMenjugate-kit®

<12m: 2 + 1 >12m: 1 x

> 2mCRM 197(AL-

phosphate)

Men C PS 10 μgCVMeningitec®

<12m: 2 + 1 >12m: 1x

> 2mTetanustoxoid(AL-hydroxide)

Men C PS 10 μgCVNeisVac-C®

Dosing(1= 0,5ml)

LisencingCarrier-proteïn

Ag componentsTypeVaccine

*Recommended for use in travelers to the “meningitis belt ” or contacts of Men A or Men C cases ; ** poorly immunogenic in < 2y oldsβ Green book UK: Recommended for travelers <12m

1

12

Men B vaccines: development

Difficulties encountered in development of Men B vaccines

Polysaccharide capsule resembles structure of foetalneural cell adhesion molecules

poorly immunogenicRisk for autoimmune disease?

Men B strains are highly heterogeneous

Solutions?Outer membrane vesicles (OMV) vaccines – monovalentOuter membrane vesicles (OMV) vaccines – multivalentMulticomponent vaccines (recombinant protein vaccines)

Dull PM et al. Vaccine 2012; 30S:b18-b25Ladhani SN et al. Vaccine 2012; 30:3710-16

13

Monovalent Outer membrane vesicles(OMV) vaccines - Trials

1-21y: 51%1-4y: -23%5-21y: 69%

1-21y1995Chile

(Boslego J et al. Vaccine 1995)

B:4:P1,15

B:4:P1,15

B:15:P1.7,16

vaccine

83%10-14y1987-88Cuba

(Sierra GV Et al. NIPH Ann 1991)

>48m: 74%24-47m: 47%<24m: -37%

3m-6y1989-91Brasil

(de Moraes JC et al. Lancet 1992)

57.2%11-16y1989-91Norway

(Bjune G et al. Lancet 1991)

efficacyAge groupperiodcountry

Management for epidemic outbreaksMain limitations:

- Strain specific respons no immunity to heterologousstrains

- Immunity of short duration (particularly in infants)

1

14

Multivalent OMV vaccines

Expression of multiple PorA- Ag (rDNA technology) (2-, 6-, 9-valent)

The Netherlands & UK (6-valent)2 trials (age: 8w - 8y)16-100% sign. Antibacterical Ab response (dependent onPorA variant)Fast lowering of Ab levels- no longterm protection

Coverage to upto ~75% circulating Men B strainsSingle protein (PorA) component

Sufficiently broad coverage?changing epidemiology?

Sadarangani M et al. Lancet Infect Dis 2010; 10:112-24

15

Multicomponent vaccine development

4CMenB: Bexsero®-Novartis3 subcapsular MenB Ag + OMV (PorA P1.4)

- Factor H binding protein (FHbp variant 1.1) (fusion with GNA2091)- neisserial adhesin A (NadA variant 3.1)- Neisseria heparin binding antigen (NHBA variant 1.2) (fusion with

GNA1030)Phase II trials (UK): schedule 3 +1

Well toleratedImmunogenic in infantsEvidence of immune memory

Phase III trials (3630 infants): schedule 3 + 1Confirmation of phase II findingsNo clinical significant interaction with routine vaccines

Estimated vaccine coverage based on MATS: Europe: 73-87%Application for EMA Marketing authorization, for use in children ≥ 2m, ado’s and adults – approval awaited

Serruto D. et al. Vaccine 2012; 30S:B87-97

1

16

Multicomponent vaccine development

rLP2086 vaccine - PfizerTwo fHbp variants

rLP2086 fromsubfamily ArLP2086 fromsubfamily B

Phase I studiesVaccine well toleratedBactericidal Ab againstall fHbp variants

Phase II trialsresults awaited

OMV based vaccine – WRAIR3 genetically modified OMV’s

6 PorA variants3 PorB variants2 fHbp variantsOpcANadA

Phase I trialsInduces bactericidal Ab response in humans

16th International Pathogenic Neisseria Conference 2008

Vipond C. et al. Vaccine 2012;30S:B10-17

13-valent vaccine

17

Other possible vaccine candidates(not all mentioned)

Avoidance of PorA –dependentstrain restriction

Serum Ab response: 8-31%

(adults)

X(antisera do mediateopsonophagocytosis)

N lactamina OMV-vaccine

Nasal IgA:√Serum Ab

response: 43-75%

Intranasal OMV-vaccines

Studies done-results awaited√

Transferrin-binding proteins

Highly conservedprotein =>

crossprotection?x√Protein NspA

advantagesSerum

bactericidal Ab humans

Serum bactericidal Ab

mice

Vaccine type/component

Sadarangani M et al. Lancet Infect Dis 2010; 10:112-24

1

18

Conclusions

major advances in past 20y bring us closer to universal prevention of meningococcal disease

Meningococcal vaccination is routine in some countriesIntroduction of CV against Men C => important decreasein Men C diseaseAvailability of low cost CV against Men A for AfricaAvailability of 4-valent CV against Men ACW135YAvailability and use of monovalent OMV vaccines forcontrole of hyperendemic clonal Men B diseasesNear future: broadly cross-protective Men B vaccines?

Antimicrobial Resistance in Humans and Animals:

Time for Action

Herman GoossensVaccine & Infectious Disease Institute

University of AntwerpBelgium

1

27 democratic European countries23 languages> 490 million people united in diversityMember States remain sovereignPartial delegation of sovereignty to common EU institutionsCouncil, Parliament & Commission in EU decision processes

What is the European Union?

2

OutlinePolitical initiativesSurveillance- Humans- Animals

Targets and interventionsAwarenessResearch- Joint programing- IMI- Horizon 2020

3

Political Initiatives

4

First Steps Towards a European Antibiotic Policy

Economic & Social Committee on Resistance to Antibiotics as a Threat to

September 1998: EU Conference on the Microbial Threat, Copenhagen & Copenhagen

Recommendations

Scientific Steering Committee on Antimicrobial

5

Many EU Presidencies on AMR

Belgium (July - December 2001):- Expert conference, coincided with Health Council meeting of Ministers in Brussels on November 15 18 November 2001-Sweden (July-December 2009):- Innovative Incentives for Effective Antibacterials

REACT meeting in September 2010.Belgium (July - December 2010):- European Strategies to Monitor and ControlInfection, Antibiotic Use and Resistance in Health-care Facilities , Brussels 8 10 November 2010Denmark (January June 2011)- Antimicrobial Resistance in Humans and

Animals: Time for Action Copenhagen 14 15 March 2011.

Other: Sweden (2003), Slovenia (2008), France (2008), Czech Republic (2009)

6

ESAC: European Surveillance of Antimicrobial Consumption

Launched in November 2001 (Belgian EU Presidency)ESAC is an international network of surveillance systems, aiming to maintain a continuous, comprehensive and comparable database on antimicrobial consumption for all Member States, candidate countries and EFTA-EEA countries Coordinator: Herman Goossens (UA)Funding organisation: DG SANCO of EC (2001-2007) and ECDC (2007-2011)Transfer to ECDC (Stockholm) in July 2011New acronym: ESAC-Net

7

Council Recommendations on the Prudent Use of Antimicrobial Agents, 15

November 2001

8

European Centre for Disease Prevention and Control (ECDC) and European Medicines Agency (EMA) pipeline analysis:

- Very few antibacterial compounds in late stage clinical development

- Gram negative infections particularly critical

London School of Economics report on incentives, - Push incentives (research funding, tax incentives, PDPs)- Pull incentives (regularory adjustments, awards, patents,

advance market commitments, pricing and reimbursements)- Combination Push/Pull (Orphan Drug incentives, Call

Option for Antibiotics, Special Designation for priority Antibiotics)

Need for a new business model for new drugs that decouples profit from use

Swedish EU Presidency Conference: "Innovative Incentives for Effective

Antibiotics", September 2009

9

Source: EMEA, 2009. http://ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf

The Antibiotic Pipeline

13 agents against Gram-positive bacteria 6 agents against Gram-negative bacteria

10

Trans Atlantic Task Force on Antimicrobial Resistance - TATFAR

EU-US Summit Washington 3 November 2009

The EU-US Summit Declaration called

transatlantic task force on urgent antimicrobial resistance issues focused on appropriate therapeutic use of antimicrobial drugs in the medical and veterinary communities, prevention of both healthcare- and community-associated drug-resistant infections, and strategies for improving the pipeline of new antimicrobial drugs, which could be better addressed by intensified

11

TATFAR Objectives

Increase the mutual understanding of US and EU activities and programmes relating to antimicrobial issues

Deepen the transatlantic dialogue

Provide opportunities to learn from each other

Promote information exchange, coordination and co-operation between the US and the EU

12

TATFAR Members

United States Department of Health and Human Services

Office of Global Health Affairs (OGHA)

Centers for Disease Control and Prevention (CDC)

Food and Drug Administration (FDA)

National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID/NIH)

European Commission: EC-Directorate General for Health and Consumers EC-Directorate General for Research and InnovationEuropean Centre for Disease Prevention and Control (ECDC)European Medicines Agency (EMA)European Food Safety Authority (EFSA)

Council of the European Union:Represented by the TRIO Presidency (Spain, Belgium, Hungary)

USA EU

13

TATFAR report

The TATFAR report was made public on 22 Sept 2011Full report available at: http://www.ecdc.europa.eu/en/activities/diseaseprogrammes/TATFAR/Documents/210911_TATFAR_Report.pdfEndorsed by the US Secretary of Health and Human Services, Kathleen Sebelius, and EU Commissioner for Health, John DalliTATFAR has identified a set of 17 recommendations in key areas where future cooperation would prove fruitful

14Conclusions14

WORKSHOP 1: How to begin, how to implement and how to sustain a national (and local) hand hygiene campaign

WORKSHOP 2: Indicators of hospital infection control and antimicrobial management

WORKSHOP 3: To roll-out a common European methodology for Point Prevalence Surveys on AM and HAI in acute care hospitals

WORKSHOP 4: Infection prevention and prudent use of antimicrobial agents in long-term care facilities

Belgian EU Presidency Workshop:November 8-10, 2010 in Brussels

15

Expert-Proposed European Strategies

Initiate or continue hand hygiene campaigns and use hand hygiene as a quality indicator Collection and monitoring of structure-of-care quality indicators and indicators of good practice (e.g. consumption of alcohol solution)ECDC Point Prevalence Surveys on HAI and AB Use (completed in all Member States by November 2012; repeated at least once every 5 years)National LTCF resident safety programmes, external audits of LTCF and monitoring

Goossens, Lancet Infect Dis 2011, April 7th

16

Danish EU Presidency Workshop:

Combating Antimicrobial Resistance: Time for Joint Action

March 14-15, 2012 in Copenhagen

17

Antimicrobial use in Animals: An example of effect of intervention by

reducing veterinarians profit from drug sale (Denmark)

New veterinary regulation on medicines adopted in 1995

Profit ontherapeuticsreduced

Reduction of total usage of prescribed veterinary medicine by 30-40%

Data: VetStat

18

Relation between use of antibiotics as growth promotion and of vancomycin resistant E. faecium in pigs

Modified from DANMAP 2007, 2008

Data as basis for action

Ban of Avoparcin

Stop use of Tylosin as growth promoter

19

20

Surveillance

21

EU Public Health Funding of Surveillance

EARSS = European Antimicrobial Resistance Surveillance System

Endorsed by European Parliament and the Council Legislation 2119/98/EC and Commission Decision 2000/96/EC

Moved to ECDC in 2010 (EARS-Net)

ESAC = European Surveillance of Antimicrobial Use

Endorsed by Council Recommendation of the 15th November 2001 on the prudent use of antimicrobial agents in human medicine (2002/77/EC).

Moved to ECDC in 2011 (ESAC-Net)

22

Correlation Between Penicillin Use and Prevalence of Penicillin-

resistant S. pneumoniae

Consumption of Penicillin (J01C) in DID, AC 2000

181614121086420

Peni

cilli

n-re

sist

ant S

. pne

umon

iae

(%)

50

40

30

20

10

0

UK SW

SI

PT

PL

NL

LU ITIE

HU

HR

FR

FI

ES

DKDE

CZ

BE

AT

Organism year of isolation [source of

information]

Antibiotic resistance

Antibiotic use -ATC group

(year of data)

No. of countrie

s

Spearman correlation (r)(confidence

interval)

P-value

S. pneumoniae2001[7]

Penicillin Penicillin J01C(2000)

19 0.84(0.62-0.94)

<0.001

Goossens et al., Lancet 2005; 365: 579-87

23

Le Point, January 2006

24

Outpatient Antibiotic Use in DID in 33 European Countries in 2009.

DID and PID data available

Adriaenssens et al. JAC 2011 66: vi79-87.

25

Outpatient Antibiotic Use in PID in 17 European Countries in 2009.

Country IT GR RU BG LT HR IE PT BE SI CZ AT FI DK EE NL SERanking PID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Ranking DID 2 1 15 8 7 5 6 4 3 13 9 12 10 11 17 16 14

DDD/package 2.6 7.3 3.0 5.7 6.6 7.4 8.6 9.0 10.9 6.8 8.1 8.1 9.5 9.3 6.5 7.4 11.8

Adriaenssens et al. JAC 2011; 66: vi79-87.

1000 DDD 333 packages 90 packages

26

Point Prevalence Surveysin Hospitals

Entire hospitalIn each in-patient ward:- Collecting the number of patients present at 8 am- Collecting information about the treated patients, only

Treated patients:- Demographic data (age/gender)- Prescription (drug, dose, route of administration)- Indication/Diagnosis- Basic quality indicators (e.g. policy compliant)

19 pre-defined diagnosis groups by anatomical site

Indication for therapy: community and hospital acquired infection or (medical/surgical) prophylaxis

27

Web-Based Data Entry

28

ECDC PPS23 countries, 66 hospitalsProtocol:

Light: 16 hospitalsStandard: 50 hospitals

19,888 patientsHAI: 7.1%Antimicrobial use: 34.6%

Most frequent types of HAI

Zarb et al, EuroSurveillance Nov 2012

22%

12%

17%

19%

22%

0% 10% 20%

Other HAI

Bloodstream infections (BSI)

Urinary tract infections (UTI)

Surgical site infections (SSI)

Pneumonia (PN)/ Lowerrespiratory tract (LRTI)

29

Prevalence (%) of HAI by hospital

0%

5%

10%

15%

20%

25%

11

13

15

20

38

59

58

34

27

63

49

30

50 2

62

14

51

61

40

37 7

48

55

41

16

18

17

46

33

24

57

21

12

36

56

19

39

43

60 5

53

22

42 4

29

45

23

28

32

44

52

35 6

54 8

47 3 1

26

31 9

25

10

Hospital number

% p

atie

nts

wit

h H

AI

Mean prevalence: 7.1% [0%-23%]

30

Use of Results at European Level

Hypothetical figures!

31

European Surveillance of Veterinary Antimicrobial Consumption

(ESVAC)

Initial investigation (September 09 December 09)

Pilot project (2009-2011) Development and implementation of protocol and data collection form (template) to obtain harmonized dataCollecting data accordingly from MS willing to participate

ESVAC is managed by the European Medicines Agency (EMA)

32

EMA-ESVACAntibiotic Use in Animals in Europe

www.belvetsac.ugent.be

Data 2007

Grave et al. JAC, 65:2037-40, 2010

33www.belvetsac.ugent.be

Antibiotic Use in Animals in Belgium and the Netherlands

0

50

100

150

200

250

2007 2008 2009 2010 2011

mg

act

ive c

om

po

un

d/

kg

b

iom

ass

The Netherlands

Belgium

Lineair (The Netherlands)Lineair (Belgium)

3434

35

35 40% E. coli resistant for ceftiofur 60% of broilers carrier of ESBL

Belgian broilers

Persoons et al., 2010

36

68 6848

30 26 2412 6 6 6 4 2 2 2

020406080

100Percentage

Pig

Herds

Frequency of Use of Antimicrobial Compounds in Belgian Fattening Pig Herds

(n=50) in 2010

Callens et al. Prev Vet Med , 106:53-62, 2012

37

Targets and Interventions

38

39

40

Scottish ESAC 2009 PPS

Hospitals included: 31Patients included: 8,732Treated patients: 28%Areas of good practice:- Greater use of narrow spectrum antimicrobials

compared to the rest of Europe

Areas where improvement is required:- Indication documented: 76% (target: 95%)- Compliance with NHS Board guidelines: 58% (target:

95%)- Surgical prophylaxis greater than one day: 30%- Cephalosporins for surgical prophylaxis: 40%

William Malcolm, Health Protection Scotland, Report March 2010

41

Results Scotland Empirical Prescribing

National compliance 83% and 4/14 NHS boards achieved target2011 - need to focus on improvement

42

Awareness

43

Belgian National Public Campaigns

When: since November 2000, annually during winter seasonOrganised by: BAPCOC (Belgian Antibiotic Policy Coordination Committee)Budget:- 400,000 EUR/annual campaign

Interventions targeting the public:- Ads on TV, radio and newspaper- Information booklets- Folders- Posters- Internet campaigns: www.antibiotics-info.be

44

Outpatient Antibiotic Use in Belgium in Packages per 1,000 Inhabitants

per Day July - June

46

Outpatient Antibiotic Use in Belgium in DDD per 1,000 Inhabitants

per Day July - June

47

Trends of the Relative Outpatient Use of Antibiotic Subgroups in

Belgium (1997-2009).

48

49

Slogans & logos

50

Images from National Campaigns on Prudent Use of Antibiotics

51

52Earnshaw S, et al. Euro Surveill 2009;14(30) &http://antibiotic.ecdc.europa.eu

2008 - Materials for general public- 32 countries participated

2009- Materials for primary care

prescribers- Website translated in all EU

languages, three TV spots developed

- 34 countries participated

2010- Materials for hospital prescribers- 36 countries participated

2011-2012- Consolidation

EAAD, 2008-2012

53

47%49%

4%

n=476

Print Online Newsagency

Number of clippings 476

Reach (print) 51,334,208Circulation (print) 17,152,770Visits (online) 54,241,600

Key Figures

Coverage in the Course of Time

EAAD 2010Media coverage

Media Type Media Distribution

53

33%

17%

48%

2%

n=476

local regional national international

CW 40 CW 41 CW 42 CW 43 CW 44 CW 45 CW 46 CW 47 CW 48 CW 49 CW 50 CW 51

Newsagency 0 0 0 0 0 0 20 0 0 0 0 0

Online 0 0 0 1 0 2 219 6 4 1 2 0

Print 1 0 1 2 3 9 122 55 12 9 6 1

0

100

200

300

400Peak Week 46

15.11 16.11 17.11 18.11 19.11 20.11 21.11

Newsagency 2 6 10 2 0 0 0

Online 6 70 74 40 24 4 1

Print 2 12 25 52 26 4 1

0

20

40

60

80

100

120

54

Eurobarometer Opinion Poll, November-December 2009

Antibiotics kill viruses. True or false?% respondents with correct answer

73%)

Special -Dec. 2009.

61 73%

41 60%

31 40%

21 30%

14 20%

55

The United States and Canada joined in 2010

Hong Kong joined in 2011

Australia joined in 2012

56

Research

57

EU Research Project Funding

FP5 (1999-2002)100+ million for 80 mainly

smaller projects on antimicrobial resistance

FP6 (2003-06)186 million for fewer, larger

and more focused projects

FP7 (2007-13)273 million by 2012;

antimicrobial resistance is a key priority

More than560 million

In 2013, research into antimicrobial resistance will be a priority area!

58

Public Funding for Research (Source : ERA Key Figures 2007, EC)

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

Ger

man

y

Fran

ce UK

Italy

Spai

n

EU C

omm

unity

Net

herla

nds

Swed

en

Belg

ium

Finl

and

Aust

ria

Den

mar

k

Portu

gal

Irela

nd

Pola

nd

Gre

ece

Cze

ch re

p.

Hun

gary

RO

man

ia

Slov

enia

Slov

akia

Bulg

aria

Luxe

mbo

urg

Lith

uani

a

Esto

nia

Cyp

rus

Latv

ia

Mal

ta

Chi

na

Japa

n

Uni

ted

Stat

es

Mio

Eur

o

Research Funding in the EU and US

EU27 + ECTransnational Collaboration

in EU 27: 10 to 15 %SINCE 1999: APPROXIMATELY 350

MILLION EURO ON AMR (1/3 IC; 1/3 ABU; 1/3 NEW TARGETS)

Competitive Federal Funding

in US : 85 to 90 %VERY LITTLE ON AMR?

59

Joint Programming

The overall aim of Joint Programming is to align national research efforts in order to make better use of Europe's precious public R&D resources and to tackle common European challenges more effectively in a few key areas.

It may involve collaboration between existing national programmes or the setting up of entirely new ones.

60

Joint Programming on AMR

Countries: BE, CH, CZ, DE, DK, ES, FI, FR, GR, IT, NL, NO, PL, RO, SE, TK, UK

Management Board (funding organisations)

Scientific Advisory Board (experts)

Strategic Research Agenda 2020 and beyond (DL date: December 2013)

Calls for proposals

Complements EU level funding

61

Members of the SAB

Herman Goossens (Chair) Antoine Andremont Fernando BaqueroMarc BontenYehuda CarmeliNiels Frimodt-MøllerBruno Gonzalez-Zorn Hajo GrundmannStephan HarbarthBirgitta Henriques NormarkPatrice Nordmann Arnfinn SundsfjordTim Walsh Paul Williams

62

Mission Statementof the SRA

The JPI on AMR will develop integrated approaches to pursue unique world-class research on AMR that will be translated into new prevention and intervention strategies that improve the public health and wellbeing of populations, and delivers economic and societal benefit throughout Europe and beyond.

63

Innovative Medicines Initiative:the Largest Public-Private

Partnership n Life Sciences R&D

2 Billion Euro

1 Billion 1 Billion

Public PrivatePartnership

EFPIA = European Federation of Pharmacological Industries and Associations

64

New Drugs 4 Bad Bugs (ND4BB)COMBACTE

Combating Bacterial Resistance in Europe

65

The future of COMBACTECLIN-, LAB- and STAT-Net

The EORTC is both multinational and multidisciplinary, and the EORTC Network comprises over 300 hospitals and cancer centers in over 30 countries which include some 2,500 collaborators from all disciplines involved in cancer treatment and research.

66

Setting sail for Horizon 2020

Europe needs cutting edge research and innovationEssential to ensure competitiveness, growth and jobsVital to tackle pressing societal challenges 3% of GDP invested in R&D: headline target of Europe 2020

67

Horizon 2020 Timeline

From 30/11 Parliament and Council negotiations on the basis of the Commission proposalsOngoing Parliament and Council negotiations on EU budget 2014-20 (including Horizon 2020)By end 2013 Adoption of legislative acts by Parliament and Council on Horizon 2020 January 2014 Horizon 2020 starts; launch of first calls

68

International K.O. Mouse Consortium

International Cancer Genomics Consortium

Continued International Cooperation

International Human Metagenome Consortium

International Human Epigenome Consortium

International Rare Disease Research

Consortium

Int. Initiative for Traumatic Brain Injury

Research

© rtguest/Fotolia.com

69

Why is Europe (Partially) Successful in Controlling AMR?

Bottom up Member States initiatives (e.g. rotating European presidencies) resulting in top down political support and commitment at European level (e.g. Council recommendations);Successful surveillance programmes on antimicrobial use and resistanceStrong leadership with close link between opinion leaders, policy makers and politicians Support of AMR research projects by the EC, providing evidence for public health interventionsEuropean antibiotic awareness day (EAAD), built on success stories of countries;

Carbapenemase producing Enterobacteriaceae: A global major public health threat ?

Y. Glupczynski

National Reference Center for multidrug-resistant EnterobacteriaceaeCHU Mont-Godinne, Yvoir, Belgium

MONT-GODINNE

Escalating antimicrobial resistance in Enterobacteriaceae

• Enterobacteriaceae = large family of bacteria (+/- 60 genera) human/animal commensals (intestine), environment (water/soil, sewage), pathogens (strict or opportunistic)

Principal species: Serratia, Citrobacter, Enterobacter, Proteus, Morganella, K. pneumoniae, E. coli (75-90% of non complicated UTIs)

Involved in health-care associated infections (e.a. K. pneumoniae, Enterobacter sp)

β-lactam agents: have been used widely for treatment of infections caused by Enterobacteriaceae since the 70-80’sWorldwide emergence of community-acquired ESBL+ strains since the early 2000’sCarbapenems: last resort antimicrobial agents for the treatment of ESBL+ infectionSince 1993: Emergence of first carbapenem-R isolates due to production of carbapenemasesTherapeutic dead-end (Almost no reserve/new drugs in the pipelines)Use of colistine (nephrotoxicity), tigecycline (inconstant activity, bacteriostatic), sometimesaztreonam (depends on type of carbapenemase, and absence of other concomitant resistance mechanisms)

Carbapenemases-Enterobacteriaceae

Reservoirs

With courtesyFrom P. Nordmann

Class BGroup 3

AmpC TEM/SHVCTX-M, KPC

OXASPM, GIM, SIM

CephsInhib-R

Pens, CephsInhib-S

Pens (Oxa++)Inhib-R/S

CarbapenemsInhib-R

K Bush, curr. Opin. Invest. Drugs 3-1284 (200

Cephalosporinases Penicillinases, ESBLs, Carbapenemases Carbapenemases

• Plasmid encoded (mobile through various genetic elements: transposons, integrons)• R to carbapenems (variable level of R) and to most other ß-lactams• Variable susceptibility to beta-lactamases inhibitors (depending on carbapenemase type)• Often co-resistant to other classes of antibiotics (aminoglycosides, trimethoprim, quinolones)

Serine ß-lactamases

Metallo-enzymes

What are carbapenemases ?

Class CGroup 1

Class DGroup 2d

Class AGroup 2

IMP, VIM, NDM

Classification of the differentcarbapenemases in Enterobacteriaceae

With courtesy from P. Nordmann

Acquired carbapenemases

• IMP- and VIM- types are integron associatedOXA-48 and KPC are IS and transposon associated

Association of carbapenemase-encoding geneswith various genetic mobile elements and different

plasmids

KPC

VIM

IMP

NDM

OXA-48 type

Transposons

integrons

Truncated IS

KPC-2 + SHV-12 + SHV-11 + OXA-9 + TEM-1 + aminoglycosides + quinolones…Colistine / Tigecycline / Fosfomycin) often remain the only active agents)

CPE often associated with several othermechanisms of resistance

KPC type

Ranges of carbapenem MICs observed in clinical isolates producing acquired

carbapenemases

MICs (mg/L)

Organism/enzyme type Imipenem Meropenem Ertapenem

Pseudomonas aeruginosa / MBLPseudomonas aeruginosa / KPCAcinetobacter baumanii / MBL

2- >64>642- >64

2- >64>322- >64

---

Acinetobacter baumannii / OXA 1- >64 1- >64 -

Enterobacteriaceae / MBL 0.5- >64 0.25- >64 0.5- >32

Enterobacteriaceae / KPC 0.5- >64 1- 64 0.5- >64

Enterobacteriaceae / OXA-48 1- >64 0.5-64 4->64

Adapted from V. Miriagou et al. Clin Microb Infect 2010; 16:112-122and from P. Nordmann; Arch Ped 2010; 17: S156-S162

Increased mortality with Infections caused by KPC producers

• A high invasive-device score was a predictor of CRE isolation (P=0.02).• The mortality in the CRE group was 33%, compared to 9% among controls (P =0.043)• Delay in effective therapy was found to increase the length of hospitalization amongsurvivors (34+/-3.2 days versus 26.5 +/- 5.4 days; P 00.2)

Why are carbas in the top chart of ß-lactamases?

•Case patients were more likely than control patients to die during hospitalization (48% vs 20%; P < .001) die from infection (38% vs 12%; P < .001).

• The timely administration of antibiotics with in vitro activityagainst CR-KP was not associated with patient survival.

KPC: Klebsiella Pneumoniae Carbapenemase

Source: Patrice Nordmann, Thierry Naas, and Laurent Poirel . Global Spread of Carbapenemase producingEnterobacteriaceae. Emerging Infectious Diseases , October 2011: Vol. 17, No. 10, pp. 1791-1798.

Mortality rate: > 50%

OXA-48 : OXAcillinase

Source: Patrice Nordmann, Thierry Naas, and Laurent Poirel . Global Spread of Carbapenemase producingEnterobacteriaceae. Emerging Infectious Diseases , October 2011: Vol. 17, No. 10, pp. 1791-1798.

CPE in Europe and different types of carbapenemases by country

(epidemiological scale of nationwide expansion)

R. Canton et al. Clin Microbiol Infect 2012; 18: 413–431

OXA-48 carbapenemase (Class D)

Plasmid-mediated resistanceMostly in Klebsiella spp. (E. coli)

Turkey, India, North AfricaUK, France, Belgium (since 2010)

Variable level of resistance to carbapenems(meropenem MICs <0.5->128)

Susceptible to 3-4 gen cephs when not Associated with other mechanisms

Resistance to penicillins (temocillinincl.); no effect of BL inhibitors

Difficult to detect (low-level R, algorithms of Expert systems not adapted)

CLSI <2010 CLSI 2010 EUCAST 2010

S R S R S RImipenem <4 >16 <1 >4 <2 >8Meropenem <4 >16 <1 >4 <2 >8Ertapenem <2 >4 <0.25 >1 <0.5 >1Doripenem NA NA <1 >4 <1 >4

Carbapenem breakpoints in Enterobacteriaceae

Disk diffusion suceptibility of CPE isolates to meropenem (CLSI guidelines 2012)

0

2

4

6

8

10

12

6 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 32 33 34 35 38

Meropenem disk inhibition diameter (mm)

n is

olat

es

VIM

KPC

OXA-48

No CPE

50% of the OXA-48 CPE isolated received by the NRCare susceptible to meropenem ‘zone by CLSI interpretive criteria

Combined tests for detection and recognition of type of carbapenemases

MER: meropenem aloneDPA: +dipicolinic acid 1,000 μgBOR: + boronic acid 600 μgCLX: + cloxacillin 750 μg

β-lactamase Inhibited byEDTA/DPA Boronic acid Cloxacillin

MBL Y N NKPC/class A carbapenemases

N Y N

OXA-48 N N NESBL N N NAmpC N Y Y

Detection of carbapenemase producersas colonizers of the intestinal flora

Gold standard: molecular biology +++

Multiplex PCR; IMP, VIM, KPC, OXA-48, NDM….

NDM-1, KPC, AmpC and ESBL Check-MDR CT101*

NDM-1 KPC, OXA-48, VIM, IMP and ESBL Check-MDR CT102*

Molecular tests: commercial tests

(Naas et al. AAC, 2010; JCM, 2011)

Mass spectrometry (MALDITOF)

Carbapenem hydrolysis: « Carba NP test »

Nordmann P, Poirel L, Dortet L. Rapid detetion of Carbapenemase-producing Enterobacteriaceae.

•Carbapenem hydrolysis pH change color change

•2 hours (incubation at 37°C)•Sensitivity 100%, specificity 100%•Low cost

Possible strategies for the use ofthe Carba NP test for detection of carbapenemases

- Rapid (<2h), simple and inexpensivetest

- Direct from colonies on the antibiogramculture plate

- From colonies of a selective screeningplate (18-24 h before AST results)

-> Results > 24 h earlier than AST

Potential interest:-Screening in outbreak setting-Epidemiologic surveillance

(selection of isolates to be sent for Confirmation and characterization of CPE)

Nordmann et al., EID; 18(9) 2012

Year Evolution2007 Sporadic cases of CPE in 2008

September 2008

Imported through transfert (Greece):

K. pneumoniae,type VIM-1

June 2010 Imported (Pakistan & Balkan countries):

E. coli,type NDM-1

Since 2010 Rapid emergence of carbapenem-resistant isolates (I/R) aux and/orcarbapenemase producing Enterobacteriaceae species.

Early reports of CPE in Belgium (2008-2010)

23

Risk Assessment Group (13/10/2011)

[email protected] (1/1/2012)

Confirmation de CPE (CNR) et signalement de cas à l’Institut Scientifique

de Santé Publique (ISP)

Recommandations pour établissements de soins &

guidelines

Résistance aux carbapénèmes

Etudes: épidémiologie

des CPE (prévalence,

incidence dans différents

secteurs de soins)CNR + ISP

Réalisation d’études

complémentaires

National alerts of Public Health authorities and actions

Centre National de Référence (CNR)

24

Number of CPE cases: 1/1 /2012 - 31/10/2012

25

June OctoberNr laboratories reporting ≥ 1 CPE cases: 32 56 Nr episodes of CPE 66

Distribution of bacterial species and types of carbapenemases involved:1/1 – 31/10/2012

SOUCHES DE CPE CONFIRMEES

Type de carbapénémase Cas de CPE

Type d’entérobactérie OXA-48 KPC-2 VIM-1 NDM GES IMI OXA-48 + VIM

nombre %

Klebsiella pneumoniae 242 32 4 1 1 280 73.5

Escherichia coli 25 1 2 28 7.4

Enterobacter cloacae 18 0 7 2 1 28 7.4

Citrobacter freundii 13 4 1 18 4.7

Klebsiella oxytoca 11 2 3 16 4.2

Enterobacter aerogenes 2 2 0.5

Serratia marcescens 1 1 0.3

Hafnia alvei 1 1 0.3

Morganella morganii 1 1 0.3

Providencia rettgeri 1 1 0.3

Plusieurs entérobactéries 5 5 1.3

n. total de souches 318 35 19 6 1 1 1 381

% 83.5% 9.2% 5.0% 1.6% 0.3% 0.3% 0.3% 100%

OXA-48 KPC-2 VIM-1 NDM TOTAL*Nombre de patients 318 35 19 6 381Age moyen (min-max)

76.4 a. (1-101)

73.4 a. (24-88)

62.1 a. (31-92)

53.3 a. (19-81)

75 a. (1-101)Sex ratio (H/F) 0.84 1.4 1.6 5 0.92

Indications /contexte pour le prélèvement (données pour 375 patients)Contexte de dépistage

58.3% 17.7% 44.4% 83.3% 54.7%Contexte clinique 41.7% 82.3% 55.6% 16.7% 45.3%Site anatomique prélevé (échantillons cliniques seulement) (données pour 169 patients)Urines 59.2% 50.0% 60.0% 57.4%Respiratoire 18.5% 28.6% 10.0% 19.5%Plaies, pus 10.0% 7.1% 8.9%Sang (hémoculture) 3.9% 3.6% 10.0% 1/6 4.7%Plusieurs sites 5.4% 3.6% 4.7%Autres sites 3.1% 7.1% 20.0% 4.7%Statut infectieux des patients CPE+ (données pour 366 patients)Colonisation 63.2% 34.4% 55.6% 83.3% 60.7%Infection 36.8% 65.6% 44.4% 16.7% 39.3%

Characteristics of CPE+ Patients

* Total: incluant les patients positifs pour GES, IMI, OXA+VIM 27

OXA-48 KPC-2 VIM-1 NDM TOTAL*Nr of patients 318 35 19 6 381Hospitalisé ou ambulant (at time of detection of CPE) (data for 374 patients)Hospitalized–Ambulatory

91.4% -8.6% 90.9% -9.1% 94.4% - 5.6% 100% - 0% 91.7% -8.3%

Hospital unit (at time of detection of CPE) (data for 338 patients)ICU, burn, oncology 19.9% 46.7% 82.4% 16.7% 25.7%Geriatrics 42.6% 13.3% 37.0%Medicine 21.3% 33.3% 33.3% 21.3%Surgery 9.9% 3.3% 17.7% 33.3% 10.1%Others, several 6.4% 3.3% 16.7% 5.9%Patients CPE+ with hospitalisation in Belgium- Foreign countries (data for 216 patients)Hospitalization/stay abroad countries

7.3% 30% 16.7% 66.7% 13%

Recent stay in Belgian hospital / NH

56.4% 40% 41.7% 16.7% 51.4%

No previous stay in hospital / NH

36.4% 30% 41.7% 16.7% 35.7%

Traitement récent avec des anti-infectieux (data for 120 patients) Recent AB exposure 83.9% 86.4% 100% 66.7% 84.2%

Characteristics of CPE +

* Total: including patients positive for GES, IMI, OXA+VIM carbapenemases28

CPE + Patients :Link with hospitalization / stay in foreign countries (n=28)

29

Infected: 44%Colonized: 56%

Countries Nr OXA-48 KPC-2 VIM-1 NDM OXA+VIMGreece 6 5 1Turkey 6 5 1Egypt 3 1 1 1India 3 3Italy 3 3Morocco 3 3Senegal 1 1Thailand 1 1Tunisia 1 1Vietnam 1 1TOTAL 28 12 9 2 4 1

30

Number CPE cases:31/10/2012 (n=381 cas) ,

Association with foreign countries(n=28 cases)

5 labos, lien avec étranger4 (66.7%)

1

2

6

1 1

2

KPC-2(n=35)

VIM-1(n=19)

OXA-48(n=318)

16 labos, lien avec étranger: 9 (25.7%)

NDM-1(n=6)

1

15

1 7

2

2

1

1


1

5

1 3 1

1


OXA-48(n=318)

31

OXA-48: Evolution from 1/1 to 31/10/2012

< 10 cas

10 à 49 cas

≥50 cas

Nombre de cas cumulés:

32

KPC-2: Evolution from 1/1 to 31/10/2012

6/10 cases linked to hospitalization

in countries abroad 1/16 cas linked to

abroad countries:7 hospitals

< 10 cas

10 à 49 cas

≥50 cas

Nombre de cas cumulés:

2H

4H

Interim guidelines - High Council of Health• Level 1: basic- Admission screening (all wards): patients transfered from hospitals from

foreign countries- If strain suspect: send to NRC (confirmation) + case reporting (IPH)

meanwhile: - standard precautions (all patients in the unit)- isolation of suspect case + contact precautions- list potential contacts + communicate if transfered

• Level 2: ≥ 1 secondary case (infected/colonised) with epidemiologic link in the unit:

- Multidisciplinary outbreak management team- List up and collect epidemiological data (all colonised/infected cases)- Screening all contacts + routine 1/week all patients in the unit + admission

screening in high risk units- Send strains to NRC (confirmation) + case reporting (IPH)- AB-policy: general policy + treatment of CPE infections- Control implementation of standard and additional precautions in the unit(s)- Limit transfer of cases (other wards, other hospital, nursing home,..)

• Level 3: if additional cases- Cohort nursing staff, admission stop in the unit, avoid/limit transfers

34

Limiting the impact of carbapenemases

• Detect resistance rapidly in the clinical laboratory– Test more than one carbapenem agent (mero, erta)– Use more than one single method (manual + automates)– MIC testing (for clinical purposes)– Phenotypical confirmatory tests (synergy tests with carbapenemase

inhibitors, …)– Reference laboratory support (molecular tests)– Development of new rapid tests

• Identify infected/colonized patients. Essential for:– Appropriate patient management– Rapid implementation of infection control procedures

• Prevents onwards cross-transmission

Recommended control measures for preventing the spread of CPE

• General recommendation– Improved sanitary measures in the outpatient setting (+long term

facilities)

• Strongly suggested– Limitation of patient transfer between healthcare facilities– Active screening of patients transferred from a high-risk institution/country– In-hospital contact precautions and cohorting for already colonized

patients (+dedicated nursing staff in case of outbreak in acute institutions)

• Also recommended, but effectiveness unclear– Application of antibiotic stewardship programmes– Restricted use of any broad-spectrum antibiotics (fluoroquinolones,

broad-spectrum cephalosporins and penicillins, and carbapenems)– Avoid unnecessarily long duration of antibiotic treatment– Promotion of hand hygiene– Environmental surface decontamination– Decolonization of patients with antiseptic bathing– Education of healthcare personnel– Closure or reduced activity of high-risk units (uncontrolled outbreaks)

Recommended control measures for preventing the spread of CPE

Acknowledgements

UCL Mont Godinne• Pierre Bogaerts• Daniel Huang• Caroline Bauraing• Catherine Berhin• Amélie Guisset • Warda Boucharhouf• Roberta Rezende

Hôpital ULB-Erasme • Ariane Deplano• Ricardo De Mendonca• Olivier Denis• Sandrine Roisin• Claire Nonhoff

Hôpital de Bicêtre, Paris• Thierry Naas• Gaelle Cuzon• Laurent Poirel• Patrice Nordmann

Institute of Public Health• Bea Jans• Boudewijn Catry

Belgian Infection controlSociety (BICS)

MONT-GODINNE

Measles outbreak 2011

Europe & Belgium

Prof. Dr. Patrick Goubau

Dr Carole Schirvel

1

Outline

• Introduction• Measles in Europe • Measles in Belgium• Lessons learned in Fédération Wallonie

Bruxelles

Measles Virus ~14 days until rashappears

sneezing, cough, saliva

One genetic serotype – same basic vaccine worldwide

WHO Manual for the laboratory diagnosis of measles and rubella virus infection. WHO/IVB/07.01

www.niaid.nih.gov

R0 = 15-20

coverage 95% MMR 2 doses

2

Clinical PresentationRhinitis, conjunctivitis, Koplik spotsFever & maculopapular rash

Infectious period4 days before to 4 days after rash onset

Complications in wellresourced countries

Otitis media (7-9%)Pneumonia (1-6%)Diarrhea (8%)Blindness, corneal scarring (1%)Acute Encephalitis (1/1000)Subacute Sclerosing Panencephalitis(1/100.000) - always fatalDeath (1-10/10.000)

Plotkin et al. Vaccines

• Committee Established in January 2003 in Belgium• Set up action plan

– Measles: 2004, Rubella: 2006 – updates every 2 years

• Participants– Measles experts (laboratory, epidemiologists)– Representatives of the communities

• Meeting 2 or 3 times a year– Follow-up of the activities & recommendations

WHO European RegionElimination of measles and rubella in by 2015

3

Oral fluid testing developed

• Non-invasive• Less painful• Easy to perform• Safe• Time point of sampling and

conservation very important

Max. 5 days after start rashGenotyping

Max. 7 days after start rashPCR (virusdetection)

7-28 days after start rashIgM

Hutse V et al. 2010, IJID

email:[email protected]://nrchm.wiv-isp.be


Bruxelles

4

Measles incidence (per million) WHO European Region

Source: WHO EURO

2010

2011

European measles outbreakthreat to children

5

Vulnerable populations

Euvac.net. Measles surveillance annual report 2010

Komitova R, et al. Euro Surveill. 2011;16(15). Parent du Châtelet I et al. Euro Surveill. 2010;15(36)

•Differences in European Region: who these vulnerable population are

•Reasons for not immunization are different

•Tailored approaches needed

6


Bruxelles

0

100

200

300

400

500

600

700

800

900

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010

Inci

denc

e of

mea

sles

* 10

0 00

0

MMR1

MMR1

Measles in Belgium

1982-1999: Sentinel network of GPs2002: PediSurv

sentinel network of pediatricians2009: Mandatory reporting

Surveillance

7

Measles cases in Belgium since 2007-2012 (Sept)

In 2007-2008: > 130 measles cases in Orthodox Jewish Families in Antwerp

In 2011 at least 566 cases

In 2012 (Sept): 94 casesLernoutT et al. Euro Surveill. 2009; 14(2) Sabbe M et al. Euro Surveill. 2011;16(16):

0

20

40

60

80

100

120

140

160

J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S O N D J F M A M J J A S

2007 2008 2009 2010 2011 2012

n 6 98 33 40 566 94

Was this outbreak unexpected?Prevalence (%) of seronegativity against measles (<150mIU/ml) (red) per

age group, Belgium, 2006

Theeten et al. Epidemiol Infect. 2011 Apr;139(4):494-504.

« WHO Elimination targets not met »

National coverage Belgium (2006-2009):MMR 1st dose: 94,5% MMR 2nd dose 83,1%

8

Vaccination status of MMR vaccine of measles

cases by age group, 2011

Measles incidence by age group, 2011

0,0

10,0

20,0

30,0

40,0

50,0

60,0

< 1 1-4 5-9 10-14 15-19 20-29 30+

Age Group (years)

Inci

denc

e/10

0 00

0

0

10

20

30

40

50

60

70

< 1 1-4 5-9 10-14 15-19 20-29 30+

Age Group

N

not vaccinated 1 dose 2 doses

Reasons for non-vaccination?• Most cases were not vaccinated • ⇐ Age < 1 year: n=64 • ⇐ For cases > 1 year, reasons for non-vaccination

(n=195):– Circumstantial 17%– Allergy 2%– Unknown 23%

Advise of homeopathic doctor 7%Anthroposophic beliefs 24%

Parental decision 27%

9

Hospitalisation - Complications• 26% hospitalisations • Hospital duration: range 1 – 14 days (median 4

days)• 31 pulmonary complications, 1 followed by septic

shock• 1 encephalitis • no deaths

Laboratory confirmation – Genotype

MVs/Ghent.BEL/09.11/1/[D4]

MVs/Brussels.BEL/08.11/[D4]

Genotype D4

activities 2011-2012• 24/03/2011 meeting of Committee for elimination of Measles & Rubella (start outbreak in Ghent

50 cases)• 04/04/2011 informative letter to hospital laboratories & hygienists (about 100 cases)• 04/04/2011 press-communication to health care professionals and to general public leading to

several interviews• 06/04/2011 Early Warning and Response System (EWRS) message• 21/04/2011 publication Eurosurveillance (about 150 cases)• 23 to 30/04/2011 European Immunization Week: active communication by communities• 05/2011 two publications in Vlaams Infectieziektenbulletin (about 230 cases)• 5 and 15/05/2011 two parliamentary questions on measles• 18/05/2011 presentation St Pierre• 27/05/2011 2nd EWRS message (adopted measures)• 10/06/2011 extra meeting of Committee (about 380 cases)• 28/06/2011 recommendations of Superior Health Council on immunization• 18/07/2011 informative letter from reference laboratory on testing during outbreak situation• 09/2011 publication in Noso Info (about 480 cases)• 21/09/2011 poster presentation European Society Clinical Virology (about 520 cases)• Monthly updates for Belgium• 17/01/2012 meeting of Committee for elimination of Measles & Rubella• 21/03/2012 EU teleconference: UEFA football championship and Olympic Games • 04/2012 press communication• 21/05/2012 meeting of Committee for elimination of Measles & Rubella

10


Bruxelles

MMR1 and MMR2

0

200

400

600

800

1000

1200

1400

1982 1984 1986 1988 1990 1992 1994 1996 1998

Inci

denc

e/10

0 00

0

Vlaamse Gemeenschap Communauté française

11

Coverage MMR1 and MMR2

Provac, ULB

Incidence of Measles cases per 1 000 000 population, Belgium, 2011

Brabant Wallon: 127/ million

Hainaut: 83/million

None of provinces < 1measles case/million population

WIV-ISP

12

MMR2 vaccination coverage

Provac, ULB

Measles cases in Fédération Wallonie Bruxelles: where contact?

N=30N=35

N>20 N=9

N=9

N>3

Concentration of susceptible in some sub-population groups “pockets of under-immunised population” but different reasons for non vaccination

13

Public health interventions whenmeasles case is notified

• Notification through MATRA/Telephone• Case confirmed/epidemiological link?• Laboratory confirmation needed?• Define the exposed collectivity (crèche, hospital, work…)• Identify exposed infividuals, ad risk groups with

collection of additional information (age, vaccinationstatus)

• Determine immunization status of close contacts• Proposition of vaccination if appropriate• Discuss possibility of immunoglobulins• Discuss of isolation measures• Communication to schools, parents, medical staff…

Recommandations for Laboratoryconfirmation changed during outbreakElimination context (non-epidemic) :> National Reference Laboratory• Saliva test : IgM/IgG , Viral detection,

Genotyping• Naso-pharyngal : Viral detection, Genotyping

Epidemic context :> Any Laboratory (importance of timeliness) • Serum : Specific IgM and IgG

NRL in case of Babies < 2yrsVaccinatedImmunocompromised and pregnant womenTravelatypical/severe cases

14

Challenges•Commitment needed: Competing priorities for the health system, economic crisis•Increasing momentum of vaccine refusals:

•General complacency in absence of diseas (low risk perception), variablepublic trust•Anti-vaccination movement•Refusal due to religious/philosophicreasons

•Unrecognized pockets of un/underimmunized vulnerable groups

Lessons learned

– Increasing the coverage (> 95%) with two doses of MMR vaccine needed– Need for sero epidemiological studies in order to identify the non-protected groups on time– Need for catch-up campaigns to address identified susceptible population groups/cohorts– Strengthening measles surveillance and vaccine coverage monitoring – Improving the communications – with the general public, with medical specialists and with the most vulnerable

Mumps, an update of the outbreak

in Flanders

28th Seminar on

diagnosis and surveillance

of infectious diseases

Wim Flipse

arts infectieziektebestrijding

Gent

mumps

Clinical criteria Any person with

Fever AND at least one of the following three:

Sudden onset of unilateral or bilateral tender swelling of the parotid or other salivary glands without other apparent cause Orchitis Meningitis

Laboratory Criteria At least one of the following three:

Isolation of mumps virus from a clinical specimen Detection of mumps virus nucleic acid Mumps virus specific antibody response characteristic for acute infection in serum or Saliva

Laboratory results need to be interpreted according to the vaccination status Epidemiological Criteria

An epidemiological link by human to human transmission ECDC

Case definition

A. Possible case Any person meeting the clinical criteria B. Probable case Any person meeting the clinical criteria and with an epidemiological link C. Confirmed case Any person not recently vaccinated and meeting the laboratory criteria In case of recent vaccination: any person with detection of wild-type mumps virus strain ECDC

Epidemic curve mumps in Flanders

0

20

40

60

80

100

120

140

160

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41number of the week

RVL

OV

AN

student parties Ghent

Start notification Flanders

festival Werchter

The facebook page

Blue =our register Red =facebook Purple=both registers Green= estimate according to capture-recapture method

0

50

100

150

200

250

9 10 11 12 13 14 15 16 17 18 19 20

Unknown cases estimated by capture-recapture method

0

10

20

30

40

50

60

70

week 38 week 39 week 40 week 41 week 42 week 43 week 44 week 45 week 46

oost-vlaanderen

west-vlaanderen

vlaams-brabant

limburg

antwerpen

Number of mumps cases by province

164

This year already 1700 cases notified

Distribution of mumpscases bij agegroup and sex

0

50

100

150

200

250

300

0- 9 10-14 15-19 20-24 25-29 30+

MF

years

Questionnaire (preliminary results)

Complaints/symptoms

Complications Vaccination status

Days of illness

Responsrate questionnaire 59%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

fever swellingparotis

unilateralswelling

bilateralswelling

headache fatigue

symptomatology mumpscases

days of illness

Obs Mean Median Mode 0- 9 years 39 6,1 5 3

10-14 years 12 5,4 5 5 15-19 years 89 8,2 8 10 20-24 years 137 8,2 7 7 25-29 years 38 11,6 10 10 30+ years 66 10,5 10 14

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

confirmedcases

hospitaladmission

meningitis orchitis confirmedcases

hospitaladmission

meningitis orchitis

before and after notification

11-6-2012

0

20

40

60

80

100

120

140

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29age

number of cases of mumps by year of age

MBR 2

MBR 1

Vaccinated according to questionnaire agegroup 15-24 years of age

n % N not vaccinated 11 4,7 232 1x MBR 61 26,3 232 2x MBR 156 67,2 232

subset of agegroup 12 to 16 years of age 2x MBR agreement questionnaire versus data Vaccinnet Kappa=0,78 (n=30)

Two years of HPV vaccination Two years of HPV vaccination in Flandersin Flanders

Karel Hoppenbrouwers (KU Leuven)Anouk Vanlander (VWVJ)

Diagnose en Surveillance van Infectieuze Aandoeningen28e seminarie – 22 november 2012

WIV-ISP

Content of the presentation

HPV-infections en HPV-vaccines

HPV vaccination in Flanders

HPV vaccination in Europe

Key factors for success

HPV-infections and pathology

There is an epidemiologic association between HPV-infection and cervical cancer (and the preceding intraepithelial lesions)

There is an epidemiologic association between HPV-infection and anogenital tumors and condylomataaccuminata

High risk HPV-infection is a necessary but not sufficient condition to develop cervical cancer

HPV-infections are very common and largely acquired soon after the onset of sexual activity

Cumulative proportional contribution of 8 HPV-types to cervical cancer in Europe and N-America (Arbyn, 2007)

65,4%

71.5%

77.1%

81.2%

84.1%

85.6%

86.8%

87.8%

100.0% +12.2%

+1.0%

+1.2%

+1.5%

+2.9%

+4.1%

+5.6%

+6.1%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Other

HPV 52

HPV 35

HPV 56

HPV 45

HPV 31

HPV 33

HPV 18

HPV 16

The virus

The capside consists of two protein molecules

‘late proteins’: L1 en L2

The genome of the virus codes for ‘early proteins’: E1, E2, en E4 t.e.m. E7

Virus-like particles (VLP)

• Neutralising epitopes are located upon the L1 capsularprotein

• Neutralising epitopes are expressed throughyeastcells/insectcells, resulting in VLP’s efficientlyexpressing the neutralising epitopes

• VLP’s resemble the round virion capsules, without DNA

• VLP’s induce antibody production without replication →no risk of infection or cancer

The vaccines

GARDASIL® CERVARIX®

TYPE VACCINE VLP L1 protein VLP L1 protein

COMPOSITION

VECTOR FOR PRODUCTION

ADJUVANS

SCHEME

PRODUCER

HPV 6 20µgHPV 11 40µgHPV 16 40µgHPV 18 20µg

Yeast cells

Al hydroxyde sulfate

0-2-6 months

Sanofi Pasteur MSD

HPV 16 20µgHPV 18 20µg

Insect cells

ASO4

0-1-6 months

GlaxoSmithKline

Health CouncilRecommendation 2007 (update 2008)

Systematic cervical screening must be continued and coverage of target groups increased

Yearly general profylactic vaccination of one birth cohort of girls between 10 and 13 years of age

Single profylactic (catch-up)vaccination campaign of additional cohorts until the age of 15 years (included) should be considered

Vaccination can be offered by the threating physician to all virgin female adolescents and young adults (14-26 years of age)

On the discretion of the threating physician vaccination can be offered on indivual basis to non-virgin female adolescents and young adults (14-26 years of age)

Implementation in Flanders

Profylactic vaccination of girls of the first year of secondary education, since September 2010

Catch-up vaccination through partial reimbursement of three doses 12 to 15 years of age (since 1 May 2008), 12 to 18 years of age (since 1 December 2008)

Individual vaccination of women > 18 years of age

Implementation strategy in Flanders

Collaboration• School Health Services, GPs, pediatricians, gynaecologists• In accordance with the strategy for HBV vaccination of pre-

adolescents

Communication• Leaflets for boys and girls, disseminated through school

health services• Agency website with FAQ’s• Letters to vaccinators with up-to-date information

Registration in Vaccinnet

Vaccination coverage in Flanders

First estimation of coverage of opportunistic vaccination in 13-14 year old girls, one year after launch of Belgian Superior Health Council recommendations (May 2007)

Study of the vaccination coverage in Flanders 2008 (Hoppenbrouwers et al., 2009)

• Birth cohort of girls: 1994• Data collection in April-May 2008 (WHO-EPI method)• Estimated coverage (compared to HBV in cohort 1994) :

25.0% at least 1 dose (HBV1: 92.5%)18.7% at least 2 doses (HBV2: 91.0%)4.2% at least 3 doses (HBV3: 89.2%)

Vaccination coverage in Flanders

First estimation of coverage in a cohort of 12 years old girls targeted for free of charge prophylactic vaccination (schoolyears 2010-2011 and 2011-2012)

HPV vaccination in Flanders (2010-2012) (Top & Paeps, 2012)• Birth cohorts of girls: 1998 and 1999• Vaccinnet: 1 September 2010 - 31 August 2012• Estimated coverage for cohorts 1998 and 1999, respectively

86.1% and 87.8% at least 1 dose84.8% and 86.6% at least 2 doses79.8% and 81.6% at least 3 doses

• 97% of doses registered by School Health Services• Slight underestimation of real coverage since not all GP’s

make use of Vaccinnet

HPV-vaccination programmes in other European countries with coverage data

17% (2009)PrivateNational healthLuxemburg

58% (2011)PHNational healthNetherlands

55% (2011)SHSNational healthSlovenia

63% (2011)SHSNational healthNorway

64% (2011)50% PH, 50% SHSNational healthSpain

65% (2011)PHNational healthItaly

84% (2011)PHNational healthPortugal

80% (2009)94% SHSNational healthUK

Countries Financing vaccine Delivery strategy Coverage (3 doses)

Flanders National health 90% SHS > 80% (2010-2012)

Denmark National health PH 79% (2011)

France 65% national health 95% private 24% (2008)

Germany National health 95% private 10% (2011)

Adapted from ECDC Guidance – Introduction of HPV vaccines in European countries – an update – September 2012

Key factors of success – The Netherlands

Gefenaite G et al. Waarom ging de eerste ronde HPV-vaccinatieprogramma mis? Infectieziekten Bulletin 2011,22(5)

Reasons for refusal mentioned by parents:Information of governement was to brief and subjectiveLack of confidence in reaction of governement in case of side effectsIgnorance about effectivity of vaccineConcern about side effectsIgnorance about HPV-infectionsConviction government is influenced by industryReligious constraints

Key factors of success

Tailored and timely information for girls/boys, their parents and vaccinators – about disease burden of HPV-infection– about the vaccination programme– about the safety and effectiveness of the vaccine

Implementation through public health and/or school health services, in close collaboration with other vaccinating professionals

Vaccinnet as a tool for ordering and registration of vaccines, also linking all vaccinators to the same vaccination programme

Key factors of success - Germany

18 Jänner 2008Expertise zeigt HPV-Impfung "mögliche" Ursache für Tod der Studentin

In 2007, two young women died - one in Germany, one in Austria - shortly after being vaccinated against HPV. Although no causal relationship between HPVvaccination and death was established in either case, reports of these two deaths in the popular press markedly lessened public confidence in the safety of the HPV vaccine. The vaccination rate among 12- and 13-year-old girls, at one time 40%, has dropped to about 10%.

New Screening Practices for HIV.

Katrien FransenARL-ITM / WHO CC

Diagnose en surveillance van infectieuze aandoeningen.WIV/ISP22/nov/2012

OUTLINE

• Current • New • Breach recommendations• Conclusions

Current HIV Screening Practices

• Peripheral laboratories. If reactive -> confirmed in one of the 7 ARLs

-> + notification under code to IPH

• Tests: serological HIV ab and/or ag-EIA (enzyme immunoassays)-CII (chemiluminescent immunoassays)-Simple / rapid (immunoassays or

agglutination assays)

Evolution of HIV Immunoassays since 1985

1st generation Sensitivity % Specificity %Purified HIV lysates 99 95-99

2nd generationRecombinant proteins and/or synthetic peptides 99.5 99

3rd generation or sandwich ELISAsLabelled antigen as conjugateDetect Ab >99.5 >99.5

4th generation or DUO assaysDetect Ag and Ab without differentiation >99.8 >99.8orDetect Ag and Ab with differentiation

Laboratory Markers in HIV Seroconversion

Unknown Status (literature)

• Many people are unaware of their HIV infection (asymptomatic) 15-50% ECDC- WVDBerghe (ITM): Venue based HIV prevalence study among MSM (flanders).14 %, fingerprick (DBS)

• Individuals that are aware engage less in risky behaviors related to sex and IDU.

- Risk of transmission 3.5 X higher

Unknown Status (literature)

• Many people are unaware of their HIV infection (asymptomatic) 15-50% ECDC- WVDBerghe (ITM): Venue based HIV prevalence study among MSM (flanders).14 %, fingerprick (DBS)

• Individuals that are aware engage less in risky behaviors related to sex and IDU.

- Risk of transmission 3.5 X higher

• Why ?- Personal perception of not being at risk of HIV- Fear of a possible positive result- Belonging to marginalised, stigmatised groups in society;

HIV Testing a Matter of Time

• Early diagnosis is essential: timely referral of patients for treatment and care

• Early treatment reduces morbidity and mortality• People diagnoses early may be less likely to

transmit the virus• Early diagnosis remains a critical public health

priority.

What is New?

• At the level of sampling, type of specimen- Finger prick (DBS), OF, self sampling…

• At the level of tests- POC tests, Simple Rapid tests (VCT)

• Combined - OF tests combined with SR and/or ELISA

Simple/Rapid Tests

Principles• Agglutination assays

• Immunofiltration assays (flow through)

• Immunochromatographic assays (lateral flow through)

• Dipsticks

SRTests (new?)

More than 100 different assays (WHO procurement list).serum, plasma, whole blood.

www.who.int/diagnostics_laboratory/en

Two 4th generation tests with WHO label:- SD BiolineTM HIV Ag/Ab Combo test (Standard diagnostics) - DetermineTM HIV-1/2 Combo (Alere)

Only one 4th generation tests CE label:- DetermineTM HIV-1/2 Combo (Alere)

SRTests with CE Label

Test kit name Supplier

Determine™ HIV-1/2 Alere

LaboQuick Anti HIV1/2 Test kit LaboQuick Turkey

Genie ™ Fast HIV1/2 Bio-Rad Laboratories

VIKIA HIV1/2 rapid test Bio Mérieux

ImmunoComb™ Alere/Orgenics, Ltd

INSTI™ HIV Antibody Biolytical Laboratories

Uni-Gold™ HIV Trinity Biotech

…

…

Determine ™ HIV-1/2 Ag/Ab Combo Rapid Test Kit Alere

Helpcenter ITM: Determine Ab/Ag

Year Test (n) HIV + (n) HIV + (%)

2006 203 4 2,00%

2007 493 0 0,00%

2008 792 10 1,30%

2009 1160 15 1,30%

2010 1278 11 0,90%

2011 1384 16 1,20%

totaal 4989 56 1,10%

CE Label Criteria: HIV Screening AssaysELISA Panel Criteria

Sensitivity (Ab) 400 HIV1 (40 nB),100 HIV2

100%

20 commercial panels, 10 extra panels

State of the art

Analytical senstivity no

Specificity 5000 blood donations200 hospitilized p,100 poss cross react

≥ 99.5%≥ 99 %

Simple / rapid

Sensitivity (Ab) id 100%

Analytical sensitivity no

Specificity 1000 blood donations,200 clinic specimens,200 pregn women,100 poten interfering

≥ 99 %

CE Label Criteria: HIV Screening Assays

Ag Panel Criteria

Sensitivity 50 HIV-1,50 SN (HIV-1, HIV-2),20 seroconversion panels

Correct identification

State of the art

Analytical sensitivity

International Standard < 50 pg/ml

Specificity 200 blood donations,200 clinical samples,50 pos interfering

≥ 99,5%

Analytical sensitivity of Ag detecting testsTest Analytical sensitivity (pg p24 ag/ml)

Vidas HIV DUO Ultra 11,5

Vidas HIV Duo Quick 13

Genscreen HIV Ag/Ab Ultra 13

Architect HIV1/2 Combo 18

Modular HIV Combi, Elecsys 126,5

AxSYM HIV1/2 Combo 21

Cobas Core HIV Combi 29

Murex HIV Combo 29

Genscreen Ag/Ab Plus 140

Vironostika HIV Uniform II Ag/Ab 150

Enzygnost HIV integral 160

Coulter HIV P24 15,7

Innotest HIV Ag mAb 9,3

HIV P24 Core 14,2

Additional Requirements for Ab/Ag

• Claims for single p24 detection

-> CE label for 4th generation tests is not sufficient-> WHO label id

Extra evaluations are needed !OrMore stringent acceptance criteria for 4th

generation tests

New: Oral Fluid Tests (no Ag)

- SRT (CE, FDA): OraQuick Advance Rapid HIV-1/2Cons: expensive (40$-60$), 3rd generation, variable in quality ? (NY), IQC and EQC ?

- Conventional ELISA using OF

18

Study ITM: Using Conventional HIV tests for HIV diagnosis on OF Specimens.

M &M: 302 HIV pos and HIV neg, OF (Oracol) versus serum

3 EIA: Vironostika HIV Ag/Ab, Enzygnost Anti HIV ½ Plus and Genscreen HIV

Samples tested at three different timepoints between 1-7 daysInfluence of drinking water just before sampling

Results: - protocol was optimized and new cut off calculation was established for each of the tests. Genscreen no change.

Other tests double sample volume

7days,Lowest misclassification rate

Sensitivity % (CI 95%) Specificity % (CI 95%)

Vironostika 97.8 (92.3 – 99.4) 100 (98.2 – 100)

Enzygnost 97.8 (92.3 – 99.4) 99.5 (97.3 – 99.9)

Genscreen 100 (95.9 – 100) 97.6 (94.5 – 99.0)

Proposed HIV Testing Algorithm using Oral Fluid Specimen

Ongoing Studies using OF at ITM

• SIALON II: European HIV/STI prevalence study (Brussels) in Gay venues (MSM)-OF + EIA (Genscreen HIV-1/2 v2 and Vironostika HIV Uni- form II Ag/Ab)-Serum (HIV incidence, Syphilis, Heb B, Heb C)

• TOL 2: Improving HIV diagnosis by using oral fluid tests in outreach settings. Swab 2 Know.-high risk population in Antwerp (MSM, SAM)

-OF self sampling, send to ARL Antwerp-webbased communication of the result and counseling

New: Home Testing, Self Testing, Self sampling.

Home testing

Pro Autonomy, less risks if status is known…Cons Expensive, no proved, consistant quality, obscure companies,

no CE label, ethical issues, link with care (for counseling and treatment)?

Self sampling

Pro Link with care, conventional tests, cheep, consistant quality,..

Cons Ethical issues…

22

Test, link and treat : the reality.The spectrum of engagement in HIV care in the United States spanning from HIV acquisition to full engagement in care, receipt of antiretroviral

therapy, and achievement of complete viral suppression. We estimate that only 19% of HIV-infected individuals in the United States have

an undetectable HIVload.

Gardner et al. CID 2011

Recommendations of BREACH

• Belgian HIV prevention summit Sept 28-29• Breack out session B on HIV testing strategies

Recommendation 1

1)Develop national Belgian guidelines for testing based especially on HIV indicator conditions and implement them in health care settings (GP and specialists)Set up of a sub working group to assess cost-

effectiveness for all testing procedures (standard and rapid tests) in Belgium.

Recommendation 2

2) About the type of HIV test-Fourth generation standard screening test must be mandatory for all laboratories in Belgium (80%).-Different ways/methods/type of tests should be explored for different target groups.

Recommendation 3

3) About the use of rapid tests

•3rd and 4th generation rapid tests are currently used in VCT screening centers and outreach programs•Rapid test has to be confirmed on blood•More 4th generation rapid tests with CE label are needed

•There is a need for regulatory rules, policy framework, specific legislation+ implementation of quality assurance guidelines to enable the use of rapid tests in Belgium•In a high risk population: the use of rapid test must be well prepared

(made by medical staff or not?, pre/post test counselling, confidentiality, location…)If rapid test are used outside VCT centers, need to implement/improve a link to care for reactive rapid tests Reimbursement to be discussed

Incentives for GPs are needed

• OF tests (only antibodies)-One is CE labeled and FDA aproved:

Oraquick Advance rapid HIV test-Can be recommended in some case (home testing) but they are expensive and need more evaluations about consistant quality (false negative)

Recommendation 4

4) About education on HIV testing/prevention-Training of the GPs (pre-counselling, confidentiality, post-test counselling, partner notification…-Training of the specialists-Training of the patients (treatment often perceived as an ‘enemy’ longer life expectancy, better quality of life,…-Breaking down the taboo about HIV (discrimination, reduce the fears about HIV tests,..) and the treatment

Last but not least.

• Need to develop tools for risk assesment and for self risk assesment (web). Ugent. Prof Dirk Avonts.

Conclusions

In order toGet more people tested, aware of their status and treated•Improve current screening practices (at all levels)•Study all aspects of new screening technologies, maintain link with care ->Get the prevalence down (1000 new infections/y)