Scaling up testing and counselling as itlooks from treatment data monitoringperspectives: The applied researchoutcomes and the policy implications itgenerates – Dutch experience

Frank de WolfHIV Monitoring FoundationAmsterdam, The Netherlandswww.hiv-monitoring.nl

Outline• HIV Monitoring Foundation & HIV counselling and testing• HIV/AIDS in the Netherlands• Antiretroviral treatment• Impact on the epidemic• Impact of time between infection and HIV diagnosis

HMF and T&C

Death

DataData

New Diagnosed cases New AIDS casesNew Infections

Data

HMF is involved in HIV care, collects data from patients followed inone of the 24 HIV treatment centres in the country and monitorschanges in the course of infection and the epidemic

Testing and counselling:

• HIV treatment centres (counselling: specifically trained nurses)

• STD out-patient facilities (municipal health services; counselling:specifically trained nurses; anonymous testing available)

• General practitioners (primary care physicians)

HIV and AIDS current situation in theNetherlands

● Less AIDS ● Less Death ● More Infections

Less AIDS and death

• Highly active antiretroviraltherapy (HAART) wasintroduced in 1996 asstandard of care for thetreatment of HIV

• Before HAART, HIV wastreated with on or acombination of two anti-HIVdrugs, with a limited effect.

0

100

200

300

400

500

600

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

DeathsAIDS cases

De Boer et al., RIVM 2006Sources AIDS: AIDS registration Health Inspectorate <2000, HMF ≥2000.Sources deaths: CBS <2002, HMF ≥2002.• After introduction of

HAART, the number ofAIDS diagnoses and HIVdeath declined

Ten years HAART in the Netherlands

1. How many are infected?2. How many infected are registered?3. How many got AIDS?4. How many died?5. How many are treated?6. And not treated?7. What’s the effect of HAART on the epidemic?

How many are infected?

18.500 (10.000-28.000)2005 estimate:Op de Coul & Van Sighem, 2006

18.500 HIV infected persons

0.00%

0.05%

0.10%

0.15%

0.20%

0.25%

1980 1985 1990 1995 2000 2005 2010

Prev

alen

ce (%

) adu

lts

Op de Coul & Van Sighem

• HIV prevalence amongst adults (age 15-49): 0.23%• Amongst MSM: 5.3%• Amongst iv drug users: 5.3%• Amongst CSW: 2.7%

How many HIV positives are registered?

18.500 (10.000-28.000)Number HIV+:Op de Coul & Van Sighem, 2006

12.059As per mid 2006:Gras et al, 2006

12059 patients are registered

• In 2005 964 new HIVdiagnoses

• In total 9254 men and 2699women >13 years of age

• In addition: 106 boys andgirls ≤13 years

• Percentage of men isincreasing since 2003

• Main risk group: MSM

0

200

400

600

800

1000

1200

19801982

19841986

19881990

19921994

19961998

20002002

20042006

year of HIV diagnosis

N

0

2 0

4 0

6 0

8 0

1 0 0

19831985

19871989

19911993

19951997

19992001

20032005

year of diagnosis

%% male% female

How many got AIDS?

18.500 (10.000-28.000)Number HIV+:Op de Coul & Van Sighem, 2006

12.059N registered:Gras et al, 2006

3.468At or after HIVdiagnose:Gras et al, 2006

3468 AIDS diagnoses• 2048 new AIDS diagnoses from 6

weeks after HIV diagnosis• 1598 after 1996• Average AIDS incidence: 2.9/100

person-years• In 1996: 9.6 and in 2005: 2• Since 2003 no major changes• 1066 AIDS diagnoses after start

HAART• AIDS incidence after start HAART

decreases sharply from 14.8 in1996 to 2.06 in 2005.

• Number of AIDS diagnoses in2005: 276

AIDS incidence per 100 person-years

0

5

10

15

20

calendar year1996 1998 2000 2002 2004 2006

AIDS incidence per 100 person-years

0

5

10

15

20

calendar year1996 1998 2000 2002 2004 2006

After HIV diagnosis

After start of HAART

Time to death within 3 years of startingHAART according to CDC-Cclassification

0.1

1

10

100

PM

LNH

LDE

MM

AC

HSV PN

RKS

AIS

OTO

XW

AS

ECA

CM

VTB

CM

YC CRS

PCP

CRC

HR

(95%

CI)

Model adjusted for calendar year of starting HAART, CD4 cell count and HIV RNAat starting HAART, age, gender and transmission risk group. Hazard ratio’s of thespecific CDC-C diseases are relative to no CDC-event.

PML: Progressive multifocalleucoencephalopathy

NHL:Non-Hodgkin lymphomaDEM: AIDS dementia complexMAC: Mycobacterium

avium/kansasiiHSV: Herpes simplex virusPNR: Recurrent pneumoniaKSA:Kaposi’s sarcomaISO: IsosporidiasisTOX: Toxoplasmosis of the

brainWAS: Wasting syndromeECA: Oesophageal candidiasisCMV: Cytomegalovirus diseaseTBC:TuberculosisMYC: Atypical Mycobacterium

infectionCRS: CryptosporidiosisPCP: Pneumocystis carinii

pneumoniaCRC: Extrapulmonar

Cryptococcosis

How many died?

18.500 (10.000-28.000)Number HIV+:Op de Coul & Van Sighem, 2006

12.059N registered:Gras et al, 2006

3.468AIDS:Gras et al, 2006

985Since 1996:Gras et al, 2006

985 deaths• Av mortality ratio: 1.48 per 100

person-years• Mortality in the total group

does not change: 1.16 in 1996and 0.84 in 2006

• Mortality is still higher ascompared to the non-infectedpopulation, but comparable toother chronic diseases

• In total 854 deaths after startof HAART

• Mortality declines after start ofHAART from 4.4 in 1996 to 1.54in 2005.

mortality per 100 person-years

0

1

2

3

4

5

6

7

calendar year1996 1998 2000 2002 2004 2006

mortality per 100 person-years

0

1

2

3

4

5

6

7

calendar year1996 1998 2000 2002 2004 2006

Mortality after HIV diagnosis

Mortality after start of HAART

Causes of death

• In 1996:• 76% HIV related• 10% non HIV related• 14% unknown

• In 2005:• 39% HIV related• 50% non HIV related• 11% unknown 0%

20%

40%

60%

80%

100%

1996 1998 2000 2002 2004 2006

calendar yearp

rop

ort

ion

non-HIV-related

HIV-related

unknown

Standardised Mortality Ratio

• SMR r : patient has r times higher probability of death than anon-infected individual

0

5

10

15

20

25

20 30 40 50 60 70age [years]

SMR

CD4=200CD4=350CD4=600SMR=1NL diabetesUK diabetes

0

5

10

15

20

25

20 30 40 50 60 70age [years]

CD4=200CD4=350CD4=600SMR=1NL diabetesUK diabetes

women men

Source diabetes data: Baan et al., Epidemiology 2004;Laing et al., Diabet Med. 1999

Predicted survival probability

• Predicted probability to reacha specific age for anasymptomatic male patientdiagnosed at the age of 34.

• Probability to reach age of 70• 72% non-infected• 68% CD4 600 cells/mm3

• 67% CD4 350 cells/mm3

• 65% CD4 200 cells/mm3

• 58% CD4 50 cells/mm3

0

0.2

0.4

0.6

0.8

1

30 40 50 60 70 80 90 100

age [years]

suriv

al p

roba

bilit

y

uninfectedHIV CD4 600HIV CD4 350HIV CD4 200HIV CD4 50

How many patients are (not) on HAART?

18.500 (10.000-28.000)Number HIV+:Op de Coul & Van Sighem, 2006

12.059N registered:Gras et al, 2006

3.468

985Deaths:Gras et al, 2006

8292In 1996:Gras et al, 2006

Untreated: 2136

AIDS:Gras et al, 2006

8292 HAART treated: Virological effect

• After the first 24 weeks ofHAART, the amount of HIVin blood has declined 3logs

• 80% are below thedetection threshold

• 388/5304 naïve patientsshow viral rebounds afterinitial success

• Incidence of viral reboundis 3.2 per 100 person-yearsof follow-up

0

1

2

3

4

5

6

diagnos is s ta r tHAART

24 wks 48 wks

log

HIV

-RNA

co

pies

/ml

plas

ma

a l lIQRIQR

Immunological effect of HAART

• Patients continuously onHAART do show anincrease of CD4 cells frommedian 221/mm3 at startto 607/mm3 after 7 yearsof treatment

• The highest increase isseen in the first 24 weeksand levels off thereafter

• The increase does notdiffer between baselinegroups

050

100150200250300350400450500

0 48 96 144 192 240 288 336Weeks from starting HAART

Diff

eren

ce fr

om b

asel

ine

(cel

ls/m

m3)

<50 50-200 200-350 350-500 >500

• In older patients and patients with viral rebounds after start ofHAART the increase in CD4 cells is less.

HIV resistance in treated patients

• HAART failure decreased inART experienced patients

• Amongst naive patients thepercentage of HAARTfailures increased slowly

• In 80% of the patientsexperiencing virologicalfailure during treatmentresistance is found

pre-treatednaïve

fraction patients failing on therapy

0.0

0.1

0.2

0.3

0.4

0.5

0.6

kalenderjaar1996 1998 2000 2002 2004 2006

• However: Resistance is measured in only 17% of the patientswith virological failure during HAART

Transmission of resistant HIVnewly diagnosed

B

percentage resistant

0102030405060708090

100

year of diagnosis1995 2000 2005

number of sequences

0

50

100

150

200

250

recent infections

A

percentage resistant

0102030405060708090

100

year of infection1995 2000 2005

number of sequences

0

10

20

30

40

50

60

70• In 6.0% of the recentinfections one or moremutations associated withresistance are found

• 3 patients with high-levelresistance; 1 to all drugclasses

• Since 2001 resistance isfound in 7.7% of the new HIVdiagnoses

• In 14 patients high-levelresistance

Effect of HAART on the epidemic?

0

100

200

300

400

500

600

1980 1985 1990 1995 2000 2005

Num

ber

of

of

inci

dent

HI

V ca

ses 0

100

200

300

400

500

1995 2000 2005year of diagnosis

num

ber

of d

iagn

oses

homosexual menhetero Mhetero FIDU

• After the initial decreasefollowing the introductionof HAART, the number ofnew HIV diagnosesincreased again, especiallyamongst MSM

• The relative high CD4 cellcounts found at diagnosisindicate that these newcases reflect more recentHIV infections

• The HIV epidemic seems togrow amongst MSM

37%

Model Framework

Death

DataData

New Diagnosed cases New AIDS cases

Estimate

New Infections

Data

Time to diagnosis

Reducedriskbehaviour

Treatment, haltsprogression andonwards transmission

Magnitude and timing constrained by risk-behaviour and time to diagnosis

Simultaneous fitting, can estimate both theseparameters

Risk-behaviour

HIV concentration over time

1

2

3

4

5

6

7HI

V

conc

entr

atio

n (l

og)

weeks months

HIV concentration over time (treated)

1

2

3

4

5

6

7HI

V

conc

entr

atio

n (l

og)

weeks months

Predictions pastNo HAART, R = 1.5

No earlier diagnosis, R = 1.2

No increase in risk, R= 0.6

No changes, R = 0.9

Model fit, R = 1.1

0

2000

4000

6000

8000

1994 1996 1998 2000 2002 2004Year

Cum

ulat

ive

infe

ctio

ns

0

2000

4000

6000

8000

1994 1996 1998 2000 2002 2004Year

Cum

ulat

ive

infe

ctio

ns

3684 infectionsHAART has prevented 4165 infectionsIncreased risk has caused 2099 extra infections

0

2000

4000

6000

8000

1994 1996 1998 2000 2002 2004Year

Cum

ulat

ive

infe

ctio

ns

Faster diagnosis has prevented 562 infections

0

2000

4000

6000

8000

1994 1996 1998 2000 2002 2004Year

Cum

ulat

ive

infe

ctio

ns

0

2000

4000

6000

8000

1994 1996 1998 2000 2002 2004Year

Cum

ulat

ive

infe

ctio

ns

Had there been no changes (“no HAART”), therewould have been 699 fewer infections

Predictions future

No changes, R = 1.1

Proportion failing halved, R = 1.0

Risk as pre-HAART, R = 0.6

Average diagnosis of 1 year, R = 0.9

All three interventions, R = 0.5

0

2000

4000

6000

8000

10000

2004 2006 2008 2010 2012 2014Year

Cum

ulat

ive in

fect

ions

Conclusions

• Sharp decline ofthe number ofAIDS diagnosessince introductionof HAART

• Mortality hasdecreased sinceHAART

• There is an increasein new HIV infections,especially amongstMSM

● Less AIDS

• AIDS definingillnesses seemto change andare assocatedwith survival

• Percentage of HIVrelated causes ofdeath has declined

• Mortality amongstHIV positives isstill higher ascompared tot nonHIV infectedpersons

• Transmission ofresistant HIV is stilllimited

● Less death ● More infections

Conclusions

• HAART only slowed down but not retract the HIV epidemic• Reduction of risk behaviour together with HAART have

resulted in retraction of the epidemic in the Netherlands• Through its effect on behavioural changes, timely diagnosis

adds to this retraction• Prevention, focussed on reducing transmission risk

behaviour was and remains crucial in reducing the HIVepidemic

• In the Netherlands, testing & counselling should again focuson high risk behaviour with the aim to in time provideeffective antiretroviral treatment for those tested positive andto achieve substantial impact on the epidemic

Testing & Counselling should beeffective

Why testing? Timely accessto treatment

Opportunity to timelychange risk behaviour

Impact on theepidemic

Next to risk behaviour,transmission depends on theamount of HIV circulating ininfected population

unaware aware

untreated treated

+

AcknowledgementsTreating physicians (*Site coordinating physicians) Dr. W. Bronsveld*, Drs. M.E. Hillebrand-Haverkort, Medisch Centrum Alkmaar, Alkmaar; Dr. J.M. Prins*, Dr. J.Branger, Dr. J.K.M. Eeftinck Schattenkerk, Dr. S.E. Geerlings, Drs. J. Gisolf, Dr. M.H. Godfried, Prof.dr. J.M.A. Lange, Dr. K.D. Lettinga, Dr. J.T.M. van der Meer, Drs.F.J.B. Nellen, Dr. T. van der Poll, Prof dr. P. Reiss, Drs. Th.A. Ruys, Drs. R. Steingrover, Drs. G. van Twillert, Drs. J.N. Vermeulen, Drs. S.M.E. Vrouenraets, Dr. M. vanVugt, Dr. F.W.M.N. Wit, Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam; Prof. dr. T.W. Kuijpers, Drs. D. Pajkrt, Dr. H.J. Scherpbier, EmmaKinderziekenhuis, AMC, Amsterdam; Drs. A. van Eeden*, St. Medisch Centrum Jan van Goyen, Amsterdam; Prof. dr. K. Brinkman*, Drs. G.E.L. van den Berk, Dr. W.L.Blok, Dr. P.H.J. Frissen, Dr. J.C. Roos, Drs. W.E.M. Schouten, Dr. H.M. Weigel, Onze Lieve Vrouwe Gasthuis, Amsterdam; Dr. J.W. Mulder*, Dr. E.C.M. van Gorp, Dr. J.Wagenaar, Slotervaart Ziekenhuis, Amsterdam; Dr. J. Veenstra*, St. Lucas Andreas Ziekenhuis, Amsterdam; Prof. dr. S.A. Danner*, Dr. M.A. van Agtmael, Drs. F.A.P.Claessen, Dr. R.M. Perenboom, Drs. A. Rijkeboer, Dr. M.G.A. van Vonderen, VU Medisch Centrum, Amsterdam; Dr. C. Richter*, Drs. J. van der Berg, ZiekenhuisRijnstate, Arnhem; Dr. R. Vriesendorp*, Dr. F.J.F. Jeurissen, Medisch Centrum Haaglanden, locatie Westeinde, Den Haag; Dr. R.H. Kauffmann*, Drs. K. Pogány, HagaZiekenhuis, locatie Leyenburg, Den Haag; Dr. B. Bravenboer*, Catharina Ziekenhuis, Eindhoven; Dr. C.H.H. ten Napel*, Dr. G.J. Kootstra, Medisch Spectrum Twente,Enschede; Dr. H.G. Sprenger*, Dr. W.M.A.J. Miesen, Dr. J.T.M. van Leeuwen, Universitair Medisch Centrum, Groningen; Dr. R. Doedens, Dr. E.H. Scholvinck, UniversitairMedisch Centrum, Beatrix Kliniek, Groningen; Prof. dr. R.W. ten Kate*, Dr. R. Soetekouw, Kennemer Gasthuis, Haarlem; Dr. D. van Houte*, Dr. M.B. Polée, MedischCentrum Leeuwarden, Leeuwarden; Dr. F.P. Kroon*, Prof. dr. P.J. van den Broek, Prof. dr. J.T. van Dissel, Dr. E.F. Schippers, Leids Universitair Medisch Centrum, Leiden;Dr. G. Schreij*, Dr. S. van der Geest, Dr. S. Lowe, Dr. A. Verbon, Academisch Ziekenhuis Maastricht; Dr. P.P. Koopmans*, Dr. R. van Crevel, Prof. dr. R. de Groot, Dr. M.Keuter, Dr. F. Post, Dr. A.J.A.M. van der Ven, Dr. A. Warris, Universitair Medisch Centrum St. Radboud, Nijmegen; Dr. M.E. van der Ende*, Dr. I.C. Gyssens, Drs. M. vander Feltz, Dr. J.L Nouwen, Dr. B.J.A. Rijnders, Dr. T.E.M.S. de Vries, Erasmus Medisch Centrum, Rotterdam; Dr. G. Driessen, Dr. M. van der Flier, Dr. N.G. Hartwig,Erasmus Medisch Centrum, Sophia, Rotterdam; Dr. J.R. Juttman*, Dr. C. van de Heul, Dr. M.E.E. van Kasteren, St. Elisabeth Ziekenhuis, Tilburg; Prof. dr. I.M.Hoepelman*, Dr. M.M.E. Schneider, Prof. dr. M.J.M. Bonten, Prof. dr. J.C.C. Borleffs, Dr. P.M. Ellerbroek, Drs. C.A.J.J. Jaspers, Dr. T. Mudrikova, Dr. C.A.M. Schurink, Dr.E.H. Gisolf, Universitair Medisch Centrum Utrecht, Utrecht; Dr. S.P.M. Geelen, Dr. T.F.W. Wolfs, Dr. T. Faber, Wilhelmina Kinderziekenhuis, UMC, Utrecht; Dr. A.A. Tanis*,Ziekenhuis Walcheren, Vlissingen; Dr. P.H.P. Groeneveld*, Isala Klinieken, Zwolle; Dr. J.G. den Hollander*, Medisch Centrum Rijnmond Zuid, locatie Clara, Rotterdam; Dr.A. J. Duits, Dr. K. Winkel, St. Elisabeth Hospitaal/Stichting Rode Kruis Bloedbank, Willemstad, Curaçao; Virologists Dr. N.K.T. Back, M.E.G. Bakker, Prof. dr. B. Berkhout,Dr. S. Jurriaans, Dr. H.L. Zaaijer, Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam; Dr. Th. Cuijpers, CLB Stichting Sanquin Bloedvoorziening,Amsterdam; Dr. P.J.G.M. Rietra, Dr. K.J. Roozendaal, Onze Lieve Vrouwe Gasthuis, Amsterdam; Drs. W. Pauw, Dr. A.P. van Zanten, P.H.M. Smits, SlotervaartZiekenhuis, Amsterdam; Dr. B.M.E. von Blomberg, Dr. P. Savelkoul, Dr. A. Pettersson, VU Medisch Centrum, Amsterdam; Dr. C.M.A. Swanink, Ziekenhuis Rijnstate,Arnhem; Dr. P.F.H. Franck, Dr. A.S. Lampe, HAGA ziekenhuis, locatie Leyenburg, Den Haag; C.L. Jansen, Medisch Centrum Haaglanden, locatie Westeinde, Den Haag;Dr. R. Hendriks, Streeklaboratorium Twente, Enschede; C.A. Benne, Streeklaboratorium Groningen, Groningen; Dr. D. Veenendaal, Dr. J. Schirm, StreeklaboratoriumVolksgezondheid Kennemerland, Haarlem; Dr. H. Storm, Drs. J. Weel, Drs. J.H. van Zeijl, Laboratorium voor de Volksgezondheid in Friesland, Leeuwarden; Prof. dr.A.C.M. Kroes, Dr. H.C.J. Claas, Leids Universitair Medisch Centrum, Leiden; Prof. dr. C.A.M.V.A. Bruggeman, Drs. V.J. Goossens, Academisch Ziekenhuis Maastricht,Maastricht; Prof. dr. J.M.D. Galama, Dr. W.J.G. Melchers, Y.A.G. Poort, Universitair Medisch Centrum St. Radboud, Nijmegen; Dr. G.J.J. Doornum, Dr. H.G.M. Niesters,Prof. dr. A.D.M.E. Osterhaus, Dr. M. Schutten, Erasmus Medisch Centrum, Rotterdam; Dr. A.G.M. Buiting, C.A.M. Swaans, St. Elisabeth Ziekenhuis, Tilburg; Dr. C.A.B.Boucher, Dr. R. Schuurman, Universitair Medisch Centrum Utrecht, Utrecht; Dr. E. Boel, Dr. A.F. Jansz, Catharina Ziekenhuis, Eindhoven; Pharmacologists Dr. A.Veldkamp, Medisch Centrum Alkmaar, Alkmaar; Prof. dr. J.H. Beijnen, Dr. A.D.R. Huitema, Slotervaart Ziekenhuis, Amsterdam; Dr. D.M. Burger, Dr. P.W.H. Hugen,Universitair Medisch Centrum St. Radboud, Nijmegen; Drs. H.J.M. van Kan, Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam; HIVMonitoring Foundation Governing Board 2006 Drs. M.A.J.M. Bos, treasurer (from July 2006), ZN; Prof. dr. R.A. Coutinho, observer, RIVM; Prof. dr. S.A. Danner,chairman, NVAB; Prof. dr. J. Goudsmit, member, AMC-UvA; Prof. dr. L.J. Gunning-Schepers, member, NFU; Dr. D.J. Hemrika, secretary, NVZ; Drs. J.G.M. Hendriks,treasurer (until July 2006), ZN; Drs. H. Polee, member, Dutch HIV Association; Drs. M.I. Verstappen, member, GGD; Dr. F. de Wolf, director, HMF; Advisory Board Prof.dr. R.M. Anderson, Imperial College, Faculty of Medicine, Dept. Infectious Diseases Epidemiology, London, United Kingdom; Prof. dr. J.H. Beijnen, Slotervaart Hospital,Dept. of Pharmacology, Amsterdam; Dr. M.E. van der Ende, Erasmus Medical Centre, Rotterdam; Dr. P.H.J. Frissen (until February 2006), Onze Lieve Vrouwe Gasthuis,Dept. of Internal Medicine, Amsterdam;

AcknowledgementsProf. dr. R. de Groot, Sophia Children’s Hospital, Rotterdam; Prof. dr. I.M. Hoepelman, UMC Utrecht, Utrecht; Dr. R.H. Kauffmann, Leyenburg Hospital, Dept. of Internal Medicine,Den Haag; Prof. dr. A.C.M. Kroes, LUMC, Clinical Virological Laboratory, Leiden; Dr. F.P. Kroon (vice chairman), LUMC, Dept. of Internal Medicine, Leiden; Dr. M.J.W. van de Laar,RIVM, Centre for Infectious Diseases Epidemiology, Bilthoven; Prof. dr. J.M.A. Lange (chairman), AMC, Dept. of Internal Medicine, Amsterdam; Prof. dr. A.D.M.E. Osterhaus (untilFebruary 2006), Erasmus Medical Centre, Dept. of Virology, Rotterdam; Prof. dr. G. Pantaleo, Hôpital de Beaumont, Dept. of Virology, Lausanne, Switzerland; Dhr. C. Rümke, DutchHIV Association, Amsterdam; Prof. dr. P. Speelman, AMC, Dept of Internal Medicine, Amsterdam; Working group Clinical Aspects Dr. K. Boer, AMC, Dept. ofObstetrics/Gynaecology, Amsterdam; Prof. dr. K. Brinkman (vice chairman), OLVG, Dept of Internal Medicine, Amsterdam; Dr. D.M. Burger (subgr. Pharmacology), UMCN St.Radboud, Dept. of Clinical Pharmacy, Nijmegen; Dr. M.E. van der Ende (chairman), Erasmus Medical Centre, Dept. of Internal Medicine, Rotterdam; Dr. S.P.M. Geelen, UMCU-WKZ, Dept of Paediatrics, Utrecht; Dr. J.R. Juttmann, St. Elisabeth Hospital, Dept. of Internal Medicine, Tilburg; Dr. R.P. Koopmans, UMCN-St. Radboud, Dept. of Internal Medicine,Nijmegen; Prof. dr. T.W. Kuijpers, AMC, Dept. of Paediatrics, Amsterdam; Dr. W.M.C. Mulder, Dutch HIV Association, Amsterdam; Dr. C.H.H. ten Napel, Medisch Spectrum Twente,Dept. of Internal Medicine, Enschede; Dr. J.M. Prins, AMC, Dept. of Internal Medicine, Amsterdam; Prof. dr. P. Reiss (subgroup Toxicity), AMC, Dept. of Internal Medicine,Amsterdam; Dr. G. Schreij, Academic Hospital, Dept. of Internal Medicine, Maastricht; Drs. H.G. Sprenger, Academic Hospital, Dept. of Internal Medicine, Groningen; Dr. J.H. tenVeen, OLVG, Dept. of Internal Medicine, Amsterdam; Working group Virology Dr. N.K.T. Back, AMC, Dept. of Human Retrovirology, Amsterdam; Dr. C.A.B. Boucher, UMCU,Eykman-Winkler Institute, Utrecht; Dr. H.C.J. Claas, LUMC, Clinical Virological Laboratory, Leiden; Dr. G.J.J. Doornum, Erasmus Medical Centre, Dept. of Virology, Rotterdam; Prof.dr. J.M.D. Galama, UMCN- St. Radboud, Dept. of Medical Microbiology, Nijmegen; Dr. S. Jurriaans, AMC, Dept. of Human Retrovirology, Amsterdam; Prof. dr. A.C.M. Kroes(chairman), LUMC, Clinical Virological Laboratory, Leiden; Dr. W.J.G. Melchers, UMCN St. Radboud, Dept. of Medical Microbiology, Nijmegen; Prof. dr. A.D.M.E. Osterhaus,Erasmus Medical Centre, Dept. of Virology, Rotterdam; Dr. P. Savelkoul, VU Medical Centre, Dept. of Medical Microbiology, Amsterdam; Dr. R. Schuurman, UMCU, Dept. ofVirology, Utrecht; Dr. A.I. van Sighem, HIV Monitoring Foundation, Amsterdam; Data collectors Y.M. Bakker, C.R.E. Lodewijk, Y.M.C. Ruijs-Tiggelman, D.P. Veenenberg-Benschop,I. Farida, Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam; C. Leenders, R. Vergoossens, Academisch Ziekenhuis Maastricht, Maastricht; B. Korsten, S.de Munnik, Catharina Ziekenhuis, Eindhoven; M. Bendik, C. Kam-van de Berg, A. de Oude, T. Royaards, Erasmus Medisch Centrum, Rotterdam; G. van der Hut, Haga Ziekenhuis,locatie Leyenburg, Den Haag; A. van den Berg, A.G.W. Hulzen, Isala Klinieken, Zwolle; P. Zonneveld, Kennemer Gasthuis, Haarlem; M.J. van Broekhoven-Kruijne, W. Dorama,Leids Universitair Medisch Centrum, Leiden; D. Pronk, F.A. van Truijen-Oud, Medisch Centrum Alkmaar, Alkmaar; S. Bilderbeek, Medisch Centrum Haaglanden, locatie Westeinde,Den Haag; A. Ballemans, S. Rotteveel, Medisch Centrum Leeuwarden, Leeuwarden; J. Smit, J. den Hollander, Medisch Centrum Rijnmond Zuid, locatie Clara, Rotterdam; H. Heins,H. Wiggers, Medisch Spectrum Twente, Enschede; B.M. Peeck, E.M. Tuyn-de Bruin, Onze Lieve Vrouwe Gasthuis, Amsterdam; C.H.F. Kuiper, Stichting Medisch Centrum Jan vanGoyen, Amsterdam; E. Oudmaijer-Sanders, Slotervaart Ziekenhuis, Amsterdam; R. Santegoeds, B. van der Ven, St. Elisabeth Ziekenhuis, Tilburg; M. Spelbrink, St. Lucas AndreasZiekenhuis, Amsterdam; M. Meeuwissen, Universitair Medisch Centrum St. Radboud, Nijmegen; J. Huizinga, C.I. Nieuwenhout, Universitair Medisch Centrum Groningen, Groningen;M. Peters, C.S.A.M. van Rooijen, A.J. Spierenburg, Universitair Medisch Centrum Utrecht, Utrecht; C.J.H. Veldhuyzen, VU Medisch Centrum, Amsterdam; C.W.A.J. Deurloo-vanWanrooy, M. Gerritsen, Ziekenhuis Rijnstate, Arnhem; Y.M. Bakker, Ziekenhuis Walcheren, Vlissingen; S. Meyer, B. de Medeiros, S. Simon, S. Dekker, Y.M.C. Ruijs-Tiggelman, St.Elisabeth Hospitaal/Stichting Rode Kruis Bloedbank, Willemstad, Curaçao; Personnel HIV Monitoring Foundation Amsterdam E.T.M. Bakker, assistant personnel (untilSeptember 2006); Y.M. Bakker, data collection AMC; R.F. Beard, registration & patient administration; Drs. D.O. Bezemer, data analysis; D. de Boer, financial controlling; I. de Boer,assistant personnel (from November 2006); M.J. van Broekhoven-Kruijne, data collection LUMC; S.H. Dijkink, assistant data monitor (from March 2006); I. Farida, data collectionAMC; D.N. de Gouw, communication manager; Drs. L.A.J. Gras, data analysis; Drs. S. Grivell, data monitor ; Drs. M.M. Hillebregt, data monitor; Drs. A.M. Kesselring, data analysis(from January 2006); Drs. B. Slieker, data monitoring; C.H.F. Kuiper, data collection St. Medisch Centrum Jan van Goyen; C.R.E. Lodewijk, data collection AMC; Drs. H.J.M. vanNoort, assistant financial controlling; B.M. Peeck, data collection OLVG; Oosterpark; Dr. T. Rispens, data monitor (until April 2006); Y.M.C. Ruijs-Tiggelman, data collection AMC;Drs. G.E. Scholte, executive secretary; Dr. A.I. van Sighem, data analysis; Ir. C. Smit, data analysis; E.M. Tuyn-de Bruin, data collection OLVG Oosterpark; Drs. E.C.M. Verkerk, datamonitoring (from June 2006); D.P. Veenenberg-Benschop, data collection AMC; Y.T.L. Vijn, data collection OLVG Prinsengracht (until May 2006); C.W.A.J. Deurloo-van Wanrooy,data collection Rijnstate; Dr. F. de Wolf, director; Drs. S. Zaheri, data quality control; Drs. J.A Zeijlemaker, editor (until April 2006); Drs. S. Zhang, data analysis (from February 2006)

Time to death within 3 years of starting HAARTaccording to CDC-C classification

in 3198 therapy naïve patients starting with <200 CD4 cells/mm3

0.1

1

10

100

PML

NHL

DEM

MAC HSV

PNR

KSA

ISO

TOX

WA

S

ECA

CM

V

TBC

MYC CR

S

PCP

CRC

HR

(95%

CI)

Model adjusted for calendar year of starting HAART, CD4 cell count and HIV RNA at starting HAART, age, gender and transmissionrisk group. Hazard ratio’s of the specific CDC-C diseases are relative to no CDC-event.PML progressive multifocal leucoencephalopathy, NHL non-hodgkins lymphoma (including primary brain lymphoma), DEM AIDSdementia complex, MAC mycobacterium avium/kansasii, HSV herpes simplex virus, PNR pneumonia recurrent, KSA Kaposi’ssarcoma, ISO Isosporiasis, TOX Toxoplasmosis of the brain, WAS Wasting syndrome, ECA esophageal candidiasis, CMVcytomegalovirus disease, TBC tuberculosis, MYC mycobacterium atypical, CRS cryptosporidiosis, PCP Pneumocystis cariniipneumonia, CRC Cryptococcosis extrapulmonar

0

2000

4000

6000

8000

10000

2005 2007 2009 2011 2013Year

Predictions future

All as in 2004 R(t) = 1.1

Risk-behavior 66% lower R(t)=0.6 (as pre-HAART)

Average diagnosis 31 year R(t) = 0.9

Assuming a constant rate of imported cases

Cu

mu

lati

ve n

um

ber

of

HIV

infe

ctio

ns

0

2000

4000

6000

8000

1995 1997 1999 2001 2003Year

Simulations past

No HAART R(t)= 1.5

No increase in riskR(t) = 0.6

As in 1994 R(t)=0.9Modelfit R(t)=1.1

No earlier diagnosisR(t) = 1.2

Ncu

mu

lati

ve o

f H

IV in

fect

ion

s

HIV Monitoring Foundation