HIV Monitoring: The effect of treatment on the epidemic
Frank de Wolf HIV Monitoring Foundation Amsterdam The Netherlands
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Registered population Per 1st June 2007:
13556 patients 13264 in NL
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292 in Curaçao 78 < 13 yrs
13264 patients registered 1200
proportion of diagnoses
0.7
1000
Number
800 600 400 200
MSM
0.6 0.5 0.4 0.3
Women HST
0.2 0.1
Men/women IVD
Men HST
0.0 06
1996
1998
20
04
05 20
02
01
03
20
20
20
20
99
98
97
00 20
19
19
19
19
96
0
2000 2002 2004 year of diagnosis
2006
year of HIV diagnosis
•Increase since 06/2006 with 1205 persons; 858 diagnosed in 2006 •12915 with a known date of HIV diagnosis •9367 between 1996 and 06/2007 •Increasing proportion of MSM since 2003 3
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Registered population 13556 patients
Per 1st June 2007:
292 in Curaçao
13264 in NL 1128 deaths
10095 in follow-up men
MSM heterosexual IDU blood vertical Other/nk 4
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78 < 13 yrs
%
7867 78 5619 71 1358 17 3 257 1 106 21 0.3 6 506
women
1963 lost-to-f’up %
2228 23 1957 88 96 4 54 2 18 1 103 5
% total 10095 100 5619 56 3315 33 4 353 2 160 39 0.4 6 609
AIDS diagnoses and death over time 1983 - 1996 • 3172 deaths • 4566 AIDS cases
600
Deaths 500
AIDS cases
400
300
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200
100
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1994
Op de Coul, 2007, RIVM Bilthoven
0 1983
1996 – 2006: • 1352 deaths; 95 in 2006 • 2712 AIDS cases; 223 in 2006
Mortality and AIDS after start cART
mortality per 100 person-years
7 6 5 4 3 2 1 0 1996
6
1998
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2000 2002 2004 calendar year
2006
AIDS incidence per 100 person-years
• 8115 (80%) of the registered patients currently in follow-up are on cART • (HIV-related) mortality and incidence of AIDS dramatically declined due to widespread treatment with cART. • 1196 (11.7%) AIDS diagnoses after start cART • 973 (9.5%) cases of death after start cART 20
15
10
5
0 1996
1998
2000 2002 2004 calendar year
2006
• After the first 24 weeks of HAART, the amount of HIV in blood has declined 3 logs • 80% are below the detection threshold • 388/5304 naïve patients show viral rebounds after initial success • Incidence of viral rebound is 3.2 per 100 person-years of follow-up
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l og H IV-RNA c opi es /m l pl as m a
Virological effect of cART 6 5 4 3 al l
2
IQR
1
IQR
0 di agn os i s
s t art H AART
24 wks
48 wks
• Patients continuously on HAART do show an increase of CD4 cells from median 221/mm3 at start to 607/mm3 after 7 years of treatment • The highest increase is seen in the first 24 weeks and levels off thereafter • The increase does not differ between baseline groups
CD4 cell count (cells/mm3)
Immunological effect of cART 1000 900 800 700 600 500 400 300 200 100 0 0
48
96
144
192
240
288
336
Weeks from starting HAART <50
50-200
200-350
350-500
>500
• In older patients and patients with viral rebounds after start of HAART the increase in CD4 cells is less.
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Failure of cART fraction patients failing on therapy
0.6 • HAART failure decreased in pre-treated ART experienced patients 0.5 naïve • Amongst naive patients the 0.4 percentage of HAART 0.3 failures increased slowly 0.2 • In 80% of the patients 0.1 experiencing virological 0.0 failure during treatment 1996 1998 2000 2002 2004 2006 kalenderjaar resistance is found • However: Resistance is measured in only 17% of the patients with virological failure during HAART
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Transmission of resistant HIV B
100
250
80
200
newly diagnosed
70 60
150
50 40
100
30 20
50
10 0
0 1995
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2000 year of diagnosis
2005
100
100
90
90
80
80
recent infections
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0 1995
2000 year of infection
2005
number of sequences
A
percentage resistant
• In 4.9% of the recent infections one or more mutations associated with resistance are found • 11 patients with intermediate/ high-level resistance; 1 to all drug classes
number of sequences
90 percentage resistant
• Since 2001 resistance is found in 8.7% of the new HIV diagnoses • In 44 patients intermediate/highlevel resistance; 2 to all drug classes
Conclusion • It’s going well
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Is it? 1200
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1000 800 Number
• The number of new HIV diagnoses seem to increase, especially amongst MSM • How come; where is the source? •80% of the known HIV infected population is treated & failure rate is low •Transmission potential in this group is low as the amount of virus circulating is low •Number of infections imported is relatively low.
600 400 200 0 19
9 5 9 9 6 9 97 9 9 8 99 9 0 0 0 0 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 7 2 2 2 2 2 2 1 1 1 1 2 2
year of HIV diagnosis
Population infected but not tested? Increasing risk behaviour? Increasing infectiousness over time?
Estimated population HIV prevalence in:
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Prevalence (%) adults
• adults (age 15-49): 0.23% • MSM: 5.3% • IV drug users: 5.3% • CSW: 2.7%
0.25% 0.20% 0.15% 0.10% 0.05% Op de Coul & Van Sighem
0.00% 1980 1985 1990 1995 2000 2005 2010
Estimated population Per end 2005:
Van Sighem & Op de Coul 2006
18500 patients (10000-28000)
Actually in f’up:
6944 (38%)
men
MSM Heterosexual ao.
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data 5120 3561 1559
Est. 12100 8500 3600
15≤age (yrs)<50
women data 1824
Est. 6400
1824
6400
total data Est. 6944 18500 3561 8500 3383 10000
Estimated population not in follow-up 18500 – 6944=
11556 (62%)
Men (12100) Est.- data %. 6980 58 MSM (8500) Heterosexual ao. (3600 m; 6400 w) 15
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4939 58 2041 57
15≤age (yrs)<50
Women (6400)
Total (18500)
Est.- data % 4576 72
Est.- data % 11556 62
4576 72
4939 58 6617 66
Model Framework Reduced risk behaviour
Time to diagnosis
New Infections
Risk-behaviour
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Treatment, halts progression and onwards transmission
Time to treatment
Time to AIDS
Time to death
Data
Data
Data
Data
New Diagnosed cases (diagnosis rate)
cART
New AIDS cases
Death
Reproduction number R(t): the average number of people an infected person at time t would infect over his whole infectious lifespan if conditions remained the same as at time t
Model outcome and observed numbers 8
1.2 1
6
0.8
4
0.6 0.4
2
0.2 0 1980
1985
1990
1995
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0 2005
d
3
750
2.5 2
500
1.5 1
250
0.5 0 1980
1985
1990
1995
2000
0 2005
New infections per year
Year
Year 17
2000
years to diagnosis
Risk behaviour rate β(t)
c
Reproduction number R(t)
To best fit to the number of new HIV diagnoses and the number of AIDS cases over time since 1984 and to best predict the number of deaths and of prevalent HIV cases over time in ATHENA, changes in the relative risk behaviour, the years to diagnosis and the reproduction number were estimated, resulting in an estimated annual number of new infections
Predictions past 8000
Cumulative infections since 1995
a
No cART + risk behaviour up + no improved diagnostics rate : 7609
6000 cART + risk behaviour up + no improved diagnostics rate: 4132
4000
3665 new infections No cART + no increased risk behaviour + no improved diagnostics rate: 2984
2000
0 1995
cART + no increased risk behaviour: 1647
1999 Year
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2003
Predictions future 10000
Cumulative infections from 2005
b
No change from 2005 : 7815
8000
Improved treatment (treatment failure halved): 7262
6000 4000
Increase of testing frequency (av time to diagnosis from3 to 1 year): 3879
2000
Reduced risk behaviour to pre-HAART levels: 1630
0 2005
cART+improved treatment+improved testing+ reduced risk behaviour: 952
2009 Year
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2013
Conclusion • Reducing risk behaviour together with timely cART treatment and timely HIV diagnosis would halt epidemic spread of HIV
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45 40
<200 CD4 cells/mmE3
35 30 25 20 15 10 5 0 before 2000
70
2001-2002 2003-2007
unknown
start cART with CD4<200
60 % with CD4<200
• Amongst the known HIV infected 20% is not on cART • 35% of the registered population enter care late; majority migrants, male and heterosexual • 45-50% of the registered population in care start cART late; majority migrants, male and heterosexual • 9% of the population entering care on time start cART to late
percentage of total entering HIV care
In addition
50 40 30 20 10
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05
06
20
04
20
03
year start cART
20
20
01
02
20
00
20
99
20
19
97
98
19
19
19
96
0
Conclusions • Reducing risk behaviour together with timely cART treatment and timely HIV diagnosis would halt epidemic spread of HIV BUT • Risk behaviour is still high and has increased in MSM • A substantial proportion of HIV positive individuals is probably unaware of being infected • About one third of the population is entering HIV care late (CD4<400 cells/mm3) • There is room for improving timely start of cART
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Policies • Adjust HIV testing behaviour • Active approach of those groups with high risk behaviour • Fight against ignorance on testing and antiretroviral treatment • Avoid late presentation • Improve follow-up of registered patients such that cART at least is started on time (i.e. before CD4 cells have decreased below 200)
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Acknowledgements HIV Monitoring Foundation, Amsterdam: Ard van Sighem Colette Smit Luuk Gras Daniela Bezemer Anouk Kesselring Shuangjie Zang Sima Zaheri Danielle de Boer Daphne de Gouw Dept Infectious Disease Epidemiology, Imperial College, London: Christophe Fraser Deidre Hollingworth Geoff Garnett Roy Anderson 24
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Centre for Infectious Disease Control, RIVM, Bilthoven Eline Op de Coul Marianne van de Sande Roel Coutinho Health Service Amsterdam: Maria Prins Ronald Geskus Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam: Maarten Boerlijst
Acknowledgments Treating physicians (*Site coordinating physicians) : Academisch Medisch Centrum bij de Universiteit van Amsterdam - Amsterdam: Dr. J.M. Prins*, Dr. J. Branger, Dr. J.K.M. Eeftinck-Schattenkerk, Dr. S.E. Geerlings, Dr. M.H. Godfried, Drs. E.D. Kerver, Prof. dr. J.M.A. Lange, Dr. K.D. Lettinga, Dr. J.T.M. van der Meer, Dr. F.J.B. Nellen, Drs. D.P. Olszyna, Dr. T. van der Poll, Prof. dr. P. Reiss, Drs. Th.A. Ruys, Drs. R. Steingrover, Drs. M. van der Valk, Drs. J.N. Vermeulen, Drs. S.M.E. Vrouenraets, Dr. M. van Vugt, Dr. F.W.M.N. Wit; Academisch Ziekenhuis Maastricht - Maastricht: Dr. G. Schreij*, Dr. S. van der Geest, Dr. S. Lowe, Dr. A. Verbon.Catharina Ziekenhuis - Eindhoven: Dr. B. Bravenboer*; Emma Kinderziekenhuis - AMC Amsterdam: Prof. dr. T.W. Kuijpers, Drs. D. Pajkrt, Dr. H.J. Scherpbier.Erasmus MC - Rotterdam: Dr. M.E. van der Ende*, Dr. I.C. Gyssens, Drs. M. van der Feltz, Drs. Mendoca de Melo, Dr. J.L. Nouwen, Dr. B.J.A. Rijnders, Dr. T.E.M.S. de Vries.Erasmus MC - Sophia - Rotterdam:Dr. G. Driessen, Dr. M. van der Flier, Dr. N.G. Hartwig.Haga Ziekenhuis, locatie Leyenburg - Den Haag:Dr. R.H. Kauffmann*, Drs. K. Pogány.Isala Klinieken - Zwolle:Dr. P.H.P. Groeneveld*.Kennemer Gasthuis - Haarlem:Prof. dr. R.W. ten Kate*, Dr. R. Soetekouw.Leids Universitair Medisch Centrum -Leiden: Dr. F.P. Kroon*, Prof. dr. P.J. van den Broek, Prof. dr. J.T. van Dissel, Dr. E.F. Schippers.Medisch Centrum Alkmaar - Alkmaar: Dr. W. Bronsveld*, Drs. M.E. Hillebrand-Haverkort.Medisch Centrum Haaglanden -locatie Westeinde - Den Haag: Dr. R. Vriesendorp*, Dr. F.J.F. Jeurissen.Medisch Centrum Leeuwarden - Leeuwarden: Dr. D. van Houte*, Dr. M.B. Polée.Medisch Centrum Rijnmond Zuid - locatie Clara - Rotterdam:Dr. J.G. den Hollander*; Medisch Spectrum Twente - Enschede: Dr. C.H.H. ten Napel*, Dr. G.J. Kootstra.Onze Lieve Vrouwe Gasthuis - Amsterdam.Prof. dr. K. Brinkman*, Drs. G.E.L. van den Berk, Dr. W.L. Blok, Dr. P.H.J. Frissen, Drs. W.E.M. Schouten.St. Medisch Centrum Jan van Goyen - Amsterdam: Dr. A. van Eeden*; Slotervaart Ziekenhuis - Amsterdam: Dr. J.W. Mulder*, Dr. E.C.M. van Gorp, Dr. J. Wagenaar.St. Elisabeth Ziekenhuis - Tilburg: Dr. J.R. Juttmann*, Dr. C. van de Heul, Dr. M.E.E. van Kasteren.St. Lucas Andreas Ziekenhuis - Amsterdam: Dr. J. Veenstra*, Dr. W.L.E. Vasmel.Universitair Medisch Centrum St. Radboud - Nijmegen: Dr. P.P. Koopmans*, Drs. C. Bleeker, Dr. R. van Crevel, Prof. dr. R. de Groot, drs. H.J.M. ter Hofstede, Dr. M. Keuter, Dr. A.J.A.M. van der Ven.Universitair Medisch Centrum Groningen - Groningen: Dr. H.G. Sprenger*, Dr. S. van Assen, Dr. J.T.M. van Leeuwen.Universitair Medisch Centrum Groningen - Beatrix Kliniek - Groningen: Dr. R. Doedens, Dr. E.H. Scholvinck; Universitair Medisch Centrum Utrecht - Utrecht: 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; Wilhelmina Kinderziekenhuis - UMC Utrecht: Dr. S.P.M. Geelen, Dr. T. Faber, Dr. T.F.W. Wolfs.VU Medisch Centrum - Amsterdam: Prof. dr. S.A. Danner*, Dr. M.A. van Agtmael, Drs. W.F.W. Bierman, Drs. F.A.P. Claessen, Dr. R.M. Perenboom, Drs. A. Rijkeboer, Drs. M.G.A. van Vonderen; Ziekenhuis Rijnstate - Arnhem: Dr. C. Richter*, Drs. J. van der Berg, Dr. E.H. Gisolf; Ziekenhuis Walcheren - Vlissingen: Dr. A.A. Tanis*.St. Elisabeth Hospitaal/Stichting Rode Kruis Bloedbank - Willemstad, Curaçao:Dr. A.J. Duits, Dr. K. Winkel; Virologists: Academisch Medisch Centrum bij de Universiteit van Amsterdam – Amsterdam:Dr. N.K.T. Back, Dr. M.E.G. Bakker, Dr. H.L. Zaaijer.Prof. dr. B. Berkhout, Dr. S. Jurriaans. CLB Stichting Sanquin Bloedvoorziening -Amsterdam: Dr. Th. Cuijpers.Onze Lieve Vrouwe Gasthuis - Amsterdam: Dr. P.J.G.M. Rietra, Dr. K.J. Roozendaal;.Slotervaart Ziekenhuis - Amsterdam: Drs. W. Pauw, Drs. P.H.M. Smits, Dr. A.P. van Zanten.VU Medisch Centrum – Amsterdam: Dr. B.M.E. von Blomberg, Dr. A. Pettersson, Dr. P. Savelkoul; Ziekenhuis Rijnstate – Arnhem:Dr. C.M.A. Swanink.HAGA, ziekenhuis, locatie Leyenburg Den Haag: Dr. P.F.H. Franck, Dr. A.S. Lampe; Medisch Centrum Haaglanden, locatie Westeinde - Den Haag: Drs. C.L. Jansen.; Streeklaboratorium Twente - Enschede: Dr. R. Hendriks.Streeklaboratorium Groningen - Groningen: Dr. C.A. Benne;.Streeklaboratorium Volksgezondheid Kennemerland - Haarlem: Dr. J. Schirm, Dr. D. Veenendaal.Laboratorium voor de Volksgezondheid in Friesland - Leeuwarden: Dr. H. Storm, Drs. J. Weel, Drs. J.H. van Zeijl; Leids Universitair Medisch Centrum Leiden: Dr. H.C.J. Claas, Prof. dr. A.C.M. Kroes.Academisch Ziekenhuis Maastricht - Maastricht: Prof. dr. C.A.M.V.A. Bruggeman, Drs. V.J. Goossens.Universitair Medisch Centrum St. Radboud - Nijmegen: Prof. dr. J.M.D. Galama, Dr. W.J.G. Melchers, Dr. Verduyn-Lunel.Erasmus MC - Rotterdam:Dr. G.J.J. van Doornum, Dr. H.G.M. Niesters, Prof. dr. A.D.M.E. Osterhaus, Dr. M. Schutten.St. Elisabeth Ziekenhuis - Tilburg: Dr. A.G.M. Buiting.Universitair Medisch Centrum Utrecht - Utrecht: Dr. C.A.B. Boucher, Dr. E. Boel, Dr. R. Schuurman.Catharina Ziekenhuis - Eindhoven: Dr. A.F. Jansz, drs. M. Wulf; Pharmacologists: Medisch Centrum Alkmaar - Alkmaar: Dr. A. Veldkamp.Slotervaart Ziekenhuis - Amsterdam: Prof. dr. J.H. Beijnen, Dr. A.D.R. Huitema.Universitair Medisch Centrum St. Radboud - Nijmegen: Dr. D.M. Burger.Academisch Medisch Centrum bij de Universiteit van Amsterdam – Amsterdam: Drs. H.J.M. van Kan; Governing Board of the HIV Monitoring Foundation 2007: Drs. M.A.J.M. Bos, Treasurer, 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. H. Polee, Member, Dutch HIV Association; Drs. M.I. Verstappen, Member, GGDDr. F. de Wolf, Director, HMF; Advisory Board: Prof. dr. sir. R.M. Anderson, Imperial College, Faculty of Medicine, Dept. of Infectious Disease Epidemiology, London, United Kingdom; Prof. dr. J.H. Beijnen, Slotervaart Hospital, Dept. of Pharmacology, AmsterdamDr. M.E. van der Ende, Erasmus Medical Centre, Dept. of Internal Medicine, Rotterdam; Prof. dr. R. de Groot, UMC- St. Radboud, Dept. of Internal Medicine, NijmegenProf. dr. I.M. Hoepelman, UMC Utrecht, UtrechtDr. R.H. Kauffmann, Leyenburg Hospital, Dept. of Internal Medicine, The Hague; Prof. dr. A.C.M. Kroes, LUMC, Clinical Virological Laboratory, LeidenDr. F.P. Kroon (vice chairman), LUMC, Dept. of Internal Medicine, Leiden; Prof. dr. J.M.A. Lange (chairman), AMC, Dept. of Internal Medicine, AmsterdamProf. dr. G. Pantaleo, Hôpital de Beaumont, Dept. of Medicine, Lausanne, Switzerland; Dhr. C. Rümke, Dutch HIV Association, Amsterdam; Prof. dr. P. Speelman, AMC, Dept. of Internal Medicine, Amsterdam.
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