HIV Monitoring: The effect of treatment on the epidemic Frank de Wolf HIV Monitoring Foundation Amsterdam The Netherlands 1
Registered population Per 1 st June 27: 13556 patients 292 in Curaçao 13264 in NL 78 < 13 yrs 2
13264 patients registered Number 12 1 8 6 4 2 proportion of diagnoses.7.6.5.4.3.2.1 Men/women IVD MSM Women HST Men HST 1996 1997 1998 1999 2 21 22 23 year of HIV diagnosis 24 25 26. 1996 1998 2 22 24 26 year of diagnosis Increase since 6/26 with 125 persons; 858 diagnosed in 26 12915 with a known date of HIV diagnosis 9367 between 1996 and 6/27 Increasing proportion of MSM since 23 3
Registered population Per 1 st June 27: 1128 deaths MSM heterosexual IDU blood vertical Other/nk men 13556 patients 13264 in NL 195 in follow-up 7867 78 2228 5619 71 1358 17 257 3 16 21 56 % 1.3 6 women 1957 96 54 18 13 292 in Curaçao 78 < 13 yrs 1963 lost-to-f up % 23 total 195 % 1 5619 56 88 4 2 1 3315 353 16 39 33 4 2.4 5 69 6 4
AIDS diagnoses and death over time 1983-1996 3172 deaths 4566 AIDS cases 6 5 4 Deaths AIDS cases 1996 26: 3 2 1352 deaths; 95 in 26 1 2712 AIDS cases; 223 in 26 1983 1984 1985 1986 1987 1988 1989 199 1991 1992 1993 Op de Coul, 27, RIVM Bilthoven 1994 1995 1996 1997 1998 1999 2 21 22 23 24 25 26 5
Mortality and AIDS after start cart 8115 (8%) 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 mortality per 1 person-years 7 6 5 4 3 2 1 1996 1998 2 22 24 26 calendar year AIDS incidence per 1 person-years 2 15 1 5 1996 1998 2 22 24 26 calendar year 6
Virological effect of cart After the first 24 weeks of HAART, the amount of HIV in blood has declined 3 logs 8% are below the detection threshold 388/534 naïve patients show viral rebounds after initial success Incidence of viral rebound is 3.2 per 1 person-years of follow-up log HIV-RNA copies/ml plasma 6 5 4 3 2 1 diagnosis all IQR IQR start HAART 24 wks 48 wks 7
Immunological effect of cart Patients continuously on HAART do show an increase of CD4 cells from median 221/mm 3 at start to 67/mm 3 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 In older patients and patients with viral rebounds after start of HAART the increase in CD4 cells is less. CD4 cell count (cells/mm3) 1 9 8 7 6 5 4 3 2 1 48 96 144 192 24 288 336 Weeks from starting HAART <5 5-2 2-35 35-5 >5 8
Failure of cart HAART failure decreased in ART experienced patients Amongst naive patients the percentage of HAART failures increased slowly In 8% of the patients experiencing virological failure during treatment resistance is found fraction patients failing on therapy.6.5.4.3.2.1 pre-treated naïve. 1996 1998 2 22 24 26 kalenderjaar However: Resistance is measured in only 17% of the patients with virological failure during HAART 9
Transmission of resistant HIV Since 21 resistance is found in 8.7% of the new HIV diagnoses In 44 patients intermediate/highlevel resistance; 2 to all drug classes B percentage resistant 1 9 8 7 6 5 4 3 2 1 newly diagnosed 25 2 15 1 5 number of sequences 1995 2 25 year of diagnosis 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 A percentage resistant 1 9 8 7 6 5 4 3 2 1 recent infections 1995 2 25 year of infection 1 9 8 7 6 5 4 3 2 1 number of sequences 1
Conclusion It s going well 11
Is it? The number of new HIV diagnoses seem to increase, especially amongst MSM How come; where is the source? 8% 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. Number 12 1 8 6 4 2 1995 1996 1997 1998 1999 2 year of HIV diagnosis 21 22 23 24 25 26 27 Population infected but not tested? Increasing risk behaviour? Increasing infectiousness over time? 12
Estimated population HIV prevalence in: adults (age 15-49):.23% MSM: 5.3% IV drug users: 5.3% CSW: 2.7% Prevalence (%) adults.25%.2%.15%.1%.5%.% Op de Coul & Van Sighem 198 1985 199 1995 2 25 21 13
Estimated population Per end 25: Van Sighem & Op de Coul 26 185 patients (1-28) 15 age (yrs)<5 Actually in f up: 6944 (38%) MSM Heterosexual ao. men women total data Est. data Est. data Est. 512 121 1824 64 6944 185 3561 85 3561 85 1559 36 1824 64 3383 1 14
Estimated population not in follow-up 185 6944= 11556 (62%) 15 age (yrs)<5 Men (121) Women (64) Total (185) Est.- data %. Est.- data % Est.- data % 698 58 4576 72 11556 62 MSM (85) Heterosexual ao. (36 m; 64 w) 4939 241 58 57 4576 72 4939 6617 58 66 15
Model Framework Reduced risk behaviour Treatment, halts progression and onwards transmission Time to diagnosis Time to treatment Time to AIDS Time to death Data Data Data Data New Infections Risk-behaviour New Diagnosed cases (diagnosis rate) cart New AIDS cases 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 Death 16
Model outcome and observed numbers 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 c d Risk behaviour rate β(t) Reproduction number R(t) 1.2 1.8 8 6.6 4.4.2 2 198 1985 199 1995 2 25 Year 3 75 2.5 2 5 1.5 1 25.5 198 1985 199 1995 2 25 Year years to diagnosis New infections per year 17
Predictions past a Cumulative infections since 1995 8 6 4 2 1995 1999 23 Year No cart + risk behaviour up + no improved diagnostics rate : 769 cart + risk behaviour up + no improved diagnostics rate: 4132 3665 new infections No cart + no increased risk behaviour + no improved diagnostics rate: 2984 cart + no increased risk behaviour: 1647 18
Predictions future b 1 Cumulative infections from 25 8 6 4 2 25 29 213 Year No change from 25 : 7815 Improved treatment (treatment failure halved): 7262 Increase of testing frequency (av time to diagnosis from3 to 1 year): 3879 Reduced risk behaviour to pre-haart levels: 163 cart+improved treatment+improved testing+ reduced risk behaviour: 952 19
Conclusion Reducing risk behaviour together with timely cart treatment and timely HIV diagnosis would halt epidemic spread of HIV 2
In addition Amongst the known HIV infected 2% is not on cart 35% of the registered population enter care late; majority migrants, male and heterosexual 45-5% 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 % with CD4<2 percentage of total entering HIV care 45 4 35 3 25 2 15 1 5 7 6 5 4 3 2 before 2 start cart with CD4<2 <2 CD4 cells/mme3 21-22 23-27 unknown 1 1996 1997 1998 1999 2 21 22 year start cart 23 24 25 26 21
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<4 cells/mm 3 ) There is room for improving timely start of cart 22
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 2) 23
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 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 24
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.ErasmusMC -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 27: 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. 25