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Prevention at an Impasse

Anti-HIV Drugs for Prevention Bernard Hirschel Division of HIV/AIDS Geneva University Hospital Geneva, Switzerland. Prevention at an Impasse. Sexual behaviour Condoms Circumcision Microbicides Vaccines. The theory is just fine…. Estimated rate of HIV after

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Prevention at an Impasse

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  1. Anti-HIV Drugs for PreventionBernard HirschelDivision of HIV/AIDSGeneva UniversityHospitalGeneva, Switzerland

  2. Preventionat an Impasse • Sexualbehaviour • Condoms • Circumcision • Microbicides • Vaccines

  3. The theoryisjust fine… Estimated rate of HIV after 10 years’ cohabitation in a heterosexual couple alwaysusing condoms Adapted from W. Cates, FHI

  4. Practice ratherlessso… Estimated rate of HIV after 10 years’ cohabitation in a heterosexual couple at typicalrates of condom use Adapted from W. Cates, FHI

  5. ART:potentiallymore efficacious(than any of the previously evaluated prevention methods)

  6. No transmission if VL « undetectable » « Rakai » Study: Transmission risk as a function of plasma viral load Quinn et al. N Engl J Med 2000

  7. Mother to Child Transmission AZT HAART % ofinfected children Adaptedfrom Coovadia and Lallemant, NEJM 2004

  8. Effect of HAART on heterosexual transmission • 476 heterosexual couples in Madrid • The “index” patient was HIV +, and consulted between 1989-2008 • Among their sexual partners, the only risk factor for HIV was exposure to the “index” patient • All partners tested to establish prevalence of HIV among partners Del Romero J, BMJ 2010

  9. Prevalence of HIV infection in the partners, at entry 44/476 0/149 Percent of partenairs infected Del Romero J, BMJ 2010

  10. Incidence of HIV infection in the partners, during follow-up Treatment Couple-years New infections No HAART 863 5 HAART 417 0 Del Romero J, BMJ 2010

  11. Condoms plus HAART in comparison to condoms alone: 3 Africanstudies • What they had in common: • Sero-discordant heterosexual couples • Condom promotion • How they differed: • Study A*, without HAART • Study B**, with HAART • Study C***, a period without HAART followed by a period with HAART * Wawer M et al. Lancet 2009 ** Bunnell R et al. Abstract 29, 15th CROI, Boston 2008; AIDS 2006 ***Donnell D, Lancet 2010

  12. Results Study A* Study B** Study C*** « before » « after » Condoms  HAART -  -  Infections %/year 12 0.5 2.23 0.39 * Wawer M et al. Lancet 2009; 374:229-37 ** Bunnell R et al. Abstract 29, 15th CROI, 2009 *** Donnell D, Lancet 2010

  13. In conclusion Circumstantialevidenceindicatesthat: • HAART lowers MTCT • HAART lowersheterosexual transmission • HAART appears more efficaciousthan condoms (or has a markedadditionaleffectwhenused in combinationwith condoms), in sero-discordant heterosexual couples

  14. What has been the effect of ART on the AIDS epidemic ? • Introduction of ART, 1990-2000 • Expansion of ART, 2000-2010

  15. NewlyDiagnosed HIV Infections in Switzerland HAART AZT Bull. OFSP 2001

  16. Newly Diagnosed HIV Infections, and N of pts on HAART in B.C., Canada Montaner J, CROI 2010

  17. 1.5 Amsterdam, MSMs New infections per seropositive individual If > 1, the epidemic grows, if < 1, it shrinks. R(t) Theoretical R(t) in 2002, without HAART, but with the 2002 sexual behavior Bezemer D et al., CROI 2001, AIDS 2008

  18. Conclusions • Introduction of ARVs in the 1990ies coincidedwith a decrease in new HIV infections • Otherthingsbeingequal, without HAART, new infections might have been 50 to a 100 percent morefrequent by 2000

  19. Newly Diagnosed HIV Infections, and N of pts on HAART in B.C., Canada IDUs only Montaner J, CROI 2010

  20. Swiss HIV Cohort: More patients withstablysuppressed viral load Adapted from Ledergerber et al. CROI 2010

  21. More patients are treated, and less are infectious (VL > 500, pink) > 500 < 500 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

  22. SwissCohort: N of pts withviremia > 500

  23. Theory: Whatyouwouldexpect The number of potentially infectiouspersonsstarts to fall.. ..and after a lag of a few years newlydiscovered infections decline in parallel

  24. Switzerland:NewlyDiagnosed HIV Infections, and N of pts withviremia > 500 in the SHCS* * SHCS = Swiss HIV CohortStudy

  25. Conclusions (2000 to 2010) 1) Expansion of treatment, and betterefficacy, diminished the pool of potentiallyinfectiouspersons 2)The number of newlydiscovered infections, afteryears of stability or evenincrease, maybedecliningagain

  26. Whatwouldhappen to the epidemic if even more infectedpersonsweretreated? 26

  27. 10 9 8 7 6 5 4 3 2 1 0 2006 2010 2014 2018 2022 2026 2030 2034 2038 Projections for British Columbia Treat 30% HIV infections per 1000 population Treat all 2006 10 14 18 22 26 30 34 38 42 2050 Montaner, Hogg et al. Unpublished, 2006

  28. Costs of treatment 109 $ Treat all Treat 30% 2006 10 14 18 22 26 30 34 38 42 2050 Hogg et al. Unpublished, 2006

  29. Costs of HAART Billions de $ Great savings Small investment 2006 10 14 18 22 26 30 34 38 42 2050 Lima VD et al. JID 2008 Hogg et al. Unpublished, 2006

  30. 50 % Treatment coverage 75 % 90 % 100 % If Lima and Montaner are right, it is enough to treat > 75% of those with CD4 counts < 350, and after a while, there will be close to zero new infections: HIV will disappear (Lima et al. JID, 2008)

  31. ARV for CD4 < 350 But if Granich and Williams are right, HIV will never be defeated by treating only those with CD4 counts below 350. One needs to test the whole population frequently, and treat all those found to be infected (green curve) 2000 2020 2040 Granich et al. 2008

  32. All models are wrong, but some are useful… Box, G.E.P., Robustness in the strategy of scientific model building, in Robustness in Statistics, R.L. Launer and G.N. Wilkinson, Editors. 1979, Academic Press: New York.

  33. 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 100 Percent of New Infections Prevented 50% 60% 70% 80% 90% Percent of Cases Treated Blower et al., Science 2000

  34. 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 Percent of New Infections Prevented 50% 60% 70% 80% 90% Depending on assumptionsregardingriskbehaviourand selection of drugresistance, at 70% of patients treated, the effect on new infections could range from 40% prevented to doubled

  35. Compared to treatingonly patients withlessthan 350 CD4 cells, universal ART wouldreducecosts by 4.9 billion US$ … • « I thereforebelievethatyou have substantiallyunderestimated, and deliberatelymisrepresented, the costs of yourproposedeliminationstrategy » Kahn JG et al. 17th CROI, 2010, abstract 965

  36. Let’sdeclare a model armistice, and insteadgetsome data ! Dabis, Newell, Hirschel, Lancet 2010

  37. HPTN* 052 Myron Cohen et al.: Randomised study to evaluate HAART in preventing sexual transmission in sero-discordant couples * HPTN: Health Prevention and Treatment Network

  38. Inclusion Criteria 1750 couples (3500 individuals), fully recruited CD4 = 350-550 cells/mm3 One partner HIV+, the other HIV- Endogamous: 93% say that they had only one sex partner during the last six months.

  39. Randomisation In the intervention group, ART starts right away, i.e. at a CD4 levelbetween 350 and 550 In the control group, according to local indication (CD4 = 200 to 250, rising more recently to 350)

  40. Endpoints Transmissions Sustainability, with a plannedfollow-up of 5+ years Results expected in 2015

  41. Limitations of HPTN052 Stable serodiscordant heterosexual couples are only part of the problem In the general population individual randomisation is not feasible, because it would necessitate tracking and testing of all sex partners

  42. Measure the incidence of HIV before and after introduction of ART, or before and after expansion of ART Examples: British Columbia (J. Montaner et al.), San Francisco, Switzerland General population:The before-and-afterapproach

  43. Switzerland:NewlyDiagnosed HIV Infections, and N of pts withviremia > 500 in the SHCS* * SHCS = Swiss HIV CohortStudy

  44. NewlyDiagnosed HIV Infections, andN of MSMswithviremia > 500 in the SHCS* MSMs * SHCS = Swiss HIV CohortStudy

  45. February to June 2008: A campaign to eliminate acute HIV infections in MSMs in Switzerland

  46. Problems with the before-and-after approach 1. Not all evidence goes into the same direction 2. B after A  B because of A (If HIV incidence falls after expansion of ART, it is not certain that the expansion caused the fall)

  47. « Childrenwhosemotherslistenend to Mozart duringpregnancy are more intelligent » « The H1N1 vaccine has causedmy multiple sclerosisbecause 5 daysafterwards I startedhaving double vision » (Tribune de Genève, 15 mars 2010) The « post hoc ergo propter hoc » - fallacyis not new…

  48. How To Do Better Compare two regions, at the same time: Region 1: Test-and-Treat Region 2: Continue as before Measure, in both regions, the number of new HIV infections Better but not perfect: The two regions will differ in many respects: Number and type of sex partners Use of condoms Prevalence of circumcision Age

  49. … but if one compared not two, but thirty regions, 15 with expanded ART, 15 without, and each time, HIV incidence falls in the « Test-and-Treat » regions but remains the same in the control regions …

  50. This is the essential idea behind the methodology called « cluster-randomized trial », where the unit of randomization is not the individual, but a community of individuals, for instance a village … but if one compared not two, but thirty regions, 15 with expanded ART, 15 without, and each time, HIV incidence falls in the « Test-and-Treat » regions but remains the same in the control regions …

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