1. Treatment as Prevention: The Effect of HAART on Infectiousness Bernard Hirschel Division of Infectious Diseases Geneva University Hospital Geneva, Switzerland

2. Prevention at an Impasse Sexual behaviour Condoms Circumcision Vaccine Microbicides

3. HIV Prevention Tools - Infection Rates (Source: W. Cates) Oral Acyclovir Percent of Persons Infected after a Decade of Use Rate during typical use Rate during perfect use Male circumcision Vaccines Microbicides Diaphragm Male condom Oral ARV 0406080 20 Female condom Abstinence

4. HAART: potentially more efficacious

5. AllMen-WomenWomen-Men « Rakai » Study: Transmission risk as a function of viral load No transmission if VL « undetectable » Quinn et al. N Engl J Med 2000;342:921-9

6. N Engl J Med 1999;341:394-402 Maternal levels of plasma HIV RNA and the risk of perinatal transmission No transmission if maternal viremia < 1000/ml Mother’s viremia of a non infected new born Mother’s viremia of an infected new born

7. Mother to Child Transmission AZT HAART % of infected children

8. Effect of HAART on MTCT 2500 babies born to HIV+ mothers with undetectable viral load at > 36 weeks 3 neonatal infections Claire Townsend et al. 15th CROI, Poster 653

9. Effects of HAART on heterosexual transmission 393 heterosexual couples in Madrid The index patient was HIV +, first consulted 1991-2003 The partners’ only risk factor for HIV acquisition was exposure to the index patient All partners were HIV-tested Castilla, et al. JAIDS 2005; 40:96-101

10. Prevalence of HIV infection in the partners Pre-HAARTHAART Pourcent des partenaires infecté(e)s

11. Castilla, et al. JAIDS 2005; 40:96-101 « HAART versus condoms » Infection rates in sex partners Ttmt of the index pt No ttmt Mono- ou bitherapy HAART Unsafe sex >1/month<1/moNever 0 2 4 6 8 10 12 0 1 2 3 4 5 6 7 8 9 10 % %

12. Condoms plus HAART in comparison to condoms alone: 2 African studies What they had in common: Transmission in Uganda Sero-discordant Couples Condom Promotion How they differed: Study A*, without HAART, evaluated the effect of circumcision on male-to-female transmission Study B**, with HAART, evaluated transmission both ways * Wawer M et al. Abstract 33 LB, 15th CROI, Boston 2008 **Bunnell R et al. Abstract 29, 15th CROI, Boston 2008

13. Results Study A*Study B** Condoms HAART- N infections observed12% ppy0.5 % ppy 95% CI9 – 150.01-3.0 * Wawer M et al. Abstract 33 LB, 15th CROI, Boston 2008 **Bunnell R et al. Abstract 29, 15th CROI, Boston 2008, AIDS 2006

14. Rwanda Follow-up of 1034 sero-discordant couples; in 248 the infected partner was on HAART In spite of condom promotion, 42 incident infections were observed HAARTNo HAART N total248786 Seroconversions240 Per cent0.85.1 * Kayitenkore K et al. 14th International AIDS Conference Toronto 2006, abstract no. MOKC101

15. In conclusion HAART lowers MTCT HAART lowers heterosexual transmission (no data on male homosexual transmission) In Africa and in Europe, HAART appears more effective than condoms, in sero-discordant heterosexual couples

16. Contents Without treatment: Relation between viremia and contagiousness Haart: Effects on viremia and contagiousness For the individual: Conclusions to draw (or not) –The Match-up: HAART versus condoms –The problematic « zero risk » –Condoms always, except… –Procreation and PEP –The 64000 $ question The epidemic: possible consequences Background to the “Swiss Statement ”

17. Let’s assume, hypothetically: –Patient A is on HAART, BLD, since 2001 –Meets patient B in 2002, who is HIV- –Patient B is still HIV- in 2004, but HIV+ in 2005 –The viruses of A and B are closely related –A and B claim to have no other sex partners Possible interpretations: 1)A infected B despite having viremia BLD 2)A infected B during a treatment interruption 3)A third individual, C, infected both A and B Zero-Risk-Problem (4):

18. Conclusions Interpretation of rare cases of transmission depends on what people tell you about their sex lives For an enjoyable discussion, see: Lewontin RC: Sex, Lies, and Social Science The New York Review of Books, Volume 42, Number 7, April 20, 1995 A difficult basis for public health decisions… Zero-Risk-Problem (5):

19. Contents Without treatment: Relation between viremia and contagiousness Haart: Effects on viremia and contagiousness For the individual: Conclusions to draw (or not) –The problematic zero risk –Condoms always, except… Procreation and PEP The 64000 $ question The epidemic: possible consequences Background to the “Swiss Statement ”

20. Condoms, except…. Both partners are infected –The principal reason to use condoms (prevention of new infections) has disapeared. –Secondary reasons which speak for condoms anyway The simplicity of the message: 100% condoms Contraception, protection against other STI Superinfection: A more virulant or more resistant HIV strain supposedly replaces a « gentler » HIV: –Theoretical construct that has never been proven. (AIDS 2003;17:F11: A patient with resistant virus is superinfected with a more sensitive virus…) –Does not apply if both partners are infected and treated, with undetectable viremia.

21. Condoms except… Desire for procreation In vitro fertilisation (IVF) –Spermatozoa contain little or no HIV, even without treatment –One can separate spermatozoa from other sperm constituents by centrifugation Arguments against –Expensive, unavailable in poor countries –Success rate of only 15% (compared to natural pregnancy rates of approximately 50% after 6 mos) –Ovarian stimulation is necessary, producing high incidence of multiple pregnancies –No virus – no risk? IVF: A solution for a non-existant problem?

22. Natural conception in sero- discordant couples 62 couples Infected partners with undetectable viremia Non-protected sex, in principal only during fertile days 78 pregnancies at term No HIV transmission Barreiro P et al. Natural Pregnancies in HIV-Serodiscordant Couples Receiving Successful Antiretroviral Therapy. J Acquir Immune Defic Syndr 2006;43:324–326.

23. Contents Without treatment: Relation between viremia and contagiousness Haart: Effects on viremia and contagiousness For the individual: Conclusions to draw (or not) The epidemic: possible consequences –The other side of the coin: desinhibition –Syphilis and HIV compared: the dog that did not bark –If one treated everybody ? –Without vaccination… Background to the “Swiss Statement ”

24. Trends in Primary and Secondary Syphilis and HIV Seroincidence among Men Who Have Sex with Men in San Francisco, 1998-2002. Buchacz, J Klausner et al. CDC, Atlanta, GA, USA, CROI 2005, Presentation # 88 The Dog that Didn’t Bark

25. How to explain the divergence between these two, when one knows that more than 50% of those with syphilis were co-infected with HIV?

26. If HAART did not lower transmission All other things being equal, the number of new infections would increase, because: -Infected persons survive thanks to treatment and stay sexually active -The non-infected, being less afraid of AIDS, drop their precautions Even today, in places like Amsterdam and Vancouver, HAART prevents at least half of all new HIV infections

27. Directed at physicians, to help in counselling Concluded that the risk of sex on HAART without condoms was « close to zero », less than the risk of sex off HAART with condoms Tightly qualified: –On HAART for at least six months –Consistently undetectable VL –No STDs –Perfect adherence Swiss statement does not –Advise against condoms –Condone unsafe sex Statement of the Swiss Federal AIDS Commission (January 2008)

28. If HAART lowers contagiousness, then Why talk about it ?

29. (1) Discrimination Based on fear (of contamination) Particularly in African women Patients who hesitate to touch or kiss their children and grandchildren « A load off their backs »

30. Cela fait des années que nous attendons avec impatience un tel document. Il enlève un poids à celles qui sont infectées par le virus, et qui craignent plus que tout être à l’origine d’une nouvelle contamination. Cette crainte contribue à notre isolement. Connaissant l’effet préventif du traitement bien conduit, nous serons doublement motivées à prendre nos pilules (..) et nous lutterons avec une détermination renouvelée contre les discriminations dont nous faisons l’objet. Lucy Serena* 28 novembre 2007 For years we have been impatiently waiting for such a statement. It takes a load off those who are infected with the virus, and who fear, more than anything, to be the source of a new infection. This fear increases our isolation. Knowing the preventive effect of treatment we will be doubly motivated to take our pills (…) and will fight with newfound resolve against discrimination and stigma. * Chairwoman of ASFAG, a self-help organisation of African women with HIV/AIDS based in Geneva

31. (2) Lawsuits Men accused of endangering others through unprotected sex (although no transmssion took place) Defending themselves saying that due to HAART and undetectable viral load, they were non-infectious Comdemned (to prison terms) anyway because official documents state the opposite

32. (3) Conception See above

33. (4) PEP In case of sexual contact with a person whose VL is undetectable, consider the numbers: –Probability of transmission (less than) 1/10’000 –Cost of PEP approx 2000 Swiss francs (or $) –Costs of PEP per infection prevented: 20’000’000 $ At those odds, you’d probably kill a few with the drugs before saving one from AIDS Not an effective use of health-care resources…

34. (5) HAART as Prevention See above Can’t really bring that forward while pretending that HAART doesn’t decrease contagiousness.

35. “Swiss Statement”: Unmet Needs for Research Reasonable data are available for heterosexual transmission, but not in MSM: Different sex practices with trauma might for instance influence infectiousness Conception through unprotected sex: Larger case series are needed - might be obtained in Africa Treatment as prevention: Population-based trials, similar to syndromic treatment for STDs or parasitic diseases, should be envisaged. They face considerable hurdles (ethical, political, financial)

36. Thank you to… Julio Montaner for the slides of his plenary conference in Toronto (August 2006) Pietro Vernazza

37. The End

38. Hogg et al. Unpublished, 2006 Treat all Treat 30% HIV infections per 1000 population 20061014182226303438422050

39. Coûts du traitement Treat all Treat 30% 20061014182226303438422050 10 9 $ Hogg et al. Unpublished, 2006

40. Costs of HAART 20061014182226303438422050 Billions de $ Small investment Great savings Lima VD et al. Expanded Access to Highly Active Antiretroviral Therapy: A Powerful Strategy to Curb the HIV Epidemic; JID 2008; volume 198, July 1. Hogg et al. Unpublished, 2006

41. Recently infected homosexuals Total Population (PHI, 2003-2006)232 Interviewed158 Express an opinion on how they were infected143 « Sure » that source had undetectable viremia 9 « Sure » that source was HIV negative 21 Jin F et al: How homosexual men believe they became infected with HIV. JAIDS 2007; 46:245-247 Zero-Risk-Problem (1):

42. Enquiry in the Swiss HIV Cohort Study: « Do you know cases of transmission where a treated patient with undetectable viremia was involve»? –1 troubling case in Geneva, 1997 Study in the litterature: –None (one possible case in Francfort has been submitted for publication) Zero-Risk-Problem (2):

43. It is impossible to prove the absence of risk –Let’s say that among 100 sero-discordant couples, there are zero infection after 2 years of observation –Would this still be zero in 1000 couples observed during 10 years? Where is the limite? Guidelines protect those who write them –The politician, or the expert who denies a risk which nevertheless turns out to be real indangers his career. The oppostite mistake has no consequences. –One can never be too prudent (said the concierge) Zero-Risk-Problem (3):

44. Costs of treatment 20061014182226303438422050 Billions of $ Small investment Great Savings Hogg et al. Unpublished, 2006

45. One could go further… Mr. X is HIV+, his wife HIV-, anxious, in vitro fertilization was not successful Non-protected sex during days 14-20 of each cycle Mrs. X takes one pill of tenofovir per day Will we one day all be like Mrs. X, taking something daily to protect against HIV ?

46. Quiz Against which other disease that used to be frequent are all the Swiss protected by a drug added to food ?

47. Effects of iodine deficiency

48. The Iodine Model: HAART in Food HIVIodine Deficiency Quantity per day 1000 mg100  g

49. -The doses are 10’000 times higher -Resistance -Toxicity There Are A Few Problems Left To Solve…

50. Speisesalz mit Jod, Fluor, und Preventivirin Sel de cuisine avec iode, fluor, et préventivirine Pack of salt, bought in Geneva, 27th November 2030 Kitchen salt with iodine, fluorate, and preventivirin

51. Contents Without treatment: Relation between viremia and contagiousness Haart: Effects on viremia and contagiousness For the individual: Conclusions to draw (or not) The epidemic: possible consequences Background to the “Swiss Statement ”