1. An update on PrEP, PEP and Treatment as Prevention Francois Venter Wits Reproductive Health & HIV Research Institute (RHI) AWAAC 2015

2. “Test & Treat / offer” vs other biological prevention

3. HIV Treatment Cascade 90-90-90 for HIV: 6.4 million PLHIV 1 st 90 - 5.7 million PLHIV know their HIV status 2 nd 90 - 4.1 million PLHIV who know their status & who are eligible are on treatment 3 rd 90 - 3.7 million PLHIV on treatment with suppressed viral loads Reduce the annual number of new HIV infections by 150,000 What Fast Track by 2020 means in South Africa

4. We are probably very close to the 3 rd 90 Second 90: probably there for women; not men – and that’s a huge problem

5. Thanks: Mitchell Warren, AVAC

6. So what do we have in the bag? T&T (including PMTCT and children) Post Exposure Prophylaxis (PEP) Pre-exposure prophylaxis (PrEP) Male circumcision Condoms Needle exchange Behaviour change (New microbicides) (Vaccines) (Cure)

7. PrEP

8. 8 Potential types of PrEP How are the antiretrovirals used? Oral pill Topical gel (microbicide) Rectal Vaginal Injection Intravaginal ring How often are the antiretrovirals used? Daily Intermittently Coitally (before/sex) How many antiretrovirals are used? Single Combination What antiretrovirals are used? Over 25 available

9. TDF/FTC approved for prevention United States Regulatory application filed for a prevention indication for TDF/FTC Brazil South Africa Thailand Status of Regulatory Approval for Daily TDF/FTC for Prevention in Host Countries Host countries with no regulatory application filed for prevention AustraliaBotswanaCanada EcuadorFranceGermany KenyaPeruTanzania ThailandUgandaUnited Kingdom

10. RCT evidence for preventing sexual HIV transmission - 2014 Efficacy Study Effect size (CI) Medical male circumcision (Orange Farm, Rakai, Kisumu) 54% (38; 66) HIV Vaccine (Thai RV144) 31% (1; 51) 0% 10 20 30 40 50 60 70 80 90 100% STD treatment (Mwanza) 42% (21; 58) 39% (6; 60) Microbicide (CAPRISA 004 tenofovir gel) PrEP for MSMs (IPREX) 44% (15; 63) Treatment for prevention (HPTN 052) 96% (73; 99) PrEP for heterosexuals (Botswana TDF2) 63% (21; 48) PrEP for discordant couples (Partners PrEP) 73% (49; 85) Abdool Karim SS & Q. Lancet 2011;378:e23-5

11. Adherence and HIV protection: oral PrEP % of blood samples with tenofovir detected HIV protection efficacy in randomized comparison HIV protection estimate with high adherence Partners PrEP TDF/FTC arm 81%75% 90% (tenofovir in blood) TDF279%62% 78% (prescription refill) BTS67%49% 70% - 84% (tenofovir in blood / pill count) iPrEx51%44% 92% (tenofovir in blood) FEM-PrEP & VOICE<30%No HIV protection N/A Baeten et al N Engl J Med 2012; Thigpen et al N Engl J Med 2012; Choopanya et al Lancet 2013; Grant et al N Engl J Med 2010; Van Damme et al N Engl J Med 2012; Marrazzo et al CROI 2013 When adherence was high, HIV protection is consistent and high.

12. PrEP safety Rates of death, serious adverse events, and laboratory abnormalities (including renal dysfunction) were low and not significantly different between those taking PrEP and those taking placebo PrEP was well tolerated Adverse effects occurred in minority of subjects GI adverse effects (e.g., nausea) more common in those receiving PrEP than placebo Occurred in < 10% and primarily during the first month only (PrEP “start up” symptoms) PrEP associated with a small change (~ 1%) in bone mineral density but without increased risk of fracture

14. $$$$$ And coverage very limited

15. “PrEP wouldn’t make me have more sex; I would just worry a lot less”

16. A fly in the ointment…. HIV testing is a major cost-driver HIV self-testing will simplify, make more efficient AND make programmes cheaper

17. Potential in Southern Africa? FSWs, MSM – verticalised services in place Pregnant women Contraception services Adolescent girls ?discordant couples?

18. RHIVA collaboration with MiET Africa and DoE with funding from the Royal Netherlands Embassy Age Group HIV Prevalence (Oct/Nov 2010) % (95% Confidence Interval) MaleFemale  14 1.0 (0.0 – 3.0) 2.2 (0.3 – 4.0) 15-161.4 (0.4 – 2.4) 3.6 (2.2 – 5.0) 17-181.2 (0.2 – 2.2) 7.9 (5.0 - 11.0) 19-201.1 (0.0 – 2.7) 16.0 (9.2 – 22.0) CAPRISA: HIV prevalence in school boys and girls in a rural South African district (grades 9 and 10)

19. PEP

20. DoH

21. Big thorny questions in PEP? Should I give antiretrovirals? (and high vs low risk) Should I give 2 or 3 drugs? Role of pre-exposure prophylaxis?

22. Big new ideas Make peace with limited data – and that we are unlikely to get better ‘pure PEP’ data Occupational vs non-occupational Safe ‘third’ drugs

23. New CDC risk table

24. Recent data… PrEP data suggests ART very effective 052: Treat the partner TDF/FTC and AZT most evidence based; CCR-5 blockers and integrase inhibitors interesting

25. Occupational versus non-occupational WHO following Society lead– dumped these categories (some ‘special occupations’ in new guidelines) BUT: major medico-legal consequences, hence may justify more monitoring “You are more at risk of HIV off-duty than on duty”

26. Should we give a third drug? Or even a second drug? NO data on this – whether adding gives additional protection or any drug being better than the other (and we probably will never know) Adds very little to current prevention BUT Simpler, less anxiety Problem is toxicity and cost

28. Which third drug? Lop/rit safer than Ataz/rit; Darunavir/rit now an option EFV – unpopular Integrase inhibitors – decrease price, excellent side effect profile

29. But… Weigh up rare but serious side effect vs very rare transmission event (for a disease that is now easy and cheap to treat)

30. WHO guidelines Almost all low quality evidence (except adherence!)

31. Big recommendations

32. <72 hours? Based on animal models and observational data BUT…

35. For slightly richer countries? WHO guidelines plus… Recommend integrase inhibitors as third drug (?rilpivarine, others) All usual suggestions around hepatitis B, followup etc etc

36. The principles for occupational and non-occupational are similar Prevention – management structures, hep B vaccines Anxiety management critical HIV/hep B baseline important Discourage unnecessary tests Encourage full completion of 28 day course Don’t dwell too hard on 2 vs 3 drugs ACTIVE side effect management

37. ‘’Treatment for prevention” (T&T) Theoretical and observational data been around for a while

38. Thanks Connie Cellum

41. Observational studies followed…

43. Viral Load and New HIV Cases in San Francisco Das M,, et al. Decreases in Community Viral Load Are Accompanied by Reductions in New HIV Infections in San Francisco. PLoS ONE 2010 n=12,512 unduplicated HIV-positive individuals.

44. ART coverage significantly decreased individual risk, KwaZulu Natal, South Africa (2004-11) Africa Centre longitudinal surveillance cohort with community and individual data Between 2004 and 2011, 1395 HIV seroconversions and over 53,042 person-years of observation (crude HIV incidence rate of 2.63 (95% C.I. 2.50 to 2.77) per 100 person-years Maps showing the estimated percentage of HIV + adults (≥15 years of age) on ART across the Africa Centre’s surveillance area (2004 to 2011) Every % point increase in ART coverage among all HIV+ adults in a community, was associated with a 1.7% decline in the hazard of HIV acquisition (p <0.001)

45. Is sex safe? HPTN 052 HR = 0.37 or 96.3% reduction in transmission Deferred Immediate %

46. Is sex safe? HPTN 052 HR = 0.37 or 96.3% reduction in transmission Deferred Immediate % And confirmed in Partners study

47. Thorn in T&T side: Individual benefit Conflicting observational studies 052 not convincing re individual data

48. START and Temprano fixed this

49. Thanks: Simon Collins

50. START and Temprano fixed this Thanks: Simon Collins David Barr: “It’s easy to say that we always knew the answer… we would have a very different answer if we lived in the d4T or AZT era…”

51. Programmes are starting to improve

52. Changing disease severity over time Source: Consolidated National report covering monthly and quarterly ART data to end March 2014 Thanks: Andrew Boulle

53. Treatment for life Thanks: Julie Fox, Guys

54. ~4 YEAR LAG BETWEEN SCALE UP OF ART AND DECLINE IN MTB INCIDENCE Figure 1: Incidence of microbiologically-confirmed pulmonary tuberculosis (per 100,000 population) and antiretroviral treatment coverage rates in HIV-infected individuals nationally in South Africa nationally and provincially from 2004 to 2012 The solid black line represents the estimated trend in PTB incidence per 100,000 population over the study period and the dotted black line the corresponding 95% confidence interval. The overlaid dotted grey line is the ART coverage per 1000 HIV positive individuals based on data from the ASSA 2008 model. Nanoo A, Izu A, Ismail, NA, Ihekweazu C, Abubakar I, Mametja D, Madhi SAM. 2015. Nationwide and regional decline in incidence of microbiologically-confirmed pulmonary tuberculosis in South Africa: a time series analysis from 2004 to 2012. The Lancet Infectious Diseases, In press

55. Let’s do a thought-experiment… Pretend you are: A cold-hearted public health official “Let’s dump prevention: lets aggressively test, and give them the best treatment, in the best system” “Why prevent when its so much easier to treat?”

57. Does this make sense? Fits current health model – just need to expand HIV testing, tinker with existing services No money on dubious behaviour change No more complicated vertical programmes No more x to stop y HIV infections No more political problems: Gay men, sex workers, IDU’s, adolescent sex education

58. Greatest impact with implementing effective strategies together From Cohen Science 2011, model from Cremin and Hallett HIV/AIDS Department

60. Your life is in the hand of (an often unreliable) distributor And it is an international problem….

61. Money IS short More scrutiny against impact

63. BHIVA 2015, activist conversation on Grindr

64. Challenges specific to T&T Retention and tracking programmes need priority Return into care HAS to be made easier Need easier, cheaper, more robust first line Adherence interventions - crisis