1. HIV/GUM research update Dr Amanda Clarke Consultant in HIV/GUM & Clinical Trials, BSUH. 16 Nov 2015 LES GPs

2. What we’ll cover GUM research ongoing HIV Prevention news HIV treatment – when to start, new strategies Cure/vaccine – where we’re at

3. GUM Research Technology: STI testing eg 3-in-1, POCT Treatment strategies eg PID study, G-tog HIPVac:HPV vaccination for pts with warts Behavioural studies/club drugs : Aurah/sante Integration with CASH: future contraception research

4. Pre Exposure prophylaxis (PrEP)

5. Evidence: population, drug, regimen PopulationTrialsReduction in HIV incidence Drug, delivery, regimen Gaps in evidence MSM and transgender iPrEX PROUD IPERGAY 44% 86% TDF/FTC Oral Daily/on demand TDF Topical Heterosexual men and women Partners PrEP TDF2 63 - 84% 62% TDF +/- FTC Oral DailyOn demand Women CAPRISA FACTS FEM-PREP VOICE 39% 0% 6% -49% - 15% TDF +/- FTC Gel/Oral Daily/on demand Adherence People who inject drugs BTS49%TDF Oral Daily Route of transmission

6. Adherence and mITT efficacy

7. Proud & Ipergay PROUD – pilot study, n=545, high risk MSM/TW Immediate daily truvada or delay 1 year + counselling/HIV testing/STI checks 3 monthly ‘Real world’ Ipergay – n= 414, placebo controlled, event driven, MSM More cost effective, less toxicity, adherence benefits? Thanks to Sheena McCormack for some of her PrEP slides

8. HIV Incidence Group No. of infections Follow-up (PY) Incidence (per 100 PY) 90% CI Overall23465.64.93.4–6.8 Immediate3243.51.20.4–2.9 Deferred20222.19.06.1–12.8 Effectiveness =86% (90% CI: 64 – 96%) P value =0.0001 Rate Difference =7.8 (90% CI: 4.3 – 11.3) Number Needed to Treat =13 (90% CI: 9 – 23)

9. FridaySaturdaySundayMondayTuesdayWednesdayThursdayFridaySaturdaySunday Ipergay : Event-Driven iPrEP 2 tablets (TDF/FTC or placebo) 2-24 hours before sex 1 tablet (TDF/FTC or placebo) 24 hours later 1 tablet (TDF/FTC or placebo) 48 hours after first intake

10. KM Estimates of Time to HIV-1 Infection (mITT Population) Mean follow-up of 13 months: 16 subjects infected 14 in placebo arm (incidence: 6.6 per 100 PY), 2 in TDF/FTC arm (incidence: 0.94 per 100 PY) 86% relative reduction in the incidence of HIV-1 (95% CI: 40-99, p=0.002) NNT for one year to prevent one infection : 18

11. Results (both studies) Stopped early – far higher rates of HIV than predicted 86% reduction in HIV both studies High rates STIs both groups (including HCV) No overall difference in sexual risk behaviour in either groups Well tolerated (few permanently due to adverse effects), GI Adherence important, exclude HIV at initiation Subsequent UK analysis – cost effective in high risk groups

12. PrEP in UK Decision re funding delayed to June 2016 Private London clinic - Dean St (£400/month) People buying on internet & asking for private Rx Several websites selling (cipla generic – Tenvir-EM - £44/month) Brighton- CNC – now providing a PrEP monitoring service (3 monthly STI/HIV/renal assessments/advice) NB: women & PrEP

16. HIV treatment

26. WHO

27. USA

28. EUROPEAN

29. UK

30. Antiretroviral therapy research ARV switches Simplification – less pills…. mono/dual therapy Toxicity reduction – eg renal/bone/CNS/CVD Additional benefits eg anti-inflammatory New formulations

31. Nanosuspensions not too far off? Latte 2 study 32w results announced, phase 2b, n=309 2 long acting formulations – rilpivirine & cabotegravir as i.m. injections Q4 weekly or Q8 weekly vs triple oral ARV 95 v 94 v 91% viral undetectablility Injection site pain in 93% Great potential for poorly adherence pts & pt choice

32. HIV Cure Research

33. Acute infection “Functional Cure” in HIV+ Child Mississippi HIV+ infant treated at 31 hrs of age with ZDV/3TC + NVP until 7 days and then with ZDV/3TC + LPV/RTV to 18 mos, after which ART was suspended [1] At 39 mos of age, remains in remission with undetectable plasma HIV-1 RNA < 20 copies/mL and normal CD4+ and CD8+ cell counts [2] Second case: A different child with high-risk HIV exposure started on triple-ART at 4 hrs of age [2] HIV infection confirmed by positive peripheral blood HIV-1 DNA at 4 hrs and HIV-1 RNA (217 copies/mL) at 36 hrs of age Plasma HIV-1 RNA undetectable by 11 days through 8 mos of age and no replication-competent HIV recovered from resting CD4+ cells at 1 and 3 mos of age Adapted from:. Persaud D, et al. CROI 2013. Abstract 48LB. 2. Persaud D, et al. CROI 2014. Abstract 75LB.

34. Acute infection “Functional Cure” in HIV+ Child Mississippi HIV+ infant treated at 31 hrs of age with ZDV/3TC + NVP until 7 days and then with ZDV/3TC + LPV/RTV to 18 mos, after which ART was suspended [1] At 39 mos of age, remains in remission with undetectable plasma HIV-1 RNA < 20 copies/mL and normal CD4+ and CD8+ cell counts [2] Second case: A different child with high-risk HIV exposure started on triple-ART at 4 hrs of age [2] HIV infection confirmed by positive peripheral blood HIV-1 DNA at 4 hrs and HIV-1 RNA (217 copies/mL) at 36 hrs of age Plasma HIV-1 RNA undetectable by 11 days through 8 mos of age and no replication-competent HIV recovered from resting CD4+ cells at 1 and 3 mos of age Adapted from:. Persaud D, et al. CROI 2013. Abstract 48LB. 2. Persaud D, et al. CROI 2014. Abstract 75LB. RELAPSED

35. Adults – acute infection Visconti cohort: French cohort 14 patients, now 27) who started ARVS early (within 10 weeks) – stopped Rx after 3 yrs, 16% ‘functional cure’ Pt on PrEP study. HIV negative at screening but HIV positive at baseline Received 7 days of oral TDF/FTC PrEP but switched to ART immediately when test results returned and remains on ART Plasma HIV-1 RNA levels: 220 c/mL at PrEP BL; 120 c/mL at 7 days of PrEP; “detected < 40 c/mL” at ~ 32 days after infection All subsequent HIV-1 RNA and DNA tests have been negative, including those performed in a colorectal biopsy Hatano H, et al. CROI 2014. Abstract 397LB..

36. Acute or chronic infection? Chronic 2007 The Berlin patient – functional cure post stem cell transplant for CLL with genetically ‘resistant’ HIV virus –CCR5 delta-32 mutation But …. 2 Boston patients with lymphoma, stem cell Tx 12 yr old boy with leukeamia, stem cell Tx Problem: toxicity of Rx, viral reservoirs, not for all

37. Acute or chronic infection? Chronic 2007 The Berlin patient – functional cure post stem cell transplant for CLL with genetically ‘resistant’ HIV virus – CCR5 delta-32 mutation But …. 2 Boston patients with lymphoma, stem cell Tx 12 yr old boy with leukeamia, stem cell Tx Problem: toxicity of Rx, viral reservoirs, not for all RELAPSED

38. Early treatment…. Window of opportunity? Treatment during primary infection may maintain high levels of HIV-specific CD4+ lymphocytes, cells thought to be vital for orchestrating cellular immunity to HIV Early treatment preserves immune responses by preventing the preferential infection and deletion of HIV-specific CD4+ cells during primary infection Some individuals treated during primary infection have been able to stop therapy with sustained virologic control In contrast, other anecdotes have described prompt and persistent viral rebound in similarly treated persons who interrupted therapy

39. Protocol Overview A two-arm (proof of concept) randomised phase II trial 39

40. Circulating virus Time HIV persists during ART ART does not eradicate HIV ART 40

41. Why can’t ART cure HIV? 41

42. TW Chun et al. J Infect Dis 2008; S. Yukl et al. J Infect Dis 2010; M. Churchill et al. Annals Neur 2010; C. Fletcher et al. PNAS 2014; M. Perreau et al. J Exp Med 2013 Where does HIV hide? 42

43. Study Hypothesis –Kick and kill hypothesis Intervention in PHI, with a combination of immediate ART, prime-boost vaccination and latency reactivation using the HDACi vorinostat will confer a significant reduction in the HIV reservoir vs. ART alone. Prime-boost vaccination for the “kill” using ChAdV63.HIVconsv prime and MVA.HIVconsv boost; HDACi for the “kick” – vorinostat. Primary End point – total HIV DNA in CD4 lymphocytes (pts will continue ARVs) 1 SPARTAC Trial Investigators. N Engl J Med. 2013 Jan 17;368(3):207-17; 2 Hicks CB. Clin Exp Immunol. 2007 Aug;149(2):211-6; 3 Evering TH, PLoS Pathog. 2012 Feb;8(2):e1002506; 4 Goujard C. Antivir Ther. 2012;17(6):1001-9. 43

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45. summary CASH – expanding research, STI testing & Rx Prevention – PrEP works in real world but £? All HIV positive people should have Rx offered ARV therapy now more about toxicity/longterm Some cases of HIV ‘cure’ failed Acute HIV – window of Rx opportunity – don’t miss it!

46. Questions?