Where are we with PrEP in Europe?

1. Where are we with PrEP in Europe? Gus Cairns Co-chair, PROUD study Editor, NAM/aidsmap.com

2. Three ways of preventing disease • Structural: change society • E.g. tobacco-advert or seatbelt legislation • Sewerage systems, better housing • ?Gay marriage? ?Gender equality? • Behavioural: change the mind • E.g. smoking cessation workshops • Diet and exercise advice • Safer-sex support • Biomedical: change the body • E.g. statins for cholesterol • Malaria/TB prophylaxis • Vaccines • VMMC for heterosexual HIV infection

3. HIV prevention methods - effectiveness

4. PrEP - effectiveness

5. Adherence is all... Courtesy Laura Waters

6. Approval and prescribing • FDA approval, USA: 16 July 2012 • Last action from EMA was Reflection Paper*, March 2012: deadline for comments, 30 June 2012: since then nothing. • BHIVA / BASHH Position Statement on PrEP in the UK: July 2011Fidler S, Fisher M, McCormack S et al • “…we recommend ad-hoc prescribing is avoided, and PrEP is only prescribed in the context of a clinical research study in the UK” • Prescriptions in USA: 1274 up to beginning of 2013: >2000 likely in 2013 • Represents only 1%-2% of Truvada prescribing • 1.6x more likely to be women • But more MSM in clinical trials (c. 3000 people in US trials/ demonstration projects) *http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/03/WC500124054.pdf

7. PROUD study • Started November 2012 • Open-label Truvada, daily, 2 years. • Randomises 50/50 to immediate PrEP or 1-year delay (+ safer-sex support, monitoring, peer-group interaction, etc) • N = 550; almost fully recruited (428 a month ago) • DSMB advisor approved continuation last month • Slower than expected recruitment at first but has filled up quicker recently (340 Nov) • Community engagement group: articles in QX Magazine, etc • Application to expand to larger study: decision September: 1000 initially, possible expansion to 2500: any larger would need multi-country collaboration • 6 month retention: 92 immediate arm, 76% on deferred arm • Some seroconversions

8. IPERGAY study • Ipergay: French study • Event-driven Truvada PrEP, before-and-after dosing. Placebo-controlled • Slow to recruit but “close to the pilot target = 300 • Expanded into Quebecend of the first phase of the trial” and have now recruited • Funding being sought to expand into Berlin and possibly other locations

9. Other US studies Courtesy Ken Mayer, IAPAC, 2012

10. PrEP: cost-effectiveness • Thirteen modelling studies • Cost per QALY gained ranged from minus $206 (i.e. cost-saving) to $230,551 • Southern Africa, general population: probably cost-effective • Peru, MSM : cost-effective in high-risk MSM if added to existing programmes • Ukraine, PWIDs: only cost-effective if added to OST programmes and in itself much less cost effective than OST • US MSM: mixed results, cost-effective in some targeted populations. • Characteristics of cost-effectiveness: • High adherence • Low drug cost (<50% of triple-combination ART) • Generally only effective in high-risk members of population

11. Who is ‘high risk’? • ‘Risk trajectory’ in MSM study, December:* 6-9 year follow-up • 15% were like this: • 23% were like this: • 63% were like this: • Risk of low-risk having a high-risk period: 0.9% *Pines HA et al. Sexual risk trajectories among MSM in the United States: implications for pre-exposure prophylaxis delivery. JAIDS, December 2013.

12. Who is ‘high risk’? 2

13. Acceptability and interest • Large numbers of acceptability studies in potential users. • UK studies*: acceptability generally related to sexual risk: higher-risk men more likely to be interested: younger men more interested in one study • Qualitative work/discussions with PROUD users: trial participants made considered decision to user PrEP, often part of a couple, worry what ‘other’ gay men will do with PrEP • US studies: greater acceptability in younger, non-white, poorer education: less knowledge or more vulnerability? • Aghaizu A et al. Who would use PrEP? Predictors of use among MSM in London. 18th Annual Conference of the British HIV Association, Birmingham, abstract O23, 2012. See abstract here.    • Thng C et al. Acceptability of HIV pre-exposure prophylaxis (PrEP) and associated risk compensation in men who have sex with men (MSM) accessing GU services. 18th Annual Conference of the British HIV Association, Birmingham, abstract P233, 2012. See abstract here. *Sigma Research, The Sigma Panel Insight Blast 6: Prospective attitudes to HIV pre-exposure prophylaxis (PrEP), 2011.

14. Side effects • Drug-specific • Side effects of tenofovir: • Acute: nausea in first week (common), headache (less common). Some evidence may affect adherence early on. • Chronic: raised creatinine (indicator of kidney problems: mildly raised after first two weeks, didn’t get worse, persisted through study (81 weeks median), immediately normalised after • Bone mineral loss: in HIV-positive subjects, c. 2% loss of bone mineral density after two years in either spine or hips (studies disagree on where). Unlikely to have clinical effects for 10-20 years. Solomon MM et al. Changes in renal function associated with oral emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 28, online edition.DOI:10.1097/QAD.0000000000000156, 2014.

15. Behavioural compensation? • In opinion studies of gay men, about a third* said they’d be likely to reduce condom use if they took PrEP, but • Number of PrEP studies in which sexual risk behaviour has increased: zero • Studies are not ‘real life’ but • PrEP comes with regular attendance, testing and monitoring, and • Targeting properly may = only giving PrEP to men who already don’t use condoms *Golub SA et al. Preexposure prophylaxis and predicted condom use among high-risk men who have sex with men. J Acquir Immune DeficSyndr, advance online publication, 2010.

16. STIs • PrEP won’t stop most STIs (tenofovir may have an effect on HBV and possibly herpes): condoms do • STIs increasing in gay men (80% of male syphilis cases is in MSM) • Will PrEP worsen this trend? Or will it at least protect from HIV those who would get STIs anyway? • HIV now treatable, with no loss in life expectancy if caught early: but still has unique combination of lifelong infection, c. 100% fatality if untreated, intense social stigma

17. Future • Injectable formulations of HIV drugs • Rilpivirine: probably dosable monthly • GSK 744 – new integrase inhibitor: successor to dolutegravir: prob 2yrs away from licence • Currently in early stage of safety/dosing trials as combined injectable PrEP • Q: Are both drugs needed? Tenofovir alone worked as well as Truvada in some PrEP studies

18. Thank you! • Thanks to Michael Brady, Sheena McCormack, Jean-Michel Molina, Ken Mayer,

19. Backup slides: condoms

20. Condoms... Data from Gay Men’s Sex Surveys, 1993-2008 and EMIS 2010: The European Men-Who-Have-Sex-With-Men Internet Survey. Findings from 38 countries See also Hickson F et al. HIV Testing and HIV Serostatus-Specific Sexual Risk Behaviour Among Men Who Have Sex with Men Living in England and Recruited Through the Internet in 2001 and 2008. Sexuality Research and Social Policy 10: 15-23. (Full text available here)

21. Why don’t people use condoms....? • Even at height of epidemic (San Francisco, 1994*), c. 30% of gay men were not using them • As many reasons as people... • Reasons may be disguised – from others and from self • Sexual dysfunction may be important, both as immediate cause and as underlying cause Katz MH et al. Impact of highly active antiretroviral treatment on HIV seroincidence among men who have sex with men: San Francisco. Am J Pub Health 92(3):388-394, 2002

22. Condoms and dysfunction • Dutch study, 2008, 435 gay men, 6% HIV+* • 10% experienced COINED (COndomINduced Erectile Dysfunction) with casual partners • If they did, 6.6 times more likely to have unprotected sex • If they had COINED at time t, 2.7x more likely to have unprotected sex at time t+6m • French study, 2005: HIV+ gay men who experienced ED 3.2x more likely to experience depression† • US study, 120 gay men: HIV- (but not HIV+) with depression 4.5x more likely to have unprotected sex.‡ *Lammers M et al. Condom induced erectile dysfunction (COINED): a unique predictor of deliberate sexual risk. XVII International AIDS Conference, THPDC205, Mexico City, 2008. † Bouhnik AD et al. Unsafe sex with casual partners and quality of life among HIV-infected men who have sex with men (MSM): evidence from a large representative sample of outpatients attending French hospitals (ANRS-EN12-VESPA). Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract MoPe10.7P10, 2005. ‡ Houston E at al. Depressive symptoms among MSM who engage in bareback sex: Does mood matter?

23. Sexual health and trauma • Sexual dysfunction, depression, recreational drug use, traumatic experience, poor social skills may all mutually reinforce each other as drivers of sexual risk in gay men. • Not using condoms may be rationalised as “I don’t like them” when the reality is “I can’t use them” • PreP may help break the sexual risk pattern by placing an emotional and temporal gap between the prevention behaviour and the risk: you’re not already ‘high’ when you try and use your ‘works’