PEP and PREP. Dr David Hawkins Chelsea and Westminster Hospital

Transcription

1 PEP and PREP Dr David Hawkins Chelsea and Westminster Hospital

2 Opportunities for biomedical interventions YEARS HOURS 72 HOURS YEARS Prior to exposure Exposure (pre-coital/ coital) Exposure (pre-coital/ coital) After infection Male circumcision Oral pre exposure prophylaxis (daily PrEP) Topical PrEP (daily gels or intra-vaginal rings (microbicides) Preventive Vaccines Oral pre exposure prophylaxis (intermittent PrEP) Coitally dependent topical PrEP (microbicides) Oral post exposure prophylaxis (PEP) Anti-retroviral therapy Immediate treatment of positive partners in discordant couples Treatment for prevention in all who test positive for HIV (TasP) All have behavioural and structural components

3 Prescribing PEP - principles PEP should be prescribed only for significant exposures where source patient is KNOWN OR STRONGLY SUSPECTED TO BE HIV POSITIVE PEP should be started ideally within 1 hour of exposure (usually not after 72 hours)

4 Efficacy of PEP Older animal studies yielded conflicting results Recent Truvada PrEP/PEP studies prevented acquisition in macaques challenged rectally for 14 weeks using low-dose (physiological) inocula Level of protection varied according to the timing of doses: Highest level of protection being offered when the first dose was administered between 22 hours and seven days prior to the exposure and a second dose two hours after ALL animals needed PEP dose No protection was observed if the first dose was delayed beyond 24 hours post-exposure

5 Retrospective case-controlled study among HCW 28-day course of zidovudine was protective, odds ratio (OR) 0.19 (95% CI %) This study has some limitations, including Small number of cases (n = 33) and cases and controls (n = 665) derived from different countries and details of exposure characteristics of cases were collected retrospectively Likelihood of receiving zidovudine was related to the likelihood of transmission

6 HIV PEP: Failures in Healthcare Personnel World-wide Cases 24 cases of ZDV failure in healthcare personnel 7 cases of combination HIV PEP failure no delay in time to seroconversion no adverse effects on natural history Potential Explanations delay in treatment dose too low / low drug levels resistant virus high inoculum exposure treatment duration too short Tomkins S, Ncube F. Occupationally acquired HIV: international reports to December Euro Surveill 2005;10:Article 2

7 Occupational PEP Considerations Source patient known to be HIV+ or at risk of HIV infection Exposure risk with infectious body fluid (i) percutaneous injury (from needles, instruments, bone fragments, significant bites which break the skin etc.); (ii) exposure of broken skin (abrasions, cuts, eczema etc.); (iii) exposure of mucous membranes including the eye Source factors: High VL; low CD4/AIDS

8 Non-occupational exposure to HIV infection

9 Risk of exposure Type of exposure Estimated risk of HIV transmission (median) Needle-stick injury 0.3% Sharing injecting equipment 0.67% Mucous membrane exposure 0.09% Receptive anal intercourse % (1.11%) Receptive vaginal intercourse % (0.1%) Insertive vaginal intercourse % (0.08%) Insertive anal intercourse % (0.06%) Receptive oral sex % (0.02%)

10 Estimated per-contact probability of HIV transmission of UPAI Jin et al. AIDS 2010; 24 o 1427 HIV -ve MSM community cohort o F/U 4537 person years (median 3.9 years) o High uptake of HIV testing and ART Insertive UAI Per contact probability (%) 95% CI Uncircumcised Circumcised Receptive UAI Withdrawl Ejaculation

11 N=700 non-randomised dual NRTI PEP within 72 hrs Seroconvertors (7) vs. non seroconvertors: more likely RAI 100% vs. 50% (p= 0.03) trend to later treatment 46 vs. 33 hrs (p=0.11) three confirmed poor adherence no molecular epidemiology

12 Rio Study High risk MSM Dual NRTI PEP initiated 109 times by 68 participants (34.0%) HIV seroconversions: 10 among non-pep users and 1 that was a PEP failure Overall seroincidence was 2.9 per 100 person-years (95% CI = 1.4, 5.1) Expected number of new HIV infections and corresponding expected seroincidence based on the risk profile were 11.8 and 3.1 respectively (P > 0.97) Sao Paulo PEP Study (Drezett 2000) Female sexual assault: < 72hrs given PEP > 72hrs no PEP 0/182 seroconverted in PEP group cf. to 4/145 (2.7%) in control group (p=0.037)

13 Table 1: Risk that source is HIV positive (UK 2014) Population group* HIV prevalence (%) Men who have sex with men UK 5.9 London 12.5 Elsewhere in UK 3.8 Brighton 13.7 Manchester 8.6 Heterosexuals (region of birth) Male Female Black African ethnicity Non Black African ethnicity Injecting drug users UK

14 Risk calculation Risk group/activity Risk of HIV transmission (unknown source) Risk of transmission (source HIV+ and detectable VL) Homosexual men/ UPAI 15% x 3% = 0.45% (1/222) 1 x 3% = 3% (1/33) UK Heterosexual woman/rvi 0.1% x 0.09% = % (1/10,000) 1 x 0.09% = 0.09% (1/1111) IVDU/ sharing equpiment 4.7% x 0.67% = 0.031% (1/3226) 1 x 0.67% = 0.67% (1/149) Recommend if risk >1/1000 Consider if risk >1/ but <1/1000

15 PARTNER Study Serodiscordant couples where HIV+ has VL<200 and HIV- NOT using PEP or PrEP 2yr interim analysis N>700; > sex acts for MSM; for heterosexuals Reporting frequent condomless sex acts

16 PARTNER Study - interim and now published NO transmissions Vaginal sex with ejaculation upper CL 1.5 per 100 CYFU MSM RAI with and without ejaculation 2.7 and 1.68 per 100 CYFU respectively

17 BASHH PEP guidelines (2015) Exposure Source HIV+ VL > 50 Source HIV+ VL<200 Source prevalence high (>10%) Source prevalence low Receptive anal sex R NR R NR Insertive anal sex R NR C NR Receptive vaginal sex R NR C NR Insertive vaginal sex C NR C NR Fellatio with ejaculation NR NR NR NR Fellatio no ejaculation NR NR NR NR Splash semen into eye NR NR NR NR Cunnilingus NR NR NR NR

18 Recommendations for PEPSE Other factors may influence the probability of HIV transmission: - Sexual assault - High viral load in donor - Concurrent STI These may influence recommendations

19 Revised BASHH PEPSE Guidelines 2015 What about UPAI with a partner who is definitively known to be undetectable? What PEP drugs? WHO guidelines revised 2014 Review of evidence within 72 hours? Too long Need for 28 days? PEP v PREP

20 Pre-exposure prophylaxis

21 How does PrEP effectiveness compare? Study Prime-boost HIV Vaccine (Thai RV144) 1% tenofovir gel (Caprisa 004, Karim et al.) TDF/FTC oral-prep in MSM (iprex, Grant et al 2010) Medical male circumcision (Orange Farm, Rakai, Kisumu) TDF/FTC oral-prep in heterosexuals (TDF2, CDC) TDF oral-prep in serodiscordant Partner (Partners PrEP) TDF/FTC oral-prep in serodiscordant Partner (Partners PrEP) Effect size (CI) 31% (1, 51) 39% (6, 60) 44% (15, 63) 57% (42, 68) 63% (22, 83) 62% (34, 78) 73% (49, 85) Immediate ART for positive 96% (82, 99) Partners (HPTN052) 0% % Efficacy

22 Why so different? Adherence

23 Does PrEP encourage compensatory risk? From placebo-controlled efficacy trials, no evidence of compensatory risk (but difficult therefore to assess impact as both arms active ) Liu et al, JAIDS 2013: 400 MSM in US Randomised 1:1:1:1 FTC-TDF vs. placebo immediately or deferred 9/12 NO difference in risk behaviours between two groups

24 Is PreP safe? > trial participants no adverse serious safety signal for TDF alone or FTC-TDF Drugs well tolerated minor GI side effects only, which lessen with time

25 Moving from Efficacy to Effectiveness

26 iprex-ole (July 2014) Open label extension of iprex 72 week data of 1603 participants (76% on daily FTC/TDF) Adherence monitored with DBS drug levels: DBS concentration c/w 2-3 tablets/week equated to 90% reduction in HIV incidence observed with 2-3 tablets per week Demand and retention in care good No evidence of compensatory risk behaviours on report or via incident STIs

27 PROUD and IPERGAY (October 2014) PROUD MRC UK pilot study of open label daily FTC/TDF 1:1 randomisation immediate vs deferred PrEP INTERIM ANALYSIS: Strongly protective effect against serocoversion. All patients on deferred arm to be moved to active agent IPERGAY Double blind placebo-controlled trial of on demand PrEP Unblinding of results to date undertaken in light of PROUD recommendation Significant reduction in active arm TBC All patients to be offered active drug

28 PROUD Pilot GMSM reporting UAI last/next 90days; 18+; and willing to take a pill every day Randomize HIV negative MSM (exclude if treatment for HBV/Truvada contra-indicated) Risk reduction includes Truvada NOW Risk reduction includes Truvada AFTER 12M Follow 3 monthly for up to 24 months Main endpoints in Pilot: recruitment and retention From April 2014: HIV infection in first 12 months

29 HIV Incidence Group No. of infections Follow-up (PY) Incidence (per 100 PY) 90% CI Overall Immediate Deferred Effectiveness =86% (90% CI: 64 96%) P value = Rate Difference =7.8 (90% CI: ) Number Needed to Treat =13 (90% CI: 9 23)

30 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

31 KM Estimates of Time to HIV-1 Infection (mitt Population) an follow-up of 13 months: 16 subjects infected 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) T for one year to prevent one infection : 18

32 Conclusions (edited) Incidence of HIV-1 infection in the placebo arm was higher than expected On Demand oral PrEP with TDF/FTC was highly effective - as good as the daily regimen followed in PROUD

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34 WHO 2015 recommendation (enabling) Oral PrEP containing TDF should be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination HIV prevention approaches (strong recommendation, high-quality evidence) Full guidelines available here: /186275/1/ _eng.pdf?ua=1

35 The price was wrong for NHSE 2M BUT NOT 10+M

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38 Danger of stalling Chaotic, unmonitored access Taking PrEP incorrectly Resistance Less renal monitoring than indicated possibly none at all Missed opportunity To reduce HIV To control STIs

39 Conclusions HIV incidence is much higher than GUMCAD implies in sub-populations of MSM Effectiveness is near perfect in the real world and the IPERGAY instruction worked just as well as daily for MSM It s your duty to tell your patients about PrEP even if you can t provide it 4,000 person years of PrEP is not enough - but it is a start

40 Residual PH questions in 2016 Is tenofovir alone ok for MSM? Can women use an event-based regimen? Is TDF/3TC as good as TDF/FTC? Can we afford it?

41 Three themes for the future New drugs in the pipeline Long-acting cabotegravir F/TAF Maraviroc Generic drugs coming soon, but not soon enough Multi-purpose technologies