Prevenção do HIV e o papel dos inibidores da integrasse

Transcription

1 Prevenção do HIV e o papel dos inibidores da integrasse Pep Coll AIDS Research Institute-IrsiCaixa Fight AIDS Foundation BCN Checkpoint 22 Agosto 2018

2 DISCLOSURES I have received a research grant from Gilead Sciences awarded to my institution I have participated in Advisory Boards of Merck, Gilead and ViiV Healthcare I am a Principal Investigator of the DISCOVER study

3 AGENDA Background: what works for PrEP Could we have better options for PrEP? Long Acting HIV drugs for PrEP: what s the evidence? Pros and Cons

4 BACKGROUND Prevention based on ARV has become a cornerstone of HIV prevention Treatment as Prevention Post-Exposure Prophylaxis Pre-Exposure Prophylaxis (PrEP)

5 What works for PrEP?

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8 What about in real world? Kaiser Permanente Northern California on PrEP (most MSM) July 2012-February 2017 NO NEW HIV INFECTIONS

9 Oral PrEP works, but can we have better options for PrEP?

10 Long Acting HIV drugs for PrEP LA formulation of Rilpivirine LA formulation of Cabotegravir Other candidates: MK-8591 (Nucleoside RTI) GS-CA1 (Capsid inhibitor) PRO 140 (monoclonal antibody) Other ways: implantable PrEP

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12 Long-Acting formulation of Rilpivirine vs. placebo N= 136 women at low risk for HIV infection Oral phase during 4 weeks, followed by 8 week intervals injections CROI Poster 2429 Source:

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14 Long-Acting formulation of Cabotegravir vs. placebo N= 199 men and women at low risk for HIV infection Ongoing, Follow-up Phase, Complete July-August 2018 Results presented at IAS 2017 Sponsored by: Division of AIDS, US National Institute of Allergy and Infectious Diseases Source:

15 Safety, Tolerability, and Pharmacokinetics of Long-Acting Injectable Cabotegravir in Low-Risk HIV-uninfected Women and Men HPTN 077 R. Landovitz, S. Li, B. Grinsztejn, H. Dawood, A. Liu, M. Magnus, M. Hosseinipour, R. Panchia, L. Cottle, G. Chau, P. Richardson, M. Marzinke, C. Hendrix, B. Tolley, A. Adeyeye, D. Burns, A. Rinehart, D. Margolis, M. McCauley, J. Eron IAS Paris, France July 25, 2017

16 HPTN 077 Study Design HIV-uninfected men and women at low risk for acquiring HIV infection, ages 18 to 65 (n=199) 3:1 3:1 Oral Oral Oral Oral Injection Phase (800mg ever 12 weeks) Injection Phase (800mg ever 12 weeks) Injection Phase (600mg ever 8 weeks) Injection Phase (600mg ever 8 weeks) Follow-up Phase Follow-up Phase Follow-up Phase Follow-up Phase

17 Grade 2 or Higher AE s Experienced by >5% of Any Arm During Injection Phase n=177 (CAB 134, PBO 43) > AE > grade 2 Respiratory tract infection Lipase increased Injection site pain Headache *Creatinine renal clearance decreased Blood glucose decreased Blood creatinine increased Blood creatine phosphokinase increased Back pain 2% 2% 7% 9% 8% 5% 10% 7% 5% 7% 0% 15% 12% 25% 23% 34% * Grade 2: < 90 to 60 ml/min or 10 to < 30% decrease from participant s baseline. Grade 3: < 60 to 30 ml/min or 30 to < 50% decrease from participant s baseline. p < p = % 44% 90% 84% 0% 20% 40% 60% 80% 100%

18 Other clinically significant events Active Arm Discontinuations due to clinical AE, n=12 Gastrointestinal, n=1 Rash, n=3 Nervous system, n=8 Seizure, n=1 Serious Adverse Events CAB 4(2.6%): Postictal vertigo, transient weakness, laryngitis, AKI PBO 2(4.2%): Cholelithiasis, SAB Seroconversion, Active CAB (Cohort 1) Detected at W77 (48W after final injection) CAB levels BLOQ at W53 and 77 Wild type virus

19 Summary CAB LA was well tolerated at doses of 800 and 600 mg in HIV-uninfected low-risk males and females Injection Site Reactions were frequent but generally mild; only 1 (0.75%) participant discontinued for injection-related AE 600 mg IM Q8W (after 4 week loading dose) consistently met prespecified PK targets for both sexes

20 ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men Martin Markowitz, 1 Ian Frank, 2 Robert M. Grant, 3 Kenneth H. Mayer, 4 David A. Margolis, 5 Krischan J. Hudson, 5 Britt S. Stancil, 6 Susan L. Ford, 6 Alex R. Rinehart, 5 William R. Spreen 5 1 The Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, New York, NY; 2 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3 Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA; Department of Medicine, University of California, San Francisco, CA; 4 The Fenway Institute, Fenway Health, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA; 5 ViiV Healthcare, Research Triangle Park, NC; 6 PAREXEL International (formerly employed by GlaxoSmithKline), Research Triangle Park, NC Markowitz et al. CROI 2016; Boston, MA. Abstract 106

21 ECLAIR study Primary objective: To evaluate the safety and tolerability of CAB LA injection Study population: Men at low risk for HIV infection (at least 1 casual sex partner in the past 24 months, no more than 3 within 3 months of screening) Markowitz et al. CROI 2016; Boston, MA. Abstract 106

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23 Primary Analysis W41: CAB LA absorption faster than predicted but concentrations lower than expected CAB, cabotegravir; C T, concentration at the end of the dosing interval; IM, intramuscular; PA-IC 90, protein binding adjusted 90% inhibitory concentration; PO, orally; SD, standard deviation Markowitz et al. CROI 2016; Boston, MA. Abstract 106 Uso exclusivo por Dto. Mëdico de ViiV HC

24 HIV Seroconversions Case 1: 24-year-old man, PBO arm, HIV seroconversion at Week 23 Case 2: 22-year-old man, CAB LA injection arm, HIV seroconversion at Week 53 (24 weeks after final injection) Study week HIV rapid test result HIV-1 RNA (c/ml) PK value (μg/ml) 29 (pre-dose, final injection) Negative < Negative < Negative 3,820,820 NQ 65 Positive 4142 NQ Subject reported unprotected sex with a casual partner between the visits at Weeks 41 and 53 No pheno/genotype resistance mutations to INIs (DTG, RAL, EVG, or CAB), NNRTIs, or NRTIs for samples collected at Weeks 53 and 65 DTG, dolutegravir; EVG, elvitegravir; ID, infectious disease; INI, integrase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NQ, not quantifiable; PK, pharmacokinetic; RAL, raltegravir. Markowitz et al. CROI 2016; Boston, MA. Abstract 106

25 Murray M et al. CROI 2016; Boston, MA. Poster 471

26 Murray M et al. CROI 2016; Boston, MA. Poster 471

27 Murray M et al. CROI 2016; Boston, MA. Poster 471

28 30 in-depth interviews including 26 trial participants and 4 clinical care providers (June-August 2015) Almost all participants experienced some level of side effects associated with LAI CAB, mostly temporary injection site soreness. Yet, all reported being satisfied and interested in continuing LAI CAB Participants described the convenience of LAI CAB and perceived advantage of not having to worry about adhering to a daily oral. Participants described the peace of mind associated with LAI CAB given the possibility for missed oral doses MSM participants, particularly in San Francisco, described a surrounding culture whereby MSM were expected to be on PrEP to be seen as safe sexual partners Kerrigan D et al. AIDS 2016, Durban

29 Kerrigan D et al. AIDS 2016, Durban

30 Primary Objective: Reduce HIV Incidence (non-inferiority, double blind, double dummy design) Inclusion criteria: Any condomless receptive anal intercourse in the 6 months prior to enrollment More than five partners in the 6 months prior to enrollment (regardless of condom use and HIV serostatus) Any stimulant drug use in the 6 months prior to enrollment Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months Sponsored by: Division of AIDS, US National Institute of Allergy and Infectious Diseases Source:

31 N= 4500 MSM and Transgender Women Ongoing (December 2016-September 2021) Step 1 Step 2 Daily oral CAB and TDF/FTC placebo CAB LA at two time points 4 weeks apart and every 8 weeks thereafter and TDF/FTC placebo TDF/FTC and oral CAB placebo TDF/FTC and injectable placebo at two time points 4 weeks apart and every 8 weeks thereafter NO placebo arm Step 3 Open-label TDF/FTC to cover the PK tail Open-label TDF/FTC to Cover the PK tail

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33 HPTN 084 Primary Objective: Reduce HIV Incidence (superiority, double blind, double dummy design) CAB LA 600mg vs. TDF/FTC Ongoing (October 2017-May 2022) N= 3200 Women Step 1 Step 2 Step 3 Daily oral CAB and TDF/FTC placebo CAB LA and oral TDF/FTC placebo at two time points 4 weeks apart and every 8 weeks thereafter Open-label oral TDF/FTC to cover the PK tail Oral TDF/FTC and oral CAB placebo Oral TDF/FTC and injectable placebo at two time points 4 weeks apart and every 8 weeks thereafter Open-label oral TDF/FTC to cover the PK tail ClinicalTrials.gov Identifier:NCT

34 Pros and Cons of LA CAB Difficulty in withdrawing therapy for adverse effects once administered Adverse events Injection site reactions: pain Potential risk for development of resistance Long pharmacokinetic tail with low drug concentrations Barriers if only prescribed and delivered at hospitals

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36 Online survey (2016) respondents in 12 European countries Recruited through dating apps/websites, Facebook and Twitter Available at: bloc_telechargement/resultprepgb_vf.pdf

37 Adherence Better adherence expected Special situations: ChemSex, stigma Pros and Cons Effectiveness Modelling study LA injectable PrEP would produce larger reductions in HIV transmission in MSM than oral PrEP 44% versus 33% (in 10 years, at a coverage level of 35%) Lancet HIV 2018

38 Satisfaction High in spite of ISR symptoms Preferences by potential users peace of mind No need for planning Pros and Cons Online survey respondents (USA) 47% prefer an injection versus 17% daily pill Biello KB et al. AIDS Behav 2017

39 Pros and Cons Potential to reduce social disparities in HIV transmission among MSM Younger Black or Hispanic More condomless anal sex Lower education level Reduced toxicity less toxicity of Integrase Inhibitors lower doses avoidance of first-pass metabolism

40 CONCLUSIONS Daily oral PrEP has proven effective in randomized clinical trials, implementation studies and in real word Efficacy strongly related to adherence LA injectable ARV may overcome barriers to adherence LA injectable ARV could be preferred by many potential users CAB is a potent Integrase Inhibitor, that formulated as LA injectable, is a promising option for PrEP

41 Muito obrigado!