La terapia è prevenzione dell’infezione da HIV Antonella Castagna Istituto Scientifico San Raffaele Milano Roma 20 aprile 2012

PEP  Al momento dell’esposizione Vantaggi: Minore durata rispetto a PrEP Difficoltà: Dati sull’efficacia limitati Difficile riscontrare il rischio (ossia quando darla) Da iniziare in < 48 ore Aderenza Impatto modesto su salute pubblica

PrEP  Prima dell’esposizione Vantaggi: efficacia discreta (proof of concept tramite gli studi iPrEX & CAPRISA 004) Difficoltà: Aderenza Somministrazione Rapporto costi/efficacia Minimizzare le resistenze

Storia e cronologia della PrEP 2001: PrEP proposta per la prima volta 2003: Trial clinico su sex workers proposto in Cambogia 2004: Proteste alla Conferenza sull’AIDS di Bangkok 2005: Inizio trial di fase II del tenofovir su sex workers in Africa occidentale – Trial sospeso in Camerun a seguito della mobilitazione degli attivisti locali 2006: Sicurezza del tenofovir riportata alla Conferenza di Toronto 2007-9: Inizio trial di fase IIB e III su IDU, MSM ed eterosessuali – Bangkok IDU, CAPRISA 004, iPrEx, Botswana, Partners PrEP, VOICE, & FemPrEP trials 2010: Risultati CAPRISA 004 e iPrEx. Discreta efficacia di gel al tenofovir e di emtricitabina-tenofovir a somministrazione orale (FTC-TDF)

Vaginal ring (sustained delivery) Injectable (long-acting) Modalità di somministrazione della PrEP: a lento rilascio, topici e sistemici Pill Gel with applicator Vaginal film Vaginal ring (sustained delivery) Injectable (long-acting) Ideal: long acting, safe, effective, low cost and user-friendly Maximize choice & optimize affectiveness Potential for combination ARVs to increase effectiveness Potential to combine ring or injections with contraception

Pipeline PrEP: farmaci candidati Fase III NNRTI: Lunga emivita, possibile sviluppo di resistenze Trial di efficacia di dapivirine ring 2011 (IPM & partner) Fase II Entry inhibitors: prevengono l’insediamento dell’HIV in cellule; non efficaci per virus X4 Oral maraviroc +/- FTC/TDF (HPTN 069) Fase I NNRTI Monthly rilpivirine (TMC-278) injectable (BMGF) Maraviroc & dapivirine vaginal ring (IPM, MTN) Studi su animali Inibitori dell’integrasi: agiscono in fase avanzata del ciclo di vita del virus, lunga emivita, possibile impiego per PEP? Raltegravir topico e orale: azione protettiva evidenziata da studi su macachi e topi umanizzati (Dobard CROI 30; Neff PloS One 2010) In futuro: farmaci o classi di farmaci diversi per la prevenzione HIV Combinazioni potrebbero essere più efficaci e meno a rischio di sviluppo resistenze

PrEP Trials

PrEP - farmaci più studiati: TDF e FTC+TDF Potente Elevata azione antivirale (tutti i sottotipi HIV-1, virus HIV-1&-2, R5 e X4) Potrebbe impedire l’attecchimento iniziale del virus (azione precoce sul ciclo di vita dell’HIV) L’FTC agisce rapidamente (il TDF è metabolizzato più lentamente) Sicuro: Buon profilo di sicurezza e tollerabilità Di facile assunzione: Numero di pillole da assumere limitato, nessuna restrizione alimentare, poche interazioni farmacologiche Tuttavia  TDF e FTC/TDF in regimi di prima linea: Possibile insorgenza di resistenze (K65R, M184V) e resistenze incrociate con NRTI

STUDIO CAPRISA 004 “Farmaco giusto (se usato), rilasciato nel posto giusto” 2010: Anno cruciale per i microbicidi Abdool Karim et al, Science 329 1168 (2010), July 2010 CAPRISA 004: Gel pericoitale all’1% di tenofovir Trial di fase 2B su 889 donne, età ≥ 18 anni, Durban, Sudafrica Coito-dipendente: da applicare 12 ore prima e 12 ore dopo il rapporto sessuale, max. 2 applicazioni in 24 ore Popolazione di studio: giovani donne (età media 23 anni), nubili, originarie sia di zone rurali (69%) sia urbane (31%) Completato nel 2010: buon profilo di sicurezza (↑ lieve diarrea rispetto a braccio placebo)

HIV incidence in CAPRISA 004 Months of follow-up 6 12 18 24 30 Cumulative HIV endpoints 37 65 88 97 98 Cumulative women-years 432 833 1143 1305 1341 HIV incidence rates (Tenofovir vs Placebo) 6.0 vs 11.2 5.2 vs 10.5 5.3 vs 10.2 5.6 vs 10.2 5.6 vs 9.1 Effectiveness (P-value) 47% (0.064) 50% (0.007) (0.004) 40% (0.013) 39% (0.017) No resistance against K65R, and 51% protection against HSV-2 acquisition (95% CI: 22% - 70%) Abdool Karim Science 2010

CAPRISA 004: L’aderenza è critica per l’efficacia contro l’HIV Alta (aderenza in impiego gel>80%) n=366 (38% pp), efficacia 54% Intermedia (aderenza 50-80%) n=181 (20% pp), efficacia 38% Bassa (aderenza <50%) n=367 (42%), efficacia 28%

Studio iPrEx “Farmaco giusto, rilasciato al momento giusto (se usato)” 2010: Anno cruciale per PrEP ad uso orale per la prevenzione dell’HIV-1 con l’iPrEx (New England: novembre 2010) 2499 MSM, randomizzato 1:1, assunzione giornaliera per via orale di FTC/TDF vs placebo 11 siti (Brasile, Ecuador, Perù, Sudafrica, Thailandia, USA) Giovani MSM ad alto rischio: 50% < 25 anni Media di 18 partner nelle 12 sett. precedenti l’arruolamento Completato nel 2010; profilo di sicurezza buono ↑ nausea 1° mese Lieve diminuzione della densità ossea (Mulligan CROI 94LB)

Updated iPrEX Efficacy Efficacia secondo analisi ‘as-treated’ (dati in Novembre 2011)

iPrEx L’aderenza è critica per l’efficacia Alta (aderenza ≥90%; visite mediche effettuate 49%) efficacia 68% Intermedia (aderenza 50-90%; visite mediche effettuate 33%) efficacia 34% Bassa (aderenza <50%; visite mediche effettuate 18%) efficacia 16%

iPrEx: Resistenze Nessuna resistenza sviluppata in 100 pz che hanno contratto l’HIV dopo l’arruolamento – Sequenziamento standard e PCR allele specifica (Leigler CROI 97LB) Resistenze osservate in 3 casi su 10 pazienti con sieroconversione iniziale – 8 nel braccio placebo  1 con ceppo HIV multi-resistente acquisito – 2 nel braccio FTC/TDF  M184V e M184I (acquisizione indeterminata)

Insegnamenti tratti dalle resistenze osservate nell’iPrEx: L’assenza di resistenze nei pz con sieroconversione non sorprende, data la bassa esposizione al farmaco Si possono verificare resistenze acquisite, indipendentemente dalla PrEP Evitare di avviare la PrEP in presenza di infezione acuta

Investigation: Ongoing PrEP efficacy studies Location Sponsor/Funder Population N PrEP Agent Status Thailand Bangkok Tenofovir Study CDC IDU 2400 TDF Fully enrolled Results 2012 Kenya, Uganda Partners PrEP Study UW / BMGF HIV discordant couples 4758 TDF, FTC/TDF Kenya, South Africa, Tanzania, Zimbabwe FEM-PrEP FHI / USAID & BMGF Women 3900 FTC/TDF 49% enrolled Results 2013 South Africa, Uganda, Zimbabwe VOICE / MTN 003 MTN / NIH 5000 Vaginal tenofovir gel (daily) 65% enrolled Closed in April 2011: 1951 women recluted “Highly unlikely to show a significant protective effect” I dati su sicurezza, efficacia, resistenze e costi di TDF e FTC-TDF guideranno la scelta del regime farmacologico per la diffusione della PrEP

Randomised, placebo-controlled efficacy and safety study ‡ FEM-PrEP Study Design1 Randomised, placebo-controlled efficacy and safety study (Kenya, South Africa, Tanzania) Endpoint-driven trial: 72 seroconversions HIV-negative women at high risk for HIV acquisition 18-35 years old Not planning to become pregnant N = 2,1202 (Planned N=3900) Placebo once daily FTC/TDF once daily Outcomes measured: HIV seroconversion, sexual behavior, adherence, drug resistance VL / viral set point, CD4 count (if infected) DSMB recommended study be stopped early on 18th April 2011 Unlikely to be able to demonstrate the effectiveness of Truvada in preventing HIV infection in the study population, even if it continued to its originally planned conclusion “Adherence was too low to adequately assess the efficacy of PrEP in FEM-PrEP”2 FHI; Press Release: April 18, 2011 Van Damme L, et al. CROI 2012. Seattle. #32LB

FEM-PrEP Results FTC/TDF Placebo Number of HIV infections 33 35 HIV incidence rate 4.7/100 PY 5.0/100 PY HR for HIV protection (vs. placebo) 0.94 (0.59 - 1.52) p = 0.81 n/a Infected Cases and Matched Controls with ≥ 10 ng/mL TDF in Plasma at Visits Defining Infection Windows P = 0.63 P = 0.12 P = 0.60 Less than 15% of cases had >10 ng/mL of tenofovir in plasma Van Damme L, et al. CROI 2012; Seattle. #32LB

FEM-PrEP Results Resistance Results FTC resistance was detected in 5 seroconverters (4 in the FTC/TDF arm and 1 in the placebo arm); most were consistent with transmitted resistance Despite poor adherence there were minimal resistance mutations Genotypic Resistance K65R K70E M184V M184I TDF/FTC 3 1 Placebo Safety Results Rates of vomiting (p=0.04) and nausea (p<0.001) were higher with FTC/TDF No difference in creatinine and phosphorus abnormalities Van Damme L, et al. CROI 2012; Seattle. #32LB

FEM-PrEP closure There are four possible explanations for the failure of the study, which enrolled 1,951 women in Kenya, South Africa and Tanzania starting in June 2009. One is that the women weren’t taking the medicines as instructed, despite assertions they were. Another is that the pill’s active ingredients didn’t get into cervical and vaginal tissues in sufficient concentrations to have an effect. The third is that the strategy doesn’t work. The final explanation is that it works but by chance didn’t in that experiment. It is possible the women who had been randomly assigned to Truvada missed an unusually large number of both birth control and Truvada pills. Blood samples drawn every four weeks will be tested to determine the drug levels of the women randomly assigned to Truvada. Alternatively, the drugs might be less effective at preventing infection through vaginal intercourse than anal intercourse (iPrEx study).

Partners PrEP Study Design Randomised, double-blind, placebo-controlled efficacy and safety study for HIV-negative partner (Kenya, Uganda) FTC/TDF once daily (n=1579 couples) Serodiscordant couples (HIV-positive partner not medically eligible for ART) N=4747* couples Randomised 1:1:1 TDF once daily (n=1584 couples) Placebo once daily (n=1584 couples) *11 couples found after randomization to be ineligible and exited study Primary Outcome: HIV infection in HIV-1 negative partner Secondary Outcomes: Safety, risk behavior, adherence DSMB recommended placebo arm be discontinued on 10th July 2011 All participants received safer sex counseling (individually and as a couple), HIV testing, free condoms, testing and treatment for STIs, and monitoring and care for HIV. Baeten J and Celum C. IAS 2011. Rome. Oral #MOAX0106 University of Washington; Press Release: July 13, 2011

Partners PrEP Primary Endpoint: HIV Seroconversion in Partner Updated Analysis with Data Through July 10, 20111,2 Modified Intention-to-Treat Analysis TDF FTC/TDF Placebo Number of HIV infections 17 13 52 HIV protection efficacy vs. placebo (95% CI) P-value 67% (44-81%) <0.0001 75% (55-87%) n/a Relative risk reduction associated with detectable study drug* (95%CI) 86% (57%, 95%)  < 0.001 90% (56%, 98%) 0.002 *Adjusting for demographic and risk factors does not substantively change estimates HIV-1 protective effects were not significantly different for TDF and FTC/TDF (67% vs. 75%; P=0.23)1 Both TDF and FTC/TDF significantly reduced HIV-1 risk in both genders “Among persons taking TDF or FTC/TDF PrEP, detection of TDF in plasma was strongly predictive of high protection from HIV-1 acquisition” 1. Baeten J, et al. CROI 2012; Seattle. Oral #29 2. Donnell N, et al. CROI 2012; Seattle. Oral #30

Partners PrEP Key Laboratory Safety Results No statistically significant difference in creatinine (Cr) elevation or phosphorus decrease adverse events Number (%) of participants TDF P-value vs. placebo FTC/TDF Placebo Confirmed Cr elevation -Grade 1 -Grade 2+ 16 (1%) 3 (<1%) 0.57 0.62 18 (1%) 2 (<1%) 0.28 12 (1%) 1 (<1%) Confirmed phosphorus decrease 142 (9%) 0.75 140 (9%) 0.80 136 (9%) Baeten J, et al. CROI 2012; Seattle. Oral #29

Partners PrEP Resistance – Pre-specified Mutations 2/8 persons who had seronegative acute HlV 1 infection when starting PrEP developed resistant virus (1 K65R, 1 M184V) No participants who acquired HIV-1 after enrollment developed mutations conferring resistance to TDF or FTC Infected at enrollment Infected after enrollment TDF n = 5 FTC/TDF n = 3 Placebo n = 6 n = 15 n = 12 n = 51 K65R 1 K70E M184V M184I Consensus resistance testing results for 92/96 infections in the study Baeten J, et al. CROI 2012; Seattle. #29

La PrEP intermittente è praticabile? Uso intermittente: per brevi periodi di esposizione al rischio (es. periconcepimento), per rapporti programmati (‘event-driven’) o assunzione programmaticamente intermittente (non giornaliera); Attuabilità dimostrata da studio sui macachi (CDC): dose da assumere > 2 ore prima e dopo l’esposizione per efficacia ottimale; Le attuali conoscenze farmacocinetiche e farmacodinamiche in materia sono sufficienti a predire la frequenza dei regimi programmaticamente intermittenti o gli ottimali tempi e dosi pre-esposizione? – Possibili variazioni in base a farmaco e sito di esposizione (vaginale, rettale, ematico) Ma… Quanto i rapporti sono programmati/programmabili e dunque è possibile essere protetti da PrEP ‘event-driven’? L’aderenza nei regimi intermittenti sarebbe effettivamente più alta che in quelli ad assunzione quotidiana?

PrEP-C Evaluation of the impact of PrEP on conception in 28 serodiscordant couples (male HIV+, female HIV -) Total Brighton Data to Oct 11 Birmingham Data to Oct 11 Numbers progressing through PrEP protocol 15 6 9 Number taking at least 1 cycle of PrEP-C 3 Pregnancies 5 2 Live births 1 Ongoing pregnancy 1 twin Miscarriages 2* (6/40; 10/40) 2* (6/40, 10/40) Number of attempts per pregnancy 3 (1-5) 3 (1-5) *1,3,5 attempts 3 (3, 4) Switch to sperm washing Methods: TDF +/- FTC was dosed before and after timed ovulatory intercourse All women had HIV & pregnancy tests >17 days following PrEP-C cycle Results: 6 of 28 couples to date have completed more than 1 cycle No HIV transmissions No PrEP discontinuation due to adverse events *same woman Early data suggests that this may be viable alternative to sperm washing in male HIV +, female HIV – couples wishing to conceive Taylor S, et al. CROI 2012; Seattle. #1061

Il Contesto

HIV prevention 2012

I dati sono sufficienti per chiedere una variazione della scheda tecnica di TDF/FTC (meeting on may 10°) Concept paper on the guidance on the non-clinical and clinical development of medicinal products for HIV prevention including oral and topical PrEP Draft

Ringraziamo Gilead per il supporto a questa iniziativa