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
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2001:
2003:
2004:
2005:
–
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


–
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PrEP proposta per la prima volta
Trial clinico su sex workers proposto in Cambogia
Proteste alla Conferenza sull’AIDS di Bangkok
Inizio trial di fase II del tenofovir su sex workers in Africa occidentale
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)
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
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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
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
47%
(0.064)
50%
(0.007)
47%
(0.004)
40%
(0.013)
39%
(0.017)
HIV incidence rates
(Tenofovir vs Placebo)
Effectiveness (P-value)
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
Sponsor/F
under
Population
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
Fully enrolled
Results 2012
Kenya, South
Africa, Tanzania,
Zimbabwe
FEM-PrEP
FHI /
USAID &
BMGF
Women
3900
FTC/TDF
South Africa,
Uganda, Zimbabwe
VOICE / MTN 003
MTN / NIH
Women
5000
TDF, FTC/TDF
Vaginal
tenofovir gel
(daily)
Location
N
PrEP Agent
Status
49% enrolled
Results 2013
Closed in April 2011: 1951 women recluted
“Highly unlikely to show a significant protective effect”
65% enrolled
Results 2013
I dati su sicurezza, efficacia, resistenze e costi di TDF e FTC-TDF
guideranno la scelta del regime farmacologico
per la diffusione della PrEP
‡
FEM-PrEP
Study
1
Design
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)
FTC/TDF once daily
Placebo 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
1. FHI; Press Release: April 18, 2011
2. Van Damme L, et al. CROI 2012. Seattle. #32LB
FEM-PrEP
Results
FTC/TDF
Placebo
33
35
4.7/100 PY
5.0/100 PY
0.94 (0.59 - 1.52)
p = 0.81
n/a
Number of HIV infections
HIV incidence rate
HR for HIV protection
(vs. placebo)
Percent (%) of women
Infected Cases and Matched Controls with ≥ 10 ng/mL TDF
in Plasma at Visits Defining Infection Windows
100
Cases
80
P = 0.63
Controls
P = 0.12
P = 0.60
60
40
38,0
35,1
25,9
21,2
20
25,7
14,8
0
Window Start
21
Window End
Both Visits
• 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
0
0
3
1
Placebo
0
0
1
0
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
22
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)
TDF once daily
(n=1584 couples)
N=4747* couples
Randomised 1:1:1
*11 couples found after randomization to be ineligible and exited study
Placebo once daily
(n=1584 couples)
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.
24
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%)
75% (55-87%)
n/a
<0.0001
Relative risk reduction
86% (57%, 95%)
associated with detectable study
drug* (95%CI)
< 0.001
P-value
<0.0001
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
P-value
vs.
placebo
Placebo
16 (1%)
3 (<1%)
0.57
0.62
18 (1%)
2 (<1%)
0.28
0.62
12 (1%)
1 (<1%)
142 (9%)
0.75
140 (9%)
0.80
136 (9%)
Confirmed Cr elevation
-Grade 1
-Grade 2+
Confirmed phosphorus
decrease
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
TDF
n = 15
FTC/TDF
n = 12
Placebo
n = 51
K65R
1
0
0
0
0
0
K70E
0
0
0
0
0
0
M184V
0
1
0
0
0
0
M184I
0
0
0
0
0
0
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?
ANRS IPERGAY Trial
(Preventative Intervention for Exposure to Risks with and for Gays)
"ON DEMAND" ANTIRETROVIRAL PRE-EXPOSURE PROPHYLAXIS FOR HIV INFECTION
IN MEN WHO HAVE SEX WITH MEN IN FRANCE AND CANADA
Version no 3.0 of 01 September 2011
PrEP-C
Evaluation of the impact of PrEP on conception
in 28 serodiscordant couples (male HIV+, female HIV -)
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
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
6
3
3
Pregnancies
5
3
2
Live births
2
1
1
Ongoing pregnancy
1 twin
0
1 twin
Miscarriages
2*
(6/40;
10/40)
2* (6/40,
10/40)
0
Number of attempts per
pregnancy
3 (1-5)
3 (1-5)
*1,3,5
attempts
3 (3, 4)
1
1
0
Switch to sperm washing
*same woman
Early data suggests that this may be viable alternative to sperm washing in
30
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