Resumen II - Fundació Lluita contra la sida · Wijng I, et al. CROI 2017. Poster #451LB Randomized...

ResumenII:Nuevosenfoquesterapéu0cosypreven0vos

ArkaitzImazUnidaddeVIHyETS

ServiciodeEnfermedadesInfecciosasHospitalUniversitarideBellvitge

Barcelona,AuditorideLaPedrera,21deFebrerode2017

Agenda

- BiterapiaymonoterapiaconDolutegravir-  EstudioSWORD(DTG+RPV)-  EstudioLAMIDOL(DTG+3TC)-  EstudioDOMONO(DTGmonoterapia)-  EstudioREDOMO(DTGmonoterapia)

- NuevosdatossobreTAF/FTC/EVG/COBI-  Pacientesnaïve:Estudios104/111:144semanas-  “Switching”:EstudioGS-US-236-0128:Mujeres

- Cobicistat:interaccionesfarmacológicas

- TARytrastornoneurocogni_voasociadoalVIH-  Maraviroc-  Cenicriviroc

- PrEP

SWORDPrimerensayoclínicoaleatorizadoenelquesedemuestralanoinferioridaddeunabiterapiasinIPrespectoaunTARtriple

ANRS 167 LAMIDOL Trial

Noncompara_veopen-label,singlearm,mul_centertrialwith2phase

InclusionCriteria-HIV-1infectedadults-NadirCD4cellcount>200/mm3-FirstlinecART:2NRTIspluseitheraNNRTI,aPIoranINSTI.Amaximumof2modifica_onsofcARTforsimplifica_onand/orintolerance(no>1)wasallowed(exceptinthelast6months).

-Absenceofresistanceonpre-therapeu_cgenotypeforNRTIs,NNRTIs,PIsand,INSTI(ifavailable)-pVL≤50cps/mLforatleast2yearsPrevious“blips”allowedifnotexceed3inthelast2yearsandthattheydidnotoccurinthelast6months

JolyV,etal.CROI2017.Poster#458


W48ofthestudy(W40ofdualtherapy):101/104(97%)areintherapeuScsuccess.

VFLostFUVF

Treatmentchange

WijjngI,etal.CROI2017.Poster#451LB

Randomizedopenlabelmul_centernon-inferiorityclinicaltrialSamplesize/power:N=104,Pa=Pb=0.95δ=-0.121-β=0.80α=0.05Inclusioncriteria:▪OncARTandHIV-RNA<50c/mlfor>6monthswithgoodcompliance▪HIV-RNA-zenith<100.000c/ml▪CD4T-cellnadir>200cells/mm3▪Nobaselineresistance,nopreviousvirologicalfailure▪HBV-immuneorwillingtobevaccinatedbeforestartofDTGmonotherapy


104oncART

ImmediateDTGmonotherapyDTG50mgQD

Con_nuecART DelayedDTGmonotherapyDTG50mgQD

152oncART Con_nuedARTconcurrentcontrol

Predefinedstudystoppingrules:AnynewIN-resistanceassociatedmuta_onsaredetectedin≥2pa_entsduringthestudyDiscon_nua_onofDTGfortreatmentfailurein≥20pa_entsatany_meofthestudy

Primaryendpoint:Comparisonofthepropor_onofpa_entsintheOT-popula_onwithHIV-RNA<200c/mlatW24.Secondary:Propor_onsHIV-RNA<200c/mland<50c/mlintheen_repopula_ononDOLUMONOatW24andW48.Post-hocanalysis:ComparisonofHIV-RNA<200c/mlinen_repopula_ononDOLUMONOwiththe‘Concurrentcontrols’group.Thisgroupconsistsof152pa_entsoncARTwhofulfilledallinclusioncriteriaandexclusioncriteria,butwhodidnotpar_cipateinthestudybutagreedtohavetheirdataused.


Endpoint: CV <200 c/mL OT

DTG-Monotherapy: 122 Montreal 26 Munich 52 Barcelona 44

Number of HIV-infected individuals controlled in three large Clinical Cohorts: 10440

HCP (Barcelona, Spain): 5000 Clinical Care Centre (Munich, Germany): 2500 Clinique Actuel (Montreal, Canada): 2940

DTG-bi- tri therapy: 1082 Montreal 402 Munich n.a. Barcelona 680

No GRM: 2

Yes GRM: 9

VFs: 11 (9%; 95% CI: 6-18%)

VFs: 64 (6%; 95% CI: 5-7%)

No GRM: 64

Yes GRM: 0

1.17% 10%

Fisher exact text p=0.17 Odds-ratio VF mono: 1.58 (95% CI: 0.73-3.13)

82% of VFs

BlancoJL,etal.CROI2017.OralAbstract#42

Results (II): Virological data •  In 5 of 11 (45%) individuals DTG was their first InSTI. •  8 of 11 (72%) had been virologically supressed for longer than 3 years •  Adherence was less than 95% in 4 of 11 •  Weeks (median,IQR) from VF until GRT: 5 (3-14)

UVL: undetectable viral load; ADH: adherence; PC: Pill count; SQ: Self questionnaire; GRT: Genotypic resistance test; GRM: genotypic resitance mutations

Pt code Prior IsSTI without VF

Weeks UVL before DTG-M

Baseline VL VLs on DTG-M ADH Weeks

to VF VL at VF Weeks to GRT VL at GRT First IN-

GRM

B001 None 768 <37 330 (8),146(10), 1393(18) 98% (PC) 8 330 8 330 155H

B002 RAL 0 (LLV) 86 (prior 71,51)

80 (16), 171 (18), 122 (32), 3228 (48) 98% (PC) 16 80 32 122 118R

B003 None 312 <37 26180 (20), 6014 (22), 10560 (28) 50% (PC) 20 26180 28 6014 148K,138K

B004 RAL (LLV/GRT:WT) 12 249

(prior <37) 123 (12), 1350 (24)

22170 (25) 82% (PC) 0 123 32 22170 92Q,155H

B007 EGV 240 <37 57 (52), 51 (64), <37 (88) 100% (PC) 52 57 64 57 97A,155H

B008 None 480 <50 190 (32), 1350 (36), 40000 (40) 88% (PC) 32 190 36 1350 148H,155H,

M001 RAL 232 21 55 (2), 168 (13), 239 (15) 60% (SQ) 0 55 16 239 148R,140S

M002 None 228 <20 538 (24), 11000 (28) 100% (SQ) 24 538 29 11000 148H,140S

C001 EVG 20 <50 306 (24), 583 (28) 100% (SQ) 24 306 24 306 118R

B005 RAL,EGV 432 <37 179 (13), 71 (14), 56 (16) 98% (PC) 13 179 14 71 No

B006 None 172 <37 355 (72), 1355 (76), 1397 (80), <37 (92) 100% (PC) 72 355 76 355 No

Median (IQR)

236 (186-402)

20 (11-28)

190 (102-343)

29 (20-34)

330 (181-3682)

BlancoJL,etal.CROI2017.OralAbstract#42

Pt code GRT-VF1 GRT-VF2 GRT-VF3

B001 Plasma-UDS: IN-155H(100%) Plasma-UDS:IN-155H(100%) Plasma-UDS:IN-155H(100%),148R(84%),138K(79%)

B002 ND Plasma-PS:RT-106I PMBC-UDS: IN-118R (7%).

B003 ND Plasma-UDS:IN- 148K(100%),138K(99%) Plasma-UDS:IN-138K(99%);140S(43%);140A(34%);148K(99%)

B004 ND ND Plasma-UDS:IN- 92Q(92%);143C(6%);155H(99%);163R(8%)

B007 ND Plasma-PS: IN-97A,155H

B008 ND Plasma-UDS: IN-138K(6%);140S(100%); 148H(100%);155H(100%) Plasma-UDS: RT-41L(98%); IN-140S(100%);148H(100%); 155H(100%)

M001 ND ND Plasma-PS: IN-68LV;138EK;140GS; 148QR

M002 ND Plasma-PS: IN-148H,G140S

C001 Plasma:PS/UDS-G118R Plasma:PS/UDS: IN-118R

B005 ND NA WT

B006 ND ND WT

Results (III): IN-resistance data •  9 of 11 (81%) VFs to DTG-M selected IN-GRM from different pathways:

•  92Q/155H : 1 patient •  97A/155H: 1 patient

•  155H/148R: 1 patients

•  118R : 2 patients

•  148K: 1 patient •  148H: 2 patients

•  148R: 1 patient

VF without GRM VF with GRM

GRT: Genotypic resistance test; GRM: genotypic resitance mutations; VF: virological failure BlancoJL,etal.CROI2017.OralAbstract#42

Agenda





- PrEP

SignificantEfficacyandLong-termSafetyDifferenceWithTAF-BasedSTRinNaïveAdults:144weeks

ArribasJR,etal.CROI2017.Poster#453


AtWeek144,medianchangefromBLineGFRwassignificantlylowerwithE/C/F/TAFvsE/C/F/TDF(1.6vs7.7mL/min;p<0.001)D/CforrenalAEs:ovs12casesD/Cforproximaltubulopathy:Ovs4cases


D/Cforboneloss:0vs6cases

HooderS,etal.CROI2017.Poster#443

Agenda





- PrEP

GervasoniC,etal.CROI2017.Poster#410

GervasoniC,etal.CROI2017.Poster#411n 212 176 46 76

Agenda




- TARytrastornoneurocogniSvoasociadoalVIH-  Maraviroc-  Cenicriviroc

- PrEP

-Maraviroc(MVC)antagonistCCR5-Cenicriviroc(CVC),antagonistadualCCR2/CCR5(enfasedeinves_gación)Amboshandemostradoreduccióndemarcadoresdeac_vacióndemonocitos/macrófagos

¿BeneficioenpacientesconHAND?

NdhlovuLC,etal.CROI2017.Poster#381


Hypothesis:“CCR2andCCR5blockadewillimprovecogni_vefunc_onbydecreasingmonocyteac_va_onandmigra_onintotheCNS.”

Neuropsychological(NP)Tes_ng:

1.LearningandMemory;2.PsychomotorSpeed;3.Execu_veFunc_on;4.WorkingMemory;5.Ayen_on;6.GrossMotor;7.Visuospa_al;

PlasmaSolubleBiomarkersbyELISAPlasmasCD163,sCD14andneopterin

N=17

CSF Inflammatory markers after Adding Maraviroc to MONotherapy darunavir/ritonavir: The CINAMMON Study Barber TJ1,2, Imaz A3, Boffito M1,2, Podzamczer D3, Pozniak A1, Fortuny R3, Davies N1, Niubó J3, Mandalia S1,2, Gazzard B1

1 Chelsea and Westminster NHS Foundation Trust and St Stephen’s AIDS Trust London UK

2 Imperial College London, UK

3 Bellvitge University Hospital, Barcelona, Spain

Use C&W/SSAT/Bellvitge logos

Methods •  CCR5tropicsubjectsonmono-DRV/rforatleast6monthswithVL<40inLondonand

Barcelona

•  Remainedonmono-DRV/rfor12weeksbeforeaddinginMVC

•  Lumbarpuncture(LP)andneurocogni_ve(NC)func_on(Cogstate)examina_onswereperformedatbaseline,week12,andfollowing24weeksofaddi_onalMVC(w36)

•  Theprimarystudyendpointwasweek(w)12tow36CSFinflammatorymarkerschangesfollowingMVC150mgqdaddi_ontomono-DRV/r800/100mgqdfor24w

•  Secondaryendpointsincludedchangesinneurocogni_vefunc_on(Cogstate),andCSFdruglevels,followingaddi_onofMVC

BarberT,etal.CROI2017.Poster#382

Agenda





- PrEP

RadzioJ,etal.CROI2017.#84

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RadzioJ,etal.CROI2017.#84RadzioJ,etal.CROI2017.#84

HillierSL,etal.CROI2017.#86LB


41 healthy HIV- women (mean age 28, 71% white) used either TFV 1% gel (40 mg) or films (40 and 10 mg)


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HeffronR,etal.CROI2017.#85

PriceL,etal.CROI2017.#87


Higher abundance of penile anaerobes was associated with increased of HIV seroconversion

On Demand Post-Exposure Prophylaxis with Doxycycline for

MSM Enrolled in a PrEP Trial

Molina JM, Charreau I, Chidiac C, Pialoux G, Cua E, Delaugerre C, Capitant C, Rojas-Castro D, Meyer L,

and the ANRS Ipergay Study Group

Hospital Saint-Louis and University of Paris 7, Inserm SC10-US19 Villejuif, Hospital Croix-Rousse, Lyon, Hospital Tenon, Paris, CHU de

Nice, AIDES, Pantin, Paris Sud University, France

Background

§  GlobalburdenofcurableSTIsishuge:>1MillionofSTIsacquiredeveryday(Newman,PlosOne2015)

§  RecentincreaseofSTIsinEuropeandUSA,especiallyamongMSMbutpre-datedPrEP(CDCFactSheet10/2016)

§  HighratesofSTIsamongMSMonPrEP

-  57%inPROUDand41%inANRSIPERGAY,mostlyasymptoma_c(McCormack,Lancet2016-Molina,NEJM2015)

§  PrEPgivesauniqueopportunitytofosterresearchintesSng,treatmentandprevenSonofSTIs

MolinaJM,etal.CROI2017.#91LBCourtesyJMMolina

Background (2) §  Could post-exposure prophylaxis (PEP) with doxycycline

reduce STI incidence in this high risk population? -  Antibiotic prophylaxis for STIs has been assessed since 1940’s with

limited success

-  Doxycycline PEP successfully used for prevention of Lyme disease, Leptospirosis and Scrub typhus (Nadelman, NEJM 2001; Takafuji, NEJM 1984; Twartz, JID 1982)

-  No known resistance to doxycycline in Chlamydia trachomatis and Treponema pallidum, but > 50-75% of Neisseria gonorrhoeae in France have low level resistance to tetracycline

-  Randomized study among 30 HIV+ MSM with prior syphilis: fewer STIs (6 vs. 15) with daily doxycycline (Bolan, Sex Trans Infect 2015)

-  Limited use of doxycycline in France for the treatment of bacterial infections mostly used for acnea and malaria prophylaxis


Study Design

On Demand PEP with Doxycycline (200 mg ~ 24h after sex, up to 72h)*

No PEP

• HIV-negative high risk MSM • Enrolled in the ANRS IPERGAY Open-label extension study

• No contra-indication to Doxy

* No more than 6 pills/week to limit AB exposure and selection pressure

§  With 276 subjects enrolled: 80% power to detect a 55% relative decrease in incidence of a first STIs with PEP (expected incidence: 40/100 PY with no PEP)

§  Visits: Baseline and every two months with serologic assays for HIV and syphilis and PCR assays for CT and NG in urine samples, anal and throat swabs

Randomized Open-Label Trial www.ipergay.fr


Study Flow-Chart

Randomized n=232

PEP Doxy n=116 No PEP n=116

Completed FU n=106 (91%)

Completed FU n=106 (91%)

D/C participation n=10 Withdrew consent n=5 Lost to follow-up n=1

Other n=4

D/C participation n=10 Withdrew consent n=3 Lost to follow-up n=3

Other n=4

Eligible n=299 Not randomized n=67 (22%) Not meeting eligibility n=10

Withdrew consent n=2 Lost to follow-up n=1

Patients declined n= 54 (19%)


KM Estimates of Time to a First STI (ITT Population)

Median follow-up of 8.7 months (IQR: 7.8-9.7): 73 subjects infected

45 in No PEP arm (incidence: 69.7/100 PY), 28 in PEP arm (incidence: 37.7/100 PY)

Hazard Ratio: 0.53 (95% CI: 0.33-0.85, p=0.008)

months 0 2 4 6 8 10

Cum

ulat

ive

prob

abili

ty o

f firs

t STI

0

0.1

0.2

0.3

0.4

0.5

No at risk : No PEP PEP

116 116

110 112

50 69

6 18

91 105

76 93

No PEP

PEP

Log-rank test p=0.007


KM Estimates of Time to a First Chlamydia (ITT Population)


21 in no PEP arm (incidence: 28.6/100 PY), 7 in PEP arm (incidence: 8.7/100 PY)

Hazard Ratio: 0.30 (95% CI: 0.13-0.70, p=0.006)

months 0 2 4 6 8 10 0

0.1

0.2

0.3

0.4

0.5


116 116

112 114

68 84

9 22

102 111

93 105

No PEP


Cum

ulat

ive

prob

abili

ty o

f firs

t STI

PEP


KM Estimates of Time to a First Syphilis (ITT Population)


10 in no PEP arm (incidence: 12.9 / 100 PY), 3 in PEP arm (incidence: 3.7 / 100 PY)

Hazard Ratio: 0.27 (95% CI: 0.07-0.98, p<0.05)

months 0 2 4 6 8 10 0

0.1

0.2

0.3

0.4

0.5


116 116

114 116

74 83

7 21

110 115

102 107

Cum

ulat

ive

prob

abili

ty o

f firs

t STI

No PEP

PEP



KM Estimates of Time to a First Gonorrhea (ITT Population)


25 in no PEP arm (incidence: 34.5/100 PY), 22 in PEP arm (incidence: 28.7/100 PY)

Hazard Ratio: 0.83 (95% CI: 0.47-1.47, p=0.52)

months 0 2 4 6 8 10

Cum

ulat

ive

prob

abili

ty o

f firs

t STI

0

0.1

0.2

0.3

0.4

0.5


116 116

112 114

64 71

9 19

103 109

92 97

No PEP

PEP



Adverse Events Nb of Participants (%) PEP Doxy

n=116 No PEP n=116

P value

Any AE 106 (91) 104 (90) 0.65 Any Serious AE 4 (3) 10 (9) 0.17 Any Grade 3 AE 4 (3) 11 (9) 0.06 Treatment D/C due to AE 8 (7)* . . Gastro-intestinal (GI) AEs 61 (53) 47 (41) 0.07 Drug-Related GI AEs 28 (24) 16 (14) 0.05

Nausea/vomiting 13 3

GI pain 14 8

Diarrhea 8 10

Other GI 6 1

* Nausea (3), vomiting (1), epigastralgia (2), abdominal pain (2), abdominal distention (1), diarrhoea (1), asthenia (1), vertigo (1), other (1)


Conclusions §  PEP with doxycycline reduced the overall incidence of

bacterial STIs by 47% in MSM on PrEP (8.7 months of FU)

§  No effect on Gonorrhea but strong reduction (70-73%) in Chlamydia and Syphilis incidence

§  Acceptable safety profile with mild/moderate GI AEs leading to D/C in only 7% of participants

§  No evidence of risk compensation

§  Analysis of antibiotic resistance pending

§  Long-term benefit of PEP yet unknown

§  Antibiotic prophylaxis for STIs still NOT recommended

§  More research needed in the field of STIs MolinaJM,etal.CROI2017.#91LBCourtesyJMMolina

AGRADECIMIENTOS

JRArribas

TBarber

JLBlanco

MLD’Antoni

GGarcia-Lerma

RHeffron

VJoly

JMLlibre

JMMolina

IWij_ng

Resumen II - Fundació Lluita contra la sida · Wijng I, et al. CROI 2017. Poster #451LB Randomized...

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