Novedades CROI 2019 (26º)

Dr. Luis Miguel Noriega

Sin conflictos de intereses

Primer curso Terapia antiviral e Infecciones
oportunistas 1998
 Novedades CROI 2019

• Cura VIH
– Tx MO
– Inhibidores de checkpoint
– Edicion génica
– Anticuerpos neutralizantes de amplio espectro (bNAbs)
• Novedades TAR
– LA CAB/RPV
– Terapias II y mutaciones INTR
– Nuevas drogas
• Efectos metabólicos de las terapias
• Plan eliminación epidemia VIH, USA
 Trasplante de MO

• CCR5
– Es el co receptor mas importante para entrar al LT CD4+

– En el gen que expresa esta proteína, se ha identificado una

deleción de 32 pares de bases, de herencia mendeliana, que
genera una proteína no funcional

– Esta presente en un bajo % de la población (1% en Europa)

– Condiciona resistencia a los virus con tropismo CCR5

CCR5
• Paciente Berlin
– Tx MO con donante CCR5 Δ32/Δ32

– 8 años sin terapia ni evidencia enfermedad LT CD4+

Timothy Brown
 Paciente de Londres

2003: Infección VIH

2003 a 2013:
EFV/3TC/TDF

Sepsis BGN, absceso dental

Colitis, reactivación CMV y EB

2013: Linfoma Hodgkin IVb

Falla a varios esquemas
Gupta. Nature. 2019;[Epub]. Gupta. CROI 2019. Abstr 29LB.
ATMENT INTERRUPTION (ATI) AFTER ALLOGENEIC CCR5-D32 HSCT FOR AML IN 2013
ANALYTIC TREATMENT INTERRUPTION (ATI) AFTER ALLOGENEIC CCR5-D32 HSCT FOR AML IN 2013
en1, Elena Knops3, Nadine Lübke 4, Annemarie
Björn-Erik 0. Jensen , Elena Knops 5, ,Nadine
Wensing JavierLübke
Martinez-Picado 6, Rolf, Javier
, Annemarie Wensing 3, Monique Nijhuis
KaiserMartinez-Picado 5, Maria
, Rolf Kaiser , Monique Nijhuis6,, Thomas
Salgado
1
Harrer
Maria Salgado 7, EvaHarrer
, Thomas Heger 3, Heger ,
, Eva 3 4
8 9
5
10
6
1
3
1
5
2
6 7 3

Johanna M. Eberhard , llona Hauber , Jacob D. Estes , Carsten Münk , Dieter Häussinger , Guido Kobbe
Johanna M. Eberhard8, llona Hauber9, Jacob D. Estes10, Carsten Münk1, Dieter Häussinger1, Guido Kobbe2
1 Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Germany; 2 Department of Hematology, Oncology and Clinical Immunology, University of Düsseldorf, Germany; 3 Institute of Virology, University of Cologne, Germany; 4 Institute for Virology, University of Düsseldorf, Germany;
5 University Medical Center Utrecht, Netherlands; 6 IrsiCaixa Institute for AIDS Research, Badalona, Spain; 7 Medicine 3, University Hospital Erlangen, Germany; 8 I. Medical Clinic and Polyclinic, Medical Center Hamburg-Eppendorf, Germany 9 Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
2 3
10 Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health & Science University, USA
ctious Diseases, University of Düsseldorf, Germany; Department of Hematology, Oncology and Clinical Immunology, University of Düsseldorf, Germany; Institute of Virology, University of Cologne, Germany; Institute for Virology, University of Düsseldorf, Germany; 4

xa Institute for AIDS Research, Badalona, Spain; 7 Medicine 3, University

BACKGROUND DiagnosesHospital
HIV Erlangen, 8
AML CR1 Germany; I. Medical Clinic and Polyclinic,
Relapse CR2 Medical
RelapseCenter
CR3 Hamburg-Eppendorf, Germany
9
GvHD Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany;
10 Division of Pathobiology and Immunology, Oregon National Primate Research#1Center, Oregon Health
#2
& Science University, USA
- As reported before (CROI 2016) a now 49y old HIV-
infected male patient did receive unmodified HSCT from AML- ICE HiDAC A-HAM, Flu-
5-Azacytidine #1, #2,
SCT DLI, #3, #4, DLI, #5,
a female 10/10 CCR5-d32 DKMS-donor in February related #1, #1, #2, HiDAC Treo #6, DLI, #7, DLI, #8
therapy #2 #3
2013 because of acute myeloid leukemia while being in
Diagnoses HIV remission
2nd complete AML CR1 (CR). Relapse CR2 2011 Relapse CR3 2012 2013 GvHD 2014 2015 2016 2017 2018
- By then proviral DNA load was 29400 cop/mL and all #1 #2
anticipated bands could be detected by western blot.
Western
- At the time of HSCT coreceptor-usage was predicted as + +/- +/- +/- +/- +/- +/- -
blot 5-Azacytidine #1, #2,
AML-R5-tropic (Sanger: ICE HiDACNGS: 0.14% X4 at 3.5%
FPR 44.5%; A-HAM, Flu- SCT
FPR, geno2pheno),#1,confirmed Resistance DLI, #3, #4, DLI, #5,
related #1, #2,by phenotypic testing profile HiDAC Treo no resistance in PR,
(TropChase). 120
#6, DLI, #7, DLI, #8 RT, IN 900
therapy #2 #3 0.14% X4 at 3.5%
- During HSCT and until November 2018 the patient FPR
800
remained on ART with undetectable viral load in 100

plasma. He had a 2nd relapse2011 2012 2013 2014 2015 2016 2017 2018 700
of AML in June 2013 but
VL
after 8 courses of 5-azacytidine and 4 donor 80 600

lymphocyte infusions CR was achieved and Chimerism

500
immunosuppression was stopped in October 2017. pVL
60
CD4 400

Western METHODS 40 300

+ +/- +/- +/- +/- +/- +/- -
blot
PBMC and tissues were analysed by ddPCR, qPCR and in situ
200
20
hybridization in several laboratories as well as humeral and 100

Resistance
T-cell responses. Infectious virus was analysed on CD4+ T-
cells (qVOA, MVOA). Patient was registered to IciStem as
0
no resistance in PR, 0
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profile
patient #19.
120
RT, IN 900
0.14% X4 at 3.5%
TropChase FPR WESTERN BLOT DNAscope RNAscope 800
gp160
gp120

100 gp41
p68
p55

p34

p25

p18
pos. control 700
neg. control
VL 02/2013
80 600
06/2014
Chimerism 02/2015
07/2015 500
pVL
60 12/2015
CD4 01/2016 400

40 POST-TRANSPLANTATION SUMMARY & CONCLUSION 300

- Concerning HIV, all PBMC samples were negative for proviral DNA by conventional and digital droplet PCR in different labs at multiple time points. - Despite low signals in ultrasensitive assays no virus could be detected in qVOA/mVOA in the Duesseldorf
patient. Taking into account the homozygous CCR5-d32 status we consider a viral rebound to be unlikely. 200
- Liquor (July 2014), rectum (April 2015, March 2016), ileum (March 2016) and bone marrow (August 2015) showed also negative test results.
Since the functional relevance is unclear an ATI is the only way to find out whether HIV has been eradicated
20 with 0.1 Mio cells from the ileum showed 1/4 replicates positive with LTR-, but negative with gag-primers. There were also 2 positive signals in T-cell subsets
- Further testing by allogeneic CCR5-d32 HSCT.
(TCM 0.2 Mio cells: ddPCR 6.7 cop/106cells, qPCR neg., TEM 0.36 Mio cells: qPCR 5 cop/106cells, ddPCR neg.) with all other subsets negative in ddPCR and qPCR. 100
- Therefore ART was stopped in November 2018 after thorough discussion with the patient.
- No HIV-DNA could be detected by PCR in lymph nodes collected 05/17, but via in situ hybridization assays (RNAscope, DNAscope) few positive signals were detected.
- Plasma viral load and proviral DNA is measured twice weekly since stopping cART, immunological follow-up
0 assays (VOA) were negative February 2016, March 2016 and May 2016 (23 Mio CD4+ Tcells, IUPM <0.031/106 CD4 T cells).
- Viral outgrowth 0
is performed monthly.
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- Mouse viral outgrowth assays (mVOA, April 2016 Rag2-/-γc-/-, April 2017 NOD-SCID IL2gR-/-) also showed negative test results.
- Despite all plasma samples being negative after ATI longer surveillance is essential.
- CTL-assays showed a strong response against HLA-A2-epitope YV9 (RT) and HLA-B7-epitope YL9 (Gag-P6), which was not present in cells from the stem-cell donor.
- The Western blot shows an incomplete pattern (gp160 slightly positive, others negative). We are grateful to the patient for his participation and commitment.

CROI 2019
se WESTERN BLOT DNAscope RNAscope
0
0
 Comparación de los 3 casos

Paciente Berlín Paciente Londres Paciente Dusseldorf

Donante CCR5 d32 Donante CCR5 d32 Donante CCR5 d32
Infección por virus CCR5 Infección por virus CCR5 Infección por virus CCR5
LMA LH LMA
2 trasplantes 1 trasplante 1 trasplante

Irradiación corporal total Sin irradiación Sin irradiación

Condicionamiento full intensidad Condicionamiento intensidad Condicionamiento intensidad

reducida reducida

GVHD leve GVHD leve GVHD leve

Quimerismo 100% Quimerismo 100% Quimerismo 100%

TAR post Tx: 0 TAR post Tx: 16 meses TAR post Tx: 66 meses
Tiempo con remisión viral: > 10 a Tiempo con remisión viral: 18 m Tiempo con remisión viral: 3 m
 Otras intervenciones para “Cura”

Edición génica
• CRISPR/Cas9: para escindir DNA de SIV en primate →
Sin desarrollo viral en PBMCs después de escisión
confirmada en tejidos (Burdo T, et al. CROI 2019; Abstr. 24)

• CCR5 “zinc finger nuclease”: edición génica con una

dosis de ciclofosfamida pre-tratamiento
→ Significativo retardo en rebote viral durante ATI y
mantención de bajos niveles de viremia (Tebas P, et al. CROI
2019; Abstr. 25)
 Inhibidores de checkpoint

Apoptosis

Bloqueo Recupera capacidad

Célula infectada PD-1
con VIH De citotoxicidad

Pembrolizumab (anti-PD-1 Ab checkpoint inhibitor) → transient increase in HIV transcription

in CD4+ T cells; early decrease in HIV DNA (Uldrick T, et al. CROI 2019; Abstr. 27)
Anticuerpos neutralizantes de amplio espectro (bNAbs)

• En bajo % de individuos con años de infección

• Actúan en múltiples sitos de envoltorio viral

• Características de los bNAbs:

– Vida ½ larga, permite uso como vacuna pasiva

– Virus resistentes a bNAb, sensibles a TAR

– Su acción puede reducir los reservorios

Nussenzweig, CROI 2019

Anticuerpos neutralizantes de amplio espectro (bNAbs)

PGT121 en adultos, Fase I

• 9 pts con alta CV, 1 dosis sc de PGT121
– 5 de 9 respondieron

– Media de caída CV: 1.7 log

– Rebote al día 21-28 con R a PGT121

• 3 con baja CV, todos con respuesta

– 2 con respuesta sostenida

• Tratamiento seguro y bien tolerado

1. Caskey. NEJM. 2016;375:2019. 3. Stephenson. CROI 2019. Abstr 145.

 bNAb: GS-9722

NK Monocyte PBMC
80 80 80
% Reduction in Infected Cells

PGT121
60 60 60 GS-9722

40 40 40

20 20 20

0 0 0

-20 -20 -20

10-4 10-3 10-2 10-1 100 101 102 103 10-4 10-3 10-2 10-1 100 101 102 103 10-4 10-3 10-2 10-1 100 101 102 103
mAb, µg/mL mAb, µg/mL mAb, µg/mL

Thomsen. CROI 2019. Abstr 356.

 bNAbs Tri específicos

• Una molécula interacciona con 3 sitios

independientes de la envoltura viral

– CD4, MPER y V1V2

• Actividad antiviral hasta 3 log copies/mL en

macacos con SHIV

• Rebote cuando Ac bajo umbral determinado

• Estudios en humanos: planificados para 2019

Pegu A. CROI 2019. Abstr 28LB

 Novedades en terapia antiviral

TAR inyectable y larga duración

• Cabotegravir (CAB) y Rilpivirina (RPV) larga duración

– ATLAS: VIH suprimido; cambio a LA CAB/RPV IM mensual o continuar TAR oral

• FLAIR: VIH virgena terapia; supresión con TAR oral; luego cambio a LA CAB/RPV IM mensual o continuar
TAR oral

• ATLAS-2M (en curso): HIV suprimido; LA CAB/RPV IM cada 4 versus cada 8 semanas

Uso II con mutaciones resistencia en INTR

• Dawning: DTG o LPV/r + 2 INTR en falla 1ª

• B/F/TAF

Swindells S, et al. CROI 2019; #139 Orkin C, et al. CROI 2019; #140.
ATLAS/FLAIR

Swindells S, et al. CROI 2019; #13, Orkin C, et al. CROI 2019; #140.9
 ATLAS/FLAIR: Seguridad y tolerancia
100
80
• Reacción sitio inyección (RSI) común FLAIR

Pacientes con RSI (%)

60

• 99% RSI G 1–2 40

20
• 88% se resuelve en ≤7 días 0
4B 8 12 16 20 24 28 32 36 40 44 48
• 1% discontinuación Semanas estudio

• Efectos adversos serios infrecuentes

ATLAS
• Alta satisfacción con preferencia de
terapia inyectable

Régimen preferido,* % (n/N)

Estudio Población
IM larga duración Diario PO
ITT-E 86 (266/308) 2 (7/308)
ATLAS[1]
Participantes que responden 97 (266/273) --

ITT-E 91 (257/238) 1 (2/238)

FLAIR[2]
Participantes que responden 99 (257/259) --

*Pregunta una vez a semana 48 Swindells S, et al. CROI 2019; #139, Orkin C, et al. CROI 2019; #140.
ATLAS/FLAIR: Emergencia resistencia en tratamiento

Resistencia basal Resistencia en falla

Sitio/subtipo VIH (HIV DNA) virológica
RT IN RT IN
ATLAS

Rusia/A1 E138E/A L74I E138A L74I

Francia/AG V108V/I, E138K Ninguna V108I, E138K Ninguna

Rusia/A1 Ninguna I74I E138E/K N155H, L74I

FLAIR

Rusia/A1 Ninguna L74I E138E/A/K/T L74I, Q148R

Rusia/A1 Ninguna L74I K101E L74I, G140R

Rusia/A1 Ninguna L74I E138K L74I, Q148R

Swindells S, et al. CROI 2019; #139, Orkin C, et al. CROI 2019; #140.
DAWNING: DTG o LPV/r + 2 INTR en falla 1ª: Eficacia a 48 sem

Brown. CROI 2019. Abstr 144, Aboud M et al, LID, 2019

DAWNING: DTG o LPV/r + 2 INTR en falla 1ª: Eficacia a 48 sem

Presencia de M184V/I ± otra mutación para INTR y uso 3TC o FTC

VIH-1 RNA < 50 copias/mL a LPV/RTV + 2 Diferencia

DTG + 2 INTRs
sem 48 en ITT-E % (n/N) INTRs %

Total 84 (261/312) 70 (219/312) 13.8

▪ M184V/I* presente 84 (220/261) 72 (182/252) 12.1
• Uso de 3TC o FTC 85 (187/220) 72 (152/210) 12.6
• No uso de 3TC o FTC 80 (33/41) 71 (30/42) 9.1
▪ No M184V/I 80 (41/51) 62 (37/60) 18.7

Uso 3TC o FTC

▪ M184V/I 82 (47/57) 68 (44/65) 14.8
▪ M184V/I + ≥ 1 INRT RAM 86 (140/163) 74 (108/145) 11.4
▪ M184V/I + ≥ 1 TAM 90 (54/60) 72 (46/64) 18.1
▪ M184V/I + K65R 85 (23/27) 68 (15/22) 17.0

Uso de TDF con K65R o ZDV con TAMs

HIV-1 RNA < 50 copias/mL a LPV/RTV + 2

DTG + 2 NRTIs Diferencia
semana 48 en ITT-E, % (n/N) NRTIs
%

Total 84 (261/312) 70 (219/312) 13.8

K65R presente 84 (80/95) 74 (68/92) 10.3

Uso de TDF en presencia de

86 (6/7) 88 (7/8) -1.8
K65R

≥ 1 TAM presente 87 (62/71) 75 (61/81) 12.0

Uso de ZDV en presencia de ≥ 1

86 (30/35) 78 (40/51) 7.3
TAM

Brown. CROI 2019. Abstr 144, Aboud M et al, LID, 2019

effi
c Bl
cy i–p
witAMay
na
h
ou l
ty se
d
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clinical ATV (n=2752%7 )(23) 40% (94
M184V/I W ild-t yp e M 1 8 4
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theou tcoHIV-1
most me s ar
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(Roche
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13-15 2.0 test, Roche
patients Diagnostics)
with virologic ΠParticipants
a. High rates (95% -100%)
with historical of
genotypic data virologic
only suppression
were assumed to have on B/F/TAF
wild-type M184
(n= 42) ( n= 235)
HIV-1 RNA and outcome data through Week 48Œwere The boosted PIb.group had more blips per participant than theP valB
e toΠ3TC or FTC
All on-treatment included P values for mean data calculated by Student’s t-test (2-tailed). P values for percentage
Mea na ge, y ea rsparticipants
(ra ng e) test. with preexisting 51 ( 29 M184V/I and
≥65) 46 ( other
20 ≥7 4)RT resista 0 .0 0
ccurs
Œ Vi M184VI no detectada, no afecta respuesta virológica en
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Methods
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a
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ip64%
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:a f
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eba sel
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followed
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i
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sit,
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asi ng
and decreases
leH I
RNA <50 c/mL
V- 1 RNA va lue≥50c (P=0.03
/ mL, Male,
susceptibility to ABC, – All 15
by Cochran-Mantel-Haenszel test )
Mean
% (n)
B/F/TAF-treated
Fisher’s Exact
– Similar to the e
CD4 count, cells/µL (range)
rate of81%
participants 648(
virologic
21 7
(34)
had
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1 blip 67
85% (200)in the over
3( 1 47 ≥2582)
0.5
0.6
ut increases susceptibility 10
РParticipants ΠPresence population
of proviral(98%)M184V/I was associated with longer tim
ses to TFV
Sta ti sti
MayŒnotEpreclude
f
fi
ca
ccyo
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utc
ly
a
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ome:p roto triple
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fp
nofovir (TFV) in either prodrug form (TDF or TAF)10-11
artiregimens
cipants wit hvir o
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icsu and
ppressi on (HI
HIV-1 subtypeon
Mea
V-
yea
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B, %boosted

g
(n)
initiation
eA RV ini
ur
compared
e4.
tia
Vi
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tion, to wild-type M184
rologi cwith
a mean
98%
15(
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f
)
ils o
of 1.3 90%blips
9(
finitiated
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≥29
i p
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ants
<0
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0.1
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h
Fi g ur e7 . P r opoM – r But
ti o some
nV/ o f participants
B/ M184V/I ARV as few as
ndF H/ T A1 F - t r e a te d P a r t i
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RNA <50 c/mL) at last on-treatment visit through Week 48 Mean time on boosted PI regimen,
May be Fi –g uMissing
re1 .St
under-reported udy
HIV-1
by1 878
the
RNA Desig
GenoSure
values atnWeek 48 were imputed using the
Archive assay11
last years (range) 1 84 I a IV- 7RNA
(0 .9 ≥20 ≥50
) c/ mL
6( 0.a
6≥20 ek 8
0.0
blips (transient viral load values above the assay limit) can occur in Baseline M184V/I
Blipsa.
Baseline ARV regimen, según M184VI
% (n) basal b.
observation carried forward (LOCF) method
c treated patients12
essfully F ig u r e 3.
FTC/TDF
B/
F/
Vi
TAF
ro lo g ic Su p
76%
DRV/RTV + RPV
p r e
(32)ssi d o n a t
86%L10a st
0 On-
(201)
B/F/
trea tm
TAF A TV/RTV + FTC

Ma yr ef –
letr Distinct
esid ua lv from
iralrWeek
e
pli ca 48
ti o snapshot
n,r andom b analysis
iolog icalf l
ucua ti on, or NRTI 1 0000
Substitutions at failure:
100 00 00 0.2
ABC/3TC 24% (10) 14% (34)
ssayΠvariation B/
StatisticalF/
13 TA F
comparisons were performed using Student’s t-test, Fisher’s exact th1 r0
o
00
u ghW eek48Str45%
DRV
M184V
atif i eb
(19) IQR
yM 18 4V/
60%1
IDete
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000
ctio n
Boosted PI 100 0 0.1
May betest, a marker forcfuture virologic failure,test
or Cochran-Mantel-Haenszel but as appropriate
impacts on clinical 200
ATV 52% (23) 40%20 (94)
0
100
outcomes a r
econf liting13-15 100
a. Participants with historical
50 genotypic data only were assumed to have wild-type M184 50

eFRe sultsies andVirologic

b. P values for mean data calculated by Student’s t-test (2-tailed). P values
1 00 for percentage data calculated by
Preexisting substitutions:
requenc Fisher’s Exact test. 1
0
K70K/R, M184M/V
10

ehods
at
me ntVisi tthroughW e ek48 ΠPresence of proviral
1
BLQ
M184V/I was associated with longer time1 since ARV
LLOQ
Preexisting
M184M/I/V

initiation compared to wild-type M184

Fi
P egruc r
eent2. oBafP sa e
rtl
ii
ne
c ipa Gnteno
s ( ty
n/ p
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– But some• participants
Confir
ed virwith
o
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fa
il
u t Winitiated
rea eek 12 wARV
ith as few as 3 yearsB/F/TA
• Discontinued ago
B/
ur
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./TDetey
AF ct io n8 i
nDeth e B/ F/TA FG r oup
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exact sem según M184VI basal I De te c•tion
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8%Π(37/42)
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1% (19/61)
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ior to–randomization available with M184V/I detected post-randomization continued in study had archived M184V/I
Participants
genotype
ce suppression
blood was on
collected
andinclud edB/F/TAF
ata
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llef f iccwere
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ly ses proviral among • a. 26% of participants without B/ F/ TAP
historical Fercent ofParticipantsh(
genotypes
P value calculated by Fisher’s exact test
4V/I
archive and theother
In genotyping
ŒŒ Baseline B/F/TAF RT
genotypes resistance
group, pre-switch substitutions
(baseline) genotypic data were obtained WT forM184V/I
= wild-type B/ F/TA F K et al, CROI 2019
Andreatta
HI V-1RNA
c suppression in the overall B/F/TAF-treated BaselineResistance
a. P value calculated by Fisher’s exact test
Any Baseline Data
Drogas en desarrollo
 MK-8591: INTTR

• MK-8591: inhibidor nucleosido de translocación de

transcriptasa reversa (INTTR) en estudios Fase II Farmacocinética de MK-8591-TP QD en adultos sanos[3]

Durante dosis
• Datos preclínicos muestran potente actividad
10.0
contra virus nativo y con multiresistencia [1]

0.25 mg MK-8591
• Vida media larga permite uso semanal o mas[2] 1.0

MK-8591-TP PBMC Concentration

0.75 mg MK-8591
5 mg MK-8591

(pmol/million cells)
• Con dosis de 0.25 mg día o 10 mg sem, el 0.1

cuociente inhibitorio de MK-8591 es mayor que en

Después de última dosis
otros INTR [3]
10.0

1.0

0.1

0 10 20 30 40
Days

1. Nakata. Antimicrobial Agents Chemother. 2007;51:2701. 2. Markowitz. Curr Opin HIV AIDS. 2018;13:294. 3. Grobler. CROI 2019. Abstr 481.
 GS-6207: First-in-Class HIV
GS-6207, Inhibidor de capside viral
Capsid Inhibitor
Estudio Fase I en humanos (1º) [1]
• Una dosis SC en 32 voluntarios sanos
• Bien tolerado
• PK permite intervalo de dosis > 12 sem

• Fase Ib GS-US-200-4072, reclutando:[2]

–• CV
HIV 10,000
capsid isaessential
400,000 at multiple
c/mL ystages
CD4+in>the
200viralcells/mm
life cycle 3
– CROI
Vírgenes
2019 feedback: y experimentados a TAR, estos últimos
www.i-Base.info UK-CABsin uso2
April 2019
CAI ni INI, sin TAR en 12 sem previo screening 4

• Randomizado, doble ciego:

– Una dosis de GS-6207 150 mg (cohorte 1)
– Aumento progresivo hasta dosis única de 450 mg
(cohortes 2-4)
– Una dosis placebo día 1
• Todos reciben BIC/FTC/TAF desde día 10

1. Sager. CROI 2019. Abstr 141. 2. NCT03739866.

 GSK 2838232: nuevo inhibidor de maduración
Objetivo: evaluar seguridad, tolerancia,
actividad y PK de dosis oral de GSK’232 + COB
Método:
• Evaluar niveles de 4 dosis de GSK’232 + 150
mg COB por 10 días
• Muestras para PK en días 1 y 10
• Seguimiento 11 d post tto. (dia 21)

Actividad antiviral de GSK’232

• Robusta reducción con 50, 100 y 200 mg

• Máximo efecto con 200 mg

Buena tolerancia
DeJesus E, et al. CROI 2019; Oral abstract #142
 tment-Experienced Participants Living With HIV-
FTR4 monotherapy substudy:
8 approximately610 participants per 12
study arm
144
[64.0–88.5]
–
[34.4–63.7]
–
[48.1–75.9]
–
[43.2–71.8]
116 (58)
[50.8–64.9]
[42.2–70.7]
23 (45)
[31.1–59.7]
s,7 Eficacia
J. L. y seguridad
4

4
Bogner,8
A. Fostemsavir
S. Primary

8
8
a 192 sem
Ye,9
Primary
en pacientes
C. Llamoso,
6 endpoint
12
Pierce,10
study – start6 of combination therapy
P. M. Lataillade11
12
a

a
Chabria,11 192*
Ackerman,11 – – –
11 105 (53)
[45.3–59.6]
22 (43)
[29.3–57.8]
*After the last subject completed their Week 48 visit, investigators were unblinded to the original assigned FTR dose and on a rolling basis over time
4

experimentados
Natal Research Institute for TB and HIV, Durban, South Africa; a
8

terapia
6
Mexico
tersburg, Russian Federation; Instituto Oulton, Córdoba, Argentina;
FTR 1200 mg QD* + RAL + TDF
12
Centre for Clinical Research, Mexico City
7 ATV/r + RAL + TDF
(from Week 64 to Week 110),4 FTR-treated subjects were switched from their double-blind dose to the open-label continuation dose of FTR 1200 mg
QD. Subjects in the REF arm were retained on open-label ATV/r 300/100 mg QD. Week 192 marks the latest study visit that all participants had an
opportunity to complete prior to the conclusion of the study.
CI, confidence interval.

are, Research Triangle Park, NC, USA; 11ViiV Healthcare, Branford, CT, USA
ontinued until the last participant completed Week 48 visit. After the last subject completed their W eek 48 visit, investigators were
ned FTR dose and on a rolling basis over time (from Week 64 to Week 110), FTR-treated subjects were switched from their
Figure 3. Virologic Response Through Week 192 (Observed)*
-label continuation dose of FTR 1200 mg QD. Subjects in the REF arm were retained on open-label ATV/r 300/100 mg QD.

100

With
participants with
97 96

CI)
(95% CI)
sition 90 91
88
90 90
92
90

<50 c/mL (95%

of Participants
87
cipants
Response
were screened, 254 were randomly assigned, Safety 81
83
85
86 86

80
gic response
eceived rates (HIV-1 RNA <50 c/mL) at Week 144
treatment. FTR-based therapy was well tolerated with no discontinuations
78 79 79

Week 192 by FDA

an time on FTR therapySnapshot foralgorithm and Observed
the combined FTR groups related 70 to the investigational agent throughout the study. 71
69

RNA <50
FTR 400 mg BID
sis were or
5 days comparable
4.5 years between
(blinded the
andFTR arms and
open-label the
phases) The60most common FTR-related adverse events (AEs; FTR 800 ofmgany BID

Percentage of
rm (Table 2 and Figure 3). grade) were headache (6%) and nausea (5%), while the
FTR 600 mg QD
most T

HIV-1 RNA
Percentage
an time of 1062.0 or 2.9 years on the REF regimen. 50
FTR 1200 mg QD
common REF-related AEs were nausea, dizzinessREF (8% each),
at Baseline
Virologic Response Through Week 192 (Snapshot)

HIV-1
and0AEs related to bilirubin elevation (e.g. jaundice, scleral
demographic and disease characteristics were broadly icterus; 8– Week18%). 24 Week 48 Week 96 Week 144 Week 192
FTR + RAL + TDF
oss all 400
treatment groups
mg BID 800 mg BID(Table
600 mg 1).
QD 1200 mg QD
REF 400 mg BID, N
A mg
800 greater
BID, N
46
percentage
42
43
of
38 REF participants
43
28 experienced
ian age was 39 years,(n=49)
60% of the participants (n=51)
were male, 600 mg QD, N 49 45 36
(n=50) (n=51) (n=50)* Grade
1200 mg QD, N2– 4-related
43 AEs, 42 Grade 3– 304 AEs, and123AEs leading 115 to * *
had HIV-1 subtype B. n (%), [95% CI]
discontinuation
REF, N 42
(Table 41
3). 31 25 23
HIV-1
4 RNA viral load at baseline39
40 (80) 34 (69) was(76)4.85 log
36 (72)c/mL and
10
38 (75) After the last subject completed their Week 48 visit, investigators were unblinded to the original assigned FTR dose and on a rolling basis over time (from Week 64
to Week 110), FTR-treated subjects were switched from their double-blind dose to the open-label continuation dose of FTR 1200 mg QD. Subjects in the REF arm
[66.3–90.0] [54.6–81.7] [62.5–87.2] [57.5–83.8] [60.4–85.7]
pa r
tici
pa nts41h a daba
(82)
se li
nevi
30 (61)
r
a llo a d≥1
35 (69)
00,0 00c/
34 (68)
mL. 36 (71) Table
of the study. 3. Cumulative AE Summary
were retained on open-label ATV/r 300/100 mg QD. Week 192 marks the latest study visit that all participants had an opportunity to complete prior to the conclusion

8
CD4 T-cell count at baseline was 229.5 cells/µL
[68.6–91.4] [46.2–74.8] [54.1–80.9] [53.3–80.5] 38%
and of
[56.2–82.5]
6
nts had <200 cells/µL.
39 (78) 24 (49) 32 (63) 29 (58) 29 (57) Efectosinadversos
Change CD4 T-Cell Counts Total
[64.0–88.5] [34.4–63.7]
[43.2–71.8] [48.1–75.9] [42.2–70.7] FTR Arms REF Treated
eline Characteristics 116 (58) 23 (45) Mean CD4
Parameter, n (%) T-cell counts increased steadily through Week 192 in
4 – – – (N=200) (N=51) Participants
FTR + RAL + TDF [50.8– 64.9] [31.1–59.7] both the combined FTR arms and the REF arm (Figure 4).
(N=251)
105 (53) REF
22 (43)
meter
2* Se une a gp120 viral evitando cambios
– BID 800 mg
400 mg
(n=50)
–BID 600 mg
(n=49)
–QD 1200 mg QD
(n=51) [45.3–
(n=50)59.6] (n=51)57.8]
[29.3–
Figure 4. Mean Change in CD4
Any event T-Cell Count
186 (93) Through 236
50 (98) Week
(94) 192*
ect completed their Week 48 visit, investigators were unblinded to the original assigned FTR dose and on a rolling basis over time
conformación necesarios para la unión
Week 110), FTR-treated subjects were switched from their double-blind dose to the open-label continuation dose of FTR 1200 mg
Grade 3–4 AEs 36 (18) 17 (33) 53 (21)
an (SD) Change in CD4 T-Cell Count

19 (38) 21 (43) 22 (43) 16 (32) 22 (43)

e REF arm were retained on open-label ATV/r 300/100 mg QD. Week 192 marks the latest study visit that all participants had an FTR 400 mg BID
500
plete prior to the conclusion of the study.
31 (62) 28 (57) 29 (57) 34 (68) 29 (57)
rval.
ars al virus
38.5 y entrada
37.0 a40.0
LT CD4+40.0 39.0 400
FTR 800 mg BID
Grade 2–4-related AEs
FTR 600 mg QD 23 (12) 20 (39) 43 (17)
From Baseline (cells/µL)

(22–57) (23–60) (26–58) (20–67) (20–69) FTR 1200 mg QD

Virologic Response Through Week 192 (Observed)* AEs leading to discontinuation
REF
300
7 (4)
265
6 (12)
272
13 (5)
280
merican 14 (28) 15 (31) 16 (31) 18 (36) 13 (25) 250 253
264
20 (40) 19 (39) 9717 (33) 16 (32) 23 96(45) SAEs* 35 (18)
199 219 8 (16) 43 (17)
179
200 159 211
16 (32) 91 15 (31) 18
90
(35) 16
90
92 (32) 15
90
(29) 134 176
87
88
86 86
Related SAEs 111
110 1141(<1)
164 2 (4) 3 (1)
85
83 100 120
119
mL 81
78 79 4.97 79 5.01 4.88 4.78 4.78 Fatal SAEs 0
3 (2) 0 3 (1)
(1.99–6.15) (2.64–6.54) (1.69–6.50) (2.15–6.82) (1.76–6.83) 0
71
n (%) 23 (46) 69 25 (51) 23 (45) 18 (36) 18 (35) *None of the SAE events occurred in >2% of participants in each treatment arm. SAEs that occurred in >1 participant overall were: overdose (n=3 FTR arms,
FTR 400 mg BID Baseline Week 24 Week 48
n=1 REF arm), and abdominal pain, accidental overdose, bone tuberculosis, and diarrhea (n=2 each, all in the FTR arms). Week 96 Week 144 Week 192
FTR 800 mg BID 400
SAE, serious BID, Nevent.49
mg adverse 41 43 42 Thompson. CROI 2019. Abstr 483.
214.0 237.0 226.0 223.5 249.0
FTR 600 mg QD 800 mg BID, N 49 38 34 28
Problemas metabólicos en TAR
 NA-ACCORD: alza peso en pacientes vírgenes a tratamiento que
inician TAR
• Análisis multivariable de ganancia de peso posterior a inicio TAR entre 2007 a 2016
• INI: N=4740; IP: N=7436; INNTR=11,825
• Mayor ganancia de peso con DTG vs RAL vs EVG; no varía por sexo o raza
• Después de 3 años de TAR, el IMC se parea con población americana promedio

Bourgi K, et al. CROI 2019; Abstr. 670

 Ganancia de peso con INI: otros estudios CROI

• Con ganancia de peso relacionada

– ACTG A5001 y A5322 desde 2007 a 2017 (N = 972)
• Mayor incremento en mujeres, raza negra y > 60 años

– HOPS: observacional de cambio terapia (N = 653)

• INI vs ni INI: 1.2 kg vs 0.3 kg, p=0.05

• DTG > RAL o EVG

– WIHS: estudio observacional en mujeres (N = 1118)

• Alza 2.14 kg mayor en quienes recibían INI

• Resultados mixtos o no asociación

– TRIO : asociado en análisis bivariable pero no en multivariable

– HPTN 077: Cabotegravir en personas sin VIH no asociado

Bourgi K et al, CROI 2019, #670; Kerchberger A et al, CROI 2019, #672; Pallela FJ et al, CROI 2019, #674; McComsey G et al, CROI 2019, #671; Landovitz R et al, CROI 2019, #34
Inhibidores de Integrasa y ganancia peso

• Ambiente obesogénico
• Uso de INIs se relacionan con aumento de
peso
• Se requieren estudios diseñados para evaluar
este impacto y ver diferencia de drogas
• Inicio TAR condiciona
• Apoyo marginalidad, manejo salud mental,
tabaco
• Fenómenos relacionados a TAR o virus

• Sobrepeso en Infección por VIH es relevante

• Mas inflamación, mas riesgo coronario, mas
diabetes
Anthony Fauci
 Fundamento científico del plan

Tratamiento como Profilaxis pre

prevención exposición (PrEP)
 Fin de la epidemia
Nuevos casos USA 2007-2017 y diferencia programas

Washington San Francisco Nueva York

Fauci A., CROI 2019

 Epidemiología Infección VIH USA

• Hay 3007 condados en USA

• En 2016/17: > 50% de los casos en 48 condados, Washington, DC y Puerto Rico

• 7 estados del sur tienen una desproporcionada frecuencia de infecciones en áreas rurales

• La mayoría de las nuevas infecciones

– HSH Afroamericanos e Hispanos/latinos

– Alta incidencia en transgenero y DIV

Fauci A., CROI 2019
Anthony Fauci, fin de la epidemia en América (¿USA?)

Diagnostico precoz nuevas Foco inicial en áreas de alta incidencia

infecciones¿Que hay de nuevo en esta iniciativa?
Tratamiento inmediato Llevar a supresión y detener
Es la primera vez que hay un esfuerzo conjunto de todas las agencias
transmisión, objetivo 60 a 90%
nuevas infecciones, y
americanas para implementar un plan en poblaciones especificas
estrategias retención
NoProteger riesgo de infección
se esta recurriendo Expandir
a re distribución de PrEP,sino
recursos, paraa llegar
fondos a uso de alpre
nuevos
comprometidos para menos 50% de2020
presupuesto los que lo requieren
Detección y enfrentamiento de Monitoreo
cluster deespecial
Atención infección Considerar
a seguir modelos exitosos cada colaboración
y a pedir caso como centinela
abierta

Fauci, CROI 2019

Muchas gracias

lnoriega@alemana.cl