CROI 2016, Boston

Santiago MorenoHospital Ramn y Cajal. IRYCIS.

Madrid

Reducing Drug Regimens:Virological Perspective

2nd Spanish HIV Clinical Forum: Intergrase Inhibitors Mlaga, 11-12 de Mayo de 2017

Lohse & Obels. Annals Intern Med 2016

Higher survival in HIV-infected personssince the introduction of HAART (3DR)

and a lower gap with the general population

Lohse & Obels. Annals Intern Med 2016

La ausencia de factores de riesgo y comorbilidades influyen en las expectativas de vida

Non-AIDS related diseases account for more than 50% of the deaths in HIV-infected persons

Hunt, JID 2014(see also : Tenorio, JID 2014)

Inflammatory Markers Predict Mortality Independent of Nadir and Current CD4 count

Gut Epithelial Barrier Dysfunction

Inflammation / Coagulation

IDO-1 Induction

Monocyte Activation

7

SMART Study: Interrupting ART Increases the Risk of Heart Disease

Adapted from Deeks SG, Phillips AN. BMJ. 2009;338:a3172 y Operskalski EA. Curr HIV/AIDS Rep. 2011;8:12-22.

Increase in Comorbidities

Low CD4+

nadir

Coinfections(HBV, HCV, CMV,

EBV y HPV)

Cumulative Exposure to ART

Ageing

Life style (smoking, )

Persistent

Inflammation

HIV infection contributes to the development of non AIDS events

Nmero de Frmacos: Evolucin del TAR

DualNRTIs

1987 First NRTI

19912Two new NRTIs approved

1994Dual NRTIs better than monotherapy

Triple combination

therapy

Sequentialmonotherapy

PI/r monotherapy

NNRTI + 2NRTIs PI/r + 2NRTIs II + 2NRTIs CCR5a + 2

NRTIs

Dualtherapy

PI/r + NRTI PI/r + NNRTI PI/r + CCR5 inh PI/r + II II + 3TC

difference=-5.9%, 95% C.I.-16.9%, +5.1%).

HIV RNA

Estudio PROTEA. HIV-1 RNA in CSF samples at Week 48

Clarke A. HIV Drug Therapy Conference, Glasgow, UK, November 2014 [oral presentation: O423A] 11

La monoterapia con IP/r se asocia con una mayor replicacin vrica persistente

EARNEST: Trial designHIV positive adolescents / adults (n=1200)

1st line NNRTI-based regimen >12m; > 90% adherence last 1mFailure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria

RANDOMIZE

PI + 2-3 NRTIs(NRTIs according to

local standard of care)

PI + RAL

PI + RAL(12 wk induction)

PI(Monotherapy)

FOLLOW-UP FOR 144 WEEKS

Primary outcome at week 96: Good HIV disease control defined as all of: Alive and no new WHO4 events from 0-96 weeks AND CD4 cell count > 250 cells/mm3 at 96 weeks AND VL10,000 c/ml without PI res. mutations at 96 weeks

Los fracasos con monoterapia con IP/r provocan un mayor desarrollo de resistencias a IP que el tratamiento con IP/r + 2 ITIAN.

VL suppression at 96 weeksPI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88PImono+ vs PI/NRTI P=0.002 P

15

X XNote: assuming susceptible if VL1000 c/ml with missing genotype at week 96 based on those with observed genotypes*One patient in RAL/PI with intermediate/high level resistance to TDF had moved to 3TC TDF ALV at week 4 due to rash

*

Los fracasos con monoterapia con IP/r provocan un mayor desarrollo de resistencias a IP que el tratamiento con IP/r + 2 ITIAN.

Chart1PI/NRTIsPI/NRTIsPI/NRTIsPI/RALPI/RALPI/RALPImono+PImono+PImono+TDF/ZDV/ABC/ddIRALLPV% of randomised patients with intermediate/high level resistance3.552.370.262.090.87018.39Sheet1TDF/ZDV/ABC/ddIRALLPVPI/NRTIs42PI/RAL021PImono+018To resize chart data range, drag lower right corner of range.

%50 by week 48

6/8 Genotype amplified

3/6 INI resistance

1 each 155H, 263K, 230R

DSMB stopped study

Authors recommend againstDTG monotherapy

Combined analysis of 3 cohorts* 11/178 (6.1%) VF 3.9% INI resistance

148R/H (3), 155H (2), 118R (2)

DTG Monotherapy RCT Stopped Due to Failures

Wijting l, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 451LB.*Blanco Jl, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 42

Chart1Week 24Week 24Week 48Week 48DTG MonocART9210089.7Sheet1Week 24Week 48DTG Mono9289.7cART100

DTG-monoterapia: 122 (1,17%)

Nmero de pacientes controlados en las 3 cohortes: 10.440

DTG-bi-triterapia: 1.082 (10%)

No MR: 2

Si MR9

Fracaso virolgico:11 (9%; IC 95%: 6-18%)

Fracaso virolgico64 (6%; IC 95%: 5-7%)

No MR 64

Si MR0

Valor exacto de Fisher p=0,17

Razn de VF mono: 1,58 (IC 95%: 0,73-3,13)

82%

FV con DTG-mono

Blanco JL et al. CROI 2017. Seattle, 13-16 Febrero 2017. Abstract 42

SALT TrialSwitching to ATV/r+3TC vs. Standard ATV/r+2NRTIs is safe and effective

Prez Molina JA. Lancet Infectious Diseases 2016 1

PADDLE: Dolutegravir + Lamivudine for Treatment-Naive Pts

Open-label, single-arm phase IV exploratory trial 18/20 pts achieved HIV-1 RNA < 50 c/mL at Wk 48

1 pt committed suicide (deemed unrelated to study drugs)

1 pt experienced PDVF at Wk 36 (BL HIV-1 RNA > 100,000 c/mL); resuppressed HIV-1 RNA without ART change by discontinuation visit (Wk 52)

3 other pts with BL HIV-1 RNA > 100,000 c/mL suppressed at Wk 48Cahn P, et al. AIDS 2016. Abstract FRAB0104LB.

Treatment-naive pts with HIV-1 RNA

> 5000-100,000 c/mL, CD4+ cell count 200

cells/mm3, HBsAg negative(N = 20)

DTG 50 mg QD + 3TC 300 mg QD (N = 20*)

*10 pts enrolled initially; additional 10 pts enrolled after confirming virologic success of first cohort at Wk 8. Primary endpoint.

Wk 48

110 Subjects No Hx of failure, No Hep B 8 week Switch to 2NRTI+DTG 40 Weeks FU on DTG/3TC

1 x VF (no resistance) 4 SAE

Suicidal ideation CK elevation post exercise Grade 4 Depression Acute Hep C

ANRS 167 LamiDol Study DTG/3TC Maintenance

Joly V, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 458.

Chart1DTG+3TC%

Dolutegravir + Rilpivirine for Maintenance of Suppression: : Snapshot Outcomes at Week 48.

Llibre J, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 44LB.

DTG+RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (

Adapted from Yukl SA, et al. J Infect Dis. 2010;202:1553-61.

N=8, time on HAART with undetectable HIV RNA 2.8 12 years

Existe la replicacin vrica persistente en tejidos

Fletcher CV. PNAS 2014. 23

Existe replicacin vrica persistente en tejidos

Variable penetration of ARV in tissue

Fletcher, 19th CROI, Seattle 2012

Variable penetration of ARV in tissue

Fletcher, PNAS 2014(see also Lorenzo-Redondo, Nature 2016)

Ongoing viral replication and subtherapeuticART concentrations in lymph nodes

26

Existe la replicacin vrica persistente en tejidos

We conclude that continued virus production from infected cells in lymphoid tissue sanctuary sites, where drug concentrations are not fully suppressive, can continue to replenish the viral reservoir and traffic to blood or lymphoid tissue

Lorenzo Redondo R. Nature. 2016

Serrano-Villar. PLoS Pathogens 2016

Effects on Mucosal Immunity of First-Line ART With EFV vs. MRV vs. MRV+RAL in combination with FTC/TDF

In the duodenum, the quadruple regimen resulted in:-greater CD8+ T-cell density decline-greater normalization of mucosal CCR5+CD4+ T-cells -increase of the nave/memory CD8+ T-cell ratio -greater decline of sCD14 levels -greater decline of duodenal HIV DNA levels

Drug distribution to colon

EFV

MRV

RAL

0.01

0.1

1

10

100

P

CD

14

+C

D1

6-C

D1

63

+ c

ell

s (

%)

c A R T M P I0

2 0

4 0

6 0

8 0

1 0 0p = 0 .0 3 1

sC

D1

4 (

ng

/ml)

c A R T M P I1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 5 0 0p = 0 .0 0 4

sC

D1

63

(n

g/m

l)

c A R T M P I0

2 5 0

5 0 0

7 5 0

1 0 0 0

p = 0 .0 0 2

LB

P (

ng

/ml)

c A R T M P I5 0 0 0

7 5 0 0

1 0 0 0 0

1 2 5 0 0

1 5 0 0 0

p = 0 .0 7

A B

C D

La monoterapia con IP/r se asocia con una mayor replicacin vrica persistente

Garca F. JIAS 2014.

Figura 1

Porcentaje de diferencia en la concentracin srica de los biomarcadores (ajustado por edad, VHC, hipertensin, raza y tabaquismo).

Castillo-Mancilla JR et al. Clin Infect Dis 2016. pii: ciw650. [Epub ahead of print]

Abreviaturas: BAFF, factor activador de las clulas B; CCL, quimioquinas C-C ligando; CXCL quimioquinasCXC ligando; GM-CSF, factor estimulante de granulocitos y macrfagos ; IFN-, interfern gamma; IL,interleucina; sCD14, CD14 soluble; sCD27, CD27 soluble; sgp130, glicoprotena soluble 130; sIL-2R,receptor soluble IL-2; sIL-6R, receptor soluble IL-6; sTNF-R2, receptor soluble del factor de necrosis tumoral;TNF-, factor de necrosis tumoral lpha; CRP, protena C reactiva.

Castillo-Mancilla JR et al. Clin Infect Dis 2016. pii: ciw650. [Epub ahead of print]

Abreviaturas: IFN-, interfern gamma; IL, interleucina; TNF-,factor de necrosis tumoral lpha; CRP, protena C reactiva.

Abreviaturas: BAFF, factor activador de las clulas B; CCL, quimioquinas C-C ligando; CXCLquimioquinas CXC ligando; GM-CSF, factor estimulante de granulocitos y macrfagos ; IFN-,interfern gamma; IL, interleucina; sCD14, CD14 soluble; sCD27, CD27 soluble; sgp130,glicoprotena soluble 130; sIL-2R, receptor soluble IL-2; sIL-6R, receptor soluble IL-6; sTNF-R2,receptor soluble del factor de necrosis tumoral; TNF-, factor de necrosis tumoral lpha; CRP,protena C reactiva.

32

Conclusiones

Desde el punto de vista clnico: La monoterapia (con IP/r o dolutegravir) no demuestra la no inferioridad

respecto al tratamiento con tres frmacos La biterapia (con IP/r o dolutegravir) es no inferior al tratamiento triple

Desde el punto de vista virolgico: Resistencias: La monoterapia (con IP/r o dolutegravir) se puede asociar con el

desarrollo de resistencias La biterapia (con IP/r o dolutegravir) no parece asociarse con el

desarrollo de resistencia Persistencia de replicacin vrica e inflamacin secundaria: La reduccin del nmero de frmacos pudiera asociarse a una replicacin

residual en tejidos que condicionara inflamacin persistente y el desarrollo secundario de comorbilidades Se debera evaluar este aspecto antes de adoptar la reduccin del

nmero de frmacos como una estrategia de rutina clnica

Dianummer 1Dianummer 2Dianummer 3Dianummer 4Non-AIDS related diseases account for more than 50% of the deaths in HIV-infected personsInflammatory Markers Predict Mortality Independent of Nadir and Current CD4 countDianummer 7HIV infection contributes to the development of non AIDS eventsNmero de Frmacos: Evolucin del TARDianummer 10Estudio PROTEA. HIV-1 RNA in CSF samples at Week 48Dianummer 12Los fracasos con monoterapia con IP/r provocan un mayor desarrollo de resistencias a IP que el tratamiento con IP/r + 2 ITIAN.VL suppression at 96 weeksLos fracasos con monoterapia con IP/r provocan un mayor desarrollo de resistencias a IP que el tratamiento con IP/r + 2 ITIAN.DTG Monotherapy RCT Stopped Due to FailuresDianummer 17SALT TrialSwitching to ATV/r+3TC vs. Standard ATV/r+2NRTIs is safe and effectivePADDLE: Dolutegravir + Lamivudine for Treatment-Naive PtsANRS 167 LamiDol Study DTG/3TC MaintenanceDolutegravir + Rilpivirine for Maintenance of Suppression: : Snapshot Outcomes at Week 48. Dianummer 22Dianummer 23Variable penetration of ARV in tissueVariable penetration of ARV in tissueDianummer 26Dianummer 27Dianummer 28Dianummer 29Dianummer 30Dianummer 31Dianummer 32