Simplificación del Tratamiento Antirretroviral

Dr. Santiago Moreno

Servicio de Enfermedades Infecciosas

Hospital Universitario Ramón y Cajal

Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

Universidad de Alcalá de Henares

Madrid

Definition: Treatment Simplification

• US Department of Health and Human Services

• Defined broadly as a change in established effective therapy to

reduce pill burden and dosing frequency, to enhance tolerability, or

to decrease specific food and fluid requirement

• GeSIDA

• A switch from a suppressive therapy regimen to a more simple one

that can maintain virological suppression

El término OPTIMIZACION es preferible

Estrategias de Optimización (Simplificación)

• Reducir el número de dosis

• Reducir el número de pastillas

• Reducir el número de fármacos

• Mejorar las condiciones de las tomas

• Interrumpir el tratamiento

• Disminuir los días de administración de fármacos

Estrategias de Optimización (Simplificación)

• Reducir el número de fármacos

• Disminuir los día de administración de fármacos

Número de Fármacos: Evolución del TAR

Dual NRTIs

1987 • First NRTI

1991–2 Two new NRTIs approved

1994 Dual NRTIs better than monotherapy

Triple combination

therapy

Sequential monotherapy

PI/r monotherapy

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

Dual therapy

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

75,2% 69,3%

10,1% 16,5%

2,3%

7,9%

11,6%

6,3%

0,8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DRV/r + 2NRTI (ITT) DRV/r mono (ITT)

difference=-5.9%,

95% C.I.-16.9%, +5.1%).

HIV RNA <50

Switch NRTI

VF

d/c - AE

d/c - other

Perc

enta

ge o

f patients

DRV-r en monoterapia no cumplió criterios de no inferioridad frente a DRV/r + 2 ITIAN (Monet, 144 sem)

HIV Med. 2012 Aug;13(7):398-405. doi: 10.1111/j.1468-1293.2012.00989.x. Epub 2012 Mar 14.

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

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

7

%<

50cp

s/m

l

• 8/77 Monotherapy >50 by week 48

• 6/8 Genotype amplified

• 3/6 INI resistance

• 1 each 155H, 263K, 230R

• DSMB stopped study

• Authors recommend against DTG 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

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

Pérez Molina JA. Lancet Infectious Diseases 2016 9

10

Metanalysis of bPI-based dual therapy: clinical trials identified

Study (n) DT group TT group

ATLAS-M1 (266) ATV/r+3TC ATV/r+2N(t)RTIs

SALT2 (286) ATV/r+3TC ATV/r+2N(t)RTIs

OLE3 (250) LPV/r+3TC LPV/r+2N(t)RTIs

DUAL4 (249) DRV/r+3TC DRV/r+2N(t)RTIs

Source: 1Di Giambenedetto S. et al. Journal of Antimicrobial Chemotherapy. 2017;72:1163-1171 2Perez-Molina JA. et al. The Lancet Infectious Diseases. 2015;15:775–84 3Arribas JR. et al. The Lancet Infectious Diseases. 2015;15:785–92 4Pulido F. et al. Clinical Infectious Diseases 2017; Aug 17. doi: 10.1093/cid/cix734

Estrategias en pacientes experimentados

11

Primary endpoint

HIV-RNA ≥50 cop/mL at week 48 Dual therapy – triple therapy (%)

SALT

ATLAS

DUAL

OLE

POOLED

1.40 (-2.80, 5.60)

-0.70 (-5.90, 4.40)

1.50 (-2.20, 5.30)

1.70 (-2.60, 6.00)

0.90 (-1.30, 3.20)

0 0%

Absolute risk difference, (95% CI) Non-inferiority margin: 4%

4% Favours DT

At 48w, 4% of patients on DT vs. 3.04% on TT had HIV-RNA ≥50 cop/mL

Difference 0.9% (95%CI, -1.3% to 3.2%)

Estrategias en pacientes experimentados

Treatment difference (DT vs. TT) was not affected by Sex, HCV infection status or type of PI

• 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.

13

ASPIRE: cambio a 3TC+ Dolutegravir

en pacientes con CV indetectable

Taiwo BO, et al. EACS 2017. Abstract PE 8/5.

Open-label, randomized, multicenter investigator-initiated clinical trial

1:1 Randomization

Week 24

Primary Endpoint Week 48

14 ASPIRE: Virologic outcomes at week

48

(FDA Snapshot)

Taiwo BO, et al. EACS 2017. Abstract PE 8/5.

N 41 41 1 0 2 4

On Study 44 45 44 45 44 45

Continue on the same cART (CONTROL)

Switch to DTG + 3TC dual therapy

Open-label

Randomisation

1 : 1 : 1

Stratifying by 3rd agent HIV+ ≥ 18 years

On triple cART

HIV RNA < 50 c/mL > 12

months

No prior VF to 3TC/FTC or

INSTI

Nadir CD4 >200 cells/mm3

HBsAg negative

W24

Switch to DTG monotherapy

W48

DOLAM: Dolutegravir-based

simplification strategies

Blanco JL, et al. EACS 2017. Abstract PE .

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 (<50 c/mL) at Week 48

Adjusted Treatment Difference (95% CI)

DTG + RPV CAR

-3.0

-0.2

2.5

Percentage-Point Difference

Virologic Outcomes

Fletcher CV. PNAS 2014.

17

Existe replicación vírica persistente en tejidos

Variable penetration of ARV in tissue

Fletcher, 19th CROI, Seattle 2012

CD

14

+C

D1

6-C

D1

63

+ c

ell

s (

%)

c A R T M P I

0

2 0

4 0

6 0

8 0

1 0 0

p = 0 .0 3 1

sC

D1

4 (

ng

/ml)

c A R T M P I

1 0 0 0

1 5 0 0

2 0 0 0

2 5 0 0

3 0 0 0

3 5 0 0

p = 0 .0 0 4

sC

D1

63

(n

g/m

l)

c A R T M P I

0

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 I

5 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 replicación vírica persistente

García F. CROI 2013; JIAS 2014.

T-cell immune activation levels in mART-treated and cART-treated patients

2

0

Petrara. PLoS One. 2017.

2

1

CD4/CD8 ratio in patients who switch cART therapy: triple drug regimen could be better than mono/dual?

Mussini C. IAS 2017. Paris. Abstract MOPEB0323

Porcentaje de diferencia en la concentración sérica de los biomarcadores (ajustado por edad, VHC, hipertensión, raza y tabaquismo).

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

Abreviaturas: BAFF, factor activador de las células B; CCL, quimioquinas C-C ligando; CXCL

quimioquinas CXC ligando; GM-CSF, factor estimulante de granulocitos y macrófagos ; IFN- ,

interferón gamma; IL, interleucina; sCD14, CD14 soluble; sCD27, CD27 soluble; sgp130,

glicoproteína 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,

proteína C reactiva.

<100% vs 100% (6-m)

Estimado p

TNF-α 11,2% <0,001

IFN-γ 14,8% 0,008

CRP 21,1% 0,006

IL-2 14,4% 0,022

IL-10 11,1% 0,023

IL-6 11,6% 0,014

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

Suboptimal cART Adherence is Associated with

Higher Levels of Inflammation Despite HIV Suppression.

LATTE-2: Cabotegravir IM + Rilpivirine IM for

Long-Acting Maintenance ART

• Multicenter, open-label phase IIb study

• Cabotegravir: integrase inhibitor

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W†

(n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W‡

(n = 115)

6 pts discontinued for AEs or death in induction analysis. *Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to

maintenance phase. †Loading dose: Day 1, CAB 800 mg + RPV 600 mg. ‡Loading dose: Day 1, CAB 800 mg + RPV 900

mg; Wk 4, CAB 600 mg.

ART-naive HIV-

infected pts with

CD4+ cell count >

200 cells/mm3

(N = 309) CAB 30 mg PO + ABC/3TC PO QD

(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32

primary analysis

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96 Wk 16: RPV

PO added

CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg)

Induction period

LATTE-2 Study Design

Week 32

Primary analysis

Dosing regimen

selection

Day 1

Randomization

2:2:1

Week 48

Analysis

Dosing regimen

confirmation

Week 96b

CAB loading dose at Day 1 (800 mg)

CAB 30 mg + ABC/3TC PO QD (n=56)

Maintenance perioda

CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)

CAB 600 mg IM + RPV 900 mg IM Q8W (n=115)

CAB 30 mg +

ABC/3TC for

20 weeks

Add RPV

PO QD

4 weeks

Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily;

Q4W, every 4 weeks; Q8W, every 8 weeks; ULN, upper limit of normal. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter

Q4W and Q8W LA extension phase beyond Week 96.

Inclusion criteria • ≥18 years old

• Naive to antiretroviral therapy

• CD4+ ≥200 cells/mm3

Exclusion criteria • Positive for hepatitis B

• ALT ≥5 × ULN

• Creatinine clearance <50 mL/min

Qualification for

maintenance • HIV-1 RNA <50 c/mL between Week -4 and

Day 1

Comparable Response Across Arms Week 96 HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)

• CAB, cabotegravir; CI, confidence interval; IM, intramuscular; ITT-ME, intent-to-treat maintenance exposed; LA, long acting; NRTI, nucleoside reverse transcriptase inhibitor;

PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine.

Virologic outcomes Treatment differences (95% CI)

Oral IM

Q8W IM

−8.4% 14.4%

Q4W IM

− 0.6% 20.5%

Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

Conclusiones • El tratamiento antirretroviral actual se encuentra en un avanzado estado de

simplificación y optimización

• En cuanto a potenciales estrategias futuras de optimización:

• Parece descartada la monoterapia con los fármacos actualmente disponibles

• Buenos datos clínicos con la disminución del número de fármacos en el régimen

• Fármacos de administración prolongada

• Cualquier estrategia futura de optimización del tratamiento antirretroviral debe tener las garantías razonables de no someter a un daño innecesario a los pacientes

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