NOVEDADES EN EL

TRATAMIENTO

ANTIRRETROVIRAL

2011

Daniel Podzamczer

Unitat VIH. Servei de Malalties Infeccioses

Hospital Universitari de Bellvitge

L’Hospitalet. Barcelona

Agenda

Cuando se inicia el TAR?

Con que pautas se inicia?

Nuevos fármacos

Nuevas estrategias en el uso de TAR

FÁRMACOS ANTIRRETROVIRALES. 2011

ANÁLOGOS DE NUCLEÓSIDOS/ NUCLEÓTIDOS (INH. TI) ZDV ddI 3TC FTC d4T ABC TDF ZDV/3TC ZDV/3TC/ABC ABC/3TC TDF/FTC

INHIB. NO NUCLEÓS. DE LA TI EFAVIRENZ NEVIRAPINA ETRAVIRINA RILPIVIRINA

INHIBIDORES DE LA ENTRADA ENFUVIRTIDE MARAVIROC (CCR5)

INHIBIDORES DE PROTEASA ritonavir SAQUINAVIR INDINAVIR NELFINAVIR LOPINAVIR/rtv ATAZANAVIR FOSAMPRENAVIR TIPRANAVIR DARUNAVIR

INHIB. DE LA INTEGRASA

RALTEGRAVIR

Principales guías de TAR

Disponible en : 1.www.gesida.seimc.org 2 http://AIDSinfo.nih.gov 3. www.eacs.eu Consultado septiembre

2008 4.Hammer S. et al JAMA. 2008;300(5):555-570

1

2

3

CUANDO INICIAR EL TAR?

Guidelines for Initiating ART in Asymptomatic Patients: 1998-2005

Panel CD4+ Cell Count, cells/mm³

US DHHS

June 1998 < 500

February 2001 < 350

April 2005 < 200

International AIDS Society-USA Panel

July 1998 Any

January 2000 < 500

July 2004 ≤ 200

British HIV Association (BHIVA)

June 1998 > 350

July 2003 201-350

July 2005 < 200

Likelihood of Achieving Normal CD4+ Cell Count Depends on BL Level

Moore RD, et al. Clin Infect Dis. 2007;44:441-446. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192.

ATHENA National Cohort Johns Hopkins HIV Clinical Cohort

Years on HAART

Me

an

CD

4+

Ce

ll C

ou

nt

(ce

lls

/mm

3)

1000

BL CD4+ Cell Count

0 48 96 144 192 240 288 336

Weeks From Starting HAART

200

400

600

800

0

1000

> 500

351-500

201-350 51-200 < 50

BL CD4+ Cell Count 200

400

600

800

0 0

1 2 3 4 5

> 350

< 200

201-350

6

Association Between Current CD4+ Cell Count & Non-AIDS Complications

Study Lower Current CD4+ Cell Count Significantly Associated With Increased Risk?

Non-AIDS malignanci

es

Renal disease/

death

CVD events/ death

Liver disease/

death

FIRST Yes Yes Trend, NS No

D:A:D Yes Yes Trend, NS Yes

CASCADE Yes NA Yes Yes

SMART Trend, NS Trend, NS Trend, NS Yes

Phillips A, et al. CROI 2008. Abstract 8.

CD4<350

CD4<200

July 15, 2010

P.inclusión:

2005-2008

Survival after ART initiated at different CD4 count levels between 200-500

The HIV-CAUSAL Collaboration, Ann Intern Med 2011

Muerte SIDA/Muerte

Kitahata M. N Eng J Med 2009; 360

NA Accord. Effect of early versus deferred antiretroviral therapy for HIV on survival

START Design

HIV-infected adults, ART-naive with

CD4+ cell counts > 500 cells/mm3

Early ART Group

Immediately initiate ART

N=2,000

Deferred ART Group

Defer ART until CD4+ <350

cells/mm3 or symptoms

develop

N=2,000

Primary endpoint: Serious AIDS & serious non-AIDS disease (375)

INSIGHT study group and collaborators

Current Status: 1600 randomised; randomisation finished < 2012 and study < 2015.

Substudies assessing various organ dysfunction incl. arteries, neuro-system & lungs.

clinicaloptions.com/hiv

HIV/AIDS Highlights From Rome

HPTN 052: HIV Transmission Reduced by

96% in Serodiscordant Couples

Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression

Total HIV-1 Transmission Events: 39

(4 in immediate arm and

35 in delayed arm; P < .0001)

Linked

Transmissions: 28

Unlinked or TBD

Transmissions: 11

P < .001

Immediate

Arm: 1

Delayed

Arm: 27

Cohen MS, et al. N Engl J Med. 2011; 365: 493-505 cortesía de JM Gatell

RECOMENDACIONES DE INICIO DE TAR 2011

DHHS EACS GESIDA

CD4<350 R R R

CD4 350-500 R C(R)1 R2

CD4 >500 C3 D(R/C)4 D(C)5

1 R = Nefropatía, TNC, L.Hodgkin, HPV cáncer; C = VHB, VHC

2 Excepto CD4 estable, carga viral baja, poca predisposición del paciente

3 50% del panel = recomendar; 50% = diferir

4 R/C = similar a 350 – 500

5 C= en VHC; VHB en tratamiento; CV > 100.000; CD4 < 14%; > 55 años ; RCV ; nefropatía VIH ; parejas discordantes con alto riesgo de transmisión

DHHS octubre 2011; EACS octubre 2011; GESIDA enero 2011

Nous diagnòstics VIH

256 274237

208172

211 190 187

95108

91122

95

122

100 110

44,0 45,9 44,1

35,332,3

35,0 32,8 32,5

60,364,0

61,155,9

50,155,3

50,0 51,6

0

50

100

150

200

250

300

350

400

450

2001 2002 2003 2004 2005 2006 2007 2008

N

0

10

20

30

40

50

60

70

80

90

100

%

<200(N) 200-350(N) <200(%) <350(%)

Evolución del retraso diagnóstico en los nuevos

diagnósticos de infección por VIH. Cataluña, 2001-2008

Gallois A, Esteve A, y Grupo de estudio Piscis

CON QUÉ INICIAR EL TAR?

FÁRMACOS ANTIRRETROVIRALES. 2011

ANÁLOGOS DE NUCLEÓSIDOS/ NUCLEÓTIDOS (INH. TI) ZDV ddI 3TC FTC d4T ABC TDF ZDV/3TC ZDV/3TC/ABC ABC/3TC TDF/FTC

INHIB. NO NUCLEÓS. DE LA TI EFAVIRENZ NEVIRAPINA ETRAVIRINA RILPIVIRINA

INHIBIDORES DE LA ENTRADA ENFUVIRTIDE MARAVIROC (CCR5)

INHIBIDORES DE PROTEASA ritonavir SAQUINAVIR INDINAVIR NELFINAVIR LOPINAVIR/rtv ATAZANAVIR FOSAMPRENAVIR TIPRANAVIR DARUNAVIR

INHIB. DE LA INTEGRASA

RALTEGRAVIR

DHHS Guidelines (OCT 2011) Preferred antiretroviral

regimens for antiretroviral therapy-naïve patients

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in

HIV-1-infected adults and adolescents. Department of Health and Human Services. October 14, 2011; 1–167

EACS Guidelines (Oct 2011).Initial combination

regimen for antiretroviral-naïve adults patients

Panel on EACS Guidelines. European AIDS Clinical Society (EACS) Guidelines. Version 6.0. October, 2011;

1–60

ARV THERAPY IN HIV-INFECTED NAIVE PATIENTS

Education

Willingness

Viral load

Social support

Disease status

Number of pills

Other diseases

0%

20%

40%

60%

80%

100%

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Any d'inici de tractament

Otros

Basado en 3AN

Basado en NN

Basado en IP/boosted

Basado en IP

Evolución anual de la pauta de inicio de TAR en los

pacientes de la Cohorte PISCIS (1998-2009)

Gallois A, Esteve A, y Grupo de estudio Piscis

TAR inicial: temas en continuo debate

Que análogos de nucleósidos?

INNTI o IP/r?

Que INNTI ?

Que IP/r?

Otros fármacos? (Inhib. Integrasa, CCR5)

Otras estrategias? (pautas sin AN)

RESISTÈNCIA TRANSMESA, PATRÓ DE MUTACIÓ Hospital Universitari de Bellvitge, 2001-2010

M46L=1

I54V, V82A=1

G48V, I54V, V82A, I84V, L90M=1 3 (0,84) 0 IP

34 (9,52)

16 (5,63)

Total

K103N=15

Altres=5

K103N=2

Y181C=1 20 (5,60) 3 (1,05) ITINN

TAMs=13

T69D=1

M184V=1

TAMs=11

T69D=1

M184V=1

15 (4,20) 13 (4,58) ITIAN

2007 - 2010 2001 - 2006 2007 – 2010

n=357

2001 – 2006

n=284

Patró de mutació (N) Nº de pacients amb resistència

(%)

J. Niubó, comunicación personal

Truvada o Kivexa producen aumento similar

de la grasa en extremidades y tronco

CROI 2010. 106 LB (G McComsey)

RPV: menor toxicidad SNC

mejor perfil lipídico, pero...

Mayor fallo virológico y selección de resistencias en pts con CV > 100.000 c/mL

DHHS (oct 2011): alternativa a EFV

Aprobado por FDA en mayo 2011

agosto 2011: TDF/FTC/RPV

Cohen C, et al. Lancet 2011; 378: 229-37

28 Cohen C, et al. AIDS 2011; 25: F7-F12

Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir

disoproxil fumarate versus efavirenz/ emtricitabine/tenofovir disoproxil fumarate for the initial

treatment of HIV infection

6th IAS Conference on HIV Pathogenesis, Treatment and Prevention

17-20 July 2011 Rome, Italy

DOLUTEGRAVIR: Rapid and Sustained Antiviral

Activity.Week 48 Efficacy Analysis (%<50 c/mL)

Pro

po

rtio

n (

%)

<5

0 c

/mL

(T

LO

VR

)

91%

88% 90%

82%

DTG 10mg

DTG 25mg

DTG 50mg

EFV 600mg

95% confidence intervals are derived using the normal approximation

1. Young B et al. CID 2011; 52: 1061-1068 2. McComsey GA et al. JID 2011; 203: 1791-1801 3. McComsey GA et al. CROI 2010. Feb 16-20

TDF/FTC impact on BMD

HOPS Cohort1

Increased rate of

bone fractures in HIV+

compared to general

population

ACTG 52022

55224S sub-study

ABC/3TC had less

impact on BMD than

TDF/FTC

Differences in fracture outcomes cannot be causally related to choice of ARV

regimen in this study

Patients and

methods Study findings

MONET Study1

DRV/r OD + 2 NRTI vs. DRV/r OD

N = 256

• Taking 2 NRTI +

either NNRTI or boosted PI at screening

• HIV RNA <50 cp/mL for ≥6 months

At 96 weeks:

• Discontinuations were slightly higher in the DRV/r monotherapy arm, compared with DRV/r + 2NRTI

• Most elevations in HIV RNA were low level (50–200

copies/mL). Patients were resuppressed either on the original randomised treatment or with intensified treatment

OK04 Study2

LPV/r BID + 2 NRTI vs.

LPV/r OD

N = 200

• Taking LPV/r + 2

NRTI for >2 months

• HIV RNA <50 cp/mL for >6 months

At 96 weeks:

•Discontinuation due to adverse events was a more frequent cause of treatment failure in the LPV/r + 2 NRTI group

•In the monotherapy group low level viremia was the main

cause for a treatment change. The majority of these patients resuppressed after restarting nucleosides

ACTG 5201 Study3

ATZ/r OD

N = 36

• Taking a PI + 2

NRTI for >48 weeks

• HIV RNA <50 cp/mL for >6 months

At 24 weeks:

•Virologic success occurred in 91% of patients

•No treatment discontinuations due to adverse effects

•No significant changes in CD4 cell count or plasma lipid levels

PI monotherapy has been investigated

in a number of studies

1. Rieger et al, IAS 2010; 2. Arribas et al, EACS 2007; 3. Swindells et al, JAMA 2006

Proportion of Subjects Responding at Week 96 (FDA-TLOVR)

MVC + ATV/r is active and well-tolerated in

a 24-week interim analysis

121 CCR5-tropic treatment-naïve patient (CD4+ counts ≥ 100 cells/µL) were

randomized to receive ATV/r with either MVC 150mg QD or TDF/FTC;

* 1 patient accidentally dosed with MVC prior to 24-hr sample draw

Mills A et al, IAS 2010

• 9/121 subjects discontinued

therapy prior to week 24 (5 MVC

arm; 4 TDF/FTC arm)

– 2 subjects in MVC arm due to

AEs (vomiting, jaundice)

– 1 subject in MVC arm due to

insufficient clinical response

• No resistance observed in 5

evaluable patients

– 3 patients on MVC

– 2 patients on TDF/FTC

1.0

0.8

0.6

0.4

0.2

0.0

ACTG 5262: DRV/r+RAL

Time to Virologic Failure (ITT approach)

Taiwo B, et al. CROI 2010. Boston. #551.

Time to Virologic Failure (VF)

1 4 12 24 36 48

Time (weeks)

Pro

ba

bilit

y o

f n

ot h

av

ing

a V

F

1.0

0.8

0.6

0.4

0.2

0.0

Time to VF by Baseline HIV-1 RNA

1 4 12 24 36 48

Time (weeks)

Pro

ba

bilit

y o

f n

ot h

av

ing

a V

F

Log Rank Test p=0.0002

HIV-1 RNA ≤ 100,000 copies/mL

HIV-1 RNA > 100,000 copies/mL

n with VF: 0 0 3 14 5 6

n at risk: 112 111 110 105 89 81

HIV-1 RNA ≤ 100,000 copies/mL

n with VF: 0 0 1 4 1 1

n at risk: 63 63 62 59 54 50

HIV-1 RNA > 100,000 copies/mL

n with VF: 0 0 2 10 4 5

n at risk: 40 45 45 45 39 31

N Engl J Med 2010; 363: 2587-2599

DISEÑO • Participantes: 2499 VIH (-) HSH ó transexuales (varones de

nacimiento) con prácticas de riesgo.

• Período: 10 julio 2007 a 17 diciembre 2009.

• Centros: 11 centros en seis países (EEUU, Perú, Ecuador,

Brasil, Tailandia y Sudáfrica)

• Intervención: - TVD ó placebo (1 c/dia).

- Visitas a semanas 0, 4, 8, 12, 18, 24

y cada 12 meses.

• “Counselling” sobre protección sexual, adherencia al

tratamiento, diagnóstico y tratamiento de ETS.

• Seguimiento 1,2 años (máximo 2,8 años).

• 36 infectados en TVD vs 64 en placebo:

44% reducción (IC 95% 15-63; p<0.005).

Oral Preexposure prophylaxis for HIV –Another

arrow in the quiver?

• 33.000.000 VIH+; 7000 nuevas infecciones/d (2.500.000/año!!)

• Medidas de prevención: métodos barrera, < prev. sangre, modif. conductas, prof. postexposición, saber sero-status, ARV embarazo/lactancia, tto ETS. Más recientes: circuncisión varones, vacunas, microbicidas vaginales.

PROF. PREEXPOSICION: eficacia 44% (IC95% 15-63) (> si niveles fármacos)

Limitaciones/dudas: -baja correlación adherencia auto-referida/niveles fármacos

-toxicidad (renal) a largo plazo (> con > adherencia!)

-resistencia a FTC (en 2 pts con infeción aguda) (y a HBV?)

-adherencia en mundo real fuera de un estudio? (fatiga...)

-efecto sobre otras medidas de prevención (preservativos),

sobre el conoc. de status VIH? sobre frecuencia sexo casual?

Michael, NL. N Engl J Med 2010; 363: 2663-5

Efficacy of Daily Oral

FTC/TDF PrEP

Trial Pop. Efficacy 95% CI

iPrEx MSM 42% 18 to 60%

Partners PrEP Men 83% 49 to 94%

Women 62% 19 to 82%

TDF2 Men 80% 25 to 97%

Women 49% -22 to 81%

FemPREP Women Discontinued for futility

Grant R, NEJM 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.

cortesía de JM Gatell

Trends in virological and clinical outcomes in

individuals with HIV-1 infection and virological

failure of drugs from three antiretroviral drug

classes: a cohort study.

Lancet Infectious Diseases 2011

(published online October 10, 2011)

• Fármacos nuevos: más eficaces, menos tóxicos, menos comprimidos y tomas

• Combos: facilitan la adherencia y la supresión viral a largo plazo

• Inicio más precoz del TAR: Mayor eficacia y menor toxicidad

TAR. Conclusiones

Inicio cada vez más precoz del TAR (350-500)

Pautas individualizadas

Siguen apareciendo nuevos ARV (RPV, DTG...)

Biterapia (útil en algunos escenarios?, faltan datos,

diferencias según pautas)

Papel de profilaxis pre-exposición en la “vida real”?