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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”?
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