Tratamiento antirretroviral
Sergio Lupo
Objetivos del Tratamiento
1 Disminuir la Carga Viral
2 Restauración y/o preservación del Sistema Inmunológico
3 Reducir la morbilidad/mortalidad relacionada al HIV
4 Mejorar la calidad de vida
SIDA
3-6 Sem Años (5-10) Meses - Años
Carga Viral CD4
Inf. Aguda
Etapa Asintomática
TAR
3-6 Sem Años (5-10) Meses - Años
Carga Viral CD4
TAR
Inf. Aguda
Etapa Asintomática
SIDA
Objetivos del Tratamiento
1 Disminuir la Carga Viral
2 Restauración y/o preservación del Sistema Inmunológico
3 Reducir la morbilidad/mortalidad relacionada al HIV
4 Mejorar la calidad de vida
3-6 Sem Años (5-10) Meses - Años
Inf. Aguda
Etapa Asintomática
SIDA
Carga Viral CD4
TAR
3-6 Sem Años (5-10) Meses - Años
Inf. Aguda
Etapa Asintomática
SIDA
Carga Viral CD4
TAR
Objetivos del Tratamiento
1 Disminuir la Carga Viral
2 Restauración y/o preservación del Sistema Inmunológico
3 Reducir la morbilidad/mortalidad relacionada al HIV
4 Mejorar la calidad de vida
3-6 Sem Años (5-10) Meses - Años
Inf. Aguda
Etapa Asintomática
SIDA
Carga Viral CD4
TAR
3-6 Sem Años
Inf. Aguda
Etapa Asintomática
Carga Viral CD4
TAR
Objetivos del Tratamiento
1 Disminuir la Carga Viral
2 Restauración y/o preservación del Sistema Inmunológico
3 Reducir la morbilidad/mortalidad relacionada al HIV
4 Mejorar la calidad de vida
EuroSIDA, November 2000.
Efectos del TAAE: Incidencia de Sida y muerte 1994-2000
0
5
10
15
20
25
30
35
9/94-3/95
3/95-9/95
9/95-3/96
3/96-9/96
9/96-3/97
3/97-9/97
9/97-3/98
3/98-9/98
9/98-3/99
3/99-9/99
>9/99
Inc
ide
nc
e (
pe
r 1
00
PY
FU
)
0
20
40
60
80
100muerteSida% en TAAE
Survival of Patients with CD4 Counts ≥500 cells/mmSurvival of Patients with CD4 Counts ≥500 cells/mm33 for >5 for >5 Years is Similar to the General PopulationYears is Similar to the General Population
Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77
Standardized mortality ratio = mortality in HIV-infected patients / mortality in general population
APROCO and AQUITAINE cohorts
0
1
2
3
4
0 1 2 3 4 5 6 7
Sta
nd
ard
ised
mo
rtal
ity
rati
o
Years with CD4+ count >500 cells/mm3
Life Expectancy and Mortality in HIV-Infected Patients
• ART-CC: Depending on when ARV therapy is started, life expectancy is 10-30 yrs less than that in uninfected pts
– Life expectancy for pts at age 20 was 32 yrs for pts with CD4+ < 100 cells/mm3 and 50 yrs for pts for CD4+ > 200 cells/mm3[1]
• AQUITAINE cohort: Pts with CD4+ ≥ 500 for 6 yrs after combination ARV therapy attained mortality similar to general population[2]
• COHERE cohort: HIV-infected men, but not women, reached mortality rates similar to uninfected population after 3 yrs of CD4+ ≥ 500 cells/mm3[3]
• ATHENA cohort: For asymptomatic HIV-infected pts diagnosed from 1998-2007 who remained ARV naive and without AIDS at Wk 24 after diagnosis, modeled life expectancy similar to age- and sex-matched uninfected controls in Netherlands[4]
– 52.7 vs 53.1 yrs, respectively
1. Antiretroviral Cohort Collaboration. Lancet. 2008;372:293-299. 2. Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-77. 3. Lewden C, et al. CROI 2010. Abstract 527. 4. Van Sighem A, et al. CROI 2010. Abstract 526.
Cuando comenzar TAR
Desarrollo de efectos adversos y toxicidadesMayor posibilidad de “cansancio por el tratamiento”Menor tiempo para la preparación del pacientePrematuro uso de drogas potencialmente superablesDesarrollo de resistencia por incompleta supresión viralPosibilidad de transmisión de resistencia
Potenciales riesgos de comenzar tratamiento temprano
Mantener indemne/evitar deterioro de la inmunidad celularDisminuir el riesgo de IO y de neoplasias asociadas al VIHDisminuir el riesgo de eventos serios no oportunistas (CV, renales, hepáticas y neoplásicas)Disminuir el riesgo de transmisión del VIH
Potenciales beneficios de comenzar tratamiento temprano
CD4 on Therapy Predicts Risk of AIDS- and Non-AIDS–Related Morbidity (DAD)
Liver-related: chronic viral hepatitis, liver failure (other); malignancy-related: malignancy, non-AIDS;
heart-related: MI, other CVD, other heart diseaseWeber R et al. 12th CROI 2005; Abstract 595
100
10
1
<50 50–99 100–199 200–349 350–499 >500
CD4+ cells/mm3
Rel
ativ
e ri
sk
HIV/AIDSCancerHeartLiver
CASCADE: Risk of AIDS and Death by CD4+ Cell Count Strata at Start of ART
• CASCADE collaboration: observational cohort of HIV seroconverters from 23 clinical cohorts in Europe, Australia, Canada similar to NA-ACCORD and ART-CC
– Current analysis included 9455 patients ≥ 6 mos after estimated seroconversion in CD4+ cell count strata up to 799 cells/mm³
– Study period: January 1, 1996 - May 31, 2009
• Endpoints
– AIDS or death
– Death
– Non-AIDS outcomes not included
CD4+ Cell Count, cells /mm3
Adjusted HR (95% CI)
0-49 0.32 (0.17- 0.59)
50-199 0.48 (0.31-0.74)
200-349 0.59 (0.43-0.81)
350-499 0.75 (0.49-1.14)
500-799 1.10 (0.67-1.79)
CD4+ Cell Count, cells/mm3
Adjusted HR (95% CI)
0-49 0.37 (0.14-0.95)
50-199 0.55 (0.28-1.07)
200-349 0.71 (0.44-1.15)
350-499 0.51 (0.33-0.80)
500-799 1.02 (0.49-2.12)
Effect of Tx Initiation on AIDS and Death
Effect of Tx Initiation on Death
Funk MJ, et al. AIDS 2010. Abstract THLBB201.
CASCADE: Absolute Risk Difference and Number Needed to Treat 3 Yrs From BL
CD4+ Cell Count, cells/mm³
Cumulative Risk for AIDS/Death, %
Cumulative Risk Diff at 3 Yrs (95% CI)
Number Needed to Treat at 3 Yrs to
Prevent 1 AIDS Event or Death (95% CI)Defer Initiate
0-49 46.6 16.6 -30.0 (-45.1 to -15.0) 3 (2-7)
50-199 20.7 5.7 -15.0 (-19.7 to -10.3) 7 (5-10)
200-349 10.3 5.5 -4.8 (-7.0 to -2.6) 21 (14-38)
350-499 6.3 3.4 -2.9 (-5.0 to -0.9) 34 (20-115)
500-799 4.9 5.2 0.3 (-3.7 to 4.2) ∞
CD4+ Cell Count
Cumulative Risk for Death Alone, %
Cumulative Risk Diff at 3 Yrs (95% CI)
NNT at 3 Yrs to Prevent 1 Death
0-49 26.8 8.6 -18.2 (-32.0 to -4.4) 6 (3-23)
50-199 9.1 1.9 -7.2 (-10.1 to -4.4) 14 (10-23)
200-349 4.1 2.7 -1.4 (-3.0 to 0.3) 74 (33-∞)
350-499 2.1 0.7 -1.4 (-2.2 to -0.6) 71 (45-165)
500-799 1.7 1.2 -0.4 (-2.0 to 1.2) 239 (49-∞)Funk, MJ, et al. AIDS 2010. Abstract THLBB201. Tables used with permission.
Resistencia primaria al VIH en pacientes vírgenes de TAR
Se analizaron 111 pacientes: el 71% fueron varones; la edad media de 38 años.El 99% adquirieron la infección por prácticas sexuales no protegidas (63% heterosexuales)
En los test realizados se encontró que el 15.3% (17) de los pacientes presentaban mutaciones mayores:
Dos pacientes tenían mutaciones para INTR (41L y 210W). No se encontró multiresistencia a los INTR.
Seis pacientes presentaron mutaciones para INNTR: K103N (4); 108I (1); 106A (1) y 10I, 63P, 77I en uno.
Nueve pacientes tuvieron mutaciones para los IP: 10V (7); 13 V(1); 36 I (1); 62 V (1); 71T (1), 71V(2) , 46L (1); 90 M (1).
Un paciente presentó resistencia a las tres familias de drogas: INTR: M41LINNTR: 101I, 103K/N , T215CIP: 13V, 15V, 20V, 36I, 62V, 63P, 71V, 90M.
IAS-USA Guidelines 2010: When to Start
Asymptomatic Infection Recommendation
• CD4+ cell count < 500 cells/mm³ • Start HAART
• CD4+ cell count > 500 cells/mm³ • Should be considered*
Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count
• Symptomatic HIV disease• Acute opportunistic infection• Pregnant women• Older than 60 yrs of age• HIV-1 RNA > 100,000 copies/mL• Rapid decline in CD4+ cell count (> 100 cells/mm³/yr)• Active HBV or HCV infection• Active or high risk for CV disease• Symptomatic primary HIV infection• HIVAN• Serodiscordant couples*Unless patient is elite controller or has stable CD4+ cell count and low HIV-1 RNA in absence of antiretroviral therapy.
Thompson MA, et al. JAMA. 2010;304;321-333.
Infección primaria
Beneficios teóricos de temprana intervención Estudios en animales favorecerían esta intervención Estudio SPARTAC (2004-2010):
371 pacientes con infección primaria en tres ramas: A. TAR por 48 semanas B. TAR por 12 semanasC. Sin tratamiento
Infecciones oportunistas
TAR temprano: evitar nuevas complicaciones oportunistas TAR tardío: evitar IRIS; evitar toxicidad; nuevas
complicaciones oportunistas ACTG 5164: menor progresión y mortalidad
¿Cuando comenzar?: otras situaciones
CAMELIA: ART Initiation at Wk 2 vs Wk 8 of TB Therapy in HIV-Coinfected Patients
• WHO 2010 guidelines recommend to[1]
– Initiate HAART in all HIV-infected patients with TB, regardless of CD4+ cell count
– Initiate TB therapy before HAART, with HAART added as soon as possible and within 8 wks of TB therapy
• CAMELIA: randomized, open-label trial of HIV-infected patients with newly-diagnosed AFB-positive TB and CD4+ cell count ≤ 200 cells/mm3 [2]
• Compared HAART initiation (d4T + 3TC + EFV) at
– Wk 2 (n = 332) vs
– Wk 8 (n = 329) of TB therapy
• All patients received standard TB therapy for 6 mos
1. WHO. Available at: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. 2. Blanc FX, et al. AIDS 2010. Abstract THLBB106.
CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients
• Significantly higher incidence of IRIS with early vs late HAART
– 4.03 vs 1.44 per 100 person-mos, respectively (P < .0001)
Blanc FX, et al. AIDS 2010. Abstract THLBB206. Graphic used with permission..
WkSurvival Probability, % (95% CI)
PEarly Arm Late Arm
5086.1
(81.8-89.4)80.7
(76.0-84.6).07
10082.6
(78.0-86.4)73.0
(67.7-77.6).006
15082.0
(77.2-85.9)70.2
(64.5-75.2).002
Factor Multivariate Adjusted HR (95%
CI)
P
Late therapy 1.52 (1.12-2.05) .007
BMI ≤ 16 1.68 (1.07-2.63) .01
Karnofsky score ≤ 40
4.96 (2.42-10.16)< .001
`
Pulmonary + extrapulmonary TB
2.26 (1.62-3.16)< .001
NTM 2.84 (1.13-7.13) < .001
MDR-TB 8.02 (4.00-16.07) < .001
Factors Independently Associated With Mortality
Survival Probability, Early vs Late Therapy
Log rank P = .0042
Wks From TB Treatment Initiation
Pro
bab
ilit
y o
f S
urv
ival 1.00
0.90
0.80
0.70
0.60
Early armLate arm
0 50 100 150 200 250
Con que drogas comenzar
IAS-USA Guidelines 2010: Recommended Agents
Preferred Agents for First-line Therapy
NRTIs • Tenofovir/emtricitabine
Plus a third agent
NNRTI • Efavirenz*
Boosted PI • Atazanavir/ritonavir*
• Darunavir/ritonavir†
INSTI • Raltegravir†
*Based on extensive clinical experience.†Based on data that indicate that this agent is comparable to key third agents but more limited experience in naive patients.
Thompson MA, et al. JAMA. 2010;304;321-333.
IAS-USA Guidelines 2010: Alternative Agents
Alternative Agents for First-line TherapyNRTIs • Abacavir/lamivudine
Plus a third agent
Boosted PI• Lopinavir/ritonavir
• Fosamprenavir/ritonavir
CCR5 antagonist • Maraviroc
Thompson MA, et al. JAMA. 2010;304;321-333.
Ventajas y desventajas de los INNTR
Ventajas Larga vida media Menor toxicidad
metabólica que los IP Preserva IP para el
futuro
Desventajas Baja barrera genética Resistencia cruzada
Rash; hepatotoxicidad Potential interacciones
(CYP450)
Ventajas y desventajas de los IP
Ventajas Alta barrera genética Cuando hay falla
virológica, rara resistencia a los IP
Preserva a los INNTR
Desventajas Complicaciones
metabólicas Intolerancia digestiva Mayor posibilidad de
interacciones medicamentosas
GS934: ZDV/3TC vs TDF/FTC más EFV (96 Semanas)
Treatment-naive patients; VL > 10,000 copies/mL;
No CD4+ cell count restrictions
(N = 517*)
TDF 300 mg/day +FTC 200 mg/day +EFV 600 mg/day
(n = 255)
ZDV/3TC 300/150 mg twice daily +EFV 600 mg/day
(n = 254)
Stratification by CD4+ cell count (< 200 vs ≥ 200 cells/mm3)
Week 144
*8 patients excluded from ITT analysis due to prior antiretroviral treatment or because never received study medication.
Gallant J, et al. IAC 2006. Abstract TUPE0064.
Current analysisWeek 96
GS934: HIV RNA < 400 and < 50 copias/mL (semana 96)
Weeks Gallant J, et al. IAC 2006. Abstract TUPE0064.
20
40
60
80
100
8 16 24 32 40 48 60 72 84 96
Res
po
nd
ers
(%)
0BL
ZDV/3TC < 400: 62%
FTC/TDF < 400: 75%P (< 400) = .004FTC/TDF < 50: 67%
ZDV/3TC < 50: 61%P (< 50) = .19
GS934: Cambios en distribución de la grasa y la función renal
• Mayores tasas de filtrado glomerular in ZDV/3TC vs TDF + FTC arm
– 108 vs 100 mL/min/1.73 m2 at Week 96; P = .006
– Difference not clinically significant
– No significant decline over time within each arm
Gallant J, et al. IAC 2006. Abstract TUPE0064.
Cambios en la grasa de los miembros por DEXA (S 48)*
n = 51 49n = 49 44
Week
0
1
2
3
4
5
6
7
8
910
48 96
6.0†7.4† ♦
■5.5‡■
8.1‡♦
†P = .034 ‡P < .001
11
To
tal
Lim
b F
at (
kg)
*No baseline DEXA data available.
GS934: Tres años de seguimiento
1. p=0.037Arribas J, Pozniak A, Gallant J, et al. Three-year safety and efficacy of emtricitabine (FTC)/tenofovir DF (TDF) and efavirenz (EFV) compared to fixed dose zidovudine/lamivudine (CBV) and EFV in antiretroviral treatment-naive patients. IAS 2007; Sydney, Australia. Abstract WEPEB029
A las 144 semanas de tratamiento la rama tenofovir/emtricitavina es más efectiva que la rama AZT/lamivudina
71% vs 58% (P = .004) de pacientes con CV< a 400
Efectos adversos: > Anemia rama AZT< de 1% de aumento de creatinina en ambas ramas< menor hipertriglicediremia y lipoatrofia en rama tenofovir
El uso de abacavir y ddI se ha vinculado a
un mayor riesgo de ataque al corazón • El estudio DAD incluye más de 30.000 pacientes
seguidos durante siete anos para comprobar la relación entre el tratamiento antirretroviral y el riesgo a sufrir infarto de miocardio.
• Se comunicó el tratamiento con abacavir aumentó el riesgo de infarto de miocardio en un 94%, mientras que asociado a ddI en un 53%.
Sabin C, Worm S, Weber R, et al. do Thymidine Analogues, Abacavir, Didanosine and Lamivudine Contribute to the Risk of Myocardial Infarction? The D:A:D Study. 15th Conference on Retroviruses
and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 957c.
• Primary endpoints
– Time to virologic failure
– Regimen completion: virologic failure or toxicity-related discontinuation of any regimen component
ACTG 5142: LPV/RTV vs EFV vs LPV/RTV + EFV
*Lamivudine plus either ZDV, d4T XR, or TDF, selected by investigator before randomization.
Antiretroviral-naive patients*;
VL > 2000 copies/mL;any CD4+ cell count
(N = 753)
LPV/RTV SGC 400/100 mg twice daily + 2 NRTIs*(n = 253)
EFV 600 mg once daily + 2 NRTIs*
(n = 250)
LPV/RTV SGC 533/133 mg twice daily + EFV 600 mg once daily
(n = 250)
Week 96Stratified for VL ≤ or > 100,000, hepatitis coinfection, and selection of NRTI
Riddler S, et al. IAC 2006. Abstract THLB0204.
• EFV + 2 NRTIs superior to LPV/r + 2 NRTIs in co-primary endpoint of time to virologic failure (P = .006)
• EFV + 2 NRTIs not significantly different to LPV/r + 2 NRTIs in co-primary endpoint of time to regimen completion (P = .02)
ACTG 5142: Comportamiento virológico en la semana 96 (ITT)
LPV/RTV + 2 NRTIs
EFV + 2 NRTIs
LPV/RTV + EFV
Pat
ien
tes
(%)
Riddler S, et al. IAC 2006. Abstract THLB0204.
VL < 50No VF No RegimenCompletion
VL < 2000
20
40
60
80
100
P = .041P = .003
67
54
867776
60
9389
73
61
92
83
ACTG 5142: Cambios en CD4+ en la semana 96
Riddler S, et al. IAC 2006. Abstract THLB0204.
P = .01
P = .96
P = .01
268285
241
0
50
100
150
200
250
300
Med
ian
CD
4+ C
han
ge,
ce
lls/m
m3
LPV/RTV + EFVEFV + 2 NRTIsLPV/RTV + 2 NRTI
LPV/RTV + 2 NRTIs
(n = 253)
EFV + 2 NRTIs(n =250)
LPV/EFV(n = 250)
Observed VF,* n 94 60 73
Genotypic assays, n 52 33 39
NRTI mutations, n (%)• M184I/V, n • K65R, n
8 (15)70
11 (33)83
4 (10)10
NNRTI mutations, n• K103N, n
2 (4)0
16 (48)9
27 (69)21
Major PI mutations,† n 0 0 2
Mutations in 2 classes, n 2 10 2
*Defined as early, lack of suppression by 1 log10 or rebound before Week 32, or late: failure to suppress to < 200 copies/mL or rebound after Week 32.†30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M.
ACTG 5142: Resistencia y falla
Riddler S, et al. IAC 2006. Abstract THLB0204.
New Grade 3/4 Event, %LPV/RTV + 2
NRTIsEFV + 2 NRTIs
LPV/RTV + EFV
Any sign/symptom 19 18 20
Any laboratory event 33 32 45
Absolute neutrophil count < 750 cells/mm3 8 5 6
LDL cholesterol > 190 mg/dL 1 3 6
Triglycerides > 750 mg/dL 6 3 14
AST > 5 x ULN 4 4 5
ALT > 5 x ULN 5 3 7
ACTG 5142: efectos adversos
Riddler S, et al. IAC 2006. Abstract THLB0204.
• Efectos adversos más comunes grado 3/4 : Dolor epigastrico, disconfort, nauseas, vomitos, cefaleas.
ACTG 5202: First-line Therapy With ABC/3TC vs TDF/FTC + EFV vs ATV/RTV
Daar E, et al. CROI 2010. Abstract 59LB.
Antiretroviral-naive patients with HIV-1 RNA
≥ 1000 copies/mL andany CD4+ cell count
(N = 1857)
TDF/FTC* 300/200 mg QD+ EFV† 600 mg QD
(n = 464)
ABC/3TC* 600/300 mg QD+ EFV† 600 mg QD
(n = 465)
Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL
TDF/FTC* 300/200 QD+ ATV/RTV† 300/100 mg QD
(n = 465)
ABC/3TC* 600/300 mg QD+ ATV/RTV† 300/100 mg QD
(n = 463)*Double blind.†Open label.
Wk 96 primary endpoint
ACTG 5202: Summary
• Comparable virologic efficacy of ATV/RTV vs EFV Similar time to virologic failure Similar proportion of patients without virologic failure at Wk 96
• Inferior virologic activity of ABC/3TC vs TDF/FTC in patients with HIV-1 RNA ≥ 100,000 copies/mL observed in both ATV/RTV and EFV arms
• Despite toxicity/tolerability differences, virologic efficacy of ABC/3TC similar to TDF/FTC in patients with HIV-1 RNA < 100,000 copies/mL Similar time to virologic failure Similar proportion of patients without virologic failure at Wk 96
Metabolic Substudy of ACTG 5202: Lumbar Spine and Hip BMD Changes (ITT)
McComsey G, et al. CROI 2010. Abstract 106LB.
P = .025P = .004
Comparison of ABC/3TC vs TDF/FTC Comparison of EFV vs ATV/RTV
Mea
n ∆
in B
MD
Fro
m
BL
to
Wk
96 (
%)
-4.0
-3.0
-2.0
0
TDF/FTCABC/3TC
-1.0
Difference: 2.0%
Lumbar Spine Hip
n = 101 97 99 96
P = .59P = .035
Mea
n ∆
in B
MD
Fro
m
BL
to
Wk
96 (
%)
-4.0
-3.0
-2.0
0
ATV/RTVEFV
-1.0
Lumbar Spine Hip
n = 107 91 105 90
Difference: 1.5%
Difference : 1.5% Difference: 0.3%
Initial loss in BMD in all arms stabilized after Wk 48 No significant differences in fracture rates between arms
Metabolic Substudy of ACTG 5202: Limb Fat Changes
McComsey G, et al. CROI 2010. Abstract 106LB.
• Similar absolute and % increases in limb fat with ABC/3TC and TDF/FTC in ITT analysis (P > 0.1) In as-treated analysis, greater
increase in limb fat with ABC/3TC vs TDF/FTC (difference: 1 kg; P = .023)
• Greater absolute and % increases in limb and trunk fat with ATV/RTV vs EFV in ITT and as-treated analyses (P < .05)
• 5% de lipoatrofias en miembros (10-20% de pérdida de grasa)
Limb Fat Primary Endpoint
ABC/3TC + EFVTDF/FTC + EFV
TDF/FTC + ATV/RTVABC/3TC + ATV/RTV
≥ 10
% L
imb
Fat
Lo
ss
Fro
m B
L t
o W
k 96
(%
)
0
20
60
80
40
n =
18.9
53
14.3
56
16.3
49
15.6
45
100
P = NS
Regimen
Nuevas drogas y estrategias para pacientes naïve
Rilpivirine 25 mg QD+ TDF/FTC 300/200 mg QD
(n = 346)
EFV 600 mg QD+ TDF/FTC 300/200 mg QD
(n = 344)
*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.
Stratification by BL HIV-1 RNA < 100,000
vs ≥ 100,000 copies/mL, NRTI use*
Wk 96final analysis
Wk 48primary analysis
Rilpivirine 25 mg QD+ 2 NRTIs†
(n = 340)
EFV 600 mg QD+ 2 NRTIs†
(n = 338)
ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
• Randomized, double-blind phase III trials
Cohen C, et al. AIDS 2010. Abstract THLBB206.
ECHO(N = 690)
THRIVE(N = 678)
Treatment-naive, HIV-1 RNA ≥ 5000 copies/mL
no NNRTI RAMs,susceptible to NRTIs
ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48
*P < .0001 for noninferiority at -12% margin.
Rilpivirine EFV
Cohen C, et al. AIDS 2010. Abstract THLBB206. Graphics used with permission.
HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL
40
0
100
20
8082.384.3
60
682686n =
ECHO THRIVEPooled
Pa
tie
nts
(%
)
82.882.9 81.785.6
338340344346
-3.6 (-9.8 to +2.5)-3.6 (-9.8 to +2.5)
6.6 (1.6-11.5)6.6 (1.6-11.5)
> 100,000 copies/mL
125/165
121/153
246/318
149/181
136/171
285/352
7781 79 8076 82
Pa
tie
nts
(%
)
40
0
100
20
80
60
Pooled THRIVEECHO
≤100,000 copies/mL
162/181
170/187
332/368
136/163
140/167
276/330
9083
9184
9084
Pa
tie
nts
(%
)
40
0
100
20
80
60
ECHO THRIVEPooled
ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events
Wk 48 Outcome Rilpivirine(n = 686)
Efavirenz(n = 682)
VF with resistance data, n 62 28
No NNRTI or NRTI RAMs,% 29 43
1 Emergent NNRTI RAM,% 63 54
• Most frequent NNRTI RAM E138K K103N
1 Emergent NRTI RAMs, % 68 32
• Most frequent NRTI RAM M184I M184V
Cohen C, et al. AIDS 2010. Abstract THLBB206. Table used with permission.
Treatment Failure in ECHO and THRIVEAdverse Events and Discontinuation
Resistance at Virologic Failure
6
0
15
3
12
94.8
346n =
VF
9.0
682686
6.7
AE
2.0
682686
Pat
ien
ts (
%) Wk 48
Outcome, %Rilpiviri
ne(n = 686)
Efavirenz
(n = 682)
P Value
DC for AE 3 8 .0005Most Common AEs of Interest,
%Any
neurologic AE
17 38 < .0001
Any psychiatric AE
15 23 .0002
Any rash 3 14 < .0001
Rilpivirine
EFV
Wk 16
Treatment naive,HIV-1 RNA
> 1000 copies/mL,
no CD4+ cell count restriction
(N = 205)
*NRTIs individually selected by trial investigators (TDF/FTC, 67%; ABC/3TC, 33%).†After Wk 48, all patients continue at dose selected for phase III trial.
S/GSK1349572 10 mg QD+ 2 NRTIs QD*
(n = 53)
S/GSK1349572 25 mg QD+ 2 NRTIs QD*
(n = 51)
S/GSK1349572 50 mg QD+ 2 NRTIs QD*
(n = 51)
EFV 600 mg QD+ 2 NRTIs QD*
(n = 50)
Arribas J, et al. AIDS 2010. Abstract THLBB205.
Dose-ranging, partially blinded phase IIb trialWk 48
SPRING-1: S/GSK1349572 vs EFV in Treatment-Naive Patients
SPRING-1: Virologic Response to S/GSK1349572 vs EFV at Wk 16
• CD4+ cell count increases 153-176 cells/mm³ on S/GSK1249572 vs 116 cells/mm3 on EFV
• No serious adverse events related to S/GSK1349572
Arribas J, et al. AIDS 2010. Abstract THLBB205. Graphic used with permission.
Wks
HIV
-1 R
NA
< 5
0 co
pie
s/m
L
(TL
OV
R),
%
96%92%90%
60%
Time to < 50 copies/mL shorterfor S/GSK1349572 dose than EFV(P < .001 for each comparison)
100
80
60
40
20
0
BL 1 2 4 8 12 16
50-mg dose chosen for phase III trial
572 10 mg572 25 mg
572 50 mgEFV 600 mg
VERxVE: Extended-Release NVP vs Standard NVP in Naive Patients at Wk 48
• Multicenter, randomized, double-blind, noninferiority study in treatment-naive patients– NVP XR 400 mg QD (n =
508) vs
– NVP IR 200 mg BID (n = 505)
– Both combined with TDF/FTC
• Inclusion criteria– HIV-1 RNA > 1000 copies/mL
– CD4+ cell count < 400 cells/mm3 if male or < 250 cells/mm3 if female
• Similar safety and tolerability for both arms
• AEs included
– Stevens-Johnson (n = 5)
– Hepatitis (n = 14)
– Rash (n = 21)
0
20
40
60
80
100
NVP IR NVP XR
81.075.9
HIV-1 RNA < 50 copies/mL (TLOVR)
Gathe J, et al. AIDS 2010. Abstract THLBB202.
Adjusted difference 4.92% (95% CI: -0.11 to 9.96)
PROGRESS: LPV/RTV + RAL vs LPV/RTV + NRTIs in Treatment-Naive Patients
Randomized, open-label, multicenter phase III trial in treatment-naive patients with HIV-1 RNA > 1000 copies/mL
– LPV/RTV 400 mg BID + RAL 400 mg BID (n = 101) vs
– LPV/RTV 400 mg BID + TDF/FTC 300/200 mg QD (n = 105)
• Relatively low mean baseline HIV-1 RNA
– 4.25 log10 copies/mL
Reynes J, et al. AIDS 2010. Abstract MOAB0101. Graphic used with permission.
Similar CD4+ cell count gain at Wk 48
– LPV/RTV + RAL: 215 cells/mm³
– LPV/RTV + NRTIs: 245 cells/mm³
0
20
40
60
80
100
Wks
0
HIV-1 RNA < 40 copies/mL (ITT-TLOVR)
8 16 24 32 40 48
83.2%
84.8%
Difference: -1.6% (95% CI: -12.0% to 8.8%)
*Statistically significant difference between arms:Wks 2, 4, 8 P < .002Wk 16 P = .038
**
*
*
Pat
ien
ts (
%)
LPV/RTV + RAL
• Mean increases in TC, TG, and HDL-C from BL to Wk 48 significantly greater in RAL arm vs NRTI arm
Reynes J, et al. AIDS 2010. Abstract MOAB0101.
Resistance Development at VF
LPV/RTV + RAL
LPV/RTV + NRTIs
Met criteria for resistance testing
4 3
• INSTI mutation (N155H)
1 0
• NRTI mutations (M184V)
0 1
0
20
40
60
80
100
TC TG HDL-C
Mea
n C
ha
ng
e F
rom
B
L,
mg
/dL
+46
+29
+99
+59
+12+8
P = .008
P = .044
P = .015
LPV/RTV + RAL LPV/RTV + NRTIs
PROGRESS: Lipids and Adverse Events at Wk 48
• Grade 3/4 laboratory events did not differ between arms, except higher risk of CPK > 4 x ULN in RAL arm
– 12.9% vs 3.8% (P = .023)
ATV/RTV‡ 300/100 mg QD +MVC 150 mg QD
(n = 60)
ATV/RTV‡ 300/100 mg QD + TDF/FTC 300/200 mg QD
(n = 61)
Treatment naive, R5 HIV only, HIV-1 RNA
≥ 1000 copies/mL, CD4+ cell count ≥ 100 cells/mm3
(N = 121)
*Prior to randomization.†PK analysis of MVC exposure in 15 MVC recipients.‡Patients without virologic failure but with jaundice and/or scleral icterus allowed to switch ATV/RTV to DRV/RTV or LPV/RTV if desired.Not powered for statistical comparisons.
Wk 48primary analysis
6-wkscreening period*
Wk 24interim analysis
Wk 16interim analysis
Wk 2PK analysis†
A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTC in Treatment-Naive Patients
• Randomized, multicenter, open-label phase IIb pilot study
Mills A, et al. AIDS 2010. Abstract THLBB203.
A4001078: ATV/RTV + MVC vs ATV/RTV +
TDF/FTC—Wk 24 Interim Analysis
• CD4 + cell count increases similar– ATV/RTV + MVC: 195 cells/mm³– ATV/RTV + TDF/FTC: 173 cells/mm³
• Grade 3/4 hyperbilirubinemia
– ATV/RTV + MVC: 59.3%
– ATV/RTV + TDF/FTC: 49.2%
• 5 patients in MVC arm, 1 patient in TDF/FTC arm switched to DRV/RTV per protocol for jaundice or scleral icterus
Mills A, et al. AIDS 2010. Abstract THLBB203.
40
0
100
20
80
HIV-1 RNA < 100K
95
80
60
7781
HIV-1 RNA 100K
HIV-1 RNA < 50 copies/mL Overall and by BL VL
22163944
Overall
8980
6160
Pat
ien
ts (
%)
n =
ATV/RTV + MVC
ATV/RTV + TDF/FTC
SPARTAN: Pilot Study of ATV + RAL vs ATV/RTV + TDF/FTC in Naive Pts
• Randomized, noncomparative, open-label, multicenter pilot study in treatment-naive patients with HIV-1 RNA ≥ 5000 copies/mL
– ATV 300 mg BID + RAL 400 mg BID (n = 63) vs
– ATV/RTV 3001/00 mg QD + TDF/FTC 300/200 mg QD (n = 31)
• Mean BL HIV-1 RNA: 4.9 log10 copies/mL
Kozal MJ, et al. AIDS 2010. Abstract THLBB204. Graphic used with permission.
Wks
0
20
40
60
80
100
BL 4 8 12 16 20 24
Pat
ien
ts (
%)
74.6%
63.3%
Primary Endpoint: HIV-1 RNA < 50 copies/mL Through Wk 24 (CVR*, NC = F)
ATV BID + RAL BID ATV/RTV QD + TDF/FTC
*CVR = modified ITT.
SPARTAN: Wk 24 Results
• No significant changes in fasting lipids observed in either arm during study period
• Trial terminated at Wk 24 due to resistance data and grade 4 bilirubin abnormalities (21%) with experimental regimen vs control arm (0%)
Resistance Through Wk 24, n
ATV + RAL(n = 63)
ATV/RTV + TDF/FTC(n = 30)
Virologic failure (HIV-1 RNA > 50 copies/mL)
11 8
• BL HIV-1 RNA > 250,000 copies/mL
8 4
Evaluable for resistance testing * (HIV-1 RNA > 400 copies/mL)
6 1
Genotypic and phenotypic RAL resistance
• N155H 2 NA
• Q148R 1 NA
• Q148R + N155H + T97A 1 NA
Phenotypic RAL resistance without genotypic evidence of resistance
1 NA
ATV resistance 0 0
TDF/FTC resistance NA 0
Kozal MJ, et al. AIDS 2010. Abstract THLBB204.
*Criteria for resistance testing: HIV-1 RNA ≥ 400 copies/mL at or after Wk 24 Rebound to HIV-1 RNA ≥ 400 any time during the
study Discontinued before achieving HIV-1 RNA < 50
copies/mL after Wk 8 with last HIV RNA ≥ 400 copies/mL
SENSE: EFV vs ETR in Treatment-Naive Patients
• Randomized, double-blind trial of treatment-naive patients with HIV-1 RNA > 5000 copies/mL
– EFV 600 mg QD (n = 78) vs
– ETR 400 mg QD (n = 79)
– Each with investigator-selected NRTIs (TDF/FTC, ABC/3TC, or ZDV/3TC)
• Primary endpoint: % of patients with grade 1-4 drug-related treatment-emergent neuropsychiatric AEs at Wk 12
• Mean change in HIV-1 RNA at Wk 12 similar between arms (-2.9 log10 copies/mL)
• More drug-related neuropsychiatric AEs in EFV arm vs ETR arm
40
0
100
20
80
46
17
60
175
Grade 1-4 Grade 2-4
EFV ETR EFVETR
10 patients discontinued in ETR and 8 in EFV arm by Wk 12
Gazzard B, et al. AIDS 2010. Abstract LBPE19.
Drug-Related Neuropsychiatric AEs
Pat
ien
ts (
%)
P < .001 P = .02
Falla al TAR: causas
Factores inherentes al paciente: (nadir CD4, comorbilidades; tratamientos previos;etc)
Resistencia a drogas Adherencia subóptima Toxicidad e intolerancias al TAR Problemas farmacocinéticos Suboptima potencia de las drogas
Selección de mutantes durante el tratamiento
Car
ga V
iral
Tiempo
Inicio de Tratamiento Cuasiespecie suceptible
Cuasiespecia resistente
Selección de cuasiespecies resistentes
Selección de mutantes durante el tratamiento
Supresión incompleta• Potencia inadecuada• NIveles de droga inadecuados• Adherencia inadecuada• Resistencia preexistente
Car
ga V
iral
Tiempo
Inicio de Tratamiento Cuasiespecie suceptible
Cuasiespecia resistente
Falla al TAR: definiciones
FallaVirológica : HIV RNA >400 copias/mL después de las 24 semanas, >50 despues de las 48 o >400 copias/mL después de la supresión viral
Falla inmunológica: Falta de mantenimiento o recuperación de los CD4
Progresión clínica: EDS después de tres meses de iniciado el TAR, excluyendo al SRI
Test de resistencia genotípica y fenotipo virtual
Mutaciones para INTR: 39A; 41L; 74V; 184V; 203D; 210W; 211K; 214F; 215Y;386I
Mutaciones para INNTR: 106A135T;189wt/I;227L
Mutaciones para Proteasa: 16D; 35D
Falla virológica: conducta
Verificar historia previa de TAR Solicitar test de resistencia Evaluar test de resistencia previa
Falla virológica: conducta
Objetivo: lograr supresión viral (CV < 50 copias) Elegir en lo posible tres drogas activas (nunca
menos de dos) Analizar opciones futuras
BENCHMRK 1 y 2: VL < 400 c/mL en W 16 de acuerdo a las drogas usadas
+ : First use in OBR– : No use in OBR
Overall Efficacy Data
––
0 20 40 60 80 100
n
447230
Efficacy by Agents in OBR
Enfuvirtide Darunavir
+
+
+
+
–
–
879844
23
639042
24
559080
47
2974191
90
7943
Raltegravir + OBR
Placebo + OBR
Patients (%)Statistical analysis: virologic failure carried forward.
Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.
VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients
• International, multicenter, single-arm, phase II study in 27 patients with RAL resistance
– S/GSK572 50 mg QD to replace RAL in failing regimen (or added if RAL already d/c) for 10 days of functional monotherapy
– Day 11-Wk 24: S/GSK572 50 mg QD continued and regimen optimized
– Median fold-change in RAL susceptibility at BL: 161 (range: 0.6 - > 166)
– Median S/GSK572 FC at BL: 1.5 (range: 0.6-35)
• Stratified by BL integrase genotype
– Group 1: Q148 + ≥ 1 secondary resistance mutations (n = 9)
– Group 2: All others (N155H and Y143H pathways) and single mutations at Q148 (n = 18)
HIV-1 RNA Response at Day 11
Group 1
(n = 9)
Group 2
(n = 18)
< 400 c/mL or ≥ 0.7 log10 c/mL decline, %
33 100
Change from baseline, log10 c/mL
-0.72 -1.82
Day 1 FC to S/GSK572 highly predictive of Day 11 virologic response (r = 0.79; P < .001)
Among 18 paired isolates evaluated on Day 1 and Day 11, no evidence of emergent RAL mutations
– In 17 subjects, < 2 FC in susceptibility
– In 1 subject, ~ 6 FC in susceptibility Eron J, et al. AIDS 2010. Abstract MOAB0105.
Futuros Antirretrovirales
Bevirimat
PIs
NNRTI
NRTI
Inhibidores de MaduracionGS-9137
Rilpivirina
Apri-citabine
Inhibidores Integrasa
Ihnibidores de Entrada (anti-gp120, CCR5)
TBR-652
2009 2010 2011 2012 2013
Elvitegravir Vicriviroc
¿Es posible erradicar al VIH?
La segunda fase podría corresponder a pérdida de macrófagos infectados o virus atrapados en células dendríticas.El reservorio corresponde a un depósito latente de CD4 + T de lenta replicación (hasta 44 meses de vida media).
¿Es posible la erradicación del VIH?
Finzi D, Hermankova M, Pierson T, et al. Science. 1997;278:1295-1300.Wong JK, Hezareh M, Gunthard HF, et a Science. 1997;278:1291-1295.
La tasa de la reserva latente es determinada por la velocidad de las células de abandonar el depósito, menos la tasa de nuevas células que entran. El TAAE impide que penetren nuevas células, pero no logra favorecer el clearence de las mismas
¿Es posible la erradicación del VIH?
¿Es posible la erradicación del VIH?
¿Es posible la erradicación del VIH?: estrategias
1) prevención de entrada de nuevas células al reservorio: se hizo con los antirretrovirales clásicos logrando disminuir la vida media de 31 a 10 meses.
2) Acelerar la activación del provirus latente facilitando su eliminación: se utilizado interleuquina 2, IL-6 , factor de necrosis tumoral-alfa e inhibidores de histona deacetilasa. Dos estudios combinando IL 2 con TAAE mostraron disminución del reservorio, pero hubo rebote con la suspensión. Se intentó combinar además con Ac anti CD3, pero hubo muchos efectos adversos.
El reservorio latente disminuyó en una media de un 75% en 3 de 4 pacientes que recibieron ácido valproico durante 3 meses después de la intensificación del TAR con enfuvirtida.
Davey RT Jr, Bhat N, Yoder C Sci U S A. 1999;96:15109-15114.Stellbrink HJ, van Lunzen J, Westby M, AIDS. 2002;16:1479-1487. Lehrman G, Hogue JB, Palmer S, Lancet. 2005;366:549-55
¿Es posible la erradicación del VIH?: estrategias
.
Levin A, Hayouka Z, Friedler A et al. Specific eradication of HIV-1 from infected cultured cells. AIDS Research and Therapy 7(1): 31. August 19, 2010
Cuando el VIH integra su genoma en el de la célula infectada, sólo inserta la cantidad suficiente para poderse replicar, ya que las células tienen un mecanismo interno por el cual son capaces de detectar la irrupción de material genético ajeno en su genoma a partir de cierta cantidad, lo que desencadena un mecanismo de muerte celular programada conocido como apoptosis.
El fundamento de la investigación fue la inducción de la integración de una mayor cantidad de material genético viral capaz de desencadenar la apoptosis celular (in vitro).
¿Es posible la erradicación del VIH?: estrategias
.
Levin A, Hayouka Z, Friedler A et al. Specific eradication of HIV-1 from infected cultured cells. AIDS Research and Therapy 7(1): 31. August 19, 2010
Para ello, los autores del estudio desarrollaron una serie de péptidos –conocidos como “mix”- que pueden penetrar en las células infectadas estimulando la integrasa del VIH.
La estimulación de la integrasa resultó en un incremento en el número de moléculas del genoma viral en el núcleo de las células infectadas, desencadenando la apoptosis y la subsiguiente erradicación de la infección.
¡GRACIAS!