tratamiento antirretroviral curso 2010[1]

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


Carga Viral CD4

TAR

Inf. Aguda

Etapa Asintomática

SIDA


Inf. Aguda

Etapa Asintomática

SIDA

Carga Viral CD4

TAR

3-6 Sem Años

Inf. Aguda

Etapa Asintomática

Carga Viral CD4

TAR

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.


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


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

(%)


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


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


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


• 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)


(n = 51)


(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?: 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


.

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).


.

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!

tratamiento antirretroviral curso 2010[1]

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