Tratamiento de un paciente infectado por VIH naïve. Dres. Arribas/Moreno

(1)

TRATAMIENTO DE UN PACIENTE INFECTADO POR

VIH NAÏVE

Dr. Jose R Arribas

vs

Dr. Santiago Moreno

(2)



 

Varón de 43 años



 

Fumador de 10 cpd



 

Padre tuvo IM a los 55 años



 

HTN desde 2007 recibe Enalapril y Amlodipina



 

HIV+ desde Abril/2010. Homosexual



 

Periodista



 

No pareja estable

(3)

Fecha

HAART

CD4

VL

Creat

HDL

LDL

TC

TG

Junio

2010

Naïve

589 49,000

1

37

140

206

143 Agosto

2010

Naïve

520 62,000

1

39

143

203

135 ¿Empezarías TARGA ya?

(4)

HAY QUE EMPEZAR TARGA YA

Dr. Moreno

(5)

¿Cuándo empezar?

Qué dicen las Guías

Categoría Clínica _cells/mmCD4 ₃ EACS 09 IAS 10 DHHS 11 GESIDA 11

Infección

sintomática Cualquier valor Tratamiento Tratamiento Tratamiento Tratamiento

Asintomática <200 Tratamiento Tratamiento Tratamiento Tratamiento

Asintomática 200–350 Tratamiento Tratamiento Tratamiento Tratamiento

Asintomática 350–500

Recomendar tratamiento en algunas situaciones

Tratamiento Tratamiento _Tratamiento

Asintomática >500

Diferir tratamiento Considerar tratamiento en algunas situaciones Considerar Tratamiento Recomendar tratamiento en algunas situaciones 50% Recomendar Tratamiento 50% Tratamiento Opcional Diferir tratamiento Considerar tratamiento en algunas situaciones

(6)

Consecuencias/beneficios del TAR

Respuesta inmunológica

Recuperación del recuento de CD4

Evitar respuesta inflamatoria crónica y disfunción inmune

secundarias a la replicación viral

Respuesta clínica

Mortalidad

Evolución a sida

Desarrollo de enfermedades no definitorias de sida

Enfermedad cardiovascular

Hepatopatía

Insuficiencia renal

Neoplasias no sida

Trastorno neurocognitivo

(7)

Recuento de CD4 basal y respuesta inmunológica

Cohorte ATHENA, Netherlands

Adaptado de Gras L, et al. J Acquir Immune Defic Syndr 2007; 45 (2): 183-192.

Semanas desde el comienzo del TARGA

R

ec

u

en

to

d

e

cé

lu

la

s

C

D

4 (c

él

s/

mm

3

)

<50 céls/mm3

50–200 céls/mm3

200–350 céls/mm3

350–500 céls/mm3

>500 céls/mm3

(7 años)

(8)

Respuesta inmunológica - EuroSIDA

Baseline CD4 (Cells/mm3₎

0 250 500 750 1000

<1 1–3 3–5 >5 Time since starting treatment

(years) C urre nt C D 4 (ce lls/ mm 3 ) 0 20 40 60 80 100 120 140

<1 1–3 3–5 >5 Time since starting treatment

(years) R at e of C D 4 in cre ase pe r ye ar (ce lls/ mm 3 )

<200 201–350 >350

Adaptado de Mocroft et al. Lancet 2007;370:407-13

(9)

When to start

Study

ART-CC

4 R ie sg o re la tivo d e SI D A ó mu ert e 2 .5 1

500 400 300 200 100 0

Umbral de CD4 (céls/mm3₎

Comparación Hazard Ratio (IC 95%)

276–375 vs 376–475 1.19 (0.96 to 1.47) 251–350 vs 351–450 1.28 (1.04 to 1.57) 226–325 vs 326–425 1.21 (1.01 to 1.46)

Retrasar el TAR a <350 cél/mcl se asocia con un aumento del riesgo de

SIDA o muerte

Gesida, Guidelines 201

1

When to Start Consortium. Sterne JA, et a. Lancet 2009;373:1352-63.

(10)

NA-ACCORD

Riesgo de mortalidad asociado al retraso en iniciar TAR

(11)

HR de mortalidad para los pacientes que inician TAR

vs.

no TAR, en función

de la situación inmunológica y virológica basal

Impacto del TAR sobre la mortalidad

HIV-CAUSAL Collaboration

Se incluyeron 62.760 pacientes (12 cohortes)

Seguimiento 3,3 a

ñ

os (inicio de seguimiento: Ene

’

96 –

Ene

’

98)

Reducción de la mortalidad del:

- 45% si comienzo del TAR con CD4 350-500

- 23% si comienzo del TAR con CD4 >500

(12)

Estudio DAD: Mortalidad por causa hepática

Estudio de cohortes observacional, prospec4vo

23.441 pacientes con infección VIH-‐1

(seguimiento 76.893 personas-‐año)

1.33 1.23 0.73 0.34 0.12 0.06 0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4

<50 50–99 100–199 200–349 350–499 ≥500

Último recuento de CD4

(cél/mcl)

Mu

er

te

s

re

la

ci

o

n

ad

as

c

o

n

e

l

h

íg

ad

o

p

o

r

10

0 p

er

so

n

as

-a

ñ

o

El mantenimiento de recuento alto de CD4 se asoció con menor frecuencia de muertes relacionadas con el hígado

(13)

Prosperi MCF, et al. Clin Infect Dis 2010; 50 (9): 1316-21.

NMDS (neoplasias malignas definitorias de Sida) NMNDS (neoplasias malignas no definitorias de Sida)

Se diagnosticaron 252 neoplasias malignas (n=6695 pacientes)

Probabilidad (KM) del 5% por 10 años desde la inclusión (IC 95% 4-6%)

Incidencia de neoplasias en función del estrato de CD4 actual

ICONA,

Italian Cohort of Naïve to Antiretrovirals

p<0,001

p=0,006

(14)

Limitaciones posibles del TAR precoz

Toxicidad de TAR

Interferencias sobre la calidad de vida del

paciente

Problemas de adherencia a largo plazo

Desarrollo de resistencias

(15)

¿Cuándo empezar?

Qué dicen las Guías

Categoría Clínica _cells/mmCD4 ₃ EACS 09 IAS 10 DHHS 11 GESIDA 11

Infección

sintomática Cualquier valor Tratamiento Tratamiento Tratamiento Tratamiento

Asintomática <200 Tratamiento Tratamiento Tratamiento Tratamiento

Asintomática 200–350 Tratamiento Tratamiento Tratamiento Tratamiento

Asintomática 350–500

Recomendar tratamiento en algunas situaciones

Tratamiento Tratamiento _Tratamiento

Asintomática >500

Diferir tratamiento Considerar tratamiento en algunas situaciones Considerar Tratamiento Recomendar tratamiento en algunas situaciones 50% Recomendar Tratamiento 50% Tratamiento Opcional Diferir tratamiento Considerar tratamiento en algunas situaciones

(16)

Recomendar

TAR en estos casos (resultados de enfermedades no SIDA [SMART]),

independientemente del recuento de CD4

(del mismo modo que los pacientes sintomáticos, las mujeres embarazadas o los pacientes con

CD4 <350)

Indicaciones de TAR en pacientes asintomáticos con infección crónica por VIH

(Recomendaciones de Gesida/Plan Nacional sobre el Sida,

Enero 2011

)

Recomendar

(17)

NO HAY QUE EMPEZAR TARGA YA

Dr. Arribas

(18)

CIPRAHT001: Randomized Trial

of When to Start ART in Haiti

Early Treatment

(Immediate ZDV/3TC + EFV)

Standard Treatment

(Delay until CD4+ <200 or AIDS

• Treatment-naive

• No hx AIDS-defining illness

• CD4 200-350

(n=816)

Primary

endpoint:

Survival

May 2009: DSMB review stopped study due to excess deaths in Defer

Treatment arm

Randomized clinical endpoint study of when to start therapy

Baseline Characteristics

Early (n=408) Standard (n=408)

Median age (years) 40 40

Male (%) 41% 44%

Median CD4+ (cells/mm3₎ ₂₈₀ ₂₈₂

Body Mass Index (kg/m2₎ _21.4 _21.0

(19)

CIPRAHT001:

Clinical Endpoints and Additional Data

Early

Standard

Hazards Ratio

_{(p value)}

Death

6

23 _{(.0011 )}

4.0 Incident

Tuberculosis

18

36 (.0125 )

2.0

 

Infectious causes of death

 

Early: 1 (gastroenteritis)

 

Standard: 17 (7 gastroenteritis, 5 TB, 4 pneumonia, 1 cholangitis/sepsis)

 

More toxicity from ART (especially anemia) and intensive need for lab f/u for those who

deferred

 

Investigators currently working with Ministry of Health to change start ART guidelines to

350 cells/mm3

Clinical Endpoints

(20)

Randomized Trial

Early Treatment

(Immediate HAART)

Standard Treatment

(Delay until CD4+ <350 or AIDS

• Treatment-naive

• No hx AIDS-defining illness

• CD4 >500

Primary

endpoint:

Survival

Randomized clinical endpoint study of when to start therapy

No tenemos

este EECC

(21)

CONCLUSIONS

The early initiation of antiretroviral

therapy before the CD4+ count fell below

two prespecified thresholds (351 & 500)

significantly improved survival, as

compared with deferred

therapy.

INTERPRETATION

Our results suggest that 350 cells per µL

should be the minimum threshold for

initiation of antiretroviral therapy, and

should help to guide physicians and

patients in deciding when to start

treatment

N Engl J Med 2009;360.

10.1056/NEJMoa0807252

The Lancet, Early Online Publication, 9 April 2009

doi:10.1016/S0140-6736(09)60612-7

(22)

(23)

CASCADE: Absolute Risk Difference and Number

Needed to Treat 3 Yrs From BL (Seroconverters)

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) Prevent 1 Death NNT at 3 Yrs to

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-∞)

(24)

The HIV-CAUSAL Collaboration

(25)

Important Limitations of Cohort Studies



 

Overall number of events low



 

Results may be affected by unmeasured confounding factors



 

Potential for lead time bias



 

Toxicity and resistance not included as endpoints



 

Different health services

(26)

Jason V. Baker and Keith Henry Ann Intern Med April 19, 2011 154:563-565;

“In real terms, patients with newly diagnosed AIDS (who have a

high mortality risk) wait to start cART in some areas in the United

States because treatment was started earlier in the fiscal year for

patients with high CD4 cell counts (when cART has less clinical

benefit)”

(27)

(28)

Earlier treatment (regardless of CD4 count)

Condition EACS DHHS IAS GESIDA

§ Hepatitis C § Recommended § AIIa § Recomendar

§ Hepatitis B § Recommended § AIII § BIIa § Recomendar

§ HIV nephropathy § Recommended § AII § BIIa § Recomendar

§ HIV-1 RNA >

100,000 copies/mL § Recommended § BII § AIIa

§ Recomendar

§ CD4 decline

>50-100/mm3_/year § Recommended § AIII § AIIa

§ Age _§

Consider (>50) §_(>60) Recommended §_(>55) Recomendar

§ Pregnancy § Recommended § AI § AIa § Recomendar

§ High CV risk § Recommended § BIIa § Recomendar

§ Malignancy § Recommended

§ Risk for

secondary HIV transmission is high, eg,

serodiscordant couples

§ BIIa § Recomendar

(29)

(30)

(31)

(32)

Composite Primary Endpoint

(Time to first event)

 

AIDS*

 

Clinical events included in 1993 CDC case definition, plus additional conditions

related to immunodeficiency (non-fatal esophageal candidiasis and herpes simplex

are excluded)

 

Non-AIDS

 

Cardiovascular disease: MI, angioplasty, CABG, stroke

 

Chronic end-stage renal disease (ESRD): initiation of dialysis, renal transplantation

 

Decompensated cirrhosis

 

Non-AIDS defining cancers (basal and squamous cell skin cancers are not

counted)

 

Death from any cause

(33)

INSIGHT Y SUS HIPOTESIS



 

LAS INTERRUPCIONES DEL TARGA SON SEGURAS



 

LA IL-2 FUNCIONA



 

SE DEBE EMPEZAR TARGA CON CD4 > 500

NO LO SON (SMART)

NO FUNCIONA (SILCAAT & ESPRIT)

(34)

¿CON QUÉ EMPEZAR, HACE FALTA ALGUNA PRUEBA

MAS?

Fecha

HAART

CD4

VL

Creat

HDL

LDL

TC

TG

Juniio

2010

Naïve

589 49,000

1

37

140

206

143 Agosto

2010

Naïve

520 62,000

1

39

143

203

135

(35)

Tests for HIV-Infected Pts Entering Care

Tests Administered to All Pts

Tests Administered to Selected Pts

§

 

HIV-1 RNA

§

 

CD4+ cell count (T-cell percentages)

§

 

Viral resistance test

§

 

Complete blood count

§

 

Blood chemistry profile

§

 

Liver enzymes

§

 

Bilirubin

§

 

Blood urea nitrogen

§

 

Creatinine

§

 

Urinalysis

§

 

Fasting blood glucose

§

 

Fasting serum lipids

§

 

Screening for syphilis

§

 

Hepatitis A, B, C

§

 

Coinfection screening

–

 

Tuberculosis

–

 

Toxoplasma gondii

§

 

Cervical Pap smear (women)

§

 

Anal Pap smear (men and women)

§

 

Pregnancy (women)

§

 

HLA-B*5701

(36)



 

Varón de 43 años



 

Fumador de 10 cpd



 

Padre tuvo IM a los 55 años



 

HTN desde 2007 recibe Enalapril y Amlodipine



 

HIV+ desde April/2010. Homosexual



 

Periodista



 

No pareja estable



 

GENOTIPO POBLACIONAL: SALVAJE



 

HLA B5701 NEGATIVO

(37)

¿CON QUÉ EMPEZAR?

Fecha

HAART

CD4

VL

Creat

HDL

LDL

TC

TG

Junio

2010

Naïve

589 49,000

1

37

140

206

143 Agosto

2010

Naïve

520 62,000

1

39

143

203

135

(38)

TARGA DE POR VIDA

Efficacy

Tolerance

Toxicity

Interactions

Comorbidities

Convenience

Cost

(39)

What to start with

Regimen

EACS

DHHS

IAS

GESIDA

§

 

TDF-FTC-EFV

§ Recommended § Preferred § Recommended § Preferente

§

 

TDF-FTC-DRV/r

§

 

TDF-FTC-ATV/r

§

 

TDF-FTC-RAL

§ Alternative § Preferred § Recommended § Preferente*

§

 

ABC-3TC-EFV

§ Recommended § Alternative § Alternative § Preferente*

§

 

TDF-FTC-LOP/r

§

 

TDF-FTC-NVP

§ Recommended § Alternative § Preferente*

1. Disponible en: http://www.gesida.seimc.org/pcientifica/fuentes/DcyRc/gesidadcyrc2010_DocconsensoTARGESIDA-PNS-verimp.pdf 2. Clumeck N et al. Available at: http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf 3. Thompson MA, et al. JAMA 2010;304(3):321-333;

(40)

HAY QUE EMPEZAR CON ABACAVIR

Dr. Moreno

(41)

A5202: Study Design

Daar, E et al. 17th_{CROI 2010. Abstract 59LB}

Sax PE et al. N Engl J Med 2009; 361: 2230-40

**Testing for HLA-B*5701 allele was permitted but not required.**

(42)

Resultados preliminares del estudio ACTG 5202: Criterio de valoración principal (estrato de carga viral

alta en el momento de la acción de DSMB)

Tiempo hasta fracaso virológico en pacientes con niveles basales de ARN-VIH ≥ 100.000 copias/mL tratados con ABC/3TC frente a TDF/FTC (análisis ITT)

Sax et al. NEJM 2009;361:2230

Pr

o

b

ab

ili

d

ad

(m

an

te

n

im

ie

n

to

s

in

fr

ac

as

o

v

ir

o

ló

g

ic

o

)

0 4 16 24 36 48 60 72 84 96 108

1,0 0,8 0,6 0,4 0,2 0,0

Semanas desde la asignación aleatoria

ABC/3TC (57 eventos)

TDF/FTC (26 eventos)

Número con riesgo 398

399 363 361 313 321 267 284 222 236 204 188 137 160 87 104 49 65 20 23 ABC/3TC TDF/FTC

Estudio ACTG 5202: ABC/3TC frente a TDF/FTC en el estrato con una CV alta

prueba de rango logarítmico, valor p < 0,001

HR (IC 95%) 2,33 (1,46, 3,72)

(43)

Estudio ACTG 5202: ABC/3TC frente a TDF/FTC en el estrato con CV baja

Criterio principal: Tiempo a fracaso virológico

ABC/3TC versus TDF/FTC con

ATV/r: HR 1.26 (IC 95% 0.76, 2.05)

Prob. de no FV a la sem 96: 88.3 vs. 90.3%, diff -2.0% (95% CI -7.5, 3.4)

EFV: HR 1.23 (IC 95% 0.77,

1.96);

Prob. De no FV a la sem 96: 87.4 vs. 89.2%, diff -1.8% (95% CI -7.5, 3.9)

(44)

HEAT: HIV-1 RNA <50 copies/mL at Week 96 by

Baseline HIV-1 RNA (ITT-E, M=F)

Smith K et al. 17th_{IAC 2008: Poster LBPE1138}

n = 188 205 155 140 343 345

• In combination with LPV/rtv QD, ABC/3TC QD was non-inferior to TDF/FTC QD, in

virologic and immunologic efficacy over 96 weeks

• The number of subjects with protocol-defined virologic failure was similar between

the two treatment groups [ABC/3TC: 14% vs TDF/FTC: 14%]

(45)

90

87 87 90

0 20 40 60 80 100 <100,000 =>100,000 ABC/3TC TDF/FTC Pe rce nt ag e of V iro lo gi c Su rvi va l

n = 188 205 155 140

HEAT: Probability of Protocol-Defined Virologic Survival by Week 48

by BL Viral Load Using the A5202 Efficacy Endpoint

(46)

Estudio D:A:D

Riesgo de infarto de miocardio y uso de análogos

de nucleósidos

CROI 2008 & Lancet 2 de Abril de 2008

(47)

No asociación entre ABC y aumento de riesgo de IAM o ECV

(48)

(49)

Ding, X et al. 18th_{CROI 2011. 27 Feb-‐2 March 2011. Abstract 808}

ABC

Non-‐ABC

(95% CI)

1

_{MH IR (95%}

CI

₎

2

# Subjects

5028

4840

Overall # MI events

reported

24/5028

22/4840

0.008% (-‐0.26%,-‐.27%)

1.02 (0.56.,1.84)

GSK

6/2341

9/2367

-‐0.11% (-‐0.43%,0.21%)

0.70 (0.25,2.00)

NIH

12/1985

9/1610

0.03% (-‐0.45%,0.51%)

1.06 (0.43,2.61)

Academic

6/702

4/863

0.31% (-‐0.53%,1.16%)

1.60 (0.46,5.62)

StraUﬁed odds raUo sensiUvity analysis excluding 8 trials with no reported MI in either treatment group similarly

found no staUsUcally signiﬁcant associaUon between MI and ABC use (OR 1.06; 95%CI 0.57-‐2.00)

1

_{Mantel-‐Haenszel Risk Diﬀerence}

2 _{Mantel-‐Haenszel Odds RaUo. This approach does not include studies with 0 events in both arms.}

Data from 26 RCT (conducted from 1996-‐2010)

(50)

Factores de riesgo para el desarrollo de enfermedad renal en

pacientes VIH

 

Fallo renal agudo

 

Bajo recuento de CD4

1,3

 

Alta carga viral

1

 

Coinfección VHC

1

 

SIDA

1

 

Uso de ciertos ARVs

3

 

Enf. Reno-vascular

 

Dislipemia

2

 

Diabetes mellitus

3.5

 

Fallo renal crónico

 

Bajo recuento CD4

4–6

 

Alta carga viral

1,4

 

SIDA

5

 

Hipertensión

5–7

 

Raza negra

6

 

Fármacos nefrotóxicos

5

 

Uso de ciertos ARVs

5,7

1. Franceschini N, et al. Kidney Int 2005; 67:1526–1531 2. Tungsiripat M & Aberg JA. Cleveland Clin J Med 2005;

72:1113–1120

3. Heﬀelﬁnger J, et al. 13th_CROI_{2006; Abstract 779} _{4. Szczech LA,}_{et al. Kidney Int}_2002;_61:_195–202

5. Mocroe A, et al. 14th_CROI_{2007; Abstract 828} _{6. Krawczyk CS,}_{et al. AIDS}_2004;_18:_2171–2178

(51)

ACTG5202: ATV/r vs. EFV

Cambio medio en aclaramiento de creatinina

ATV/r

ABC/3TC

ATV/r

EFV EFV

TDF/FTC

N= 377 330 338 287 394 352 360 327

Wk 48, p=0.17

Wk 96, p=0.33 Week 96 Wk 48, p=0.001 Wk 96, p<0.001

Week 48

A5202: Overall: As-‐Treated

p-‐values: ATV/r vs. EFV

Ch

an

ge i

n Ca

lcu

la

ted

Crea

4n

in

e Cl

ea

ra

nce,

(mL/

mi

n)

(52)

FR relacionados con nefrotoxicidad por TDF

■

 

ERC previa

■

 

Bajo peso corporal

■

 

Edad avanzada

■

 

Administración conjunta con otros fármacos nefrotóxicos

■

 

Recuento bajo de linfocitos CD4

■

 

IO previas

■

 

“comorbilidad”

■

 

HTA

■

 

Dolor crónico (un marcador de uso de AINEs)

■

 

Uso simultáneo de IPP

■

 

Determinados haplotipos del gen ABCC2 (MRP2) y del ABCC4 (MRP4)

Nelson M.R AIDS 2007

Goicoechea M .J.Infect.D.2008

(53)

ACTG 5224s

(54)

NO HAY QUE EMPEZAR CON ABACAVIR

Dr. Arribas

(55)

Summary of Clinical Trial and Cohort Analyses

of ABC Use and CVD Risk

Study Design CV Events Effect of ABC?

D:A:D[1] _{(N = 33347)} _{Observational cohort} _{Prospective, predefined} _Yes

FHDH[2]_{(N = 1173)} _{Case control study} _{MI retrospectively validated} Yes

1st yr of exposure

SMART[3]_{(N = 2752)} RCT, observational

analyses Prospective, predefined Yes

STEAL[4]_{(N = 357)} _RCT _Prospective _Yes

GSK analysis[5]

(N = 14174) 54 RCTs Retrospective database search No

ALLRT ACTG A5001[6]

(N = 3205) 5 RCTs

Retrospective by

2 independent reviewers No

1. Lundgren JD, et al. CROI 2009. Abstract 44LB. 2. Lang S, et al. CROI 2009. Abstract 43LB. 3. SMART. AIDS. 2008;22:F17-F24. 4. Carr A, et al. CROI 2009. Abstract 576. 5. Cutrell A, et al. IAC 2008. Abstract WEAB0106. 6. Benson C, et al. CROI 2009. Abstract 721. Thanks to Peter Reiss, MD, PhD, for permission to reproduce the table. Reiss P. CROI 2009. Abstract 152.

All or majority of pts antiretroviral-experienced at ABC initiation

All or majority of pts antiretroviral-naive at ABC initiation

(56)

SMART: CVD risk with ABC

Lundgren J, et al. XVII IAC, Mexico City, 2008. #THAB0305

Unadjusted hazard ratio Adjusted for CV risk factors

0,1 1 10

Hazard ratio (95% CI) of CVD

CVD, expanded definition (n=112)‏

CVD, minor (n=58)‏

MI (n=19)‏

CVD, major (n=70)‏ 1.8

4.3 2.7 1.9

12.6 13.0

Favors other NRTIs

► ◄

Favors ABC

CVD risk with ABC compared with other

NRTIs

0,1 1 10

>5 CV

risk factors

Ischemic abnormalities on ECG

*p=0.1; **p>0.4; †_{adjusted for CV risk factors}

**

3.1

At study entry:

Hazard ratio

†

_{(95% CI) of CVD, expanded}

definition

Favors other NRTIs

► ◄

Favors ABC

3.1

*

CV risk factor present CV risk factor absent

CVD risk for ABC use based on baseline

CV risk factors

(57)

A5202: ATV/r vs. EFV

Median Changes in Fasting Lipids and Creatinine Clearance

In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r

Median Change in Fasting Lipids (Week 48, mg/dL)

Daar E, et al. 17th CROI; San Francisco, CA; February 16-‐19, 2010. Abst. 59LB.

Change in Calculated Creatinine Clearance, (mL/min)

TC LDL HDL TG

ABC/3TC

ATV/r 29 13 8 24

EFV 40 21 12 15

P-value <0.001 0.002 <0.001 0.26

TDF/FTC

ATV/r 10 2 5 14

EFV 22 10 8 13

P-value <0.001 0.002 <0.001 0.26

Week 48 Week 96

ABC/3TC

ATV/r 3.1 6.1

EFV 4.3 7.8

P-value 0.17 0.33

TDF/FTC

ATV/r -0.9 -2.6

EFV 4.1 4.9

P-value 0.001 <0.001

(58)

What to start with

Regimen

EACS

DHHS

IAS

GESIDA

§

 

TDF-FTC-EFV

§

 

TDF-FTC-DRV/r

§

 

TDF-FTC-ATV/r

§

 

TDF-FTC-RAL

§ Alternative § Preferred § Recommended § Preferente*

§

 

ABC-3TC-EFV

§

 

TDF-FTC-LOP/r

§

 

TDF-FTC-NVP

§ Recommended § Alternative § Preferente*

1. Disponible en: http://www.gesida.seimc.org/pcientifica/fuentes/DcyRc/gesidadcyrc2010_DocconsensoTARGESIDA-PNS-verimp.pdf 2. Clumeck N et al. Available at: http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf 3. Thompson MA, et al. JAMA 2010;304(3):321-333;

(59)

HAY QUE EMPEZAR CON UN NO NUCLEOSIDO

O CON UN INHIBIDOR DE LA INTEGRASA

Dr. Moreno

(60)

Estudio

Comparación

Eficacia

FOCUS

EFV vs SQV/r qd

EFV > SQV/r

CLASS

EFV vs APV/r

EFV > APV/r

AI 424-034*

EFV vs ATV (tubos PPT)

EFV = ATV

ACTG 5142

EFV vs LPV/r

EFV > LPV/r

Sierra Madero J, et al

EFV vs LPV/r

EFV > LPV/r

ACTG 5202

EFV vs ATV/r

EFV=ATV/r

Efavirenz o IPs/r?

89 vs 77%

37 vs 32%

72 vs 49%

71 vs 51%

Efavirenz

(Resistencia IP/r)

70 vs 53%

CD4 < 200

Montaner J et al, medGenMed. 2006; 8(2): 36. Published online 2006 May 10. Bartlett JA et al, J Acquir Immune Defic Syndr 2006;43:284–292. Squires K et al J Acquir Immune Defic Syndr 2004;36:1011–1019. Riddler S, et al. NEJM 2008;358:2095-2106. Sierra Madero J, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. TUAB0104. Sax PE, et al., 17th International AIDS Conference, México City, México, 2008; Oral #THAB0303. NIAID Press Release, Feb 28, 2008;

http://www3.niaid.nih.gov/news/newsreleases/2008/actg5202bulletin.htm

(61)

Moviéndonos hacia regímenes más simples

Dosis

Nº comps/caps

Comentarios

2007

1 comp QD

Efectos adversos mínimos o nulos,

buena PK, no restricciones de

comida.

2003

3 ps, QD

Generalmente bien tolerado;

efectos GI, efectos SNC (EFV)

TDF/ [FTC or

3TC] / EFV

2005

2 ps QD

Efectos adversos mínimos o nulos,

buena PK, no restricciones de

comida.

Régimen

(62)

Tiempo al cambio del tratamiento

0 .25

.5

.75

1 Cumu

lat

ive

Inci

dence o

f trea

tment

ch

ange

0 3 6 9 12 15 18 21

Months from cART initiation

0 .25

.5

.75

1 Cumu

lat

ive

Inci

dence o

f trea

tment

ch

ange

0 3 6 9 12 15 18 21

Months from cART initiation

Overall TDF+FTC+EFV TDF+FTC+NVP TDF+FTC+LPV/r TDF+FTC+ATV/r ABC+3TC+EFV TDF+FTC+EFV TDF+FTC+NVP TDF+FTC+LPV/r TDF+FTC+ATV/r ABC+3TC+EFV

Crude HR (95% CI)

1.00 2.00 (1.22 – 3.26) 2.09 (1.38 – 3.17) 1.26 (0.67 – 2.37) 2.00 (1.26 – 3.17)

p < 0.001

Adjusted HR (95% CI) 3

1.00 1.89 (1.14 – 3.14) 1.96 (1.29 – 2.99) 1.21 (0.65 – 2.28) 1.85 (1.12 – 3.05)

p = 0.002

Global TDF+FTC+EFV TDF+FTC+NVP TDF+FTC+LPV/r TDF+FTC+ATV/r ABC+3TC+EFV

Cambios de tratamiento [N (%)] 209 (23.6%) 93 (17.6%) 21 (35.0%) 63 (35.6%) 13 (20.3%) 19 (35.2%) Seguimiento (personas-año) 596 368 42 110 38 38

Tasa de cambios (x100personas-año) 35.0 25.2 50.0 57.3 34.4 50.1

Percentil 20 del tiempo al cambio del ART inicial

7.3 11.4 2.8 4.0 5.4 4.5

(63)

STARTMRK – % de pacientes con CV<50 c/mL (IC 95%)

(ITT: Non-Completer = Failure)

281 279 281 279 281 279 278 280 280

282 282 282 282 281 282 280 281 281

Raltegravir 400 mg b.i.d.* Efavirenz 600 mg q.h.s.*

Number of Contributing Patients

Weeks Pe rc en t o f Pa ti en ts w ith H IV R N A <5 0 C o p ie s/ m L

0 2 4 8 12 16 24 32 40 48

0 20 40 60 80 100

82%

∆

-4% (IC95:

-10,3

a

1,9

)

86%

*In combination with TDF/FTC

(64)

HAY QUE EMPEZAR CON UN INHIBIDOR DE LA

PROTEASA

Dr. Arribas

(65)

A5202: Study Design

HIV-1 RNA

≥

1000 c/mL

Any CD4+ count

≥

16 years of age

Stratified by screening HIV-1 RNA

(< or

≥

100,000 c/mL)

ART-‐naïve

(n=1857)

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/r

QD

ATV/r

QD

EFV

QD

EFV

QD

(66)

A5202: Probability of No Virologic Failure

and CD4+ Change at Week 96

Pe

rc

en

t w

ith

ou

t V

iro

lo

gi

c

Fa

ilu

re

HR 1.26

(0.76,2.05) (0.77,1.96) HR 1.23 (0.82,1.56) HR 1.13 (0.70,1.46) HR 1.01

HIV RNA <100,000 c/mL

Strata

_{All Subjects}

CD4 Change (cells/mm

3

₎

_{250 251}

_{252 221}

P=

0.89

0.002

(67)

A5202: Percent of Failures with

Emergence of Major Resistance Mutations

*

p-‐values: ATV/r vs. EFV (among failures)

*_{Major mutaGons deﬁned by IAS-‐USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR}

ABC/3TC

TDF/FTC

p<0.0001 _p=0.0003 p<0.0001 p=0.046

Pe

rce

nt

(68)

A5202: ATV/r vs. EFV

Median Changes in Fasting Lipids and Creatinine Clearance

In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r

Median Change in Fasting Lipids (Week 48, mg/dL)

Change in Calculated Creatinine Clearance, (mL/min)

TC LDL HDL TG

ABC/3TC

ATV/r 29 13 8 24

EFV 40 21 12 15

P-value <0.001 0.002 <0.001 0.26

TDF/FTC

ATV/r 10 2 5 14

EFV 22 10 8 13

P-value <0.001 0.002 <0.001 0.26

Week 48 Week 96

ABC/3TC

ATV/r 3.1 6.1

EFV 4.3 7.8

P-value 0.17 0.33

TDF/FTC

ATV/r -0.9 -2.6

EFV 4.1 4.9

P-value 0.001 <0.001

(69)

NNRTIs vs ITI vs PIs

Regimen

Advantages

Disadvantages

NNRTI based

§  Long half-lives

§  Less metabolic toxicity than with some PIs

§  PI options retained for future use

§  Low genetic barrier to resistance—single mutation

§  Cross-resistance between NVP and EFV

§  Risk of resistance to other regimen components with NNRTI failure

§  Rash; hepatotoxicity

§  Potential drug interactions (CYP450)

ITI based

§  Virologic response noninferior to EFV

§  Fewer drug-related adverse events and lipid changes than EFV

§  No food effect

§  Fewer drug-drug interactions than PI- or NNRTI-based regimens

§  Less long-term experience in ART-naïve patients than with boosted PI- or NNRTI-based regimens

§  Twice-daily dosing

§  Lower genetic barrier to resistance than with boosted PI-based regimens