What to Start With? - jornadesvih.org · *EFV safety in pregnancy not established – avoid in...

Tratamiento Antiretroviral Barcelona, 19 de Junio del 2004

Dr. Jose Luis Blanco Arevalo

Hospital de Dia de VIH

Servicio de Enfermedades Infecciosas

-Un paseo por la Historia…

-El TARV: pasado y presente

-NRTIs e IP: mejor combinacion/secuenciacion

-Avances en el TARV:

- Simplificacion

- Resistencias

- Nuevos farmacos

- Vacunas

1981: AIDS: 5 cases of Pneumocystis carinii pneumonia in

previously healthy men in the Los Angeles area were

reported by the CDC

1983 LAV: Montagnier and colleagues isolate

Lymphadenopathy-Associated Virus from lymph node

cells of a patient with lymphadenopathy

1984: HTLV-III: Gallo and colleagues link Human T-

Lymphotropic Virus III to AIDS on the basis of

seroepidemiology. LAV and HTLV-III are later renamed

HIV-1.

1986: HIV-2: Clavel and colleagues isolate HIV-2 from West

Africa

Discovery of human lentiviruses

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00

Year

Death

s 1

00 p

ers

on

-years

Mortality in HIV-1-Infected Patients (1984-2000).

H. Clinic Cohort (No.=4,500). Barcelona, Spain.

a b

c

d

1NRTI No Tx

Perez Cuevas. Tesis Doctoral

a: AZT; b: Profilaxis IOs

Antiretroviral Activity:

An Historical Perspective H

IV R

NA

ch

an

ge (

log

10 c

/mL

)

1987: AZT

Monotherapy

0

-0.5

-1

-1.5

-2

-2.5

-3

Fischl, NEJM, 1987

Hamilton, NEJM, 1992

24-week response



IV R

NA

ch

an

ge (

log

10 c

/mL

)

1994:

Two-Drug Therapy

1987: AZT

Monotherapy

24-week response

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

Fischl, NEJM, 1987


Eron, NEJM, 1995;

Hammer, NEJM, 1996

24-week response



IV R

NA

ch

an

ge (

log

10 c

/mL

)

1994:

Two-Drug Therapy

1997:

HAART

1987: AZT

Monotherapy

24-week response

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

0

-0.5

-1

-1.5

-2

-2.5

-3

Fischl, NEJM, 1987


Eron, NEJM, 1995;

Hammer, NEJM, 1996

Gulick, NEJM, 1997;

Cameron, Lancet, 1998

24-week response 24-week response

EUROSIDA: Incidence of AIDS and death

1994 - 2002

1

10

100

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-

3/00

3/00-

9/00

9/00-

3/01

3/01-

9/01

>=9/01

Calendar period

Co

mb

ined

AID

S a

nd

death

rate

an

d 9

5%

co

nfi

den

ce in

terv

als

(p

er

100 P

YF

U)

Events (N) 522 351 227 292 146 87 140 105 84 88 114 80 69 53 73

Test for trend

0.92 (95% CI 0.88 – 0.95); p < 0.0001

Mocroft et al, Lancet (in press)

Pneumocystis carinii

pneumonia

Mycobacterium avium

complex disease

Cytomegalovirus

retinitis

Toxoplasmosis 20

40

60

80

100

1993 1994 1995 1996 1992 1997

Incid

en

ce p

er

1000 P

ati

en

t – Y

ears

120

140

HAART

Year

Incidence of Selected OIs, 1992–1997

Kovacs JA et al. N Engl J Med 2000; 342:1416–1429.

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00

Year

Death

s 1

00 p

ers

on

-years HAART

Mortality in HIV-1-Infected Patients (1984-2000).

H. Clinic Cohort (No.=4,500). Barcelona, Spain.

a b

c

d

2NRTI 1 NRTI No Tx

Perez Cuevas. Tesis Doctoral

a: AZT; b: Profilaxis IOs; c: 2NRTIs; d: HAART

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1997 1998 1999 2000 2001

Cardiovascular causes

Accidental causes

Invasive bacterialinfection

Neoplasias

End-stage liver disease

AIDS-related illnesses

Causes of Death in HIV-Infected Patients:

Barcelona H. Clinic Cohort (1997-2001)

Milinkovic A et al. XIV Int AIDS Confernce. 2002; Abs TuPeC4758

-El TARV: pasado y presente

Approved Antiretrovirals

87 91 92 94 95 96 97 98 99 00 88 89 90 01 04 03 02

nNRTI

Sustiva

Rescriptor

Viramune

Reyataz

PI Norvir

Invirase

Agenerase

Crixivan

Fortovase

Kaletra Viracept

FI

Fuzeon

93

NRTI

Hivid

Combivir

Videx Retrovir Zerit

Epivir

Trizivir

Viread

Ziagen

Emtriva

http://www.biology.arizona.edu/immunology/tutorials/AIDS/treatment.html

Ciclo del VIH-1

NRTI

NtRTI

NNRTI

PI

0%

20%

40%

60%

80%

100%

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

otros 2NRTI+1NNRTI 2NRTI+2IP 2NRTI+1IP 2NRTI+1NNRTI+2IP 3 NRTI 2 fármacos 1 fármaco

PAUTAS INICIALES

Bartlett. CROI; 2000

Ensayos clínicos comparativos (ITT) Carga viral <

50 copias/ml a las 48 semanas

mediana

Régim

en (

ensayo c

línic

o)

d4T + 3TC + EFV (GS-903)

TDF + 3TC + EFV (GS-903)

0 10 20 30 40 50 60 70 80 90 100

d4T + ddI + EMV (MKC-302)

AZT + 3TC + APV (PROAB 3301)

AZT + 3TC + IDV (DMP-006)

AZT + 3TC + ABC (CNA3005)

d4T + ddI + IDV (START II)

AZT + 3TC + IDV (AVANTI 2)

AZT + ddI + NVP (INCAS)

AZT + 3TC + IDV (START II)

AZT + 3TC + NFV (AVANTI 3)

AZT + 3TC + IDV (CNA3005)

AZT + 3TC + IDV (START I)

d4T + 3TC + EMV (MKC-302)

d4T + ddI + 3TC (Atlantic)

d4T + 3TC + IDV (START I)

d4T + ddI + NVP (Atlantic)

2 NRTIs + SQV-SGC (NV-15355)

AZT + 3TC + ABC (CNAB3003)

d4T + ddI + IDV (Atlantic)

AZT + 3TC + EFV (DMP-006)

d4T + 3TC + EFV (DMP-043)

d4T + 3TC + LPV/RTV (M98-863)

d4T + 3TC + NFV (M98-863)

ddI + FTC + EFV (Saag)

ddI + d4T + EFV (Saag)

Criterios para decidir una terapia

antirretroviral

Potencia Eficacia

Tolerancia Toxicidad

Adherencia Número de tomas/pastillas

Resistencias Patrón mutaciones

Rápidez de aparición

Resistencias cruzadas

Significado clínico

PI-based

Amprenavir + RTV + (3TC or FTC) + (ZDV or

d4T)

Atazanavir + (3TC or FTC) + (ZDV or d4T)

Indinavir + (3TC or FTC) + (ZDV or d4T)

Indinavir + RTV + 3TC + (ZDV or d4T)

Lopinavir/ritonavir + FTC + (ZDV or d4T)

Nelfinavir + 3TC + (ZDV + d4T)

Saquinavir + RTV + 3TC + (ZDV or d4T)

Recommended regimens for

treatment-naïve patients: DHHS 03/04 Preferred regimens

*EFV safety in pregnancy not established – avoid in pregnant women or women with pregnancy potential

**Only when an NNRTI- or a PI-based regimen cannot or should not be used as first-line therapy

Alternative regimens

NNRTI-based

Efavirenz* + FTC + TDF

Efavirenz* + (3TC or FTC) + ddI

Nevirapine + (3TC or FTC) + (ZDV or d4T or

ddI)

Lopinavir/ritonavir +

3TC + (ZDV or d4T)

Efavirenz* +

3TC + (ZDV or TDF or d4T)

Triple NRTI**

Abacavir + 3TC + (ZDV or d4T)

www.aidsinfo.nih.gov

HAART (for initial therapy)

NRTI NNRTI PI/r OTHER Total

2 1 3

2 1 3

3 3

1 1 2

2 1 1 4

1 1

How to combine NRTI ?

How to select a backbone of 2 NRTI ?



Contraindicated:

Any combination with ddC (toxicity)

d4T + ZDV (interactions)

d4T + ddI in pregnant women (toxicity)



Preferred combinations:

3TC + ZDV

TNF

ABA

ddI

d4T*



Other possible alternatives

d4T + ddI ( ACTG378)

TNF + ABA (Abate, Advanz 2)

ddI

Robbins et al. NEJM 2003; N=620



Possible alternatives?

TNF + ddI



Possible alternatives?

TNF + ddI

Lower CD4 response

Higher rate of pancreatitis

Early virological failure

!!!!

Martinez E et al. Lancet 2004

No. Pancreatitis

No. %

ddI +X +Y 182 1 0.5

TNF+X +Y 208 0 0

ddI+TNF+Y 185 5 2.7

Leon A D et al. Lancet 2004 (submitted)

EFA + NEV+

TNF + ddI TNF + ddI

No. 10 4

Failure at 3mo. 5 2

Resist. Mutations

EFANEV

L74V K65R

Cual es el mejor IP de inicio????

IDV o NFV o LOP/r????

Es posible la secuenciacion de IPs????

INDINAVIR vs LOPINVIR/r

GLB 635_Gatell D ay 2_02 5

Initial EFV HAART for BetterHIV RNA Suppression

ITT:NC=F (Initial Cohort at 144 Weeks)

100

80

60

40

20

0

100

80

60

40

20

0144132120108968472604836241612840

*

*

* ** * * * * * * * * * * *

EFV + AZT + 3TC

EFV + IDV

IDV + AZT + 3TC

55%

34%

34%

EFV + AZT + 3TC

EFV + IDV

IDV + AZT + 3TC

N = 151 150 149 151 146 144 147 154 154 153 152 152 152 149 148

N = 147 144 144 146 145 138 145 147 148 148 148 147 147 144 144

N = 148 145 145 146 146 142 146 147 148 145 146 146 146 145 142

*Statisticall y significant dif ference between EFV + AZT + 3TC an d ID V + AZT + 3TC, P.05.

Tashi ma. 1st IAS; Buenos Aires ; 2001. Abstrac t 810.

Patien

ts W

ith H

IV R

NA

<400 (

%)

TIme, W ks

006 006

LPV/r Suppresses HIV RNA

Through 5 Years

100 86 72 68 Sample Size:

0

20

40

60

80

100

0 24 48 72 96 120 144 168 192 216 240 264

Week

Pro

po

rtio

n <

level

of

qu

an

tita

tio

n

On-treatment

ITT noncompleter=failure (N=100)

99% 94%

67% 64%

<400 <50

Eron J, et al , 43rd ICAAC, Chicago, September 2003, H-844 Study 720

NELFINAVIR vs LOPINVIR/r

Durability of Virologic Response M98-863

79%

58%

p<0.001, Cox proportional hazards model

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60 72 84 96

Weeks

Perc

en

t R

esp

on

din

g

Lopinavir/ritonavir (n=326)

Nelfinavir (n=327)

King M et al. 9th CROI, Seattle, 2002, #470

La elevación de TG y Col-tot en pacientes tratados con LPV/r varía en

función de la combinación y el tratamiento previo

0

10

20

30

40

M98-863 M97-720 M97-765 M98-957

Chol

TG

60 semanas 144 semanas 96 semanas 48 semanas

Naive Tto. previo

LPV/r + d4T + 3TC LPV/r + NNRTI + NRTIs

Murphy. AIDS 2001;15:1.

Resistencia a Kaletra en pacientes pretratados: Respuesta

virológica respecto al genotipo y fenotipo basal

0

20

40

60

80

100

0-5 6-7 8-10

Nº de mutaciones basales para KaletraP

orc

en

taje

0

20

40

60

80

100

< 10 10 - 40 > 40

Sensibilidad basal a Kaletra

Po

rcen

taje

< 400 copias/mL < 50 copias/mL

1.- Danner S, et al. 41st ICAAC. Chicago, 2001.

93% 89%

73%

60%

25% 25% 33% 33%

62% 71%

87% 91%

M98-957 sem. 721

- Mejorar la eficacia – ADH

Disminuir la toxicidad asociada

Rescatabilidad de fracasos

OBJETIVOS

Paterson. Ann Intern Med 2000;133:21.

Relación entre adherencia (medida por MEMS) y eficacia virológica

La adherencia debe ser muy elevada (superior al

95%)

81

64

50

25

6

0

25

50

75

100

>95% 90%-95% 80%-90% 70%-80% <70%

% d

e p

acie

nte

s c

on

C

V

ind

ete

cta

ble

P = .00001

Zona de mayor riesgo de resistencias Adherencia

0

20

40

60

80

100

0 4 8 16 32 48 64 72 80 88

DOT <400

SAT <400

Fischl. 8th CROI; 2001; Chicago. Abstract 528.

Week

Patients: Antiretroviral-naive

patients in prison on 3- or

4-drug combinations under DOT vs

SAT

Conclusions

— HAART works when taken properly

— DOT group superior at all time points

— Within SAT group, 4-drug regimens had

lowest response (57%)

— EFV-containing regimens had the best

virologic response rates

— Lower toxicity rate in DOT group

HAART is Highly Effective

When Taken as Directed

Pa

tie

nts

Re

ac

hin

g U

nd

ete

cta

ble

HIV

RN

A L

OQ

40

0 (

%)

Directly Observed Therapy (DOT)

vs Self-administered Therapy (SAT)

Como mejorar la adherencia???

1) Preguntemos a los pacintes….

2) Que nos dice la experiencia…

52

46

45

27

20

20

19

19

18

17

17

16

14

13

10

9

0 10 20 30 40 50 60

Too busy/simply forgot

Away from home

Change in daily routine

Felt depressed/overwhelmed

Took drug holiday/medication break

Ran out of medication

Too many pills

Worried about becoming 'immune'

Felt drug was too toxic

Wanted to avoid side effects

Didn't want others to notice

Reminder of HIV infection

Confused about dosage direction

Didn't think it was improving health

To make it last longer

Were told the medicine is no good

Gifford AL JAIDS 2000; 23: 386-395

Reasons given for missing

antiretroviral doses (structured

questionnaire)

possible interventions

simplify dosing schedule

decrease pill burden

other

%

n=133

¿Porqué los pacientes no toman el TAR?

0

10

20

30

40

50

60

70

80

90

100

One Two Three Four

Dose-taking* Dose-timing**

Number of doses per day

Me

an

ad

he

ren

ce

(%

)

*Dose-taking: taking the prescribed number of pills each day (76 studies).

**Dose-timing: taking pills within the prescribed time-frame (14 studies).

Adherence as a Function of Number of Daily Intakes A Literature Review Across Various Treatment Disciplines

¿Si tiene que tomar un determinado nº de pastillas cada día cómo prefiere tomarlas?

Más de 8 pastillas

8 pastillas

6 pastillas

4 pastillas

3 pastillas

Todo una vez al día Dividirlo y tomardo en dos dosis al día

31% 69%

38% 62%

59% 41%

84% 16%

92% 7%

Moyle ICDTHI, Glasgow, 2002 Poster 99

Impacto del nº de pastillas/día en la

preferencia de dosifición

Didanosina (ddI)

Peso> 60 kg

1x400 QD

2x200 QD

2x100 BID

Evolución

Originariamente BID

Lamivudina (3TC)

1 x 150 BID 2 x 150 QD 1 x 300 QD

Evolución

Originariamente BID

Estavudina (d4T)

Peso> 60 kg

1 x 40 BID 1 x 100 QD

2003

Evolución

• Efavirenz

• Didanosina (ddI)

• Tenofovir

• Lamivudina (3TC)

• EstavudinaCLP (d4TCLP)

• Amprenavir+ritonavir

Aprobados por EMEA o FDA

Fármacos que por sus características PK intrínsecas pueden administrarse QD

Aprobados por EMEA o FDA


•Emtricitabina (FTC)

•Atazanavir

No aprobados, pero con estudios que avalan o sugieren su posible uso

• Nevirapina

• Abacavir ?


“Simplificacion” de los IP

El RTV como “booster”

Basic Pharmacology Principles

IC90

IC50

Cmin

Cmax

Time

Dosing Interval

Area of Potential Replication

Area Under the Curve

(AUC)

PK Benefit

Incomplete

Suppression

Leads to Resistance

More Complete

Suppression Increases

Durability of Response

Current Single

PI Regimens Dual PI Regimens

With PK Enhancement

Plasma drug

levels

High peak

contribute to

toxicity

Low trough

insufficient to

completely block

replication

Drug required

to block

replication

Low peak levels may

reduce side effects

High trough levels

increase potency

Two-drug

Combination may

increase potency

Rational for Boosted or Dual PIs

Margen de “perdón”

0,01

0,1

1

10

Zona de presión selectiva máxima

Concentr

ació

n (m

g/m

l)

0 2 4 6 8 10 12

Cvalle media de LPV

Tiempo (h) tras la administración

RTV como “booster”

LPV*

LPV (potenciado por RTV)

0

1

2

3

4

8 7 6 5 4 3 2 1 0

Tiempo después de la dosis (horas)

SQV

Co

nc

en

tra

ció

n e

n p

las

ma

(µ

g/m

L)

IDV IDV* SQV*

* Sin potenciar con ritonavir

0 4 8 12 16 20 24

0.01

0.1

1

10

EC50 (wild-type HIV)

Farmacocinética de Lopinavir/ritonavir

400/100mg BID

Tempo após dose (horas)

Tratamiento de la TUBERCULOSIS

….. y porqué no????

AZT+3TC+IDV AZT+3TC

AZT+IDV

AZT o D4T+3TC+IDV AZT o D4T+3TC

IDV

D4T+3TC+SQV +NFV D4T+NFV

SQV+NFV

ACTG 343. Havlir. N Engl J Med 1998

Trilege .Pialoux. N Engl J Med 1998

Flandre. AIDS, 2002; 16: 561-568

ADAM .Reijers. Lancet 1998

Contraindicado simplicar TAR a < 3 fármacos

¿Fármacos mas potentes? ¿<CV + tiempo?

INDUCCION-MANTENIMIENTO

3-4 farmacos 1-2 fármacos

ACTG 343: Inducción-mantenimiento

Zidovudine, indinavir and lamivudine

Indinavir

Zidovudine and lamivudine

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18

Number at risk

AZT, IDV and 3TC 105 101 98 94 44 6 3 2 0

AZT and 3TC 104 96 83 78 34 5 3 3 1

IDV 100 99 88 85 39 6 4 3 1

Duration of maintenance therapy (weeks)

Pro

po

rtio

n w

ith

vir

al s

up

res

sio

n

Havlir et al. NEJM 1998

Estrategia a reevaluar con diferente duración de la inducción, nadir de carga viral o tratamiento de mantenimiento O con diferente objetivo?

Simplificacion : SI

…. pero hasta donde????

SIMPLIFICACION

Inicio de TARV = Virus controlado

155 154 148 145 135156 150 150 142 136

149 140 137 126 119

Nevirapine

EfavirenzAbacavir

Kaplan-Meier estimates of the proportion of patients with plasma HIV -1 RNAbelow 200 copies/mL by intent-to-treat analysis

Months0 3 6 9 12

0

.25

.5

.75

1

Abacavir

Efavirenz

Nevirapine

Log-rank test:

abacavir vs efavirenz P=0.034

abacavir vs nevirapine P=0.122

efavirenz vs nevirapine P=0.537

global P=0.075

133 124 117 104138 121 102 93

131 125 104 92

155156

149

Nevirapine

EfavirenzAbacavir

Kaplan-Meier estimates of the proportion of patients with plasma HIV-1 RNAbelow 200 copies/mL by on-treatment analysis

Months0 3 6 9 12

0

.25

.5

.75

1

Abacavir

Efavirenz

Nevirapine

Log-rank test:




global P=0.018

Kaplan-Meier estimates of the proportion of patients with plasma HIV -1 RNAbelow 200 copies/mL by ITT (switching = failure)

0.00

0.25

0.50

0.75

1.00

Abacavir

Efavirenz

Nevirapine

Months0 3 6 9 12

155 133 126 123 118156 133 124 116 112

149 132 129 115 110

NevirapineEfavirenzAbacavir

Log-rank test:




global P=0.713

0.00

0.25

0.50

0.75

1.00

Abacavir

Efavirenz

Nevirapine

Months

155 154 147 144 135156 148 145 141 136

149 140 137 123 118

0 3 6 9 12

NevirapineEfavirenzAbacavir

Kaplan-Meier estimates of the proportion of patients with plasma HIV-1 RNAbelow 200 copies/mL by ITT (missing = failure)

Log-rank test:




global P=0.042

NEFA STUDY. E Martinez NEJM, 2003

Summary of all-NRTI regimens

Less potent than standard

HAART regimens:

» ZDV/3TC/ABC1

» ddI+ d4T + 3TC2

Not compared with

standard HAART

regimens:

» ZDV/3TC/ABC + TDF3

Unacceptably high rates

of virologic failure

» TDF + ABC + 3TC4,5,6

» TDF + ddI + 3TC7

» ABC + ddI + d4T8

1. Gulick R, et al. 2nd IAS, Paris 2003, #41; 2. van Leeuwen R, et al. AIDS 2003;17:987-99; 3. Elion R, et al. 11th CROI, San Francisco 2004, #53; 4. Farthing C, et al. 2nd IAS, Paris 2003, #43; 5. Gallant JE, et al. 43rd ICAAC, Chicago 2003, #840; 6. Landman R, et al. 11th CROI , San Francisco 2004, #52; 7. Jemsek J, et al. ibid, #51; 8. Gerstoft J, et al. AIDS 2003;17:2045-52

Failure of ddI + 3TC + TDF QD Single-site pilot study

ARV-naïve (n=24), VL >10K c/mL

» No K65R, M184V, L74V, or >3 TAMs at entry

Endpoint: VL <50 c/mL at Week 24

Median HIV RNA 4.91 log10 c/mL

» 38% >100K

Median CD4+ 133 cells/mm3

» 58% <200

Study terminated early due to poor outcome

• Median therapy duration 16 (range 7–23) weeks

Jemsek J, et al. 11th CROI, San Francisco 2004, #51

Change in median VL

Week VL

(log10 c/mL)

4 –0.75

12 –0.61

24 or EOT –0.49

• High rate of genotypic resistance:

» 20/22 pts with M184V/I (2 seen at Wk 4)

» 10/22 pts with K65R; 7/10 with K65R/wt mix

suggestive of evolving resistance

EOT = end of therapy

Mejorar la eficacia – ADH

Disminuir la toxicidad asociada

- Rescatabilidad de fracasos

OBJETIVOS

Generación de Resistencias a los FARV

• Elevada tasa de error de la TI

• Plasticidad de las proteínas virales

• Elevada cinética de replicación

Métodos Genotípicos. Secuenciación

plasma Aislamiento

ac.nucleicos

RNA cDNA RT-PCR

Amplicones

de DNA

secuenciados

STOP

STOP

STOP

STOP

electroforesis

TAATTAGCATCCTGAAAA

TTTCACGGACAATGCTA

AAACTATAATAGTACAGC

TGAAGGAGGCTGTAGAA

ATTAATTGTACAAGACCC

AACAACAATACAAGAAA

AAGTATACACCTAGGAC

CAGGGAGATCATTTTAT

GCAACAGGAGACATAAT

AGGGGATATAAGACAAG

CACATTGTAACATCAGTA

GAGCAACATGGAAAAA

CACTCTAGAACAGATAG

TTAAAAAATTGAAAGAT

CAATTTAAGAATAAAAC

AATAGTCTTTAACAATCC

TCAGGAGGGGACCTAG

AAATTGTAACGCACAGT

TTTAATTGTGGAGGGGA

ATTTTTCTA

International AIDS Society–USA Topics in HIV Medicine

Volume 9 Issue 6 December 2001

PLASMA

(³ 200 µl)

total RNA cDNA PR/RT GENES

RT PCR

linearized

genome

HIV genome

of lab. virus

CD4+ T-cells

(MT4)

Intracellular,

homologous

recombination

Infectious HIV D viral genotypes

Susceptibility

Assay

extraction

Gene transfer/

electroporation Deletion of protease (PR)-

reverse transcriptase (RT) gene

D viral genotypes

HIV genome

minus PR/RT gene

Viral Recombinant Assay (Virco)

Resultados determinación resistencias fenotípicas

• Utilidad de los test de resistencias :

Métodos Fenotípicos y Genotípicos

VIRADAPT

GART

HAVANNA

ARGENTA

NARVAL

VIRA 3001

KAISER

CCTG-575

VIHRES

.........

Beneficio limitado a corto plazo

C.V. < 1 log10 (G/F vs SOC)

C.V. < 200 cpm = 15%-35%

Estratégias para superar la resistencia

Schapiro J, 2000

Barreras a la resistencia

0 4 8 12 16 20 24

0.01

0.1

1

10

EC50 (wild-type HIV)

Coeficiente inibitório

Cmin/EC50

Farmacocinética de Lopinavir/ritonavir

400/100mg BID

Tempo após dose (horas)

IQ = Coeficiente inhibitorio

• Cmin / EC50 (90/95)

• Concentración mínima da droga dividida

por la cantidad de la droga necesaria

para inibir 50% del virus wild-type (90%

o 95%)

0.0

0.1

1.0

10.0

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hours)

APV 1200mg BID (N=61) APV 600mg BID + RTV 100mg BID (N=12)

Plasma

Total APV

Concentration

(µg/ml)

Mean IC50 for multi-PI failure patients,

protein-adjusted

Mean IC50 for wild-type virus, protein-

adjusted

R. Wood, St Petersburg 15-17 December 2000

Drug Concentration

Theoretical Model of Relationship of

Plasma Drug Levels to Clinical Outcome

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 6 10 15 20 25 30 35 40 50 60

Cli

nic

al B

en

efi

t %

Increasing

viral suppression

Maximum

viral suppression

Increasing

Drug toxicity

What is the Drug

Level necessary for

success vs. failure

vs. toxicity?

(e.g., Therapeutic

Index)

Inhibidores de la transcriptasa inversa Inhibidores proteasa

Análogos

nucleósidos

No análogos

nucleósidos

Nucleótidos

Emtricitabina

(FTC)

Capravirina Tenofovir Tipranavir

Amdoxovir

(DAPD)

TMC 125 GS-7340 Atazanavir

L/D Fd4C MIV 140 DPC 681/684

SPD 754/756 UC781 / CSIC TMC 114

MIV-310 DPC 083/961 Fos-Amprenavir (908)

Nuevos fármacos antirretrovirales

Nuevas formulaciones: d4T-LR (100 mg qd), efavirenz (caps. 600 mg); nelfinavir (tab. 625 mg)

NRTIs

FTC

DAPD

DOTC

NNRTIs TMC-125; capravirine

PIs

Atazanavir

Tipranavir

TMC-114

Fusion inhibitors

T-20

T-1249

Co-receptor

Blockers Schering C,D

AMD 070

Integrase

inhibitors Merck compounds

L-870,810

Attachment blockers

PRO 542

VIH

Linfocito CD4

gp120

gp41

Correceptores

Receptores

CD4

gp120

gp41

Correceptores

gp41

HR2

HR1

TORO 1 Study: Week 24

-1.70

-0.76

-2

-1

0

(Delta=0.93, p<0.0001) Least Squared Means Log Change from Baseline - ITT Population (LOCF)

optimized background

(OB) regimen alone

enfuvirtide (T-20)

+ OB

N=165

N=326

Lalezari, NEJM 2003 (in press)

N=491, VL 158K, CD4 80, 3-class experienced (avg. 12 drugs)

… pastillas, pastillas, pastillas….

DOCTOR, ESTOY HARTO!!!!!

The Berlin Patient

Treated soon after acute HIV infection with HU, ddI,

IDV

baseline VL 80,000 - 89,000 pre-treatment

treatment interrupted briefly twice in first four months of

treatment: viral rebound during first interruption but not

the second

VL remained undetectable after third time treatment

stopped

Lisziewicz J et al. NEJM 1999; 340: 1683-1684.

The Berlin Patient

Lisziewicz J et al. NEJM 1999; 340: 1683-1684.

Structured Treatment Interruption

(STI)

Detection

threshold

= on HAART Time

STIs During Chronic Infection

¿¿¿????

Structured

Therapy

Interuption

1998-2003

R.I.P.

STIs During Chronic Infection

Thirty-six years ago, President

Kennedy…gave us a goal of reaching the

moon, and we achieved it - ahead of time

Let us today set a new national goal for

science in the age of biology. Today, let

us commit ourselves to developing an

AIDS vaccine within the next decade

- President Bill Clinton, 1997

HIV-1 Vaccines

HIV Vaccine Approaches

recombinant protein (gp120)

synthetic peptides (V3)

live-attenuated virus

whole-inactivated virus

naked DNA

live-vectored vaccine (bacterial, viral)

HIV Vaccine Approaches

“… brindo hasta la cirrosis por la vacuna del SIDA…..”

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