VIH: ¿QUE HAY DE NUEVO EN EL MANEJO DE LA TARV? · VIH: ⍈¿QUE HAY DE NUEVO EN EL MANEJO DE LA TARV?⍉ Dr.Esteban Cortés Sedano Jefe Programa VIH/SIDA Hospital del Salvador

VIH: “¿QUE HAY DE NUEVO EN EL MANEJO DE LA TARV?”

Dr.Esteban Cortés Sedano

Jefe Programa VIH/SIDA

Hospital del Salvador

Declaración de intereses:

• Sin contrato con industria • Auspicio EACS-Oct.2013 Bruselas Laboratorio Jansen • Auspicio IAS- Julio 2013 Kuala Lumpur Laboratorio Glaxo • Curso “Interacciones drogas” 3d Abril 2013 Buenos Aires Laboratorio BMS • Auspicio Glasgow Nov.2012 Glasgow Laboratorio Glaxo • Auspicio AIDS-Julio 2012 Washington D.C.

Laboratorio Abbot

¿ Qué hacemos?

• Alto % de pacientes no controlados

• Alto % de pacientes no indetectables

Alto % de transmisión

HPTN 052: Immediate vs Delayed ART in

Serodiscordant Couples

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed ART Initiate ART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm3.

• Primary efficacy endpoint: virologically linked HIV transmission

• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death

• Couples received intensive counseling on risk reduction and use of condoms

DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results

Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression

Total HIV-1 Transmission Events: 39 (4 in immediate arm and

35 in delayed arm; P < .0001)

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

P < .001

Immediate Arm: 1

Delayed Arm: 27


HPTN 052: HIV Transmission Reduced by 96% in

Serodiscordant Couples

HPTN 052: Multivariate Analysis of Factors

Associated With Linked Transmissions

Variable HR 95% CI

Treatment, immediate vs delayed 0.04 0.01-0.28

Baseline CD4+ count, per 100 cells/mm3 decrease 1.24 1.00-1.54

Baseline HIV-1 RNA, per 1 log10 copies/mL increase 2.85 1.51-5.41

Baseline condom use, 100% vs < 100% 0.33 0.12-0.91

Sex of infected partner, male vs female 0.73 0.33-1.65


61% of transmissions occurred from infected patient with CD4+ cell count > 350 cells/mm3

All transmissions occurred prior to starting ART

82% of transmissions occurred in African patients

HPTN 052: Primary Clinical Events During

Follow-up

• 41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy

– Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases)

Failure

Pro

bability

0

0.10

0.15

0.20

0.25

Yrs Since Randomization

0 1 2 3 4 5

0.05

HR: 0.6 (95% CI: 0.4-0.9; P = .01)

Delayed (n = 65)

Immediate (n = 40)

877 886

701 700

317 333

86 85

32 36

25 29

Number at risk

Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

HPTN 052

• Reducción de transmisión de 96%

Si estos resultados fueran provocados por una vacuna, FDA y OMS lo hubiesen aprobado al instante.

Se confirma la eficacia del tratamiento como estrategia de prevención ¡¡¡¡¡ TEST & TREAT !!!!!

Drogas ARV aprobadas 1987 - 2013

0

5

10

15

20

25

30

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

AZT ddI ddC d4T

3TC

SQV

RTV

IDV

NVP

NFV

DLV

EFV

ABC

APV

LPV/r TDF

ENF

ATV

FTC

FPV TPV DRV

ETR RAL

MVC

RPV EVG

DTG

Drogas ARV Desafíos y necesidades:

Desafíos

• Adherencia

• Toxicidad

• Actividad

• Resistencia

• Formulación

Necesidades

• Mejorar tolerabilidad

• Reducir toxicidades

• Penetración reservorios

• Exploración nuevos targets

• Mejorar actividad:

– Cepas “wild type”

– Cepas resistentes

Replicación Viral

REPLICACION VIH

TARV: Esquema inicial:

3ª 3ª

3ª 3ª

Esquema base de 2 drogas

(“Back bone” ) +

TARV: Esquema inicial:

EFV o NVP ATV/RTV

LOP/RTV FSP/RTV

AZT/3TC ( Combivir )

3TC/ABC ( Kivexa )

TDF/FTC ( Truvada ) +

Replicación Viral

Terapia Antiretroviral

Inhibidores de: 1. Transcriptasa reversa

ANALOGOS NUCLEOSÍDICOS

NO ANALOGOS NUCLEOSÍDICOS

2. Proteasa

3. Integrasa

4. Fusión

5. Coreceptor R5





2. Proteasa

3. Integrasa

4. Fusión

5. Coreceptor R5

Inh-nucleosídicos

• Zidovudina , AZT, Retrovir®

• Lamivudina, 3TC,Epivir®

• Emtricitavina, FTC, Emtriva®

• Abacavir, Ziagen® • Stavudina, d4T, Zerit®

• Didanosina, DDI, Videx®

• Tenofovir, Viread®





2. Proteasa

3. Integrasa

4. Fusión

5. Coreceptor R5

No-Nucleósidos

• Efavirenz - Stocrin®

• Nevirapina - Viramune®

• Etravirina - Intelence®

No-Nucleósidos

• Efavirenz - Stocrin®

• Nevirapina - Viramune®

• Etravirina - Intelence®

• RILPIVIRINA- Edurant

FDA aprueba Complera ®

12 – agosto - 2011

Rilpivirina + Emtricitavina + Tenofovir

Echo Thrive

Inhibidores de Proteasa

• Ritonavir = Norvir®

• Lopinavir = Kaletra®

• Atazanavir = Reyataz®

• Fosamprenavir = Telzir®

• Darunavir = Prezista®

• Tipranavir = Aptivus®

Inhibidores de..

• Integrasa : RALTEGRAVIR ( Isentress®)

• CCR5 : MARAVIROC ( Celsentri®)

• Fusión : ENFUVIRTIDE- T20 ( Fuzeon® )

Co-formulados:

• Zidovudina + Lamivudina = Combivir ®

• Lamivudina + Abacavir = Kivexa ®

• Emtricitavina + Tenofovir = Truvada ®

• FTC + TDF + Efavirenz = Atripla ®


Ritonavir = Norvir®

Lopinavir = Kaletra®

Atazanavir = Reyataz®

Fosamprenavir = Telzir®

Darunavir = Prezista®

Tipranavir = Aptivus®


Lopinavir/r = Kaletra®

Atazanavir/r = Reyataz®

Fosamprenavir/r = Telzir®

Darunavir/r = Prezista®

Tipranavir/r = Aptivus®


Ritonavir = Norvir ®

=> POTENCIADOR, sin

actividad antiviral en las dosis

utilizadas.

Nuevo Potenciador

Cobicistat

Cobicistat: Pharmacokinetic (PK) Booster

• Pharmacoenhancer; no antiretroviral activity

• 2000X more soluble than RTV

• Potent CYP 3A inhibitor; weak CYP2D6 inhibitor

• does not inhibit CYP1A2, CYP2C9, or CYP2C19

• no activity against other enzymes or transporters (UGT, PGP)

Mathias Clin Pharmacol Ther 2010;87:322

Cobicistat: Pharmacokinetic (PK) Booster

•Human PK: cobi vs. RTV vs. placebo

– Inhibition of midazolam clearance (a measure of CYP 3A activity) is similar: cobi 92-95%; RTV 100 mg 95%

•Inhibits a renal tubular transporter called toxin extrusion protein 1 (MATE1); creatinine ↑ 0.1-0.2; no ∆ in GFR

•Can combine with PIs or IIs; now approved with EVG

Mathias Clin Pharmacol Ther 2010;87:322

Cobi and ATV

Ramanathan ICAAC 2009 #A1-1301

Phase III: TDF/FTC + ATV with RTV vs. Cobi

• Randomized, double-blind • Study pop: HIV+, treatment-naïve, VL >5K (N=692)

• Conclusion: Cobi non-inferior to RTV

Gallant JID 2013;208:32-9

85% (cobi)

87% (RTV)

∆ = 2%

(95% CI -7.4%, +3.0%)

non-inferiority margin

-12%

Discontinuations due

to adverse events:

7% in both groups

Newer Formulations of Approved Drugs

• TDF/FTC/EVG/cobi Sax Lancet 2012;379:2439

DeJesus Lancet 2012;379:2429

• ATV/cobicistat Gallant JID 2013;208:32-9

• DRV/cobicistat Kakuda IAS 2013 #MOPE029

• TAF/FTC/DRV/cobi www.clinicaltrials.gov

Antiretroviral Drug Approval: 1987 - 2013

0

5

10

15

20

25

30

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013

AZT ddI ddC d4T

3TC

SQV

RTV

IDV

NVP

NFV

DLV

EFV

ABC

APV

LPV/r TDF

ENF

ATV

FTC

FPV TPV DRV

ETR RAL

MVC

RPV EVG

DTG





2. Proteasa

3. Integrasa

4. Fusión

5. Coreceptor R5

Elvitegravir = EVG

Inhibidor de Integrasa:

RALTEGRAVIR

(EVG)

• Strand transfer HIV integrase inhibitor • In vitro IC50 0.2 nM (16 nM protein-adjusted) • Active against MDR HIV Shimura K J Virol 2008;82:764

• Resistance: Substitutions in IN; X-resistant to RAL • PK:

– metabolized by CYP 3A4 moderate inducer (~EFV) and glucuronidation

– 30% orally bioavailable; 99% protein bound – boosted with RTV 100 mg qd AUC 20X, T1/2 9 hours

(EVG)

• Phase I: up to -2.0 log cps/ml VL at d11 DeJesus JAIDS 2006;43:1

• Phase II: TDF/FTC/EVG/cobi comparable to TDF/FTC/EFV at 48 wks (N=71) Cohen AIDS 2011;25:F7

• FDA approved in 2012

Phase 3: TDF/FTC/EVG/c vs TDF/FTC/EFV

TDF/FTC/EVG/c QD

EFV/FTC/TDF Placebo

n=350

EFV/FTC/TDF QHS

TDF/FTC/EVG/c QD

n=350

Rx-naïve Any CD4

count (N=700)

Randomized 1:1

Stratified by HIV-1 RNA

(>100,000 c/mL)

Conducted in US + PR

Wk 48 Wk 192

Primary Endpoint: % <50 copies/mL at Week 48 – FDA snapshot analysis (ITT), 12% noninferiority margin BL: 89% men; VL ~4.765; CD4 ~390 Sax Lancet 2012;379:2439

Phase 3: Efficacy

• CD4 at week 48: +239 (QUAD) vs. +206 (EFV) p=0.009

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t

% <50

at wk 48

88% 84%

7% 7% 5% 9%

virologic

non-suppressed

No W48

data

-12% 0% 12%

TDF/FTC/EVG/c

TDF/FTC/EFV

Favors

EFV

Favors

EVG

95% CI for difference

-1.6 3.6 8.8

Sax Lancet 2012;379:2439

Phase 3: Resistance EVG combo

(n=348) EFV combo

(n=352)

Subjects analyzed for resistance*, n (%) 14 (4) 17 (5)

Subjects with resistance to ARV regimen, n (%) 8 (2) 8 (2)

Any primary integrase-R, n 7

E92Q 7

T66I 1

Q148R 1

N155H 1

Any primary NNRTI-R n 8

K103N 7

V108I 2

Y188Y/F/H/L 1

G190A 1

Any primary NRTI-R, n 8 2

M184V/I 8 2

K65R 3 2

Sax Lancet 2012;379:2439

Ph 3: TDF/FTC/EVG/c vs TDF/FTC+ ATV/r

TDF/FTC/EVG/c QD

ATV/r+ FTC/TDF Placebo QD

n=350

ATV/r+FTC/TDF QD

TDF/FTC/EVG/c Placebo QD

n=350

Treatment-naïve

(N=700)

International

Stratified by VL (>100,000 c/mL) Wk 48 Wk 192 Primary Endpoint: % with <50 copies/mL at Week 48 – FDA snapshot analysis, 12% non-inferiority margin BL: ~90% men, VL ~4.87, CD4 ~370


Phase 3: Efficacy

• No difference in CD4 cell recovery

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t

% <50

at wk 48

90% 87%

5% 5% 5% 8%

Virologic

non-supression

No

W48 data

-12% 0% 12%

TDF/FTC/EVG/c

TDF/FTC + ATV/r

Favors

ATV/r

Favors

EVG

95% CI for difference

-1.9 3.0 7.8


Phase 3: Resistance EVG combo

(n=353) ATV/r combo

(n=355)

Subjects analyzed for resistance*, n (%) 12 (3) 8 (2)

Subjects with resistance to ARV regimen, n (%) 5 (1) 0

Any primary integrase-R, n 4 –

E92Q 1 –

T66I 1 –

Q148R 2 –

N155H 2 –

Any primary PI-R, n – 0

Any primary NRTI-R, n 4 0

M184V/I 4

K65R 1


Approved Single Tablet Regimens

TDF/FTC/EFV (2006)

TDF/FTC/RPV

(2011)

TDF/FTC/EVG/c (2012)

ATRIPLA

COMPLERA

STRIBILD

Dolutegravir = DTG


RALTEGRAVIR

ELVITEGRAVIR

SPRING 2: 2 NRTI + [DTG vs. RAL] Study population: Rx-naïve, VL >1000 (N=822)

Raffi Lancet 2013;381:784

wk 96

81%

76%

Few

addi-

tiona

l AE

Raffi

IAS

2013

#TU

LBP

E15

ABC/3TC + DTG vs. TDF/FTC/EFV

Walmsley ICAAC 2012. #H-556b.

Week

TDF/FTC/EFV QD

ABC/3TC + DTG

QD

BL 2 4 8 12 16 24 32 40 48

0

10

20

30

40

50

60

70

80

90

100

Pro

po

rtio

n (

%)

of

Su

bje

cts

<

50

c/m

L H

IV-1

RN

A

ABC/3TC + DTG

88%

TDF/FTC/EFV

81% WK 48 difference in response +7.4%

(95% CI: +2.5% to +12.3%; p=0.003);

excludes -10% threshold

DTG regimen superior to EFV regimen

Study pop: Rx-naïve patients (N=822)

ABC/3TC/DTG

19th Conference on Retroviruses and Opportunistic Infections

March 5-8, 2012, Seattle, Washington

● Phase IIb dose-ranging, partially blinded, N~200 ART-naïve patients

– A priori, maximum tolerated dose to be selected for Phase 3

● All arms include 2 NRTI backbone given once daily

● Primary endpoint: % <50 c/mL at 16 weeks (TLOVR)

● Planned analysis: % <50 c/mL at 96 weeks (TLOVR)

ING112276 Study Design

HIV-1 RNA >1000 c/mL

CD4 ≥200 cells/mm3

1:1:1:1 Randomization

EFV 600 mg

DTG 50 mg

DTG 25 mg

DTG 10 mg

Stratified by

• HIV RNA >100,000

or ≤100,000 c/mL

• ABC/3TC or TDF/FTC

Week 96 Week 16 Week 24 Week 48

DTG 50 mg

Open label



● Phase IIb dose-ranging, partially blinded, N~200 ART-naïve patients

– A priori, maximum tolerated dose to be selected for Phase 3

● All arms include 2 NRTI backbone given once daily

● Primary endpoint: % <50 c/mL at 16 weeks (TLOVR)

● Planned analysis: % <50 c/mL at 96 weeks (TLOVR)

ING112276 Study Design

HIV-1 RNA >1000 c/mL

CD4 ≥200 cells/mm3

1:1:1:1 Randomization

EFV 600 mg

DTG 50 mg

DTG 25 mg

DTG 10 mg

Stratified by

• HIV RNA >100,000

or ≤100,000 c/mL

• ABC/3TC or TDF/FTC

Week 96 Week 16 Week 24 Week 48

DTG 50 mg

Open label



Dolutegravir: Week 96 Efficacy Analysis (<50 c/mL)

95% confidence intervals are derived using the normal approximation.

88%

78% 79%

72%

Pe

rce

nt

Su

bje

cts

wit

h H

IV-1

RN

A <

50 c

/mL

(T

LO

VR

)

Week



● DTG administered once daily with two NRTIs was associated with

good treatment response at all doses

– Proportion with HIV RNA <50 c/mL for selected 50mg dose (88%)

compares favorably with EFV (72%) through 96 weeks

– No INI mutations detected through 96 weeks

● Fewer subjects treated with DTG discontinued therapy due to

adverse events when compared to EFV

● Data through 96 weeks continue to support 50mg once daily for

INI-naïve subjects, and provide evidence for durable efficacy and

tolerability for DTG in combination therapy

Conclusions

EACS: DOLUTEGRAVIR

• ESTUDIO SINGLE: • SUPERIOR A EFAVIRENZ

• ESTUDIO FLAMINGO • Dolutegravur + Darunavir/r

+

TRUVADA ó KIVEXA





2. Proteasa - potenciadores

3. Integrasa

4. Fusión

5. Coreceptor R5

Strategy: Newer ART Agents (partial

list) NRTI NNRTI PI Entry

Inh

II

Phase 3 TAF cenicriviroc

Phase 2 apricitabine

BMS-986001

dexelvucitabine

festinavir

BILR 355

doravirine

(MK-1439)

BMS-663068

ibalizumab

PF-232798

S/GSK‘744

Phase

1/2

elvucitabine TMC

310911

HGS004

Phase 1 RDEA 806 CTP-298

CTP-518

PPL-100

SPI-256

SCH532706

VIR-576

BI 224436

INH-1001

Inh-nucleosídicos ( NRTI )

Zidovudina , AZT, Retrovir ®

Lamivudina, 3TC,Epivir ®

Emtricitavina, FTC, Emtriva ®

Abacavir, Ziagen ®

Tenofovir, Viread

Stavudina, d4T, Zerit ®

Didanosina, DDI, Videx ®

Inh-nucleosídicos ( NRTI )

Zidovudina , AZT, Retrovir ®

Lamivudina, 3TC,Epivir ®

Emtricitavina, FTC, Emtriva ®

Abacavir, Ziagen ®

Tenofovir, TDF, Viread

Stavudina, d4T, Zerit ®

Didanosina, DDI, Videx ®

TENOFOVIR ( TDF )

TOXICIDADES A LARGO PLAZO

– INSUFICIENCIA RENAL

– OSTEOPOROSIS ACELERADA

=> contraindicaciones de uso

Tenofovir

Excreción renal

1- Filtración glomerular

2- Reabsorción en túbulos proximales

vía OAT (transporte de aniones orgánicos)

3- Secreción activa apical en

túbulos proximales vía MRP 2/4

Excreción renal de tenofovir

Rodriguez-Nóvoa y col. CID 2009:48:e108-116

Nefrotoxicidad por tenofovir

• Disfunción tubular proximal:

Sindrome de Fanconi

Injuria renal aguda

Diabetes insípida nefrogénica

Hipokalemia severa

• Disminución del filtrado glomerular

Nefrotoxicidad por tenofovir

Fosfaturia Hipofosfatemia

Glucosuria con glucemia normal

Proteinuria tubular

Uricosuria Hipouricemia

Aminoaciduria

Bicarbonaturia Acidosis metabólica

SINDROME

DE

FANCONI

Mecanismos de nefrotoxicidad por TDF


TOXICIDAD MITOCONDRIAL

CITOTOXICIDAD DIRECTA

Disfunción tubular proximal por TDF

• 161 pacientes tratados con TDF > 1 año

• Anormalidades tubulares: 101 ptes (63%)

• Disfunción tubular proximal (DTP): 17 ptes (10.6%),

• DTP: Niveles plasmáticos de TDF significativamente mayores, exposición más prolongada.

• Parámetro de DTP más sensible: relación α1-microglobulina/creatinina

Ezinga y col. Netherlands, 19th CROI, 2012: Abstract #603

Niveles plasmáticos de TDF

• 222 pacientes tratados con TDF

(prom.23.5meses)

• Factores significativamente

asociados con los niveles

plasmáticos de TDF:

- Edad

- BMI

- eGFR

- Drogas ARV concomitantes

Calcagno y col. Itali, 19th CROI, 2012: Abstract #604

Mecanismos de nefrotoxicidad por TDF


Inhibición

por IP/r

Aumento de niveles

intracelulares de TDF

Disminución del filtrado glomerular en esquemas

con y sin TDF C

am

bio

eG

FR

(M

DR

D)

4

2

0

-2

-4

-6

-8

-10

-12

1.41 0.53

-1.08

-3.65

-4.02

-5.21

-7.42

-11.22

No TDF

TDF

Semanas

12 (p=<0.0001) 24 (p=<0.0001) 52 (p=<0.0001) 104 (p=<0.0001)

Horberg y col. JAIDS 2010; 53 : 62-69.

Disminución del filtrado glomerular en esquemas

con TDF e IP/r: Swiss Cohort C

am

bio

eG

FR

resp

ecto

a T

DF

+ E

FV

(0)

4

2

0

-2

-4

-6

-8

-10

-12

TDF + LPV/r (n= 269)

TDF + ATV/r (n= 187)

Meses

Young y col. AIDS 2012; 26 (5) : 567-567.

6 12 18

TDF + EFV: n= 484

TAF

FUMARATO ANAFELAMIDA TENOFOVIR

0.5

0

-0.5

-1

-1.5

-2

Tenfovoir Alafenamide Fumurate ( TAF

) (formerly GS-7340)

Pro-drug of tenofovir TAF: 14-Day Monotherapy

Markowitz CROI 2011 Abstract 152LB

TDF 300 mg QD (n = 10) TAF 50 mg QD (n = 10)

TAF 150 mg QD (n = 10)

Ch

an

ge in

VL

Fro

m B

aseli

ne

(lo

g10 c

/mL

)

Day 0 7 14 21 28 35

TDF vs. TAF: Drug Delivery

Ruane JAIDS 2013;63:449

TAF: Drug Levels

TFV Plasma Levels

CROI 2013: TAF

• TAF does not interact with renal transporters

OAT 1 or OAT 3 and does not exhibit OAT-

dependent cytotoxicity in vitro

• In patients with severe renal failure, TAF 25

mg resulted in no clinically relevant changes

in TAF exposure (vs. healthy controls) Ramanathan CROI 2013

#529

Sauvageon CROI 2013 #539

Emergence of Drug Resistance: TAF vs. TFV

Margot, HIV Drug Resistance Workshop 2013

Zolopa CROI 2013 # 99LB

TAF Phase 2 GS-US-292-0102 – Week 24 Analysis Study population: Rx-naïve, VL >5000, CD4 >50 (N=170)

0

10

20

30

40

50

60

70

80

90

100

2 4 8 12 16 24

% S

ub

ject

s H

IV-1

RN

A <

50

c/m

L (M

=F, I

TT)

Time (Weeks)

TAF/FTC/EVG/c 88% (n=112)

TDF/FTC/EVG/c 90% (n=58)

Change in CD4+ cell count: – TAF +163 cells/μL – TDF +177 cells/μL (p = 0.76)

Change in serum creatinine at Week 24 – TAF +0.07 mg/dL – TDF +0.12 mg/dL (p=0.02)

TAF/FTC/EVG/COBI

0 12 24

-2

0

2

Time (Weeks)

Mean

% c

han

ge in

BM

D

0 12 24

-2

0

2

Time (Weeks)M

ean

% c

han

ge in

BM

D

Percent Change in Bone Mineral Density (DEXA) GS-US-292-0102 – Week 24 Analysis

SPINE

Proportion of subjects with no decrease in BMD – Spine: TAF 38%; TDF 12% – Hip: TAF 41%; TDF 23%

HIP

-0.8

-2.5

-0.3

-2.0

p = 0.002 p < 0.001

Zolopa CROI 2013 # 99LB

17

TAF Phase 2 Program

Study population: Rx-naïve, VL >5000, CD4 >50 (N=150)

TAF/FTC/DRV/COBI

TDF/FTC + DRV + cobi placebos

TAF/FTC/DRV/cobi

TAF/FTC/DRV/cobi placebo

TDF/FTC + DRV + COBI

299-0102 Status:

Fully

enrolled

n=100

n=50

TAF Phase 3 Program (clinicaltrials.gov; started

1/13):

TAF/FTC/EVG/cobi vs. TDF/FTC/EVG/cobi

No-Nucleósidos ( NNRTI )

Efavirenz - Stocrin®

Nevirapina - Viramune®

Etravirina - Intelence®

RILPIVIRINA - Edurant

Rilpivirine (FDA-approved NNRTI 2011; safety 2+ years)

Long-Acting (RPV-LA) parenteral

• RPV-LA once-monthly IM possible Baert Eur J Pharm Biopharm

2009

• RPV-LA achieves tissue levels –10X higher in LN (animals) v’ant Klooster AAC 2010

–CVF and rectal tissue equal, vaginal tissue lower, rectal fluid much lower Else PK Workshop 2012

• RPV-LA single IM administration (3 doses) clinical and PK study in HIV-negative (N=33) Jackson CROI 2012 #35

• Pilot safety study with RPV-LA and 744LAP in HIV-negative (N=40) Spreen IAS 2013 #WEAB0103

Doravirine (MK-1439)

• Investigational NNRTI

• Pre-clinical

–Potent at low miligram dose

–Cytotoxicity and animal toxicity studies negative

–Not a CYP450 inhibitor or inducer

–Metabolized by CYP3A4

–Active in vitro against viral strains with K103N, Y181C,

G190A or K103N/Y181C

• Clinical

–Multiple doses in 40 HIV- men X 10d:

• no rash/CNS events (except HA)

• PK supportive of once-daily dosing

Lai ICAAC 2012 #H-551

Anderson CROI 2013 #527

Doravirine (MK-1439): Phase Ib Double-blind, randomized, placebo-controlled

Study population: HIV+, treatment-naïve (N=18)

Anderson, CROI 2013;

#100


RALTEGRAVIR

ELVITEGRAVIR

DOLUTEGRAVIR

GSK 1265744 (744) • Integrase inhibitor similar to DTG; similar resistance

• 2-2.5 log cps/ml ↓ in HIV+ individuals (5+30 mg oral)

• Nanotechology formulation; SC + IM injections

• T ½ 21-50 days!

• Supports monthly or quarterly dosing

• Safety: ISR and nodules with SC dosing

• Pilot study with

RPV-LA

Spreen IAS 2012 #TUPE040; Yoshinaga ICAAC 2012 #H-550; Taoda Glasgow 2012

#P206

GSK744 LAP: PrEP Study in Macaques

• Study population: male macaques (N=16)

• Study treatment:

– GSK 744LAP 50mg/kg X 2, 4 weeks apart

– Placebo

• Weekly SHIV rectal challenge X 8

• Results (preliminary)

– GSK 744LAP: no infections

– Placebo: all infected

Andrews CROI 2013 #24LB

Combination of GSK ‘744-LAP + RPV-LA

Phase 1 pilot study, randomized, repeat dose-escalation study with oral lead-in (of ‘744) in HIV- individuals (N=47)

– Monthly and quarterly dosing of 744-LAP IM with co-dosed monthly RPV-LA SC

– Endpoints: Safety, tolerability, PK

– Results: generally safe and well-tolerated with grade 1 ISR most common; target drug concentrations achieved

Spreen IAS 2013 #WEAB0103

CD4 Attachment Inhibitor:

Fuzeon SC

needs:

• novel mechanism of action

REPLICACION VIH

BMS-663068: Oral HIV Attachment Inhibitor

• Prodrug of BMS-626529

• Inhibits CD4 binding by

binding to gp120

• PK suggest QD or BID

dosing without boosting

• ↓ baseline susceptibility

in some pts due to

envelope polymorphisms;

screened by baseline IC50

Nettles JID 2012;206:1002

Study pop: CD4 >200, VL >5000 off ART X >8 wks or ART-naive (N=50)

CCR5 Antagonist

needs:

• once-daily dosing

CCR2

Antagonist

• potential anti-inflammatory properties

Cenicriviroc

Cenicriviroc (CVC): CCR5/CCR2 Antagonist • Randomized, double-blind, placebo-controlled, dose-escalating

• Study population: HIV+, rx-exp, no ART X >6 wks, VL >5K, CD4 >250

• 5 dose cohorts (randomized 4:1)

• CVC (n≥8): 25, 50, 75, 100 and 150 mg once-daily

• PBO (n=2)

Cohen C, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. K-111

Lalezari JAIDS 2011;57:118 10d qd dosing

CVC 202: Phase 2 VL <50 copies/mL (ITT-FDA Snapshot)

38

Su

bje

cts

wit

h H

IV-1

RN

A

<50

c/m

L, %

(±

SE

)

20

40

60

80

100

BL 4 12 24 Weeks

76% 73%

71%

CVC 100 mg CVC 200 mg EFV

CVC 100 mg (N=59) 0 3 11 25 37 44 42 45

2 2 4 17 28 13 40 41

0 4 5 12 16 18 19 20

CVC 200 mg (N=56)

EFV (N=28)

1 2 8 16 20

Gathe CROI 2013 #106LB

Study population: Rx-naïve, VL >1000, CD4 >200,

documented R5 virus (N=143)

All arms with TDF/FTC

randomized

2:2:1

55 51 47

54 50 44

28 22 21

Me

an

ch

an

ge

fro

m b

as

eli

ne

in

sC

D1

4 le

ve

ls,a

x 1

06 n

g/L

(±

SE

)

CVC 100 mg

CVC 200 mg

EFV

CVC 100 mg

CVC 200 mg

EFV

CVC Study 202: sCD14* changes from

baseline

Gathe CROI 2013 #106LB

* Biomarcador asociado a deterioro neurocognitivo

……. entonces,

¿qué hay de nuevo?

• Rilpivirina (NNRTI )

• Cobicistat ( potenciador )

• Elvitegravir ( inh.integrasa )

• Dolutegravir ( inh.integrasa ) – 1 vezal día

• Rilpivirina parenteral (NNRTI )

• Doravirina ( NNRTI )

• Formulaciones en un comprimido


• Formulaciones en un comprimido:

– ATRIPLA : TDF + FTC + EFZ

– COMPLERA : TDF + FTC + RiL

– STRIBILD : TDF + FTC + EVG + c

– ABC + 3TC + DTG

– TAF + FTC + DRV + c


• Rilpivirina

• Cobicistat

• Elvitegravir

• Dolutegravir

• Rilpivirina parenteral

• Doravirina ( NNRTI )

• GSK 744 Inh.integrasa parenteral

• BMS 608 Inhibidor de fusión (oral )

• Cenicriviroc ( CCR5-CR2 antagnonista) antiviral y antiinflamatorio

Drogas ARV Desafíos y necesidades:

Desafíos

• Adherencia

• Toxicidad

• Actividad

• Resistencia

• Formulación

Necesidades

• Mejorar tolerabilidad

• Reducir toxicidades

• Penetración reservorios

• Exploración nuevos targets

• Mejorar actividad:

– Cepas “wild type”

– Cepas resistentes

Lo más importante NO es conocer detalladamente las drogas…

Lo más importante es confirmar la eficacia del tratamiento como estrategia de prevención ¡¡¡¡¡ TEST & TREAT !!!!!

Agradecimientos

1.- R.M. Gulick, MD, MPH

Professor of Medicine

Chief, Division of Infectious Diseases

Weill Cornell Medical College

New York City

2.- Dr.Isidoro Prudente

Director médico GSK

3.- Staff Programa Hospital de Salvador

Gracias

Documents

VIH: ¿QUE HAY DE NUEVO EN EL MANEJO DE LA TARV? · VIH: ⍈¿QUE HAY DE NUEVO EN EL MANEJO DE LA TARV?⍉ Dr.Esteban Cortés Sedano Jefe Programa VIH/SIDA Hospital del Salvador