00002-E-1 – 1 December 2003

Anti-HIV drugs 2010-2011

Andrea De Luca, M.D.

Institute of Clinical Infectious Diseases. Catholic University, Rome

2nd Division of Infectious Diseases, University Hospital of Siena,

Italy

CD4 +

HIV RNA

time

HAART

MortalityOpportunistic infections

Goals of antiretroviral therapy

00002-E-3 – 1 December 2003

Probability (%) to develop full blown AIDS in the subsequent 3 years by CD4 counts and HIV RNA levels before and after the introduction

of antiretroviral therapy

Without therapy

With therapy

00002-E-4 – 1 December 2003

New AIDS cases per year of diagnosis in Italy

Limitations of antiretroviral therapy

morbidity and mortality but…

Eradication impossible because of latently infected CD4+ memory T cells

Emergence of drug resistance

LIFE-LONG CHRONIC TREATMENT NECESSARY

TolerabilityAdherence

00002-E-6 – 1 December 2003

Antiviral potency and developmentof drug-resistance

Antiviral potency

Ris

k of

dev

elop

men

t of

dru

g-re

sist

ance

poor suboptimal high

Poor pharmacokineticsSuboptimal adherence

Drug pressure selects

resistant virus

Inadequate drug pressure to select

resistant virus

Complete viral suppression

Increasing adherence

RT

Provirus

ProteinsRNA

DNA

RNA

DNA

DNA

RT Viral regulatoryproteins

Viral protease

Reversetranscriptase

Viral integrase

RNA

RNA

Attachment, fusion and entry

DNA

DNA

DNA

Viral zinc-fingernucleocapsid

proteins

00002-E-8 – 1 December 2003

Antiretroviral drugs and classes licensed for use in developed countries

Nucleoside/

nucleotide RT

inhibitors

Non-nucleoside

RT inhibitors

Protease inhibitors Fusion

inhibitors

Integrase

inhibitors

CCR5

antagonists

Zidovudine Nevirapine Saquinavir/rit Enfuvirtide Raltegravir Maraviroc

Didanosine Efavirenz (Ritonavir)

(Zalcitabine) (Delavirdine) Indinavir/rit

Lamivudine Etravirine Nelfinavir

Stavudine Fosamprenavir/(rit)

Abacavir Lopinavir/rit

Tenofovir Atazanavir/ (rit)

Emtricitabine Tipranavir/rit

Darunavir/rit

00002-E-9 – 1 December 2003

NRTI

Historical ARV drugs. Still difficult to avoid

Essential component of ART regimens (2 NRTI+ x)

Alone: Low/intermediate potency, intermediate genetic barrier

Class-toxicity: mitochondrial toxicity (lipoatrophy, peripheral

neuropathy, pancreatitis, hyperlipemia)

Individual components related to organ-specific toxicities (bone

marrow, renal/bone, cardiovascular)

00002-E-10 – 1 December 2003

NNRTI

High potency, low genetic barrier to resistance (except 2nd

generation)

Toxicity: cutaneous (rash, SJS), liver, lipid (modest)

Individual components: organ-specific (EFV: CNS, teratogenicity;

NVP: liver)

00002-E-11 – 1 December 2003

PI

Potent, high genetic barrier (ritonavir-boosted)

Class-toxicity: metabolism (lipid, glicidic, lipodystrophy, cardiovascular)

Ritonavir toxicity (gastrointestinal, lipids)

Lopinavir and fosamprenavir probably cause diarrhea per se

Specific toxicities: hyperbilirubinemia (atazanavir), cutaneous reactions

(sulpha component of fosamprenavir and darunavir), nephrolithiasis

(indinavir>atazanavir)

00002-E-12 – 1 December 2003

FI, INSTI, CCR5 antagonists

All potent drugs but low/intermediate genetic barrier to

resistance

FI: injection site reactions

Other drugs: very modest toxicity – Raltegravir: CNS/psychiatric, muscle– Maraviroc: liver

00002-E-13 – 1 December 2003

ART: Recent /Future developments

Goal (virologic suppression) achieved in 85-90% of patients in trials and

clinical practice (drug naive and experienced patients)

Towards more simple regimens (one pill/day)

Increased genetic barrier

Improved tolerability

Further improvements: – Less medium-long term toxicity (metabolic, cardiovascular, renal/bone)– PK boosting without ritonavir

00002-E-14 – 1 December 2003

New treatments and strategies for naive patients

00002-E-15 – 1 December 2003

ARTEMIS: Wk 96 Lipid and Anthropometric Substudy

Randomized noninferiority trial of

DRV/RTV vs LPV/RTV, both with

TDF/FTC, in naive pts– DRV/RTV noninferior to LPV/RTV at Wk

48. At Wk 96, DRV/RTV met superiority criteria vs LPV/RTV

In anthropometric analysis at Wk 96,

no increase in median midwaist:midhip

ratio in either study arm

Changes in BMI, body weight,

midwaist, chest, hip, and

circumferences similar between arms

and not clinically relevant

DRV/RTV

LPV/RTV

TC LDL-C HDL-C TG 0

10

20

30

40

50

26

35

17 15

5 8

18

56

Med

ian

Incr

ease

at W

k 96

(m

g/dL

)

Baraldi E, et al. IAS 2009. Abstract MOPEB034.

Statistically greater % increases in TC, TG in

LPV/RTV arm than DRV/RTV arm (P < .001)

60

00002-E-16 – 1 December 2003

STARTMRK: Metabolic, Body Composition Changes at Wk 96 With RAL vs EFV

DeJesus E, et al. CROI 2010. Abstract 720. Adapted with permission of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. All Rights Reserved.

Mea

n C

hang

e (m

g/dL

)

0

40

50

20

30

10

-10TC HDL-C LDL-C TG Glucose

App

endi

cula

r F

at M

ean

Per

cent

(S

E)

Cha

nge

40

20

30

10

0

0 48 96Wks

56 46 38

55 40 37

EFV

RAL

Contributing Patients, n

18.1

17.7 17.0

18.2P < .001

P < .001

P < .001

P < .001

P = .025

RAL

EFV

00002-E-17 – 1 December 2003

MERIT: Wk 96 Response With MVC vs EFV in Naive Pts

MERIT-ES: reanalysis of MERIT trial using enhanced phenotypic tropism assay suggested noninferiority of MVC to EFV when additional pts with D/M-tropic virus identified by enhanced assay excluded[1]

Wk 96 efficacy analysis included only MERIT-ES population[2]

Similar proportions in MVC and EFV with VL < 50 copies/mL at Wk 96

CD4+ increase at Wk 96 greater with MVC vs EFV (+212 vs +171 cells/mm³)

EFV more likely discontinued for AEs: 15.5% vs 6.1% on MVC

MVC more likely discontinued for insufficient response: 12.5% vs 5.9% on EFV

EFV + ZDV/3TC MVC + ZDV/3TC

MERIT MERIT-ES

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c/

mL

(%

)

69.3 65.3 68.3 68.5

Wk 48

62.458.5

Wk 96

MERIT-ES

60.7 60.5

n 361 360 303 311 203 210 303 311

ITT, NC = F Modified ITT

TLOVR

1. Saag M, et al. ICAAC/IDSA 2008. Abstract 1232a. 2. Heera J, et al. IAS 2009. Abstract TUAB103. 3. Nelson M, et al. IAS 2009. Abstract MOPEB040.

Higher levels of dyslipidemia on EFV

5/15 pts who discontinued EFV for tolerability developed NNRTI mutations in follow-up[3]

00002-E-18 – 1 December 2003

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

00002-E-19 – 1 December 2003

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

Pat

ient

s (%

)

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

Pat

ient

s (%

)

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

Pat

ient

s (%

)

40

0

100

20

80

60

ECHO THRIVEPooled

00002-E-20 – 1 December 2003

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 THRIVE

Adverse 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

ient

s (%

)

Wk 48 Outcome, % Rilpivirine(n = 686)

Efavirenz(n = 682)

P Value

DC for AE 3 8 .0005

Most Common AEs of Interest, %

Any neurologic AE 17 38 < .0001

Any psychiatric AE 15 23 .0002

Any rash 3 14 < .0001

Rilpivirine

EFV

00002-E-21 – 1 December 2003

GS-9350–Boosted Elvitegravir + FTC/TDF Noninferior to EFV/FTC/TDF in Naive Pts

Cohen C, et al. CROI 2010. Abstract 58LB. Reproduced with permission.

Wk 24 stratum-weighted difference: +5%

(95% CI: -11.0% to 21.1%)HIV

-1 R

NA

< 5

0 c/

mL

(%

)

100

80

60

40

20

0

Wk0 4 8 12 16 20 24

GS-9350/EVG/FTC/TDFEFV/FTC/TDF

8390

ITT, M = F

Cobicistat (GS-9350): investigational CYP3A

inhibitor (boosting agent)

GS-9350/EVG/FTC/TDF(n = 48)

EFV/FTC/TDF (n = 23)

Treatment-naive pts with CD4+

≥ 50 cells/mm3, HIV-1 RNA

≥ 5000 c/mL, no NRTI, NNRTI, or PI

resistance

(N = 71)

Wk 24 primary endpoint

analysis Wk 48

Elvitegravir: investigational integrase inhibitor

00002-E-22 – 1 December 2003

GS-9350–Boosted ATV Virologic Efficacy Similar to ATV/RTV in Naive Pts

Cohen C, et al. CROI 2010. Abstract 58LB. Reproduced with permission.

Wk 24 stratum-weighted difference: -1.9%

(95% CI: -18.4% to 14.7%)HIV

-1 R

NA

< 5

0 c/

mL

(%

)

GS-9350–Boosted ATV + FTC/TDF

(n = 50)

RTV-Boosted ATV + FTC/TDF

(n = 29)

Treatment-naive pts with CD4+

≥ 50 cells/mm3, HIV-1 RNA

≥ 5000 c/mL, no NRTI, NNRTI, or PI

resistance

(N = 79)

Wk 24 primary endpoint Wk 48 100

80

60

40

20

0

Wk

0 4 8 12 16 20 24

RTVGS-9350

8684

ITT, M = F

Phase II study comparing cobicistat (GS-9350) vs ritonavir as

boosting agent for atazanavir

00002-E-23 – 1 December 2003

Wk 16

Treatment naive,HIV-1 RNA

> 1000 copies/mL,no CD4+ cell count

restriction

(N = 205)

*NRTIs individually selected by trial investigators (TDF/FTC, 67%; ABC/3TC, 33%).†After Wk 48, all patients continue at dose selected for phase III trial.

S/GSK1349572 10 mg QD+ 2 NRTIs QD*

(n = 53)

S/GSK1349572 25 mg QD+ 2 NRTIs QD*

(n = 51)

S/GSK1349572 50 mg QD+ 2 NRTIs QD*

(n = 51)

EFV 600 mg QD+ 2 NRTIs QD*

(n = 50)

Arribas J, et al. AIDS 2010. Abstract THLBB205.

Dose-ranging, partially blinded phase IIb trialWk 48

SPRING-1: S/GSK1349572 vs EFV in Treatment-Naive Patients

00002-E-24 – 1 December 2003

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 (T

LOV

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

00002-E-25 – 1 December 2003

ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts

NVP either once daily or twice daily

noninferior to ATV/RTV at Wk 48

Rates of AEs similar overall but higher rate

of discontinuation due to toxicity in NVP

arms (13.6% vs 3.6%)

HIV

-1 R

NA

< 5

0 c/

mL

at W

k 48

(%

)

40

0

100

20

80

Any NVP

65.366.8

60

P = .63

ITT, NC = F

NVPQD

NVPBID

67.0 66.5

Outcome at Wk 48, %

NVP QD(n = 188)

NVP BID(n = 188)

ATV/RTV(n = 193)

Virologic failure 11.2 12.8 14.0

Investigator-defined virologic failure

5.9 11.2 1.6

No confirmed response at Wk 48

5.3 1.6 12.4

Soriano V, et al. IAS 2009. Abstract LBPEB07.

ATV/ RTV

n = 376 193 188 188

00002-E-26 – 1 December 2003

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)

00002-E-27 – 1 December 2003

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

ient

s (%

)

LPV/RTV + RAL

00002-E-28 – 1 December 2003

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

hang

e F

rom

BL

, m

g/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)

00002-E-29 – 1 December 2003

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

ient

s (%

)

n =

ATV/RTV + MVC

ATV/RTV + TDF/FTC

00002-E-30 – 1 December 2003

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

ient

s (%

)

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.

00002-E-31 – 1 December 2003

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

00002-E-32 – 1 December 2003

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 12Gazzard B, et al. AIDS 2010. Abstract LBPE19.

Drug-Related Neuropsychiatric AEs

Pat

ient

s (%

)

P < .001 P = .02

00002-E-33 – 1 December 2003

Switch/simplification studies

00002-E-34 – 1 December 2003

BL HIV-1 RNA < 100,000 c/mL

BL HIV-1 RNA ≥ 100,000 c/mL

ATV (n = 210)

ATV/RTV (n = 209)

Squires K, et al. IAS 2009. Abstract WELBB103. Graphic used with permission.

HIV

-1 R

NA

< 5

0 c/

mL

at W

k 84

(%

)

Overall Results0

20

40

60

80

10086

80.885

7987

82

ARIES: Boosted vs Unboosted ATV Maintenance: Wk 84 Results

00002-E-35 – 1 December 2003

SPIRAL: Switch to RAL Noninferior to Maintaining PI/RTV Regimens

0

20

40

60

80

100

Switch to RAL

Continue PI/RTV

86.689.2

Free of Treatment Failure at Wk 48 (ITT, S = F)

Patients With VFRAL

(n = 4)PI/RTV(n = 6)

Prior VF 1 3

Prior suboptimal ART 2 3

Prior resistance mutations 1 5

Resistance test at VF 1 4

Mutations 0 3 (PR, RT)

Martinez E, et al. AIDS. 2010;24:1697-1707.

Mean Change From Baseline to Wk 48, %

Switch to RAL

Continue PI/RTV

P Value

Triglycerides -22.1 +4.7 < .0001

TC -11.2 +1.8 < .0001

LDL-C -6.5 +3.0 < .001

HDL-C -3.2 +5.8 < .0001

Total to HDL-C ratio

-4.9 -1.3 < .05

00002-E-36 – 1 December 2003

MONET Trial: 96-Wk Efficacy Results of Switch to DRV/RTV Monotherapy

Randomized, open-label trial of switch to

DRV/RTV monotherapy vs continuing

DRV/RTV HAART in virologically

suppressed pts

DRV/RTV monotherapy noninferior vs

DRV/RTV HAART at Wk 48[1]

Monotherapy NOT noninferior with switch =

failure analysis at Wk 96[2]

– Δ -5.8% (95% CI: -16.0% to +4.4%)

If resuppression with intensification included

as success, then monotherapy noninferior

at Wk 96– Δ +1.4% (95% CI: -5.5% to +8.3%)

1. Arribas JR, et al. IAS 2009. Abstract TUAB106LB. 2. Rieger A, et al. AIDS 2010. Abstract THLBB209.

HIV-1 RNA < 50 copies/mL, ITT, TLOVR (%)

40

0

100

20

80

Wk 48[1]

85.384.3

60

DRV/RTV monotherapy (n = 127)DRV/RTV + 2 NRTIs (n = 129)

80.674.8

Wk 96[2]

Switch = failure 92.1 90.7

Switch allowed

00002-E-37 – 1 December 2003

Treatment-experienced individuals

00002-E-38 – 1 December 2003

0 10 20 30 40 50 60 70 80 90 100

BENCHMRK PL

BENCHMRK

DUET PL

DUET

MOTIVATE PL

MOTIVATE

POWER PL

POWER

0 10 20 30 40 50 60 70 80 90 100

BENCHMRK PL

BENCHMRK

DUET PL

DUET

MOTIVATE PL

MOTIVATE

POWER PL

POWER

%

48w

96w

Evolving efficacy of antiretroviral regimens in multiexperienced patients (percent <50 copies/ml)

00002-E-39 – 1 December 2003

Pooled DUET 96-Wk Results: ETR + DRV/RTV-Containing OBR in Exp’d Pts

HIV

-1 R

NA

< 5

0 c/

mL

(%

)(I

TT

-TL

OV

R)

40

0

100

20

80P < .0001

Wk 48 Wk 96

39

60

36

5760

P < .0001

Randomized trial of ETR vs placebo, both with

DRV/RTV-containing OBR in multiclass-

resistant pts– Superior virologic suppression with ETR at Wks 24

(primary endpoint) and 48

Superior virologic suppression maintained at

Wk 96 in ETR vs placebo arm[1]

– Higher response with ETR irrespective of number of active agents, baseline ETR FC, weighted score, sex, race, and age

Greater mean change in CD4+ cell count with

ETR vs placebo – +123 vs +86 cells/mm³ (P < .0001) No new safety signals in Wks 48-96[2]

– New rash in < 1% of pts

– CNS adverse effects similar between arms in Wks 48-96

ETR (n = 599)

Placebo (n = 604)

1. Mills A, et al. IAS 2009. Abstract MOPEB036. 2. Nelson T, et al. IAS 2009. Abstract MOPEB038.

00002-E-40 – 1 December 2003

ODIN: QD vs BID Darunavir/Ritonavir + OBR in Treatment-Experienced Patients

Cahn P, et al. CROI 2010. Abstract 57.

QD DRV/RTV 800/100 mg + OBR*(n = 294)

Treatment-experienced adults with stable HAART for

≥ 12 wks, HIV-1 RNA> 1000 copies/mL, CD4+

> 50 cells/mm3, no DRV RAMs

(N = 590)

Wk 48

*OBR included ≥ 2 active NRTIs.

Stratified by baseline HIV-1 RNA ≤ and

> 50,000 copies/mL

BID DRV/RTV 600/100 mg + OBR* (n = 296)

Primary PI mutations in < 2% of patients in either arm

00002-E-41 – 1 December 2003

ODIN: HIV-1 RNA < 50 copies/mL at Wk 48 Overall and by Screening HIV-1 RNA

Similar CD4+ cell count increase between arms– QD DRV/RTV : +100 cells/mm3

– BID DRV/RTV : +94 cells/mm3

Cahn P, et al. CROI 2010. Abstract 57. Reproduced with permission.

100

Pts

Wit

h H

IV-1

RN

A

< 5

0 co

pies

/mL

(%

)

80

60

20

00 12 24 36 48

40

84Wks

Difference in response, QD vs BID:ITT = 1.2% (95% CI: -6.1%, 8.5%)

QD DRV/RTV 800/100 mgBID DRV/RTV 600/100 mg

72.170.9

100

Pts

Wit

h H

IV-1

RN

A

< 5

0 co

pies

/mL

(%

)

80

60

20

050,000

40

Screening HIV-1 RNA (copies/mL)

> 50,000

78.4 76.8

52.8 52.8

n = 222 224 72 72

00002-E-42 – 1 December 2003

ODIN: Virologic Failure Not Statistically Different Between Arms

Resistance Emergence in Pts With Virologic Failure and Paired Genotypes/Phenotypes

QD DRV/RTV + OBR BID DRV/RTV + OBR

Development of new RAMs,* n (%)

Primary PI 1 (1.7) 0

Any PI 7 (11.7) 4 (9.5)

Loss of susceptibility,† n (%)

Darunavir 1 (1.7) 0

Any PI 2 (3.4) 0

Cahn P, et al. CROI 2010. Abstract 57.

*Patients with paired baseline/endpoint genotypes evaluated (n = 60 in QD arm and n = 42 in BID arm).†Patients with paired baseline/endpoint phenotypes evaluated (n = 59 in QD arm and n = 41 in BID arm).

00002-E-43 – 1 December 2003

ODIN: Significantly Lower Rate of Lipid Abnormalities With DRV/RTV QD vs BID

Cahn P, et al. CROI 2010. Abstract 57.

AEs,* % QD DRV/RTV + OBR

(n = 294)

BID DRV/RTV + OBR

(n = 296)

P Value

Serious AEs 5.4 9.1 --

Grade 2-4 treatment-emergent laboratory abnormalities*

Total cholesterol† 10.1 20.6 < .0007

LDL-C† 9.8 16.7 < .019

Triglycerides 5.2 11.0 < .014*No significant differences in grade 3/4 AEs, AEs leading to treatment discontinuation, GI AEs, ALT levels, or AST levels.

00002-E-44 – 1 December 2003

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.

00002-E-45 – 1 December 2003

Resource-limited settings/special populations

ART in special populations: patients starting TB therapy for active disease

CD4 cell

count

recommendation Type of ART/comments

<350 Recommend ART as soon as TB

treatment tolerated

EFV-based > NVP

>350 Recommend ART as soon as TB

treatment tolerated (data

insufficient)

EFV-based >NVP

unavailable Recommend ART as soon as TB

treatment tolerated

EFV-based >NVP

00002-E-47 – 1 December 2003

SAPiT: Optimal Time to Initiate ART in HIV/TB-Coinfected Patients

Early ART ART initiated during intensive or

continuation phase of TB therapy (n = 429)

Sequential ART ART initiated after TB therapy

completed (n = 213)

HIV-infected patients diagnosed with TB and

CD4+ cell count < 500 cells/mm3

(N = 642)

Primary endpoint: all-cause mortality

00002-E-48 – 1 December 2003

Abdool Karim SS, et al. CROI 2009. Abstract 36a. Graphic reproduced with permission.

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Sur

viva

l

Months Postrandomization

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Intensive phase of TB

treatment

Post-TB treatmentContinuationphase of TB

treatment

Early ARTSequential ART

SAPiT: Increased Survival With Concurrent HIV and TB Treatment

00002-E-49 – 1 December 2003

CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients (CD4<200)

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

50 86.1 (81.8-89.4)

80.7 (76.0-84.6) .07

100 82.6 (78.0-86.4)

73.0 (67.7-77.6) .006

150 82.0 (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 MortalitySurvival Probability, Early vs Late Therapy

Log rank P = .0042

Wks From TB Treatment Initiation

Pro

babi

lity

of

Sur

viva

l 1.00

0.90

0.80

0.70

0.60

Early arm wk 2Late arm wk 8

0 50 100 150 200 250

00002-E-50 – 1 December 2003

ART in special populations:pregnant women

Primarily consider mother’s need of ART and act accordingly (same as

guidelines for adults)

Used to prevent mother-to-infant transmission as well

Avoid EFV in first trimester (teratogenic)

Prevention of MTCT: conflicting data on pros and cons of single dose NVP to

mother and infant (negligible reduction in transmission in mothers who

breastfeed, selection of resistance to non-nucleosidic RT inhibitors); same

applies to other suboptimal therapies

00002-E-51 – 1 December 2003

BAN Study: Both Regimens Equally Effective at Preventing Transmission

Maternal HAART and infant

NVP regimens both significantly reduced

HIV-1 transmission by breastfeeding to

infants at Wk 28

Grade 3/4 adverse events generally

comparable across arms, except – Significantly higher rate of neutropenia in

women on maternal HAART vs control arm (6.7% vs 2.0%; P < .0001)

– Substantially higher number of hypersensitivity reactions in infants on NVP vs control arm (16 vs 0 events)

Age (Wks)E

stim

ated

Pro

babi

lity

of

Bei

ng H

IV P

osit

ive

1 4 8 12 16 20 24 280.00

0.02

0.04

0.06

0.08

Control vs maternal HAART: P = .0032

Control vs infant NVP: P < .0001Maternal HAART vs infant NVP: P =.1203

6.4%

3.0%

1.8%

Chasela C, et al. IAS 2009. Abstract WELBC103.Graphic used with permission..

Control

Maternal HAART

Infant NVP

00002-E-52 – 1 December 2003

WHO 2009 recommendations for PMTCT in mothers who do not need ART for their own health