International AIDS Society Paris 2003 Rosy Weston Senior Principal Pharmacist Jefferiss Wing...

International AIDS SocietyParis 2003

Rosy Weston

Senior Principal Pharmacist

Jefferiss Wing Pharmacy

St. Mary’s NHS Trust

Objectives

• To discuss combination antiretroviral drug therapy following feedback from the IAS meeting………

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Outline

• Antiretroviral Therapy– Triple nucleoside combinations

• Abacavir and tenofovir

– FTC (emtricitabine)

– Nucleoside sparing regimens

– Atazanavir and boosted PI regimens

– Enfuvirtide (T-20)

– New formulations – nelfinavir, saquinavir

– Simba study

Triple Nucleosides• Triple nucleoside combinations

– Easy to take• Fixed dose combinations e.g. Trizivir Combivir

– Future drug combos – abacavir + lamivudine, tenofovir + FTC

– Minimal drug interactions– Preserve other drug classes for future

So just how good are triple nucleosides?

• Concerns re triple nucleosides in VL > 100,000copies/ml

• Not recommended as first line in BHIVA, IAS or DHHS guidelines

ACTG5095

Adapted from Gulick RM et al Presentation 9-41

Trizivir®

(Combivir®

and EFV placebo)

3 nucleosides

Combivir®+EFV

(Trizivir® placebo)

Control arm

Trizivir®+EFV

(Combivir®

placebo)

4 drug arm

Randomized trial with HIV+, ART-naïve subjects n=1147 (evaluable)

• Comparison of 3 PI-sparing regimens in naïve patients• Interim analysis

Double blind + placebo controlled

ACTG5095

Adapted from Gulick RM et al Presentation 9-41

Primary Objective

• compare ability of these 3 regimens to decrease HIV-1 RNA to <200copies/mL

•To compare the time to virologic failure*

* Virological Failure Definition

• confirmed HIV-1 RNA 200 copies/mL at least 16 weeks after randomisation

•To determine the safety/tolerability of the regimens

ACTG 5095: Study Subjects

• N = 1147 subjects enrolled

• 81% men, 19% women

• 40% white, 36% black, 21% latino, 2% other

• 11% with history of IDU

• Mean baseline:

– HIV-1 RNA: 4.85 log10 (71,434) copies/ml

• 57% <100,000 copies/ml

• 42% >100,000 copies/ml

– CD4: 238 cells/mm3

• Median follow-up of 32 weeks (range 0-80)

Presentation 9-41Gulick RM et al

ACTG 5095: Proportion of subjects with HIV-1 RNA <200 and <50 cps/ml

89% (85, 93%)83% (78, 88%)

pt estimate (95% CI) at wk 48

74% (65, 83%)

61% (50, 72%)


ACTG 5095: Time to first virologic failure


ACTG 5095: CD4 cell responses


ACTG 5095: Resistance Results

Subjects on ZDV/3TC/ABC with virologic failure (n=82)• At baseline:

– 78 (95%) wild type – 3 (4%) RTI-associated substitutions– 1 (1%) sequence not available

• At virologic failure: Trizivir Arm– 18 (22%) wild type– 28 (34%) M184V alone– 9 (11%) M184V + RTI-associated substitutions– 2 (2%) RTI-assoc. subs. (without M184V)– 22 (27%) seq. not attempted (HIV RNA <500 cps/ml)– 3 (4%) could not be sequenced

(Subjects on pooled EFV arms not reported)Gulick RM et al Presentation 9-41

What is the conclusion from this study?• In treatment naïve patients – Trizivir is

inferior to EFV containing combinations for both rates and time to virological failure

• Concern over the resistant mutations at failure

• Is this unique to Trizivir?• Triple nucleoside combinations• ??? Baseline Viral load?

Abacavir / tenofovir

• Increasingly popular choice of nucleoside backbone in patients on second/third regimen.

• Lamivudine often included in patients on previous multiple Rx

• Easy to take – 3 pills daily

• Abacavir once daily NOT licensed

ABC/3TC/TDF in naïve patients(pilot study demonstrating early virological failure)

• Pilot study to assess efficacy and tolerability of once daily ABC+3TC+TDF in treatment of HIV-infected naïve patients n=19

• Definition of non-responder– No reduction in HIV-1 RNA by 2log10 by week 8 and/or

rebound in viral load after initial suppression

• Baseline Characteristics– Mean HIV-1 RNA 147,164 copies/ml– Mean CD4 cell count 277 cells/mm3

Farthing C, Khanlou H, Yeh V Presentation 9-43

ABC/3TC/TDF in naïve patients(pilot study of early virological failure)

Farthing C, Khanlou H, Yeh V Presentation 9-43

Results: ABC+3TC+TDF Mean HIV RNA

(n=19) Baseline (log10)

Virologic Failure 11 (58%) 5.098*Patient non-compliance 2 (10%) -Adverse event (ABC HSR) 1 (5%) - Responders 5 (27%) 4.173*

Genotypic analysis showed: • M184V alone in 5 patients 45% of failures (n=11)• M184V+K65R in 4 patients 36% of failures

ABC/3TC/TDF in naïve patients(pilot study of early virological failure)

Conclusions• These preliminary results in 19 patients raise

concerns about the potency of ABC+3TC+TDF as a regimen administered once daily in HIV-1 treatment naïve patients, particularly in those patients with baseline HIV-1 RNA >100,000 copies/ml

Presentation 9-43Farthing C, Khanlou H, Yeh V

ABC/3TC/TDF in naïve patientsOther studies:

Study ESS30009Phase III open label, multicentre, randomised 1:1 (n=345)2 arms: A. (ABC+3TC) fixed dose tablet + EFV OD

vs B. (ABC+3TC) fixed dose tablet + TDF OD

• Unplanned interim analysis unexpected failures• Similar results at week 16 to those of Farthing et al.• Tenofovir arm stopped July 13, 2003French study (no other details available)• same design (ABC+3TC+TDF in naives)• similar results - stopped early July 2003

Possible reasons?

• Absorption?• Intracellular interaction?• Resistance development?• Pharmacokinetics unsuitable for ONCE daily

therapy?

• Intracellular studies planned• QUAD therapy with TZV+TDF……?

And the story continues ……

GlaxoSmithKline –issued a dear Dr letter - 29th July

As a result of recent interim analysis and termination of studies they recommend…….

• Do not initiate Abacavir + lamivudine + tenofovir in naïve patients (especially not ONCE daily abacavir)

• Patients on this combination should be closely monitored for early virological failure

What about induction – maintenance?

• Four drugs down to three– ESS40013- preliminary results

ESS40013 (TZV+ EFV in naïve patients)

48 week results

Objectives• To test 4-drug induction and 3-drug maintenance approach to ART.

Subjects received:– Induction with Trizivir + EFV (48 week) then if vRNA <50

copies/ml randomised to either:– Maintenance with Trizivir without EFV (48 weeks)– Maintenance with Trizivir + EFV (48 weeks)

• Baseline Characteristics– n=448 in Induction phase– Mean HIV-1 RNA 5.04 log10 copies/l (56% 100,000copies/ml)– Mean CD4+ cell count 245 cells/mm3 (48% <200)

Markowitz M et al Presentation 9-42


48 week results


% patients <50copies/mL• ITT (Observed) 90%• ITT (M=F) 61%

Stratified by entry % <50c/mL Median time to <50c/mL• <100,000 copies/mL 95% 16 weeks• 100,000 - 749 999 86% 17 weeks 750 000 copies/mL 90% 35 weeks

Most common treatment emergent RT mutations were:• M184V (46%) and K103N (41%) • Warning bells –similar mutation pattern ACTG 5095, Farthing

etc………


48 week results


37% discontinued 55 patients (11%) discontinued due to AEsDrug related AEs >10% incidence• nausea, fatigue, dreams, dizziness, rashes, sleep disorders, vomiting and

headaches• 33 (7%) consent withdrawal• 28 (6%) for virological failure

• 7% had abacavir hypersensitivity reaction

Discussion –why such a high drop out?In patients able to tolerate quad combination did OK

High viral loads took longer to get below undectable

• Nucleoside (cytosine) analogue

• One capsule, once daily, without food restrictions

• Long intracellular half-life

• Favorable safety profile

• Proven efficacy in treatment-naïve & treatment-experienced patients

• US FDA approval with broad indication, July 2003

• Expected to be available in UK October 2003

• Emtriva™

Emtricitabine – FTC

FTC

• 301 study: FTC/d4T with ddI/EFV

• ANRS 99: simplification to FTC/ddI/EFV

FTC : 301 study• FTC similar to 3TC• Od dosing 200mg

capsules • ? Slower resistance

development• May be co-formulated

with TDF• Active against HBV

• RCT: d4T vs TFC with ddI/EFV – Placebo controlled– Median F/U 60w

0%

10%

20%

30%

40%

50%

60%

70%

80%

<400 <50

FTC

d4T

P=0.0001

Raffi et al Presentation 9-38

Summary: FTC 301

• Once-daily FTC-containing regimen was statistically superior to twice-daily d4T-containing regimen– Significantly lower rate of virologic failure when used

with a backbone of once-daily ddI+EFV

• FTC-containing regimen was better tolerated and had fewer discontinuations than d4T-containing regimen

• FTC-ddI-EFV is a very potent and safe once-daily combination (ITT : 74% < 50cp/ml at 48 weeks)

Raffi et al Presentation 9-38

ALIZE-ANRS 99 Study (FTC/DDI/EFV od versus

continued PI-based HAART in HIV infected patients with undetectable HIV-1 RNA)

48 week resultsProspective, open label, multi-centre, non-inferiority study to assess the efficacy and safety of a once daily regimen of FTC/DDI/EFV in patients controlled with a PI-containing regimen NNRTI naïve

Viral load <400 copies/ml

• Patients (n=350) were randomised to either: – continue PI containing regimen (n=177)

– switch to a once daily regimen FTC/DDI/EFV (n=178)

(5 pills taken at bedtime)

Molina JM et al and the ALIZE Study Group Presentation 9-37

Simplification : ANRS 99

• FTC/ddI/EFV (all od) vs continued HAART

• n=350

• NNRTI naïve

• VL <400 copies at baseline

• 48 weeks; ITT

95%87%

0%10%20%30%40%50%60%70%80%90%

100%

<50

odc/t

Molina JM et al and the ALIZE Study GroupPresentation 9-37

P=0.01

BIKS Study (Bi-therapy Kaletra

Sustiva) (lopinavir/ritonavir +efavirenz combination)

24 week resultsPilot, ongoing, multicentre, open label study to evaluate LPV/rtv 533mg/133mg bd + EFV 600mg od in HIV infected patients NNRTI-naïve patients

If PI-experienced - fewer than 5 LPV associated mutations

• To assess NRTI-sparing regimens as alternative HAART

• Baseline characteristics– 86 patients enrolled - 65 ART-naïve and 21 experienced (12 PI-naïve)

– Mean baseline CD4 = 307 cells/mm3

– Mean baseline VL = 4.84 log10 copies/mL

Ferre V et al and BIKS Study Group Presentation 9-36

BIKS Study (lopinavir/ritonavir +efavirenz combination)

24 week resultsEfficacy results

– % patients with VL <400 copies/mL = 78% (ITT) 93% (AT)

– % patients with VL <50 copies/mL = 64% (ITT) 76% (AT)

– mean increase in CD4 count (cells/mm3) was 162 at week 24

– Viral rebound occurred in 4 patients

• 2 patients had blips - HIV RNA <400 copies/mL on subsequent control

• 1 patient was non adherent• 1 patient had confirmed

virological failure


0102030405060708090

100

<400 <50

OT

ITT

BIKS Study (lopinavir/ritonavir +efavirenz combination)

24 week resultsSafety and Tolerability results

– grade 3 and 4 clinically relevant adverse events were recorded in 34 patients (40%)

• hypercholesterolaemia n=29• hypertriglyceridaemia n=13• asymptomatic hepatic cytolysis n=3

Conclusions– The dual combination of LPV/rtv + EFV shows similar virological

efficacy to NRTI-based regimens with acceptable tolerability– Durability of antiviral effect will be assessed at week 48 of follow

up– Complete week 48 results available Q4 2003


Boosted PIs vs Unboosted• Draft BHIVA guidelines recommend boosted PIs are

‘preferred’ So which one is best ?• Od versus bd, pill burden, resistance profile, lipid

profile

• Concerns re Kaletra and lipid profiles• Atazanavir –just how potent is it ?• Saquinavir /ritonavir 1600mg /100mg od

–toxicity/tolerability issues

Atazanavir

• Once daily protease inhibitor 400mg od – 2 x200mg capsules with food

• Early access programme in UK– Current use as unboosted PI

– Caution drug interactions with tenofovir and efavirenz which decrease the atazanavir levels

• Licensed in the USA ‘Reyataz’

Atazanavir: concerns re potency

• Atazanavir = nelfinavir

• Nelfinavir < efavirenz

• Atazanavir = efavirenz ???

• Re-analysis of 034 study……

TLOVR Response (SE) Through Week 48 (LOQ = 400 c/mL) - Treated Subjects / / AI424034

ATV EFVN=404 N=401

0

20

40

60

80

100

WeeksB/L 4 8 12 16 20 24 28 32 36 40 44 48

TLOVR Response (SE) Through Week 48 (LOQ = 50 c/mL) - Treated Subjects / / AI424034

ATV EFVN=404 N=401

0

20

40

60

80

100

WeeksB/L 4 8 12 16 20 24 28 32 36 40 44 48

ATV-EFV difference estimate (95% CI): at LOQ = 400 copies/ml, 5.2 (-1.2, 11.7); at LOQ = 50 copies/ml, -4.9 (-11.4, 1.5)*TLOVR (Time to Loss Of Virologic Response)AI424-034

Pa

tie

nts

(%

)P

ati

en

ts (

%)

Virologic Response* ThroughWeek 48 (ITT) – Primary End Point

WeeksWeeks

ATV (N = 404)

EFV (N = 401)<400 copies/mL

7070

6464

3232

3737

<50 copies/mL

• Duplicated samples were assayed after collection in PPT or EDTA tubes

• 584 subjects (300 on ATV, 284 on EFV) were evaluable

– 88% of the 661 subjects treated for 48 weeks

– 73% of all 805 patients treated in the main study

ATVATV

EFVEFV

EDTAEDTA

93% 93%

96%96%

PPTPPT

83%83%

85% 85%

EDTAEDTA

86%86%

93%93%

PPTPPT

53%53%

57%57%

LOQ <400 copies/mLLOQ <400 copies/mL LOQ <50 copies/mLLOQ <50 copies/mL

Effect of Using PPT vs EDTA Tubeson Viral Load Measurements

Screening: prior PI failureScreening: prior PI failure

1:1 randomization (N1:1 randomization (N = 300)= 300)

Group IGroup I

ATV 400 mg qd

Group IIGroup II

+ 2 NRTIs

LPV/RTV 400/100 mg bid

+ 2 NRTIs

146146

115115

BMS-043

*Protocol-planned analysis which includes all subjects randomized through April 2, 2002 (24 weeks of therapy)

Treated: Treated: 144144

Efficacy cohort*: Efficacy cohort*: 144144

Study DesignStudy Design

Presentation 23- 117

BMS-043HIV RNA Mean Change—Co-Primary End Point 1

Efficacy Cohort

114114 106 106 105 105 103 103 102 102 95 95115115 112 112 112 112 109 109 108 108 102 102

ATVATVLPV/RTVLPV/RTV

ATV–LPV/RTV TAD estimate (97.5% CI) = 0.31 (0.06, 0.55)

HIV

RN

A M

ean

Ch

ang

e (S

E)

HIV

RN

A M

ean

Ch

ang

e (S

E)

(lo

g(l

og

1010 c

op

ies/

mL

) c

op

ies/

mL

) ATV (N = 114)

LPV/RTV (N = 115)

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

WeeksB/L 4 8 12 16 20 24


ATV

LPV/RTVLPV/RTV

*P*P<0.0001<0.0001††PP<0.05<0.05

Lipids in Study 043 Mean % Change From Baseline at Week 24

-2-6

12

-2

17

5

55

18

-30

-10

10

30

50

TC LDL-C HDL-C TGM

ean

% C

han

ge

*

*

†


BMS-045-24 week results

ATV 300 mg qdRTV 100 mg qd

ATV 400 mg qd SQV 1200 mg qd

LPV 400 mg bidRTV 100 mg bid

Weeks 1Weeks 1-2-2: maintain NRTIs & replace PI/NNRTI: maintain NRTIs & replace PI/NNRTI

Weeks 2Weeks 2--48: replace NRTIs with tenofovir 300 mg qd + 1 NRTI48: replace NRTIs with tenofovir 300 mg qd + 1 NRTI

Subjects who failed Subjects who failed 2 regimens & 2 regimens & 1 ARV from each class1 ARV from each class

1:1:1 randomization (N = 358)1:1:1 randomization (N = 358)

120120 115115 123123RandomizedRandomized

Study DesignStudy Design

Presentation 23- 118Presentation 23- 118Presentation 23- 118

BMS-045 HIV RNA Mean Change From Baseline Through Week 24

HIV

RN

A M

ean

Ch

ang

e (S

E)

(lo

g10

co

pie

s/m

L)

ATV 300/RTV – LPV/RTV TAD estimate (97.5% CI) = 0.14 (-0.09, 0.37)ATV 300/RTV – LPV/RTV TAD estimate (97.5% CI) = 0.14 (-0.09, 0.37)ATV 400/SQV – LPV/RTV TAD estimate (97.5% CI) = 0.31 (0.07, 0.55)ATV 400/SQV – LPV/RTV TAD estimate (97.5% CI) = 0.31 (0.07, 0.55)

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

WeeksB/L 4 8 12 16 20 24

LPV/RTV (N = 123)

ATV 300/RTV (N = 120)

ATV 400/SQV (N = 115)

Antiviral Efficacy in Randomized SubjectsAntiviral Efficacy in Randomized Subjects


62

42

* TLOVR: Time to Loss of Virologic Response* TLOVR: Time to Loss of Virologic Response

44

23

64

39

<400 copies/m

<50 copies/mL

Virologic Response at Week 24

% Responders (ITT: TLOVR*)

ATV 300/RTVn=120

ATV 400/SQVn=115

LPV/RTVn=123


CD4 Cell Mean Change From Baseline Through Week 24CD4 Cell Mean Change From Baseline Through Week 24

9083

59

0

20

40

60

80

100

120

140

B/L 2 4 8 12 16 20 24

Weeks

CD

4 M

ean

Ch

ang

e (S

E)

(cel

ls/m

m3)

ATV 300/RTV (n=120)

ATV 400/SQV (n=115)

LPV/RTV (n=123)

ATV 300/RTV – LPV/RTV: -18.4 (-44.3, 7.5)ATV 400/SQV – LPV/RTV: -44.9 (-74.5, 15.3)

Time-Averaged Difference Estimate (95% Cl)


AEs of Interest

Total

Diarrhea

Subjects, N (%)

ATV 300 / RTVN = 119

ATV 400 / SQVN = 110

LPV / RTVN = 118

Total bilirubin* 54 (45) 20 (19) 1 (<1)

ALT/SGPT 4 (3) 4 (4) 3 (3)

AST/SGOT 4 (3) 2 (2) 1 (<1)

Patients, N (%)

ATV 300/RTVN = 119

ATV 400/SQVN = 108

LPV/RTVN = 118

045: Grade 3-4 Laboratory Abnormalities

*Dose reductions, N (%): 9 (8) in ATV 300/RTV arm. No treatment discontinuations*Dose reductions, N (%): 9 (8) in ATV 300/RTV arm. No treatment discontinuations


(5% of Subjects)and AEs of Interest

Total

Subjects, N (%)

ATV 300 / RTVN = 119

ATV 400 / SQVN = 110

LPV / RTVN = 118

3 (3) 5 (5) 13 (11)

Antidiarrhoeal Medication:

Loperamide

Patients, N (%)

ATV 300/RTVN = 119

ATV 400/SQVN = 110

LPV/RTVN = 118

Incidence of Use of Anti-diarrhoeal Medicines

3 (3) 6 (5) 18 (15)


Grade 2 – 4 RelatedAEs

(5% of Subjects)and AEs of Interest

Total

Diarrhea

Jaundice

Nausea

Vomiting

Scleral lcterus

Subjects, N (%)

ATV 300 / RTVN = 119

ATV 400 / SQVN = 110

LPV / RTVN = 118

26 (22)

3 (3)

7 (6)

2 (2)

0

4 (3)

29 (26)

5 (5)

2 (2)

8 (7)

4 (4)

0

26 (22)

13 (11)

0

2 (2)

1 (1)

0

5% of Patients

Total

Diarrhoea

Jaundice

Nausea

Vomiting

Scleral icterus

Patients, N (%)

ATV 300/RTVN = 119

ATV 400/SQVN = 110

LPV/RTVN = 118

26 (22)

3 (3)

7 (6)

2 (2)

0

4 (3)

29 (26)

5 (5)

2 (2)

8 (7)

4 (4)

0

26 (22)

13 (11)

0

2 (2)

1 (1)

0

045 - Grade 2-4 Related Adverse Events


*Both ATV regimens vs LPV/RTV:P-value <0.0001*Both ATV regimens vs LPV/RTV:P-value <0.0001

Lipids: Mean % Change From Baseline at Week 24

-8 -10-7

-2

-9 -11

-1

-14

3

-4

31

0

-30

-10

10

30

50

TC LDL-C HDL-C TG

Mea

n %

Ch

ang

e

*

*ATV 300/RTV

LPV/RTVLPV/RTV

ATV 400/SQVATV 400/SQV

Censoring: Patients on Lipid Lowering Therapy Excluded


Conclusions • ATV 300 mg boosted with RTV 100 mg once daily demonstrated efficacy

similar to a standard of care (LPV/RTV) in the highly treatment-experienced patients through Week 24

• ATV 400/SQV was less effective than LPV/RTV• ATV boosted with RTV was associated with a more favorable lipid profile than

LPV/RTV

• ATV 300/RTV was safe and well tolerated

– Diarrhoea was more common on LPV/RTV– Total bilirubin increases were not clinically significant, did not lead to

treatment discontinuations, and was not associated with hepatotoxicity

MaxCMin 2: Design

* Stratification according to HIV-1 RNA / < 400 c/ml and region

PI naïvePI failure

PI intolerance

Lopinavir / ritonavir 400 / 100 mg bid

Saquinavir soft gel / ritonavir1000 / 100 mg bid

Randomisation 1:1 *

Clinical indication for a ritonavir -boosted PI treatment

2nd IAS 2003 Paris, France : Session 58 LB23, Youle et al

MaxCMin2 48 week data

Phase IV randomised open label trial comparing safety and efficacy of Lopinavir/rtv (400/100mg BID) compared with Saquinavir/rtv (1000/100mg BID)

• Concomitant use of > 2NRTI/NNRTI agreed prior to randomisation

• Patients were 79% male, 45% homosexual, 52% were PI experienced and 33% ART naive


MAXCMIN2 Trial 48 week data

MEASURE LPV / RTV ARM SAQ / RTV ARM P value

HIV-RNA <50copies/ml

ITT(exposed-switch inc)

64% 56% P>0.05


ITT(exposed-switch = failure)

60% 52% P>0.05


OT

70 75% P>0.05

Discontinued PI 13% 29% P=0.001

Clinical toxicity profile similar in both arms


Risk of virological failure – ITT/e

Primary efficacy analysis of protocol 0.

000.

250.

500.

751.

00

Pro

port

ion

who

hav

e no

t fai

led

base week 4 week 12 Week 24 week 36 week 48analysis time (weeks)

treatment = saquinavir treatment = lopinavir

Virological failure - ITT/e

Lopinavir/r 163 162 156 150 136 97

Saquinavir/r 161 159 142 128 114 82

Log rank test: p=0.0006

Proportional hazards test: p=0.75


MaxCMin2 48 week data

• Virological failure:– Higher in r/SAQ arm (p=0.0006)

• Treatment discontinuation:– Higher in r/SAQ arm (p=0.0001)

– Fortovase formulation • GI intolerance?

Enfuvirtide (T-20)

• Recently licensed• Injectable• New class of antiretroviral

• 48 week results of TORO studies• Predictors of 24 week success

TORO 1 & TORO 2: Protocol study design

– 6

Stable regimen

Screening period

ENF+OB

OB

BL 8 16 24 48

– 4

Sample for

GT/PT*

Weeks

Randomized 2:1, thenstart ENF+OB or OB

Switch permitted at virological failure** or at week 48

*GT = Genotypic Testing; PT = Phenotypic Testing

**Criteria for virological failure based on 2 consecutive values: 1. <0.5 log10 decrease from baseline starting at week 6 and 82. <1.0 log10 decrease from baseline starting at week 14 and 163. 2 log response and >1 log rebound at any time

Data following virological failure not included in primary efficacy analysesKatlama LB2

TORO 1 & TORO 2: BL characteristics and prior ARV experience

ENF+OB OB(N=661) (N=334)

BL RNA (median, log10 copies/mL) 5.2 5.1

BL CD4+ cell count (median, cells/mm3) 88 97

Number of prior ARVs (median) 12 12

Years since initiating ARVs (median) 7 7

Prior NRTI (median, years) 6.3 6.3

Prior NNRTI (median, years) 1.4 1.5

Prior PI (median, years) 3.8 4.0

Katlama

The treatment benefit seen at week 24 is maintained at week 48:

Percent responders at week 24 and week 48 (ITT, DC+VF=F)

47.2

37.432.7 30.4

15.9 18.324.9

12.015.017.1

6.3 7.8

0

20

40

60

80

100

% o

f p

ati

ents

ENF+OB OB

2 visits required to confirm viral load response

Week<50

copies/mL

48 48 481 log drop

from BL<400

copies/mL

N=661 N=334

All comparisons ENF+OB vs. OB P<0.0001

24 24 24

Katlama

CD4+ cell count adjusted means change from baseline – intent-to-treat population

(LOCF) TORO 1 & TORO 2

71

91

3545

0

50

100

24 48Study week

Ch

an

ge

fro

m B

L(c

ells

/mm

3)

ENF+OB OB

P<0.0001

P<0.0001

Katlama

The time to virological failure* was longeron ENF+OB compared to OB

ENF+OB

OB

0.00

0.25

0.50

0.75

1.00

Time to virological failure (weeks)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Pro

po

rtio

n w

ith

ou

t vi

rolo

gic

al f

ailu

re

Median time to VF 32 weeks vs. 11 weeks, P<0.0001

* Protocol definedKatlama

Incidence of injection site reactions (ISRs)* by study week and by grade, 48 weeks

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Weeks

% o

f p

atie

nts

wit

h I

SR

s

Mild tenderness

Moderate pain

Severe pain requiring analgesics or limiting usual activities

* based on pain or discomfort,% of patients remaining on study

Katlama

48 Week combined TORO 1 & TORO 2exposure adjusted AEs

(5 per 100 patient-years) ENF+OB OB

N (Per 100 patient-years)

Total exposure (patient-years) 557.04 162.13

bronchitis 50 (9.0) 24 (14.8)

appetite decreased 48 (8.6) 8 (4.9)

asthenia 43 (7.7) 14 (8.6)

anxiety 42 (7.5) 11 (6.8)

herpes simplex 41 (7.4) 15 (9.3)

abdominal pain 39 (7.0) 15 (9.3)

myalgia 39 (7.0) 9 (5.6)

pruritus 37 (6.6) 16 (9.9)

skin papilloma 37 (6.6) 5 (3.1)

*pneumonia 37 (6.6) 1 (0.6)

influenza 36 (6.5) 10 (6.2)

lymphadenopathy 33 (5.9) 2 (1.2)

folliculitis 32 (5.7) 13 (8.0)

pain in limb 32 (5.7) 13 (8.0)

dyspepsia 30 (5.4) 17 (10.5)

dry mouth 30 (5.4) 13 (8.0)

constipation 30 (5.4) 9 (5.6)

night sweats 28 (5.0) 12 (7.4)

dry skin 28 (5.0) 7 (4.3)

Incidence of bacterial pneumonia in

TORO trials and historical controls

Generaladult

population*

HIVinfected cohorts*

HIV Patients with CD4+

<200 cells/mm3*

0

2

4

6

8

10

ENF+OB OB

Inci

den

ce p

er

100

per

son

-yea

rs

6.6

0.6

Range1.5–2.9

Range9–10

Range5–9

*Boschini et al. Clin Inf Dis, 1996; 23, 107 Hirschtick et al. NEJM, 1995; 333, 845 Polsky et al. Ann Int Med, 1986; 104, 38 Caiaffa et al. Am J Resp Crit Care Med, 1994; 150, 1493 Wallace et al. Am Rev Resp Dis, 1993; 148, 1523

TORO

Multiple logistic regression for all patients:HIV-1 RNA <400 copies/mL at week 24

0.1 1 10

Better

Odds Ratio for RNA < 400 copies/mL (95% CI)

Enfuvirtide Treatment

BL CD4+ (per 100/mm3)

Prior PIs (n)Prior LPV/r

Active ARVs in OB (n)LPV/r in OB

BL log10 HIV-1 RNA

WorseMontaner

Simplified model for patients initiating enfuvirtide treatment*

Factor Odds ratio 95% C. I. P-value

Disease stage

BL CD4+ count (>100 cells/mm3) 2.4 (1.6, 3.5) <.0001

BL plasma HIV-1 RNA (<100K) 1.8 (1.2, 2.6) <.0022

Treatment history

No. of prior ARVs (10) 1.8 (1.2, 2.6) 0.0058

Activity of background regimen

2 active ARVs in background 2.8 (2.0, 4.0) <.0001

* HIV RNA<400 copies/ml at week 24

Montaner

1523

47

59

80

2

50

34

19

3*

*

*

*

*

% of patients with viral load <400 copies/ml at week 24 by number of positive prognostic

factors by simplified model

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4

% o

f P

atie

nts

Number of positive prognostic factors

140 188 192 101 4061 93 100 56 24N=

ENF + OB OB

* p<0.05

Montaner

T-20 Conclusions (Montaner et al)

• ENF added to an OB provided significant benefit across all studied sub-groups of triple-class experienced patients in TORO 1 and TORO 2

• Greatest benefit associated with ENF: CD4 100 cells/mm3

Viral load <100,000 copies/mlL Up to 10 prior ARVs Two or more active ARVs in background

• Patients with all 4 positive prognostic factors achieved 80% <400 copies/ml at week 24

Saquinavir 500mg tablet

• Bioavailability study

• Healthy volunteers

• 500mg bio equivalent to 200mg hard gel capsules when dosed with ritonavir

• 1000mg /100mg bd with food

• Reduction in pill

• No data on tolerability

Hijazi Y Poster 534

Nelfinavir 625mg

• 2 tablets bd instead of 5 bd

• No patients reported severe diarrhoea.

• After 4 weeks – 8.1% moderate to

severe diarrhoea on 250mg

– 1.6% on 625mgM Johnson P548

Reducing risk of transmission from mother to child transmission

through breastfeeding: SIMBA study

• Breastfeeding benefits mother and infant– social, cultural, financial and health aspects

• Risk of postnatal transmission though breastfeeding– estimated between 10%-15%– accounts for 40% of all MTCT

Vyankandondera J, et al Presentation 45LB - LB8


through breastfeeding: SIMBA study• Design:

– HIV+ women on AZT/DDI (n=405)• 36 weeks gestation to 1 week postpartum

– infants (randomised 1:1)• n= 199 3TC syrup daily• n= 198 NVP syrup daily

– duration of breastfeeding• 3TC 106 days (IQR 87-158)• NVP 100 days (IQR 87-148)


SIMBA studyInfant HIV transmission and safety

Results 3TC (n=199) NVP (n=198)HIV+ 17 (8.5%) 13 (6.5%)

deaths (HIV+) 5 (2.5%) 8 (4.1%)

HIV diagnosis Intrauterine 13 (6%) 11 (5.5%)early postnatal (<4 weeks) 2 (1%) 1 (0.05%)(late postnatal (>4 weeks) 1 (1%) 1 (0.05%

• Total SAEs 30 (15.1%) 43 (21.7%) (grade 3+4)



through breastfeeding: SIMBA study

• Conclusions– Combination of prophylactic ART given to breastfed

infants from HIV+ mothers and breastfeeding counselling reduces postnatal transmission from 15% to 1% in first month of life

– effective and affordable

– HIV+ mothers can safely breastfeed and not run the risk of her baby starving in resource-poor settings

– Strategy could reduce stigma in these settings

International AIDS Society Paris 2003 Rosy Weston Senior Principal Pharmacist Jefferiss Wing...

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Transcript of International AIDS Society Paris 2003 Rosy Weston Senior Principal Pharmacist Jefferiss Wing...