international aids society paris 2003 rosy weston senior principal pharmacist jefferiss wing...
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![Page 1: International AIDS Society Paris 2003 Rosy Weston Senior Principal Pharmacist Jefferiss Wing Pharmacy St. Mary’s NHS Trust](https://reader035.vdocuments.site/reader035/viewer/2022070412/56649f005503460f94c15802/html5/thumbnails/1.jpg)
International AIDS SocietyParis 2003
Rosy Weston
Senior Principal Pharmacist
Jefferiss Wing Pharmacy
St. Mary’s NHS Trust
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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
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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
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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
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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
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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
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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
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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%)
Presentation 9-41Gulick RM et al
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ACTG 5095: Time to first virologic failure
Presentation 9-41Gulick RM et al
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ACTG 5095: CD4 cell responses
Presentation 9-41Gulick RM et al
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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
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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?
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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
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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
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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
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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
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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
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Possible reasons?
• Absorption?• Intracellular interaction?• Resistance development?• Pharmacokinetics unsuitable for ONCE daily
therapy?
• Intracellular studies planned• QUAD therapy with TZV+TDF……?
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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
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What about induction – maintenance?
• Four drugs down to three– ESS40013- preliminary results
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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
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ESS40013 (TZV+ EFV in naïve patients)
48 week results
Markowitz M et al Presentation 9-42
% 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………
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ESS40013 (TZV+ EFV in naïve patients)
48 week results
Markowitz M et al Presentation 9-42
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
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• 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
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FTC
• 301 study: FTC/d4T with ddI/EFV
• ANRS 99: simplification to FTC/ddI/EFV
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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
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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
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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
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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
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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
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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
Ferre V et al and BIKS Study Group Presentation 9-36
0102030405060708090
100
<400 <50
OT
ITT
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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
Ferre V et al and BIKS Study Group Presentation 9-36
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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
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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’
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Atazanavir: concerns re potency
• Atazanavir = nelfinavir
• Nelfinavir < efavirenz
• Atazanavir = efavirenz ???
• Re-analysis of 034 study……
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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
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• 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
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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
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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
Presentation 23- 117
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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
*
*
†
Presentation 23- 117
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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
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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
Presentation 23- 118
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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
Presentation 23- 118
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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)
Presentation 23- 118
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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
Presentation 23- 118
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(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)
Presentation 23- 118
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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
Presentation 23- 118
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*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
Presentation 23- 118
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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
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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
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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
2nd IAS 2003 Paris, France : Session 58 LB23, Youle et al
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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
HIV-RNA <50copies/ml
ITT(exposed-switch = failure)
60% 52% P>0.05
HIV-RNA <50copies/ml
OT
70 75% P>0.05
Discontinued PI 13% 29% P=0.001
Clinical toxicity profile similar in both arms
2nd IAS 2003 Paris, France : Session 58 LB23, Youle et al
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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
2nd IAS 2003 Paris, France : Session 58 LB23, Youle et al
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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?
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Enfuvirtide (T-20)
• Recently licensed• Injectable• New class of antiretroviral
• 48 week results of TORO studies• Predictors of 24 week success
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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Reducing risk of transmission from mother to child transmission
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)
Vyankandondera J, et al Presentation 45LB - LB8
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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)
Vyankandondera J, et al Presentation 45LB - LB8
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Reducing risk of transmission from mother to child transmission
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