International AIDS Society Paris 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………

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

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

Randomized trial with HIV+, ART naïve subjects n=1147 (evaluable) Trizivir ® ( Combivir ® and EFV placebo) 3 nucleosides Combivir ® + EFV (Trizivir ® placebo) Control arm

Double blind + placebo controlled Adapted from Gulick RM et al

Trizivir ® + EFV (Combivir ® placebo) 4 drug arm

Presentation 9-41

ACTG5095

•

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 Adapted from Gulick RM et al Presentation 9-41

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 log 10 (71,434) copies/ml 57% <100,000 copies/ml

•

42% >100,000 copies/ml

–

CD4 : 238 cells/mm 3

• Median follow-up of 32 weeks (range 0-80) Gulick RM et al Presentation 9-41

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

pt estimate (95% CI) at wk 48 89% (85, 93%) 83% (78, 88%) 74% (65, 83%) 61% (50, 72%)

Gulick RM et al Presentation 9-41

ACTG 5095: Time to first virologic failure

Presentation 9-41 Gulick RM et al

Gulick RM et al

ACTG 5095: CD4 cell responses

Presentation 9-41

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%) 22 (27%) 3 (4%) RTI-assoc. subs. (without M184V) seq. not attempted (HIV RNA <500 cps/ml) 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  2log 10 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/mm 3 Farthing C, Khanlou H, Yeh V Presentation 9-43

ABC/3TC/TDF in naïve patients

(pilot study of early virological failure) Results: Virologic Failure Patient non-compliance Adverse event (ABC HSR) Responders ABC+3TC+TDF Mean HIV RNA (n=19) 11 (58%) Baseline (log 10 ) 5.098* 2 (10%) 1 (5%) 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 Farthing C, Khanlou H, Yeh V Presentation 9-43

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

ABC/3TC/TDF in naïve patients

Other studies: Study ESS30009 Phase 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, 2003 French 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 - 29 th 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 log 10 copies/l (56% 100,000copies/ml) – Mean CD4+ cell count 245 cells/mm 3 (48% <200) Markowitz M et al Presentation 9-42

ESS40013

(TZV+ EFV in naïve patients) 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%  750 000 copies/mL 90% 17 weeks 35 weeks Most common treatment emergent RT mutations were: • M184V (46%) and K103N (41%) • Warning bells –similar mutation pattern ACTG 5095, Farthing etc……… Markowitz M et al Presentation 9-42

ESS40013

(TZV+ EFV in naïve patients) 48 week results 37% discontinued 55 patients (11%) discontinued due to AEs Drug 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 Markowitz M et al Presentation 9-42

Emtricitabine – FTC

• 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™

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 Raffi et al

80% 70% 60% 50% 40% 30% 20% 10% 0% <400

P=0.0001

<50 FTC d4T

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 results

Prospective, 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

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 95% 87% <50

P=0.01

Molina JM et al and the ALIZE Study Group

od c/t

Presentation 9-37

BIKS Study (Bi-therapy Kaletra Sustiva)

(lopinavir/ritonavir +efavirenz combination)

24 week results

Pilot, 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/mm 3 – Mean baseline VL = 4.84 log 10 copies/mL Ferre V et al and BIKS Study Group Presentation 9-36

BIKS Study

(lopinavir/ritonavir +efavirenz combination)

24 week results

Efficacy 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/mm 3 ) 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

100 90 80 70 60 50 40 30 20 10 0 <400 <50 OT ITT

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

BIKS Study

(lopinavir/ritonavir +efavirenz combination)

24 week results

Safety and Tolerability results – grade 3 and 4 clinically relevant adverse events were recorded in 34 patients (40%) • hypercholesterolaemia • hypertriglyceridaemia n=29 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

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……

Virologic Response* Through Week 48 (ITT) – Primary End Point

100 100 ATV (N = 404) EFV (N = 401) 80 80

   

<400 copies/mL

     

70 64 60 60

 

40



20

    

<50 copies/mL 20 0 B/L 4 0 B/L 8 4 12

 

16 8



12 20 24 Weeks 20 28 24 32 28 36 32 40 36 ATV-EFV difference estimate (95% CI): at LOQ = 400 copies/ml, 5.2 (-1.2, 11.7);



ATV N=404



*TLOVR (Time to Loss Of Virologic Response) EFV N=401 Weeks AI424-034 ATV



N=404



EFV N=401 44

 

40 48 37 32 44 TLOVR Response (SE) Through Week 48 (LOQ = 50 c/mL) - Treated Subjects / / AI424034

 

48

Effect of Using PPT vs EDTA Tubes on Viral Load Measurements • 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

ATV EFV LOQ <400 copies/mL EDTA 93% PPT 83% 96% 85% LOQ <50 copies/mL EDTA 86% PPT 53% 93% 57%

BMS-043

Study Design Screening: prior PI failure 1:1 randomization (N = 300) Group I ATV 400 mg qd + 2 NRTIs Group II LPV/RTV 400/100 mg bid + 2 NRTIs Treated: 144 Efficacy cohort*: 144 *Protocol-planned analysis which includes all subjects randomized through April 2, 2002 (



24 weeks of therapy) 146 115

Presentation 23- 117

BMS-043

HIV RNA Mean Change—Co-Primary End Point 1

Efficacy Cohort 0.0

-0.5

-1.0

ATV (N = 114) LPV/RTV (N = 115) -1.5

-2.0

-2.5

B/L ATV LPV/RTV 114 115 4 8 12 Weeks 16 20 106 112 105 112 103 109 102 108 ATV –LPV/RTV TAD estimate (97.5% CI) = 0.31 (0.06, 0.55) 24 95 102

Presentation 23- 117

50

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

TC LDL-C HDL-C TG 55 * ATV LPV/RTV 30 17 12 18 10 -10 -2 * -6 † 5 -2 -30 *P<0.0001

†P<0.05

Presentation 23- 117

BMS-045 -24 week results

Study Design Subjects who failed



2 regimens &



1 ARV from each class 1:1:1 randomization (N = 358) Weeks 1-2: maintain NRTIs & replace PI/NNRTI ATV 300 mg qd RTV 100 mg qd ATV 400 mg qd SQV 1200 mg qd LPV 400 mg bid RTV 100 mg bid Weeks 2-48: replace NRTIs with tenofovir 300 mg qd + 1 NRTI Randomized 120 115 123

BMS-045

HIV RNA Mean Change From Baseline Through Week 24

Antiviral Efficacy in Randomized Subjects 0.0

-0.5

ATV 300/RTV (N = 120) ATV 400/SQV (N = 115) LPV/RTV (N = 123) -1.0

-1.5

-2.0

-2.5

B/L 4 8 12 Weeks 16 20 24 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)

Presentation 23- 118

Virologic Response at Week 24

% Responders (ITT: TLOVR*) <400 copies/m <50 copies/mL ATV 300/RTV n=120 64 39 ATV 400/SQV n=115 44 23 LPV/RTV n=123 62 42 * TLOVR: Time to Loss of Virologic Response

Presentation 23- 118

CD4 Cell Mean Change From Baseline Through Week 24 140 120 100 80 60 40 20 ATV 300/RTV (n=120) ATV 400/SQV (n=115) LPV/RTV (n=123) 0 B/L 2 4 8 Weeks 12 Time-Averaged Difference Estimate (95% Cl) ATV 300/RTV ATV 400/SQV – – LPV/RTV : -18.4 (-44.3, 7.5) LPV/RTV : -44.9 (-74.5, 15.3) 16 20 24 90 83 59

Presentation 23- 118

045: Grade 3-4 Laboratory Abnormalities

AEs of Interest Total Total bilirubin* Diarrhea ALT/SGPT AST/SGOT ATV 300 / RTV N = 119 ATV 400 / SQV N = 110 54 (45) 4 (3) 4 (3) 20 (19) 4 (4) 2 (2) LPV / RTV N = 118 1 (<1) 3 (3) 1 (<1) *Dose reductions, N (%): 9 (8) in ATV 300/RTV arm. No treatment discontinuations

Presentation 23- 118

Incidence of Use of Anti-diarrhoeal Medicines

(



5% of Subjects) Loperamide ATV 300 / RTV N = 119 ATV 400 / SQV N = 110 LPV / RTV N = 118

Presentation 23- 118

045 - Grade 2-4 Related Adverse Events

Grade 2 – 4 Related (



5% of Subjects) AEs ATV 300 / RTV N = 119 ATV 400 / SQV N = 110 LPV / RTV N = 118 1 (

<

1)

Presentation 23- 118

Lipids: Mean % Change From Baseline at Week 24

Censoring: Patients on Lipid Lowering Therapy Excluded TC LDL-C HDL-C TG 50 30 ATV 300/RTV ATV 400/SQV LPV/RTV 10 3 * -10 -8 -9 -30 -10 -11 -4 -7 -1 0 -2 -14 *Both ATV regimens vs LPV/RTV:P-value <0.0001

31 *

Presentation 23- 118

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

Clinical indication for a ritonavir-boosted PI treatment

PI naïve PI failure PI intolerance

Randomisation 1:1 *

Lopinavir / ritonavir 400 / 100 mg bid Saquinavir soft gel / ritonavir 1000 / 100 mg bid

* Stratification according to HIV-1 RNA  / < 400 c/ml and region 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 2nd IAS 2003 Paris, France : Session 58 LB23, Youle et al

MAXCMIN2 Trial 48 week data

MEASURE

HIV-RNA < 50copies/ml ITT(exposed-switch inc) HIV-RNA < 50copies/ml ITT(exposed-switch = failure) HIV-RNA < 50copies/ml OT Discontinued PI

LPV / RTV ARM

64% 60% 70

SAQ / RTV ARM

56% 52% 75% 13% 29%

P value

P>0.05

P>0.05

P>0.05

P=0.001

Clinical toxicity profile similar in both arms 2nd IAS 2003 Paris, France : Session 58 LB23, Youle et al

Risk of virological failure – ITT/e Primary efficacy analysis of protocol

Virological failure - ITT/e Log rank test: p=0.0006

Proportional hazards test: p=0.75

Lopinavir/r Saquinavir/r

base week 4 week 12 Week 24 analysis time (weeks) treatment = saquinavir week 36 treatment = lopinavir week 48

163 161 162 159 156 142

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

150 128 136 114 97 82

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

Randomized 2:1, then start ENF+OB or OB Screening period Sample for GT/PT* – 6 – 4 Stable regimen ENF+OB Switch permitted at virological failure** or at week 48 OB Weeks BL 8 *GT = Genotypic Testing; PT = Phenotypic Testing 16 24 **Criteria for virological failure based on 2 consecutive values: 1. <0.5 log 10 decrease from baseline starting at week 6 and 8 2. <1.0 log 10 decrease from baseline starting at week 14 and 16 3.



2 log response and >1 log rebound at any time Data following virological failure not included in primary efficacy analyses

Katlama LB2

48

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

BL RNA (median, log 10 copies/mL) BL CD4+ cell count (median, cells/mm 3 ) Number of prior ARVs (median) Years since initiating ARVs (median) Prior NRTI (median, years) Prior NNRTI (median, years) Prior PI (median, years) ENF+OB (N=661) 5.2

88 12 7 6.3

1.4

3.8

OB (N=334) 5.1

97 12 7 6.3

1.5

4.0

Katlama

100

The treatment benefit seen at week 24 is maintained at week 48: Percent responders at week 24 and week 48 (ITT, DC+VF=F)

ENF+OB N=661 OB N=334 80 All comparisons ENF+OB vs. OB P<0.0001

60 47.2

37.4

40 32.7

30.4

24.9

18.3

20 17.1

15.0

15.9

12.0

7.8

6.3

0 Week 24 48



1 log drop from BL 2 visits required to confirm viral load response 24 <400 48 copies/mL

Katlama

24 48 <50 copies/mL

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

100

(LOCF) TORO 1 & TORO 2

ENF+OB OB 91 P<0.0001

71 P<0.0001

45 50 35 0 24 Study week 48

The time to virological failure* was longer on ENF+OB compared to OB

1.00

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

0.75

0.50

ENF+OB 0.25

OB 0.00

0 4 8 12 16 20 24 28 32 36 40 Time to virological failure (weeks) 44 * Protocol defined 48 52 56

Katlama

100

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

Mild tenderness Moderate pain 80 Severe pain requiring analgesics or limiting usual activities 60 40 20

Katlama

0 0 4 8 12 16 20 24 Weeks * based on pain or discomfort, % of patients remaining on study 28 32 36 40 44 48

48 Week combined TORO 1 & TORO 2 exposure adjusted AEs (  5 per 100 patient-years) ENF+OB OB N (Per 100 patient-years) Total exposure (patient-years) bronchitis appetite decreased asthenia anxiety herpes simplex abdominal pain myalgia pruritus skin papilloma *pneumonia influenza lymphadenopathy folliculitis pain in limb dyspepsia dry mouth constipation night sweats dry skin 557.04 162.13 50 (9.0) 24 (14.8) 48 (8.6) 8 (4.9) 43 (7.7) 14 (8.6) 42 (7.5) 11 (6.8) 41 (7.4) 15 (9.3) 39 (7.0) 15 (9.3) 39 (7.0) 9 (5.6) 37 (6.6) 16 (9.9) 37 (6.6) 5 (3.1) 37 (6.6) 1 (0.6) 36 (6.5) 10 (6.2) 33 (5.9) 2 (1.2) 32 (5.7) 13 (8.0) 32 (5.7) 13 (8.0) 30 (5.4) 17 (10.5) 30 (5.4) 13 (8.0) 30 (5.4) 9 (5.6) 28 (5.0) 12 (7.4) 28 (5.0) 7 (4.3)

Incidence of bacterial pneumonia in TORO trials and historical controls

10 8 6 Range 5 –9 Range 9 –10 4 2 Range 1.5

–2.9

0 General adult population* HIV infected cohorts* HIV Patients with CD4+ <200 cells/mm 3 * *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 6.6

ENF+OB TORO 0.6

OB

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

Enfuvirtide Treatment BL CD4+



BL log 10



(per 100/mm HIV-1 RNA 3 ) Prior PIs (n) Prior LPV/r Active ARVs in OB (n) LPV/r in OB 0.1

1 10 Odds Ratio for RNA < 400 copies/mL (95% CI) Worse Better

Montaner

Simplified model for patients initiating enfuvirtide treatment* Factor Disease stage BL CD4+ count (>100 cells/mm 3 ) BL plasma HIV-1 RNA (<100K) Treatment history No. of prior ARVs (  10) Activity of background regimen  2 active ARVs in background

* HIV RNA<400 copies/ml at week 24

Montaner Odds ratio 95% C. I.

P-value 2.4

1.8

1.8

2.8

(1.6, 3.5) (1.2, 2.6) (1.2, 2.6) (2.0, 4.0) <.0001

<.0022

0.0058

<.0001

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

100 90

factors by simplified model

ENF + OB OB * p<0.05

80 80 70 60 50 47 59

* *

50 34 40 30 20 15 23

* *

19 10 0

*

2 3 0 1 2 3 Number of positive prognostic factors 4 N=

Montaner

140 61 188 93 192 100 101 56 40 24

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/mm 3  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 625mg M 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

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

SIMBA study Infant HIV transmission and safety Results 3TC (n=199) HIV+ deaths (HIV+) 17 (8.5%) 5 (2.5%) HIV diagnosis Intrauterine 13 (6%) early postnatal (<4 weeks) 2 (1%) ( late postnatal (>4 weeks) 1 (1%) • Total SAEs (grade 3+4) 30 (15.1%) NVP (n=198 13 (6.5%) 8 (4.1%) 11 (5.5%) 1 (0.05%) 1 (0.05% 43 (21.7%) ) Vyankandondera J, et al Presentation 45LB - LB8

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