MEASURING UP Clinical performance of boosted saquinavir in

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MEASURING UP – Clinical performance of boosted saquinavir in diverse treatment groups David Cooper

MEASURING UP – Clinical performance of boosted saquinavir in diverse treatment groups David Cooper

MEASURING UP – Clinical performance of boosted saquinavir in diverse treatment groups David Cooper

MEASURING UP – Clinical performance of boosted saquinavir in diverse treatment groups David Cooper

Why boost protease inhibitors? • Improved pharmacokinetic profile • Fewer pills, less often •

Why boost protease inhibitors? • Improved pharmacokinetic profile • Fewer pills, less often • Greater convenience • Greater potency against resistant virus?

There are two types of boosting 1. Cmax boosting – for PIs with poor

There are two types of boosting 1. Cmax boosting – for PIs with poor intrinsic bioavailability 9000 Cmax 8000 7000 SQV-sgc/r 1600/100 mg qd SQV-sgc 1200 mg tid 6000 [SQV] (ng/ml) 5000 4000 3000 2000 1000 0 0 5 10 15 Time (hours) 20 25

There are two types of boosting 2. Half-life boosting – for PIs with good

There are two types of boosting 2. Half-life boosting – for PIs with good bioavailability but short half-life PI PI/r mean conc (ng/ml) main effect on half-life little effect on Cmax 0 1 2 4 6 Time (hours) 8 10 12

Examples of Cmax and half-life boosting Mainly Cmax boosting Mainly half-life boosting Saquinavir Indinavir

Examples of Cmax and half-life boosting Mainly Cmax boosting Mainly half-life boosting Saquinavir Indinavir Lopinavir Amprenavir

Ritonavir-based boosting Advantages Disadvantages Better adherence P 450 complete inhibition Better trough levels Ritonavir

Ritonavir-based boosting Advantages Disadvantages Better adherence P 450 complete inhibition Better trough levels Ritonavir toxicities Co-formulation Drug interactions

PI levels Effect of drugs on PI concentration CYP 3 A 4 inhibitors boost

PI levels Effect of drugs on PI concentration CYP 3 A 4 inhibitors boost PI levels ritonavir atazanavir delavirdine ketoconazole nelfinavir indinavir grapefruit juice CYP 3 A 4 inducers reduce PI levels garlic St John’s wort nevirapine efavirenz rifampicin lopinavir?

Boosted protease inhibitors Licensed • Lopinavir/ritonavir 400/100 mg bid • Saquinavir/ritonavir* 1000/100 mg bid

Boosted protease inhibitors Licensed • Lopinavir/ritonavir 400/100 mg bid • Saquinavir/ritonavir* 1000/100 mg bid • Amprenavir/ritonavir 600/100 mg bid Under evaluation • Indinavir/ritonavir 800/100 mg bid *approved for use in Europe, registration in other areas in progress

PI adverse events Gastrointestinal Lipodystrophy APV IDV LPV/r NFV RTV SQV * Hepatitis Nephrolithiasis

PI adverse events Gastrointestinal Lipodystrophy APV IDV LPV/r NFV RTV SQV * Hepatitis Nephrolithiasis Hyperbilirubinaemia Retinoid effects Rash Paresthesia Asthenia * Diarrhoea = drug causes toxicity; = main toxicity. Adapted from Bartlett JG. 2002 Abbreviated Guide to Medical Management of HIV Infection. Johns Hopkins University School of Medicine, 2002

Not all PIs are the same in terms of effects on lipids and overall

Not all PIs are the same in terms of effects on lipids and overall AE profile

Max. Cmin 1: the first head-to-head comparison of boosted protease inhibitors Clinical indication for

Max. Cmin 1: the first head-to-head comparison of boosted protease inhibitors Clinical indication for ritonavir-boosted PI treatment PI-naive PI failure PI intolerance Randomization 1: 1 Indinavir/r 800/100 mg bid Saquinavir/r 1000/100 mg bid 158 patients 148 patients Cahn et al. 14 th IAC. 2002; abstract We. Or. B 1265

Max. Cmin 1: baseline characteristics Parameter IDV/r % of total SQV/r Gender (male) 74

Max. Cmin 1: baseline characteristics Parameter IDV/r % of total SQV/r Gender (male) 74 82 CDC, clinical cat. C 28 ART-naïve 22 28 PI-experienced 63 32 59 Median HIV-1 RNA (log 10 copies/ml) 4. 0 Median CD 4+ (cells/mm 3) 280 4. 0 272 Cahn et al. 14 th IAC. 2002; abstract We. Or. B 1265

Max. Cmin 1: Percentage of patients with HIV RNA <400 copies/ml at 48 weeks

Max. Cmin 1: Percentage of patients with HIV RNA <400 copies/ml at 48 weeks ITT/e (switch included), ITT/e/switch = failure and “on-treatment” analysis % patients 100 80 90 77 79 94 P = 0. 014 68 60 53 IDV/r SQV/r 40 20 0 IDV/r SQV/r ITT/e/s "On-treatment" n = 158 n =148 158 148 94 107 e = exposed to treatment Cahn et al. 14 th IAC. 2002; abstract We. Or. B 1265

Max. Cmin 1: Percentage of patients with HIV RNA <50 copies/ml ITT/e (switch =

Max. Cmin 1: Percentage of patients with HIV RNA <50 copies/ml ITT/e (switch = failure) % patients 100 Saquinavir/r 1000/100 mg bid 80 60 40 Indinavir/r 800/100 mg bid P = NS 20 0 0 4 12 24 36 48 Time (weeks) Gerstoft et al. ICAAC. 2002; abstract H-172

Max. Cmin 1: CD 4 T cell increase over 48 weeks Saquinavir/r 1000/100 mg

Max. Cmin 1: CD 4 T cell increase over 48 weeks Saquinavir/r 1000/100 mg bid Change in CD 4 count (cells/mm 3) 100 80 60 Indinavir/r 800/100 mg bid 40 P = NS 20 0 0 4 12 24 36 48 Time (weeks) Gerstoft et al. ICAAC. 2002; abstract H-172

Time until an initial grade 3 or 4 adverse even for patients treated with

Time until an initial grade 3 or 4 adverse even for patients treated with SQV/r or IDV/r Adverse events Proportion of subjects without a grade 3/4 AE 1. 00 Saquinavir/r (1000/100 mg bid) 0. 75 Indinavir/r (800/100 mg bid) 0. 50 0. 25 Log-rank test: P <0. 001 0. 00 0 4 12 24 36 Analysis time (weeks) 48 Cahn P et al. 14 th IAC. Barcelona, 2002; abstract We. Or. B 1265

Max. Cmin 1: Median % change from baseline in fasting lipid levels (ITT/e) %

Max. Cmin 1: Median % change from baseline in fasting lipid levels (ITT/e) % increase from baseline IDV/r : Median baseline value TC / LDL / TG (mmol/l): 4. 7/3. 1/1. 6 SQV/r : Median baseline value TC / LDL / TG (mmol/l): 4. 8/3. 2/1. 7 ** 30 25 20 * P < 0. 01 ** P < 0. 05 * * ** 139 128 121 Week 48 ** ** 15 10 5 0 Total cholesterol 85 78 Week 4 73 60 Week 48 LDL cholesterol 143 132 129 Week 48 Triglycerides (Indication in bars of number of measurements (patients) at each time point) Gerstoft et al. ICAAC. 2002; abstract H-172

Interim analysis of a phase IV, randomized, open-label, multicentre trial to evaluate safety and

Interim analysis of a phase IV, randomized, open-label, multicentre trial to evaluate safety and efficacy of lopinavir/ritonavir (400/100 mg bid ) versus saquinavir/ritonavir (1000/100 mg bid) in adult HIV-1 infection. The Max. Cmin 2 trial Ulrik Dragsted (Hvidore, Denmark) Plenary session 14. 5 Thursday 21 November 2002 11: 20 – 11: 40

Double protease inhibitor boosting Protease inhibitor 1 Boost Protease inhibitor 2 Patients with extensive

Double protease inhibitor boosting Protease inhibitor 1 Boost Protease inhibitor 2 Patients with extensive treatment experience and high viral load Ritonavir 100 mg bid Boost

Double protease inhibitor boosting Saquinavir (1000 mg bid) Boost Lopinavir (400 mg bid) Patients

Double protease inhibitor boosting Saquinavir (1000 mg bid) Boost Lopinavir (400 mg bid) Patients with extensive treatment experience and high viral load Ritonavir 100 mg bid Boost

Trials of double boosted SQV/LPV/r 1000/400/100 mg bid n SQV/LPV/r + NRTIs Efficacy Ruiz

Trials of double boosted SQV/LPV/r 1000/400/100 mg bid n SQV/LPV/r + NRTIs Efficacy Ruiz 24 36% <80/ml at 24 wks Hellinger 28 42% <50/ml at 24 wks Smith 36 61% > – 0. 8 log at 4 wks Zala 23 40% <500/ml at 48 wks SQV/LPV/r without NRTIs Staszewski 42 1) Ruiz et al. 9 th CROI. 2002; poster 421 -W 3) Smith et al. XIV IAC. 2002; poster Tu. Pe. B 4547 5) Staszewski et al. ICAAC. 2002; poster V 9 median 3. 5 log at 24 wks 2) Hellinger et al. 9 th CROI. 2002; poster 451 -W 4) Zala et al. XIV IAC. 2002; poster Tu. Pe. B 4492

Cmax boosting: saquinavir boosted with atazanavir and ritonavir Dose (mg): SQV concentration (ng/ml) 10000

Cmax boosting: saquinavir boosted with atazanavir and ritonavir Dose (mg): SQV concentration (ng/ml) 10000 1600 SQV/400 ATV qd 1 1600 SQV/100 RTV qd 2 1200 SQV tid 3 1000 ATV exposure unaffected by SQV coadministration 100 10 0 5 10 15 Time (hours) 20 25 1) O’Mara et al. 7 th CROI. 2000; abstract 504. 2) Burger et al. 3 rd Int. Workshop on Clin. Pharmacology of HIV Therapy. 2000. 3) Saag et al. 39 th ICAAC. Chicago; 1999, abstract 330

HIV RNA change (log 10 copies/ml) BMS-009: SQV/ATV qd vs SQV/RTV bid in patients

HIV RNA change (log 10 copies/ml) BMS-009: SQV/ATV qd vs SQV/RTV bid in patients with prior failure SQV/ATV 1200/400 mg (n = 34) 0. 0 SQV/ATV 1200/600 mg (n = 28) – 0. 5 SQV/RTV 400/400 mg (n = 23) – 1. 0 – 1. 5 – 2. 0 BL 4 8 12 16 20 24 28 32 36 40 44 48 Time (week) Group: ATV 400: ATV 600: RTV: Number at risk 34 30 30 30 28 23 24 22 23 20 20 17 29 23 18 29 20 14 29 22 13 26 21 11 23 18 12 22 18 11 Haas et al. 41 st ICAAC. 2001; abstract LB 16

Summary (1) • There is a need for treatments with good long-term safety and

Summary (1) • There is a need for treatments with good long-term safety and tolerabilty • Not all PIs have the same lipid or other AE profiles • In Max. Cmin 1, saquinavir/r 1000/100 mg bid and indinavir 800/100 mg bid were both highly potent in suppressing viral replication • Saquinavir/r 1000/100 mg bid appears to be better tolerated than indinavir/r

Summary (2) • Double PI boosted regimens such as saquinavir/lopinavir/r 1000/400/100 mg bid are

Summary (2) • Double PI boosted regimens such as saquinavir/lopinavir/r 1000/400/100 mg bid are a potential option for heavily pre-treated patients • Is atazanavir an alternative booster to ritonavir?