What are the most promising opportunities for dose optimisation?
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1 What are the most promising opportunities for dose optimisation? Andrew Hill Liverpool University, UK
2 Global Financial Crisis How can we afford to treat million people with HIV in the future?
3 Lowering costs of HIV treatment and care Use generic drugs, in fixed-dose combinations Improve synthesis of antiretrovirals economies of scale Use new antiretrovirals which are cheaper to make Dose optimisation Rational use of diagnostics: less CD4 testing, cheap HIV RNA testing, less or no use of resistance testing. Simple models of medical care (e.g. nurse-led care, with doctor only as back-up). 3
4 The dilemmas of HIV dose-selection For several HIV drugs, Phase 2 data showed no difference in efficacy between doses, but higher doses were selected for Phase 3 and registration (e.g. EFV, LPV/r, ZDV, d4t, 3TC) Some ARV s showed clear dose-response for efficacy in Phase 2 (e.g. TDF, FTC, GSK-572). Drug development has to be rapid, to maximise return on investment. Dose-selection is made early, and then not reassessed. High doses are often selected from Phase 2. Safety can be dose-related, and is often only fully understood after drugs are approved: 4 e.g. lipoatrophy, mitochondrial toxicity, cardiovascular risk, renal toxicity.
5 What are the best opportunities for doseoptimisation? The drug should have strong efficacy, low current costs of production, and/or potential for re-formulation Phase 2 trials show strong efficacy at lower than approved doses. Potential for safety benefits at lower than approved doses Candidates: NRTIs: 3TC, (ZDV, d4t?), NNRTIs: EFV PI s: DRV/r, (LPV/r?) Other drugs may already have strong efficacy and low production costs NRTI: TDF Integrase: GSK-572 Drugs should fit into current and future algorithms for HIV treatment in developing countries 5
6 Minimum costs of ARV s, per person-year Drug (dose) Current cost Potential cost of new dose d4t 30 BID $24 $19 (20 BID, weight <60kg) TDF 300 OD $87 $87 ZDV 300 BID $93 $62 (200 BID, weight <60kg) 3TC 300 OD $32 $16 (150 OD) EFV 600 OD $75 $50 (400 OD) NVP 200 BID $37 $37 RPV 25 OD $30? $30? ETR 200 BID $913 $150 (re-formulation / upscale) LPV/r 400/100 BID $440 $264 (200/100 BID) ATV/r 300/100 OD $307 $219 (200/100 OD) DRV/r 400/100 BID $1095 $330 (400/50 BID / reformulation) RAL 400 BID $1113 $1113 GSK OD $40? $40? CHAI ARV Price Lists, Nov 2010
7 Treatment algorithms to optimise sequencing / diagnostics Current treatment algorithm 1 st line: TDF/3TC/EFV $200 CD4 count / HIV RNA Resistance testing 2 nd line: ZDV/3TC/LPV/r $550 CD4 count / HIV RNA Resistance testing 3 rd line: DRV/r/ETR/RAL $3121 Resistance tests used to decide On 2 nd and 3 rd line Empirical switching 1 st line: TDF/3TC/EFV HIV RNA > adherence counselling 2 nd line: DRV/r/GSK-572/3TC HIV RNA > adherence counselling 3 rd line: DRV/r + ETR / 3TC No cross-resistance between 1 st and 2 nd line. Minimal cross-resistance to 3 rd line.
8 Zidovudine The originally approved dose was 1500mg per day. Early ACTG trial showed survival benefit of ZDV 600mg daily versus 1500mg daily. Other trials showed trends for improved survival with lower ZDV dose (e.g. 400mg daily, in Nordic MRC trial) Cohort studies in HAART era suggest that lower dose ZDV (200mg BID) improves anaemia and maintains efficacy. In Europe, 250mg BID was the approved dose of ZDV until the late 1990s. This dose is still available for sale in Europe. A 300mg tablet was then introduced, and Combivir included 300mg ZDV. 200mg BID may be a better dose for those with weight <60 kg 8
9 ZDV low dose trial Cameroun starts recruitment in 3Q2010 Inclusion: Treatment naïve patients 48 week study (DSMB review at interim analysis) ZDV 200 mg BID + 3TC / NNRTI n=68 Follow-up 136 subjects ZDV 300mg BID + 3TC / NNRTI n=68 Follow-up 9 Endpoints: anaemia, HIV RNA reductions Interim results could justify a large Phase 4 trial
10 Meta-analysis of d4t 30(20) vs 40(30)mg BID HIV RNA<50 copies/ml at 24 weeks in randomized trials The doses of d4t were adjusted for weight: Standard dose = 40mg for weight >60kg, 30 mg for weight <60kg Lower dose = 30mg for weight >60kg, 20 mg for weight <60kg 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 10 40(30) dose 30(20) dose HIV NAT 002 ARV 065 ETOX Barcelona Madrid
11 Safety benefits of d4t 30(20) BID dose Munich cohort: Patients on d4t 30(20) mg BID: More likely to remain on treatment (p=0.02) Less likely to develop peripheral neuropathy (13% vs 26%, p=0.001) Cameroun study (n=243): patients on d4t 30 BID were 80% less likely to develop lipoatrophy than those on 40mg BID dose. Koegl et al 2003, EACS, Warsaw Cournil et al 2010, Antivir Ther 15: 1039
12 d4t dosing: 30(20)mg BID, weight adjusted 144 weeks Body weight US FDA Weight adjusted dose dose Weight >60kg 40mg BID 30mg BID Weight <60kg 30mg BID 20mg BID 144 weeks
13 Could we compare dose-optimised d4t with TDF in a new trial? ART-naïve patients (N = 1100) randomized 1:1 d4t 30(20)/3TC + NNRTI TDF/3TC + NNRTI Multicentre, randomised, 96 weeks Endpoints: HIV RNA, all Grade 3 adverse events, lipoatrophy, renal function
14 EFV (efavirenz) Licensed by US FDA in 1998, at 600mg OD dose. Available as 200mg and 600mg tablets Phase 2 trial (DMP-005) showed no difference in efficacy between 200, 400 and 600mg OD doses, combined with ZDV/3TC. DMP-004 trial (functional monotherapy) showed transient advantage for 600mg versus 400mg OD dosage, but not consistent across analyses Evidence for higher EFV levels in women, low body weight, African-Americans (partly related to genotype)
15 DMP-005 trial: ZDV/3TC + EFV 200, 400, 600mg od HIV RNA < 400 copies/ml 100 Percent HIV RNA < Efavirenz 200 mg + ZDV/3TC Efavirenz 400 mg + ZDV/3TC Efavirenz 600 mg + ZDV/3TC EFV 200 mg N = EFV 400 mg N = EFV 600 mg N = Weeks in study Haas et al. 5th CROI Abstract 698
16 DMP-005 trial summary EFV Treatment group 200mg OD 400mg OD 600 OD N week efficacy data Percent HIV RNA <400 86% 85% 79% Percent HIV RNA <50 83% 68% 67% Percent HIV RNA <1 50% 39% 59% 16 week CD4 rise (mean) Results sustained to Week 24 Haas et al. 5th CROI Abstract 698
17 ENCORE-1 trial (NCHECR, Sydney) Funding: Bill and Melinda Gates Foundation ART-naïve patients (N = 600) randomized 1:1 TDF/FTC + EFV 600 OD TDF/FTC + EFV 400 OD Multicentre, randomised, double-blind, 96 weeks Enrollment starts May 2011
18 Phosphorylation of 3TC to active form: 3TC-Triphosphate 3TC Terminates the viral DNA chain following incorporation by preventing further addition of new bases to the chain Phosphorylation (x3) Competes with dctp for incorporation into the viral nucleic acid chain Active 3TC-TP
19 3TC (lamivudine) Evaluated in Phase 2a trials at doses from 35 to 1400 mg per day. Phase 2b at 150 mg vs 300 mg BID No strong evidence for dose-related differences in efficacy, either in monotherapy or with ZDV. High level resistance developed rapidly at all 3TC doses Two PK trials suggest non-linear PK for the active metabolite (3TC-triphosphate) above the 150 mg OD dose. Approved doses: mg BID (initial approval) 300mg OD (later approval) 150mg OD? Target optimised dose?
20 3TC: plasma and triphosphate concentrations: 300 mg BID versus 150mg BID PK sub-study of Phase 3 programme Plasma 3TC triphosphate concentrations were slightly higher for 300mg BID versus 150mg BID dose: AUC 0-12 : 1.27 (95% C.I ) C min : 1.65 (95% C.I ) Did this higher 3TC-TP AUC and C min translate into better efficacy for the 300mg BID dose, versus 150 BID? Moore K et al, AIDS 1999, 13:
21 3TC in dose-ranging trials no effect of 3TC dose on HIV-1 RNA reductions 1.0 NUCA 3001 trial ZDV+3TC ZDV+3TC 150mg bid 300mg bid n=80 n= NUCA 3002 trial ZDV+3TC ZDV+3TC 150mg bid 300mg bid n=81 n= Log HIV RNA Change to Week Eron et al: NEJM 1995, 333:1662 Bartlett et al: Ann Int Med 1996, 125:161
22 3TC: switch from 150 BID to 300 OD dose PK cross-over trial: 150 BID to 300 OD Plasma 3TC triphosphate Cmin was slightly lower for 300mg OD versus 150mg BID dose: AUC 0-24 : 0.99 (95% C.I ) C 24,SS : 0.82 (95% C.I. 0.58, 1.14) Did this lower 3TC-TP C min translate into worse efficacy for the 300mg OD dose, versus 150 BID? Yuen G et al, Antimicrob Ag Chemother 2004, 48:
23 EPV20001: 3TC 300 mg OD versus 150mg BID HIV RNA <50 copies/ml at Week 48 ITT TLOVR analysis As Treated analysis difference = +1.5% (-9.7, +6.6%) difference = -4.8% (-10.1, +0.6) HIV RNA <400: 64% vs 63% HIV RNA <400: 97% vs 97% HIV RNA <50 by Week 48 (%) n=278 n=276 n=223 n=225 DeJesus et al 2004, CID 39,
24 ENCORE-2 trial, 3TC-TP: 18-27% lower for 3TC 150 OD versus 300 BID dose Will these differences in 3TC-TP levels translate into differences in HIV RNA suppression rates, if the new 150 OD dose is compared with 300 OD in randomised trials? Basic mixed Full mixed model model Dose Arm Period Dose Dose (OD) Parameter Geometric mean (90% CI) GMR (90% CI) P value P value P value GMR (90% CI) 150 mg AUC ( ) 300 mg pmol.h/10 6 cells 59.5 ( ) 150 mg C (1.0, 1.52) 300 mg pmol/10 6 cells 1.49 (1.19, 1.86) 150 mg C max 2.95 (2.47, 3.51) 300 mg pmol/10 6 cells 4.10 (3.59, 4.69) 0.73 (0.64, 0.83) < (0.64, 0.86) 0.82 (0.68, 0.99) (0.68, 1.01) 0.70 (0.61, 0.82) < (0.61, 0.85)
25 LPV/r (lopinavir/ritonavir) Evaluated in Phase 2 trials at the 200/100, 400/100 and 400/200 mg BID doses (naïve patients) Abbott 720 trial Pharmacokinetics of 200/100 mg BID and 400/100 mg BID doses were similar The 200/100 mg BID dose showed the strongest efficacy in naïve patients, similar PK to the 400/100 mg BID dose, but was not taken to Phase 3 The main adverse events of LPV/r GI and lipid elevations, have been associated with higher LPV levels LPV/r now available as 200/50 mg tablets, with significantly higher LPV bioavailability (15-25%) than original 133/33 mg capsule formulation used in the registrational trials. 25
26 Abbott-720 trial: LPV/r pharmacokinetics Murphy R, et al. AIDS 2001, 15: 1-9
27 Abbott-720 trial: RNA < 400 copies HIV RNA suppression to <400 copies/ml to Week 48 for LPV/r 400/100 and 200/100 mg BID 100 LPV/r 200/100 mg BID Proportion <400 copies LPV/r 400/100 mg BID Week Murphy R, et al. AIDS 2001, 15: 1-9
28 DRV/r (darunavir/ritonavir) Approved dose is 600/100 mg BID for pre-treated patients, 800/100 OD for naïve patients. Boosting effect of 50mg ritonavir slightly lower than 100mg If DRV/r is kept for 3 rd line treatment (after ATV/r or LPV/r), then BID dosing should be maintained. 400/50 BID should be sufficient for most PI experienced patients. In the Phase 2 POWER trials, a 400/100 OD dose was effective for patients sensitive to DRV, but not for DRV resistant patients. If DRV/r is to be used in PI naïve patients, should we evaluate a 400/50 once daily dose? 28
29 DRV/r (darunavir/ritonavir): PK by RTV dose Cross-over PK trial in healthy volunteers (n=21) DRV/r 800 mg OD, with RTV doses of 20, 50 and 100mg OD PK parameter 800/50 OD 800/100 OD GMR (90% CI) AUC 24h ngh/ml 68,510 77, ( ) Cmax, ng/ml 6,144 6, ( ) Cmin, ng/ml 1,452 1, ( ) 29 TMC114-C181 trial
30 DRV/r Phase 2 trials: %HIV RNA >1 log reduction at Week 24, by dose and baseline DRV resistance DRV FC <4 (sensitive) 400/ / / /100 4 OD OD BID BID DRV/r dose group DRV FC >4 (resistant) 400/ / / /100 4 OD OD BID BID DRV/r dose group Katlama C et al AIDS 2007, 21: Haubrich et al AIDS 2007, 21: F11-F18
31 Potential Cost savings from dose optimisation and reformulations Current treatment algorithm 1 st line: TDF/3TC/EFV $200 2 nd line: ZDV/3TC/LPV/r $550 Dose-optimised / re-formulations 1 st line: TDF/ 3TC150 /EFV 400: $160 d4t/ 3TC150 / EFV 400: $85 TDF/3TC150/ GSK-572: $143? d4t/ 3TC150/ GSK-572 $78? 2 nd line: DRV/r 400/50 OD GSK-572 3TC $276? (-50%) 3 rd line: DRV/r + ETR / RAL $ rd line: DRV/r(400/50 BID) + ETR / 3TC $496? (-84%)
32 Conclusions We could improve the safety profile of ARV treatment and save up to $3.4 billion per year by a programme of dose optimisation, combined with re-formulation and rational use of diagnostics. Large, well-powered non-inferiority trials are required to prove the efficacy of the new doses versus the approved doses. There is enough evidence to support starting Phase 3 pivotal trials of DRV/r, LPV/r, d4t and ZDV now. For 3TC and ATV/r, Phase 2 efficacy trials would be needed, to justify progressing to pivotal trials in the future. Dose optimisation involves high-cost, long-term trials. The economics should be compared with other ways to improve treatment and care for developing countries. 32
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