Integrase Inhibitoren AREVIR-GenaFor-Meeting Bonn, 10.-11. April - - PowerPoint PPT Presentation
Integrase Inhibitoren AREVIR-GenaFor-Meeting Bonn, 10.-11. April 2008 Dr. med. Stefan Esser Universittshautklinik Essen Die zweite Welle antiretroviral wirksamer Substanzen Wamsley S, 15th CROI 2008 Boston USA The second HAART-Wave: Neue
AREVIR-GenaFor-Meeting Bonn, 10.-11. April 2008
Wamsley S, 15th CROI 2008 Boston USA
virale RNA virale RNA Reverse Transkriptase/ Ribonuklease H provirale DNA provirale DNA virale Proteine virale Proteine
mRNA mRNA zelluläre DNA zelluläre DNA
Reverse Transkriptase Inhibitoren:
Reverse Transkriptase Inhibitoren:
Protease Inhibitoren:
Protease Inhibitoren:
Nukleus
HIV HIV
Integrase Inhibitoren:
*Raltegravir *Elvitegravir
Entry- Inhibitoren:
*Maraviroc *Vicriviroc
Entry- Inhibitoren:
*Maraviroc *Vicriviroc
Protease Integrase gp41 gp41 gp120 gp120
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CD4-T-Lymphozyt
Maturations (Reifungs) Inhibitoren Maturations (Reifungs) Inhibitoren
Mature Provirus Gap Repair Nuclear Membrane Nuclear Entry Virale DNA Synthesis 1 Assembly on Viral DNA in a Nucleoprotein Complex 2 In-Dependent Processing
3a Target DNA Binding 3b Concerted Target DNA Cleavage and Joining 3 Strand- Transfer
HIV-1 Integrase Inhibitoren Strand Transfer Inhibitoren = MK-0518
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Gap Repair
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EFV or RAL at 100, 200, 400 or 600 mg BID – Mean HIV RNA 4.6–4.8 log10 c/mL – Mean CD4+ 271–338 cells/mm3 – All susceptible at baseline
– More CNS AEs with EFV Virologic failures
– Two with integrase mutations; both N155H, 1 with multiple mutations – 3TC resistance (n=4) – K65R (n=1)
– K65R and G190E
Markowitz M, et al. 4th IAS, Sydney 2007, #TUAB104
100 80 60 40 20 0 2 4 8 12 16 24 32 40 48 Week
RAL 200 mg BID (n=40) RAL100 mg BID (n=39) RAL 400 mg BID (n=41) RAL 600 mg BID (n=40) EFV 600 mg QD (n=38)
Patients with HIV RNA <50 c/mL (%)
HIV RNA <50 c/mL (95% CI) [NC=F] Change from baseline
10 20 30 40 50 60 TC LDL TG TC:HDL Mg/dL RAL EFV
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HIV-infected patients with triple-class resistance and HIV-1 RNA > 1000 copies/mL (BENCHMRK-1: N = 352; BENCHMRK-2: N = 351) Placebo + OBR* (BENCHMRK-1: n = 118; BENCHMRK-2: n = 119) Raltegravir 400 mg twice daily + OBR* (BENCHMRK-1: n = 232; BENCHMRK-2: n = 230) Planned follow-up: Week 156 *Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted. Current Analysis: Week 48
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† GSS/PSS = total ART in OBT to which patient's virus showed geno/phenotypic sensitivity by
Phenosense GT assay. Enfuvirtide and darunavir use in naïve patients were each counted at +1 active agent and added to GSS/PSS. 25 27 % new darunavir in OBT 20 21 % new enfuvirtide in OBT 18 / 33 19 / 29 % PSS† 0 / 1 29 / 41 30 / 33 % GSS† 0 / 1 3 / 19 / 2 6 / 13 / 2 % Hepatitis B+ / % Hepatitis C+ / both 10 (12) 11 (12) Median yrs of prior ARTs (Mean # ART) 89 94 %with AIDS 31828 (4.5) 40519 (4.6) GM Viral Load, copies/mL (log10HIV RNA) 105 140 Median CD4 Count, cells/mm3 81 75 % Caucasian 87 84 % Male 44 (8) 46 (9) Mean Age, yrs (SD) Placebo + OBT N = 118 Raltegravir + OBT N = 232 Universitätshautklinik Essen
* Definition of virologic failure: 1) <1 log10 ↓ HIV RNA from baseline and HIV RNA >400 copies/mL at wk 16, OR 2) virologic relapse: >1 log10 ↑ HIV RNA above nadir or >400 copies/mL from nadir after response <400 copies/mL(on 2 consecutive measurements at least 1 week apart).
(3) 4 (2) 4 Discontinued due to adverse event (7) 8 (3) 6 Discontinued study (51) 60 (14) 33 Entered Open-Label post VF* phase (42) 50 (83) 193 Continuing in Double-Blind phase (100) 118 (99) 232 Treated 118 234 Randomized (%) N (%) N Placebo + OBT Raltegravir + OBT Universitätshautklinik Essen
Change From Baseline in CD4 Cell Count (cells/mm3) and Log10 HIV RNA (BENCHMRK-1, Observed Failure Approach)
For change from baseline in CD4 cell counts, p-value was derived from a mixed-effects model adjusted for: baseline CD4 cell count, stratum, treatment, visit, interactions between visit and previous variables. For change from baseline in log10 HIV RNA level, p-value was derived from a parametric regression model adjusted for: baseline HIV RNA level(log10), first enfuvirtide use in OBT, first darunavir use in OBT and active PI in OBT.
120 49 83 31
p<0.001 p<0.001 p<0.001 p<0.001
Note: Baseline carried forward for virologic failures.
Percent of Patients Achieving HIV RNA <50 Copies/mL(95% CI)
(BENCHMRK-1, Non-Completer=Failure Approach)
* +OBT; p-value was derived from a logistic regression model adjusted for baseline HIV RNA level (log10), first enfuvirtide use in OBT, first darunavir use in OBT, active PI in OBT. At Week 48, HIV RNA <400 copies/mL was achieved in 74% of the raltegravir group vs 36% of the placebo group (p<0.001)
232 231 231 230 229 232 229 230 231 118 118 118 118 117 118 118 118 118 Raltegravir* Placebo* 0 2 4 8 12 16 24 32 40 48 Weeks 20 40 60 80 100 Percent of Patients with HIV RNA <50 Copies/mL Number of Contributing Patients
65% 31% p<0.001 p<0.001 62% 33%
Raltegravir+OBT Placebo+OBT (N=232) (N=118) Difference from Placebo† % % % (95% CI) p-Value Mean follow-up (weeks) % patients with: Any AE 54.5 90.9 38.6 84.7 6.20 (-0.7, 14.4) 0.105 Drug-related‡ AE 48.7 54.2
0.366 Serious AE 19.8 17.8 2.03 (-7.1, 10.2) 0.774 Serious drug-related AE 3.0 0.8 2.17 (-1.8, 5.4) 0.275 Deaths 1.3 2.5
0.409 Discontinued due to AE 1.7 3.4
nps§
† Tests of significance were performed on the percentage of patients with at least one adverse event in the category. The 95% CIs were
calculated using Miettinen and Nurminen's method. p-Values were generated using the Fisher exact test.
‡ Determined by the investigator to be possibly, probably, or definitely drug related. § nps=not pre-specified for statistical analysis.
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Percent of Patients with Drug Related‡ Clinical Adverse Events (≥2%, any intensity) in BENCHMRK-1
Raltegravir+OBT Placebo+OBT (N = 232) (N = 118) Mean Follow-Up (weeks) % Patients With: Abdominal Distension 54.5 0.4 38.6 3.4 Abdominal Pain 1.3 3.4 Diarrhoea 6.9 14.4 Nausea 3.9 6.8 Vomiting 2.6 7.6 Fatigue 2.2 Injection Site Nodule 0.4 2.5 Injection Site Pain 2.6 1.7 Injection Site Reaction 7.3 11.9 Arthralgia 2.2 Headache 3.0 6.8 Insomnia 1.7 3.4 Lipodystrophy Acquired 1.7 3.4 Pruritus 2.2 Subcutaneous Nodule 1.7 2.5
‡ Determined by the investigator to be possibly, probably, or definitely related to any drug in the treatment regimen.
1.9 – 3.4 x ULN
Grade 3 Serum creatinine (mg/dL) ≥ 3.5 x ULN Grade 4 >500 Grade 4 1.7 1.7 251 - 500 Grade 3 Fasting glucose (mg/dL) 0.8 3.0 >1200 Grade 4 1.7 4.3 751 - 1200 Grade 3 Fasting triglyceride (mg/dL) 4.2 11.6 >300 Grade 3 Fasting cholesterol (mg/dL) 6.4 7.8 ≥190 Grade 3 Fasting LDL-C (mg/dL) 0.8 1.7 <25 Grade 4 0.8 0.9 25 – 49.999 Grade 3 Platelet count (103/µL) 0.4 <6.5 Grade 4 0.8 1.3 6.5 -7.4 Grade 3 Hemoglobin (gm/dL) 0.9 <0.50 Grade 4 2.5 2.6 0.50 -0.749 Grade 3 ANC (103/µl) Placebo (N=118) Raltegravir (N=232) Toxicity Criteria* Laboratory Test (Unit)
* Grades 3 and 4 per DAIDS toxicity criteria. Universitätshautklinik Essen
Percent of Patients with Grade 3 or Grade 4 Laboratory Abnormalities in BENCHMRK-1 (cont.)
Laboratory Test (Unit) Toxicity Criteria* Raltegravir (N=232) Placebo (N=118) Total bilirubin (mg/dL) Grade 3 2.6 – 5.0 x ULN 2.6 0.8 Grade 4 >5.0 x ULN 1.7 AST (IU/L) Grade 3 5.1 – 10.0 x ULN 2.6 2.5 Grade 4 >10.0 x ULN 0.4 0.8 ALT (IU/L) Grade 3 5.1 – 10.0 x ULN 5.2 2.5 Grade 4 >10.0 x ULN 1.3 1.7 Alkaline phosphatase (IU/L) Grade 3 5.1 – 10.0 x ULN 0.4 1.7 Grade 4 >10.0 x ULN 1.3 0.8 Pancreatic amylase (IU/L)§ Grade 3 2.1 – 5.0 x ULN 3.9 2.5 Grade 4 >5.0 x ULN Lipase (IU/L) Grade 3 3.1 – 5.0 x ULN 1.7 0.8 Grade 4 >5.0 x ULN Creatine kinase (IU/L) Grade 3 10.0 – 19.9 x ULN 3.4 2.5 Grade 4 ≥20.0 x ULN 1.3
*Grades 3 and 4 per DAIDS toxicity criteria.
§Defined as (number of patients meeting the specific serum pancreatic amylase criteria) / (number of patients with serum amylase test result).
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to placebo + OBR
32 had ≥ 1 mutations in integrase
Q148K/R/H
– N155H + (E92Q,V151I, T97A, G163R, L74M) – Q148K/R/H + (G140S/A, E138K) – Other pathways may exist, eg, Y143R/C + (L74A/I, E92Q, T97A, I203M, S230R)
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BENCHMRK-1 Week 48 Outcome[1] RAL + OBR (n = 232) Placebo + OBR (n = 118) P Value HIV-1 RNA < 50 copies/mL (NC = F), % 65 31 < .001 HIV-1 RNA < 400 copies/mL (NC = F), % 74 36 < .001 Mean change in CD4+ cell count vs baseline, cells/mm3 120 49 < .001 BENCHMRK-2 Week 48 Outcome[2] RAL + OBR (n = 230) Placebo + OBR (n = 119) P Value HIV-1 RNA < 50 copies/mL (NC = F), % 60 34 < .001 HIV-1 RNA < 400 copies/mL (NC = F), % 71 38 < .001 Mean change in CD4+ cell count vs baseline, cells/mm3 98 40 < .001
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BENCHMRK-1 & 2 Combined Efficacy Percent of Patients with HIV RNA <50 copies/mL at Week 48 by Baseline HIV RNA and CD4 Cell Count
Virological failures carried forward
Subgroup
Baseline HIV RNA copies/mL ≤100,000 >100,000 Baseline CD4 cells/mm3 ≤50 >50 and ≤200 >200
Raltegravir + OBT Placebo + OBT
Percent of Patients N
Total
20 40 60 80 100 64 73 48 50 67 76 34 43 16 20 39 44 228 152 76 75 82 71 443 287 156 139 167 136
BENCHMRK-1 & 2 Combined Efficacy† Percent of Patients With HIV RNA <50 copies/mL at Week 48 by Selected ARTs in OBT
Enfuvirtide Darunavir
+ + + +
+ : First use in OBT
Percent of Patients
Raltegravir + OBT Placebo + OBT
Total
20 40 60 80 100 34 68 57 47 20 64 89 80 69 60 443 44 45 75 191 228 22 23 47 90
Subgroup
Cooper DA, et al. CROI 2008. Abstract 788. Steigbigel R, et al. CROI 2008. Abstract 789.
Patients with VL < 50 c/mL, % Patient Group RAL + OBR Placebo + OBR All patients 64 (n = 443) 34 (n = 228) GSS at baseline 45 (n = 112) 3 (n = 65) 1 67 (n = 166) 37 (n = 92) ≥ 2 75 (n = 158) 59 (n = 68) PSS at baseline (number of fully active agents, FC < lower cutoff) 51 (n = 65) 2 (n = 44) 1 61 (n = 137) 29 (n = 69) ≥ 2 71 (n = 221) 48 (n = 108) PSS at baseline (number of fully or partially active agents, FC < upper cutoff) 52 (n = 33) 8 (n = 12) 1 48 (n = 71) 13 (n = 54) ≥ 2 70 (n = 313) 43 (n = 153)
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In HIV-infected, treatment-experienced patients failing antiretroviral therapy with triple-class resistant HIV:
antiretroviral and immunological efficacy compared to placebo plus OBT, which is sustained through Week 48. – In patients receiving new, active antiretroviral therapies in OBT, up to 89% achieved HIV RNA < 50 copies /mL at Week 48
primary residues, Q148 or N155, in combination with at least one
compared to placebo in combination with OBT. – Few adverse experiences leading to discontinuation – Risk of developing malignancy is comparable between raltegravir and comparator groups, whether only the Phase III data are examined, or all Phase II and Phase III data are included.
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HIV-infected patients; VL ≥ 1000 copies/mL; any CD4+ cell count; ≥ 1 PI mutation (N = 278) CPI/RTV + OBR* (n = 63) *OBR = NRTIs ± ENF (NNRTIs excluded). †TPV and DRV permitted after Week 16.
‡Discontinued at Week 16 by DMSB.
Elvitegravir/RTV 20/100 mg + OBR*†‡ (n = 71) Elvitegravir/RTV 50/100 mg + OBR*† (n = 71) Elvitegravir/RTV 125/100 mg + OBR*† (n = 73) Stratified by ENF in OBR Week 24
Zolopa A, et al. CROI 2007. Abstract 143LB.
Week 16
dose-finding study
– Primary endpoint: time-weighted average change from baseline in HIV RNA through 24 weeks (DAVG24)
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3 3 3 3 Median # ARVs in OBT including T-20 19 (26%) 17 (24%) 12 (17%) 12 (19%) First use of T-20 35 (48%) 34 (49%) 35 (49%) 32 (51%) Genotypic Sensitivity Score (GSS) = 0 for all NRTIs in OBT 11 10 11 11 IAS Protease Resistance Mutations, median # 157 (±158) 243 (±223) 180 (±196) 158 (±150) CD4 cells, mean (±SD) cells per mm3 4.71 (±0.81) 4.47 (±1.07) 4.66 (±0.79) 4.54 (±0.80) HIV RNA, mean (±SD) log10 copies/mL 53 (73%) 47 (66%) 48 (68%) 54 (86%) Caucasian 62 (85%) 63 (89%) 70 (99%) 54 (86%) Male 44 44 44 44 Age, median years GS-9137 125 mg N = 73 GS-9137 50 mg N = 71 GS-9137 20 mg N = 71 CPI N = 63
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37% of CPI patients switched to GS-9137 beginning at Week 16 GS-9137 20 mg patients switched to open-label GS-9137 125 mg beginning at Week 16 (dashed line)
4 8 12 16 20 24
CPI (n=63) GS-9137 20 mg (n=71) GS-9137 50 mg (n=71) GS-9137 125 mg (n=73) Week Mean Change From Baseline in HIV RNA log10 Copies/mL
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Elvitegravir 20-mg arm terminated after Week 16 because of poor virologic response; patients offered open-label elvitegravir 125 mg/day Darunavir and tipranavir initially excluded from elvitegravir arms due to lack of information on potential drug-drug interactions After absence of interactions demonstrated, protocol changed at Week 16 to allow addition of darunavir or tipranavir to study regimen in remaining elvitegravir arms. No assessment of darunavir susceptibility; no prior use counted as susceptible
– By Week 16, PI added by 4 patients receiving elvitegravir – By Week 24, PI added by 15% of patients receiving elvitegravir
Zolopa A, et al. CROI 2007. Abstract 143LB. Universitätshautklinik Essen
Zolopa A, et al. CROI 2007. Abstract 143LB.
mean 11 protease mutations
27% included TPV
arms met noninferiority criteria for DAVG24 vs CPI
demonstrated significantly greater mean decrease in HIV-1 RNA at Weeks 16 and 24 vs CPI
Time-Weighted Average Δ From Baseline in HIV-1 RNA at Week 24 (DAVG24)
*Pairwise comparison vs CPI/RTV.
Week 16 HIV-1 RNA < 50 copies/mL,% CPI 30 Elvitegravir 50 mg 38 Elvitegravir 125 mg 40 Elvitegravir 50 mg (n = 71) Elvitegravir 125 mg (n = 73) Δ VL at Wk 24 (DAVG24) CPI (n = 63)
P = .02* P = .27* Universitätshautklinik Essen
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*Data from elvitegravir 125 mg patients after addition of a PI were excluded.
Zolopa A, et al. CROI 2007. Abstract 143LB.
Elvitegravir 125 mg with no active drugs in OBR (n = 26) Elvitegravir 125 mg with ≥ 1 active NRTI or first use of ENF (n = 47)*
4 8 12 16 20 24
P < .001 Week Mean Change From Baseline in HIV-1 RNA, log10 copies/mL 2
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inferiority for DAVG24 – GS-9137 125 mg group was statistically superior to CPI group for both DAVG16 and DAVG24
that was durable when combined with an active OBT
and the GS-9137 arms
abnormalities, or study drug discontinuation for the GS 9137 arms
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