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Tipranavir Report from 2003 European AIDS Conference (EACS)
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Reported by Jules Levin 9th European AIDS Conference (EACS) 1st EACS Resistance & Pharmacology Workshop October 26–29, 2003 Warsaw, Poland
Summary. This report contains information reported on tipranavir in 2 posters at the European Conference completed last week (Oct 29, 2003). The first poster reports durable viral load reductions after 80 weeks on tipranavir therapy in a patient population experienced with prior use and resistance to protease inhibitors. After 80 weeks the median change in viral load was –2.55 log 10 with low dose regimen and –2.43 log 10 with high dose regimen, and the median CD4+ cell count increased by 175 cells and 143 cells. The most frequently observed adverse events were diarrhea, nausea, and increased GGT. The second poster reports 24 weeks study results for a highly experienced group of 216 patients with extensive resistance to protease inhibitors: APV: 38%, IDV: 79%, LPV: 36%, NFV 70%, RTV: 78%; SQV: 71%. One or more of these primary PI mutations were present in study patients: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M. Patients were not permitted into study if they had more than one of 82L/T, 84V, or 90M. The trial was a multicenter, double-blinded evaluation of 3 TPV/r doses (500 mg/100 mg, 500 mg/200 mg, and 750 mg/200 mg, all twice daily). The 500/200 dose is selected for development. All patients had triple-class experience, 2 PI-regimen experience, at least 1 primary PI mutation. Antiviral effectiveness by tipranavir was demonstrated: patients taking dose selected for development (500/200) had -0.55 log reduction (ITT-LOCF); 47.5% of patients in the 500/200 arm had a ≥1 log 10 decrease in viral load (OT) (40% ITT-LOCF). Patients taking higher dose 750/200 had greater viral load suppression, -1.7 log at week 24 but worse safety profile (GI, ALT, lipids). GI side effects were the most common: diarrhea, nausea, and vomiting were the most common adverse events, reportedly occurring primarily during the first 4 weeks. Grade 3/4 ALT and triglycerides elevations in 11% and 27%, respectively, of patients were reported.
Tipranavir: phase II study, 80 week follow-up
Long-term 80-week follow-up of highly treatment-experienced (HTE) patients on tipranavir-based antiretroviral therapy (BI 1182.2)
D Neubacher 1 , M Markowitz 2 , L Slater 3 , R Curry 1 , V Kohlbrenner 1 , S McCallister 1
Boehringer Ingelheim Pharmaceuticals, Inc.; 2 Aaron Diamond AIDS Research Center, New York, NY; 3 Infectious Disease Institute, University Hospital, Oklahoma City, OK.
ABSTRACT
BACKGROUND
Tipranavir (TPV), the first non-peptidic protease inhibitor (NPPI), has a uniquely robust resistance profile, demonstrating activity in protease inhibitor (PI)-resistant patients.
OBJECTIVE
The objective of this 80-week follow-up study was to determine the durability of TPV-based therapy in PI-experienced patients.
METHODS
BI 1182.2 was a Phase II, randomized, multicenter, open-label study in NNRTI-naive patients who had clinically failed ≥2 PI-containing regimens.
Patients were randomized to either low-dose (LD; n=19) or high-dose (HD; n=22) ritonavir-boosted (100 mg) TPV, plus efavirenz and one new NRTI.
Initially, patients in the high-dose group were treated with 200 mg of ritonavir, and a 300-mg hard-filled capsule (HFC) formulation of TPV was used. However, the introduction of a 250-mg Self-Emulsifying Drug Delivery System (SEDDS) formulation of TPV during the trial allowed the TPV dose to be reduced from 1200 mg to 500 mg in the LD arm, and from 2400 mg to 1000 mg in the HD arm, all twice daily.
RESULTS
The median baseline viral load was 4.43 log 10 copies/mL, and the median baseline CD4+ count was 273 cells/mm3. 61% percent of patients completed 80 weeks of treatment. The estimated time to treatment failure was 395 days with LD, and 483 days with HD.
After 80 weeks the median change in viral load was –2.55 log 10 with LD and –2.43 log 10 with HD, and the median CD4+ cell count increased by 175 cells/mm 3 and 143 cells/mm 3, respectively. The most frequently observed adverse events were diarrhea, nausea, and increased GGT.
CONCLUSION
These results indicate that TPV-based therapy can provide a durable response in the majority of PI-experienced patients.
INTRODUCTION
Tipranavir (TPV) is the first in a new class of non-peptidic protease inhibitors (NPPI) and retains antiviral activity against a wide range of patient-derived HIV isolates resistant to peptidic protease inhibitors (PIs) in vitro. Results of Phase II studies in highly treatment-experienced patients suggest that 16–20 protease gene mutations at baseline, including 3 or more PRAMs (protease inhibitor resistance-associated mutations), may be required for reduced susceptibility to TPV.
This uniquely robust resistance profile suggests that TPV will be effective in patients who have experienced PI failure. TPV is now being developed with a Self-Emulsifying Drug Delivery System (SEDDS) formulation, which doubles the bioavailability of TPV from the previous hard-filled capsules (HFC) formulation.
TPV concentrations are also markedly enhanced in the presence of low-dose ritonavir (RTV). The SEDDS formulation of TPV + low-dose RTV (TPV/r) therefore allows for twice-daily dosing and a greatly reduced pill burden.
Here we report data from an open-label, Phase II, 80-week follow-up trial examining the durability of 2 different doses of TPV/r + EFV + 1 new NRTI, in patients who had failed 2 or more PI-containing regimens. Although this study was initiated with the HFC formulation, the majority of patients switched to the SEDDS formulation before reaching 48 weeks. Patients in this study were assessed according to virologic and immunologic responses, as well as adverse events.
METHODS DESIGN
Phase II, open-label, randomized, parallel-group, 80-week follow-up trial
ENTRY CRITERIA
--HIV RNA >5,000 copies/mL
--CD4+ cell count •50 cells/mm 3
--Failure of •2 PI regimens
--NNRTI naive
MEASUREMENTS
--Roche Amplicor HIV Monitor •PCR Method (limit of detection 400 copies/mL)
--Roche Amplicor UltraSensitive •PCR Method (limit of detection 50 copies/mL)
DOSING
LOW DOSE (n=19)
TPV HFC 1200mg bid + RTV 100 mg bid
TPV SEDDS 500 mg + RTV 100 mg bid + EFV (Sustiva) 600 mg qd + 1 new NRTI
HIGH DOSE (n=22)
TPV HFC 2400 1000 mg bid + RTV 200 mg bid
TPV SEEDS 1000 mg bid + RTV 100 mg bid + EFV (Sustiva) 600 mg qd + 1 new NRTI
Patients initially took TPV 300-mg hard-filled capsules (HFC) and then switched to TPV 250-mg soft- elastic capsules (SEDDS) when these became available.
BASELINE CHARACTERISTICS
Mean age: 41-44. 64%-74% white. 26% black. Mean viral load 4.51-4.46 log copies/ml. Mean CD4 counr: 290-314.
RESULTS
74 % of low-dose patients and 50% of high-dose patients completed 80 weeks of TPV-based therapy (61% of all patients). For patients taking low dose, 90% completed 24 weeks, 84% completed 48+ weeks, and 74% completed 80+ weeks. For patients taking high dose: 68% completed 24 weeks, 59% completed 48+ weeks, and 50% completed 80+ weeks.
LONG TERM VIROLOGIC RESPONSE
After 16 weeks on therapy both dose groups achieved full viral suppression , which appears to be fully maintained in terms of log change in viral load at week 80: -2.43 log for high dose and –2.55 for low dose.
Using on-treatment analysis, 90% on high dose and 43% on low dose had <50 copies/ml at week 80. In low-dose patients 90% had <50 copies/ml at week 48, but this fell to 43% at week 80. Using <400 copy test, 90% using high dose and 64% using lowdose had undetectable VL.
Median CD4 increase was +143 for high dose group and +175 for lowdose group.
Using Kaplan-Meier Curve estimates, the estimated median time-to-treatment failure was 395 days for the low-dose group and 204 days for the high-dose group. By 100 days on treatment about 20% on lowdose and 37% on high dose had a probability for treatment failure. *Virologic failure was defined as loss of viral load <400 copies/mL.
ADVERSE EVENTS
(most frequently reported adverse events (>15% of all patients) during the study considered to be related to TPV
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Low dose |
Hi dose |
| Diarrhea |
26% |
72% |
| Nausea |
31% |
31% |
| Increased GGT |
26% |
18% |
| Hyperglceridemia |
21% |
18% |
| Dizziness |
15% |
18% |
| Fatigue |
15% |
18% |
| Increased ALT |
5% |
27% |
| Vomiting |
10% |
22% |
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*Elevated GGT are likely due to hepatic enzyme induction. Increases in GGT were not considered to be clinically relevant.
CONCLUSIONS by Study Authors
--The majority (61%) of patients completed 80 weeks of TPV-based therapy
--Both TPV/r-based regimens provided durable viral suppression during 80 weeks of treatment in a majority of PI-experienced patients
--Time-to-treatment failure was 395 and 483 days, respectively, in the low-dose or high-dose groups
--Both high-dose and low-dose regimens were effective and durable over 80 weeks at suppressing viral load in patients who had previously failed 2 or more PI-containing regimens
--Good immunologic response was maintained in both regimens, as evidenced by median increases in CD4+ cell counts of 143–175 cells/mm 3 at 80 weeks
--The most frequently observed adverse events considered to be related to TPV were diarrhea and nausea
--Results suggest that the TPV/r 500/200 dose currently being studied in Phase III clinical trials, which is bracketed by the doses in this study, will provide an important treatment option for PI-experienced patients, which is bracketed by the doses in this study, will provide an important treatment option for PI-experienced patients
Tipranavir/ritonavir (TPV/r) demonstrates potent efficacy in multiple protease inhibitor (PI)-experienced patients at 24 weeks: BI 1182.52
V Kohlbrenner 1 , J Gathe 2 , G Pierone 3 , K Arasteh 4 , R Rubio 5 , R LaLonde 6 , P Piliero 7 , S McCallister 1 , S Garfinkel 1 , R Chaves 1 , S Spinosa 1 , C Dohnanyi 1 , A Quinson 1 , D Mayers 1
Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT; 2 Houston, TX; 3 Treasure Coast Infectious Disease Consultants, Vero Beach, FL; 4 Epimed GmbH, Berlin, Germany; 5 H. 12 Octubre Pabellon de Medicina Communitaria Unidad de VIH, Madrid, Spain, 6 Montreal Chest Institute, Montreal, Quebec; 7 Albany Medical College, Albany, NY
ABSTRACT
BACKGROUND
Tipranavir (TPV), the first non-peptidic protease inhibitor (NPPI), has a uniquely robust resistance profile, demonstrating viral-load responses against multiple PI-resistant HIV-1 both in vitro and in clinical studies.
OBJECTIVE
BI 1182.52 was designed to determine the optimal dose of TPV/r for use in Phase III trials, evaluating efficacy at 2 weeks and safety at 4 weeks. All randomized patients were followed for at least 24 weeks.
METHODS
The trial was a multicenter, double-blinded evaluation of 3 TPV/r doses (500 mg/100 mg, 500 mg/200 mg, and 750 mg/200 mg, all twice daily). All patients had triple-class experience, 2 PI-regimen experience, at least 1 primary PI mutation, and HIV-RNA >1000 copies/mL.
RESULTS
The 216 patients randomized were evenly distributed among arms with regard to demographics, baseline viral load (median 4.53 log 10 copies/mL), CD4+ cell count (median 177 cells/mm 3), and prior treatment experience.
Prior PI experience ranged from 36.6% for lopinavir to 79.6% for indinavir.
Overall there was a median -0.92 log 10 change in viral load (on-treatment analysis) at 24 weeks. After 24 weeks, 31.5%, 40.3%, and 45.1% in the 500/100, 500/200, and 750/200 arms, respectively, had a ≥1 log 10 decrease in viral load (intent to treat; non-completers considered failures). Diarrhea and vomiting were the most common adverse events, occurring primarily during the first 4 weeks.
CONCLUSION
All 3 doses of TPV/r demonstrated potent antiviral efficacy, with an acceptable safety profile during 24 weeks of treatment. Phase III trials at the 500/200 dose are ongoing.
INTRODUCTION
Tipranavir (TPV) is a non-peptidic protease inhibitor (NPPI), and retains broad and potent in vitro antiviral activity against a wide range of patient-derived HIV isolates resistant to peptidic protease inhibitors.
TPV-based therapy produces durable virologic suppression over 80 weeks in patients who previously failed 2 or more PI-containing regimens. Prior results from TPV Phase II studies have indicated that 16 to 20 protease gene mutations and more than two PI resistance-associated mutations (PRAMs) are required for reduced susceptibility to TPV.
The BI 1182.52 study was a multicenter, double-blinded evaluation of 3 TPV/r doses (500 mg/100 mg, 500 mg/200 mg, and 750 mg/200 mg, all twice daily) in patients with triple-class experience, 2 PI-regimen experience, and at least 1 primary PI mutation.
Prior analyses of this study have indicated that relative to the 500/100 and 750/200 doses, the 500/200 dose provides optimal and consistent plasma levels of drug, good viral suppression, and an acceptable tolerability profile, based on data up to 4 weeks. In the analysis presented here, patients were assessed at 24 weeks according to prior PI experience, virologic suppression, immunologic responses, and adverse events.
ENTRY CRITERIA
--Triple-class–experienced HIV-1+ patients failing at least 2 PI-based regimens
-- >18 years of age
--HIV RNA >1000 copies/mL
MEASUREMENTS
--Change in HIV-1 RNA detected with Roche UltraSensitive, Version 1.5
--Any CD4+ cell count
--One or more primary PI mutations: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M
--Not more than one of 82L/T, 84V, or 90M
Patient Demographics
71-73 patients in each of 3 study arms. Average age: 42. 85% male. 77% white, 22% black. Median viral load 4.50 log. Median CD4 count 140-160.
PRIOR PI EXPERIENCE
APV: 38% IDV: 79% LPV: 36% NFV 70% RTV: 78% SQV: 71%
RESULTS
At 24 weeks, the 3 treatment groups combined showed improvements in CD4+ cell count of a median 10.5 (500/100), 18.5 (500/200), and 46.5 (750/200) cells/mm3.
VIROLOGIC OUTCOME
--The overall median change in viral load (OT) at 24 weeks was similar at -0.92 log 10
--The overall median change in viral load (ITT-LOCF) at 24 weeks was -0.60 log 10
--No significant difference between arms was observed
--patients taking 750/200 had –1.07 log reduction at week 24 (ITT-LOCF)
--patients taking 500/200 had -.55 log reduction (ITT-LOCF)
--patients taking 500/100 had –0.25 log reduction (ITT-LOCF)
--At 24 weeks, 23 (36.5%), 29 (47.5%), and 32 (65.3%) patients in the 500/100, 500/200, and 750/200 arms, respectively, had a ≥1 log 10 decrease in viral load (OT)
--At 24 weeks, 23 (31.5%), 29 (40.3%), and 32 (45.1%) patients in the 500/100, 500/200, and 750/200 arms, respectively, had a ≥1 log 10 decrease in viral load (ITT-NCF)
--No significant difference across arms was observed
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500/100 |
500/200 |
750/200 |
| Total of any AE |
58% |
68% |
68% |
| Diarrhea |
30% |
33% |
31% |
| Nausea |
29% |
24% |
17% |
| Vomiting |
12% |
7% |
16% |
| Fatigue |
4% |
11% |
9% |
| Headache |
4% |
8% |
9% |
| Abdominal pain |
7% |
8% |
4% |
| Aggravated diarrhea |
1% |
4% |
9% |
| Hypertriglyceridemia |
4% |
3% |
6% |
| Asthenia |
1% |
1% |
4% |
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Grade 3/4 lab abnormalities
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500/100 |
500/200 |
750/200 |
| AST |
2.7% |
6.9% |
7% |
| ALT |
5.5% |
11.1% |
21.1% |
| Bilirubin |
0 |
0 |
2.8% |
| Cholesterol |
1.4% |
2.8% |
5.6% |
| Triglycerides |
16% |
27% |
22% |
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CONCLUSIONS by Study authors
--An acceptable safety profile was observed during the 24 weeks of treatment in the 500/100 and 500/200 arms
--TPV-based therapy was effective in the 500/200 and 750/200 groups in patients with triple-class and 2 PI-regimen experience and at least 1 primary PI mutation
--In this uncontrolled study, increases in CD4+ cells in advanced patients were observed with all 3 treatment doses
--Results indicate that TPV will provide an important option for PI-experienced patients ÑPhase III trials at the 500/200 dose are ongoing based on the optimal efficacy and safety profile that was observed with this dose in this dose-finding trial
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