HIV Infections
Conditions
Keywords
treatment experienced
Brief summary
The main purposes of this study are: demonstrate the safety and efficacy of TPV/r among HCV or hepatitis B virus (HBV) co-infected HIV+population, three-class (NRTI, NNRTI, and PI) experienced, with documented resistance to more than one PI. Determine pharmacokinetic data in this co-infected population and potential utility of using therapeutic drug monitoring (TDM) in improving efficacy outcomes.
Interventions
DRUGtipranavir
DRUGritonavir
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. HIV-1 infected males or females at least 18 years of age. 2. Three-class (Nucleoside reverse transcriptase inhibitor (NRTI), Non nucleoside reverse transcriptase inhibitor (NNRTI), and Protease inhibitor (PI)) treatment-experienced (a minimum of 3-months duration for each class) with resistance to more than one PI (on the screening resistance testing). Patients that are NNRTI-naïve patients but who have genotypically documented NNRTI-resistance mutations on past or screening resistance testing would be eligible. 3. CD4+ T lymphocyte count ≥50 cells/µl and HIV-1 VL ≥1000 copies/mL at screening. 4. The ARV study treatment regimen must consist of new TPV/r in combination with an OBR of 2-4 agents of the following: N(t)RTIs (NRTI or NtRTI), enfuvirtide (ENF), and/or, where available, an Expanded Access Program (EAP) investigational agent (Section 3.3). In total, patients are to have an ARV study treatment regimen consisting of at least 3 agents (TPV/r and two OBRs). 5. Chronic hepatitis C Virus (HCV) infection demonstrated by HCV-ribonucleic acid (RNA) positivity or, Chronic hepatitis B (HB) infection demonstrated by anti HBc IgG Antibody and HB Surface Antigen positivity. 6. Acceptable screening laboratory values that indicate adequate baseline organ function. 7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< Division of AIDS (DAIDS) Grade 3. 8. Acceptable medical history, as assessed by the investigator. 9. Any AIDS defining illness listed in the Appendix 10.3.1 should be accepted as long as is resolved, asymptomatic or stable on treatment for at least 12 weeks before screening (Visit 1); the AIDS defining events listed below are not acceptable History of Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any malignancy. 10. A reliable method of barrier contraception will be used by all female patients who are of reproductive potential, for at least three months prior to Visit 3, during the trial, and 30 days after completion or termination from the trial. 11. Karnofsky performance score ≥70.
Exclusion criteria
1. Prior tipranavir use. 2. Known hypersensitivity to any of the ingredients to the tipranavir or ritonavir formulations. 3. ARV medication naive. 4. Genotypic resistance to Tipranavir (TPV) (defined as a TPV mutation score of more than 7). 5. Patients on recent drug holiday, defined as off ARV medications for at least 7 consecutive days within the month prior to screening. 6. Decompensated liver disease, including presence or history of ascites, variceal bleeding, or hepatic encephalopathy or having ever been diagnosed as having hepatic insufficiency of Child Pugh class B or C. 7. Female patients of childbearing potential who: * have a positive serum pregnancy test at screening, * are breast feeding, * are planning to become pregnant, * are not willing to use a barrier method of contraception, or * are only willing to use an estrogen-containing medication, e.g., ethinyl estradiol, as a method of contraception. 8. Use of investigational medications within 30 days before study entry or during the trial except for those investigational ARV drugs permitted during the trial as stated in inclusion criteria 6. 9. Use of concomitant drugs that may significantly reduce plasma levels of the study medications. 10. Use of immunomodulatory drugs or antineoplastic agents within 30 days before study entry or during the trial. 11. Inability to adhere to the requirements of the protocol, including active substance abuse, as defined by the investigator. 12. Anticipated need for an interferon-based regimen in the 48 weeks following the study entry. 13. Any other or additional plausible cause for chronic liver disease, including the presence of other viruses known or suspected to cause hepatitis. 14. Any active infection or neoplasm currently being treated. 15. Patients with history of hemorrhagic stroke or intracranial aneurysm. 16. Patients with history of ischemic stroke, neurosurgery, skull trauma and/or intracranial pathology (arteriovenous malformation, brain tumors and cerebral venous thrombosis) within 4 weeks prior to screening (Visit 1) as assessed by investigator. 17. Patients with current history of alcohol abuse defined as alcohol consumption that would interfere with patient's compliance or result in biological abnormalities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response at Week 48 | 48 weeks | Treatment response is a confirmed virologic response, defined as a viral load less than 50 copies/mL at two consecutive measurements at least 5 days apart, without death, permanent discontinuation, or introduction of a new antiretroviral |
| The Primary Safety Endpoint Was the Occurrence of Dose-limiting Hepatotoxicity During the Study. | From the start of the study through 48 weeks. | Dose-limiting hepatotoxicity was defined as Grade 4 ALT or AST elevation confirmed in 48h or any evocative symptoms or signs of hepatitis, if it not clearly attributable to another cause. Patients who experienced dose-limiting hepatotoxicity stopped TPV/r and were considered treatment failures for the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Viral Load Less Than 400 Copies/mL at Each Visit | After 4 weeks of treatment until the end of the trial | Patients with a viral load of less than 400 copies/mL at each visit as measured from a plasma sample. |
| Occurrence of ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48 | Baseline, 24 and 48 weeks | Occurrence of greater than or equal to 1 log10 drop in viral load from baseline at all visits, including visits at Weeks 24 and 48 |
| Change in Viral Load From Baseline at Each Visit | After 4 weeks of treatment until the end of the trial | Change in viral load (measured from a plasma sample) from baseline at each visitPatients with a viral load of less than 400 copies/mL at each visit as . |
| Time to Treatment Failure | After Day 1 of treatment until the end of the trial | For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL. |
| Time to New AIDS or AIDS Related Progression Event or Death | After Day 1 of treatment until the end of the trial | Time to new AIDS or AIDS related progression event or death as defined by AIDS defining and/or AIDS-related illnesses. |
| Change in CD4+ and CD8+ Cell Counts From Baseline to Week 48 | after 2 weeks of treatment till Week 48 | Change from baseline to Week 48 for CD4+ and CD8+ cell counts. Samples were obtained for CD4+ and CD8+ as measurements of viral suppression during antiretroviral therapy. |
| Change in Ratio of CD38+/CD8+ From Baseline to Week 48 | after 2 weeks of treatment till Week 48 | Change from baseline to Week 48 for the ratio of CD38+ to CD8+ cell counts. Samples were obtained for CD38+ and CD8+ as measurements of viral suppression during antiretroviral therapy. |
| Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit | After 4 weeks of treatment until the end of the trial | Virologic response defined as viral load less than 50 copies/mL |
| Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48 | after 2 weeks of treatment till Week 48 | Tipranavir (TPV) and Ritonavir (RTV) trough concentrations from plasma samples at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48 |
| Patients Adherence With Study Medication Based on Pill Count | After 4 weeks of treatment until the end of the trial | number of pills actually taken divided by the planned number of pills the patient should take |
| Occurrence of Tipranavir (TPV) Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured | After 2 weeks of treatment until the end of trial | A high inhibitory quotient (IQ), the ratio of trough plasma drug concentration to the protein-adjusted viral IC50, is a useful indicator of the potential efficacy margin of antiretroviral drugs. The IQ for TPV is calculated by the formula IQ = TPV Ctrough / (3.75 x Z x fold change of the patients virus), where Z = wild type control IC50 IIIB. |
| Occurrence of Tipranavir (TPV) Trough Concentration >120 μM | After 2 weeks of treatment until the end of trial | Patients with TPV trough above 120 μM are at high risk of developing a Grade 3 or 4 ALT or AST elevations. The risk of Grade 3 or greater transaminase elevations appeared to be uniform at TPV trough concentration below 120 μM. Hence, for this study the TPV trough should be maintained below 120 μM. |
| Post-dose Tipranavir (TPV) and Ritonavir (RTV) Concentrations at Week 4 | Week 4 | Post-dose Tipranavir (TPV) and Ritonavir (RTV) plasma concentrations at Week 4 |
| Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Baseline through 48 weeks | Frequency of patients (%) with possible clinically significant abnormalities of laboratory measurements (haematology, differentials (automatic and absolute), coagulation, electrolytes, enzymes, substrates, urinalysis, serology and T-cells) |
| Change in Ratio of CD3+ CD8+ CD38+ HLA DR From Baseline to Week 48. | after 2 weeks of treatment till Week 48 | Change from baseline to Week 48 for the ratio of CD3+ CD8+ CD38+ HLA DR . Samples were obtained for CD3+ CD8+ CD38+ HLA DR as measurements of viral suppression during antiretroviral therapy. |
| Occurrence of Viral Load Less Than 400 Copies/mL at Weeks 24 and 48 | 24 and 48 weeks | Patients with a viral load of less than 400 copies/mL at Weeks 24 and 48 as measured from a plasma sample. |
Countries
Argentina, Brazil, France, Germany, Italy, Spain, United States
Participant flow
Recruitment details
With FDA and EMEA agreement, the trial was prematurely discontinued before reaching the target number of patients to be entered due to poor recruitment. For this reason analyzing and reporting data as planned for primary and secondary endpoints have not been performed. No objectives were reached and no conclusion can be drawn from this study.
Pre-assignment details
One patient has been randomised by mistake in Brasil and so he was not treated
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules | 4 |
| Therapeutic Drug Monitoring Tipranavir (TPV) 500mg and Ritonavir (RTV) 200mg BID capsules as initial dose, increased to TPV/r 750mg/200mg BID capsules, or decreased to TPV/r 500mg/100mg BID capsules or TPV/r 250mg/200mg BID capsules | 6 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | included patients who discontinued | 1 | 1 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Standard of Care | Therapeutic Drug Monitoring | Total |
|---|---|---|---|
| Age, Continuous | 46.00 years STANDARD_DEVIATION 2.9 | 45.20 years STANDARD_DEVIATION 5.4 | 45.50 years STANDARD_DEVIATION 4.4 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 4 | 2 / 6 |
| serious Total, serious adverse events | 1 / 4 | 2 / 6 |
Outcome results
Primary
The Primary Safety Endpoint Was the Occurrence of Dose-limiting Hepatotoxicity During the Study.
Dose-limiting hepatotoxicity was defined as Grade 4 ALT or AST elevation confirmed in 48h or any evocative symptoms or signs of hepatitis, if it not clearly attributable to another cause. Patients who experienced dose-limiting hepatotoxicity stopped TPV/r and were considered treatment failures for the analysis.
Time frame: From the start of the study through 48 weeks.
Primary
Treatment Response at Week 48
Treatment response is a confirmed virologic response, defined as a viral load less than 50 copies/mL at two consecutive measurements at least 5 days apart, without death, permanent discontinuation, or introduction of a new antiretroviral
Time frame: 48 weeks
Population: The trial has been stopped due to a poor enrollment
Secondary
Change in CD4+ and CD8+ Cell Counts From Baseline to Week 48
Change from baseline to Week 48 for CD4+ and CD8+ cell counts. Samples were obtained for CD4+ and CD8+ as measurements of viral suppression during antiretroviral therapy.
Time frame: after 2 weeks of treatment till Week 48
Population: The trial has been stopped due to a poor enrollment
Secondary
Change in Ratio of CD38+/CD8+ From Baseline to Week 48
Change from baseline to Week 48 for the ratio of CD38+ to CD8+ cell counts. Samples were obtained for CD38+ and CD8+ as measurements of viral suppression during antiretroviral therapy.
Time frame: after 2 weeks of treatment till Week 48
Population: The trial has been stopped due to a poor enrollment
Secondary
Change in Ratio of CD3+ CD8+ CD38+ HLA DR From Baseline to Week 48.
Change from baseline to Week 48 for the ratio of CD3+ CD8+ CD38+ HLA DR . Samples were obtained for CD3+ CD8+ CD38+ HLA DR as measurements of viral suppression during antiretroviral therapy.
Time frame: after 2 weeks of treatment till Week 48
Population: The trial has been stopped due to a poor enrollment
Secondary
Change in Viral Load From Baseline at Each Visit
Change in viral load (measured from a plasma sample) from baseline at each visitPatients with a viral load of less than 400 copies/mL at each visit as .
Time frame: After 4 weeks of treatment until the end of the trial
Population: The trial has been stopped due to a poor enrollment
Secondary
Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements
Frequency of patients (%) with possible clinically significant abnormalities of laboratory measurements (haematology, differentials (automatic and absolute), coagulation, electrolytes, enzymes, substrates, urinalysis, serology and T-cells)
Time frame: Baseline through 48 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Red Blood Cell count - decrease | 25.0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Bilirubin, total - increase | 0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | AST/GOT, SGOT - increase | 50.0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Hematocrit - decrease | 25.0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Prothrombin time - increase | 0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Bilirubin, direct - increase | 0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | ALT/GPT, SGPT - increase | 25.0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Triglyceride - increase | 0 percentage of participants |
| Standard of Care | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Lipase - increase | 0 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Triglyceride - increase | 25.0 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Red Blood Cell count - decrease | 0 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Prothrombin time - increase | 20.0 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | AST/GOT, SGOT - increase | 33.3 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Lipase - increase | 16.7 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Bilirubin, total - increase | 16.7 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | ALT/GPT, SGPT - increase | 33.3 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Bilirubin, direct - increase | 16.7 percentage of participants |
| Therapeutic Drug Monitoring | Frequency of Patients (%) With Possible Clinically Significant Abnormalities of Laboratory Measurements | Hematocrit - decrease | 16.7 percentage of participants |
Secondary
Occurrence of ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48
Occurrence of greater than or equal to 1 log10 drop in viral load from baseline at all visits, including visits at Weeks 24 and 48
Time frame: Baseline, 24 and 48 weeks
Population: The trial has been stopped due to a poor enrollment
Secondary
Occurrence of Tipranavir (TPV) Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured
A high inhibitory quotient (IQ), the ratio of trough plasma drug concentration to the protein-adjusted viral IC50, is a useful indicator of the potential efficacy margin of antiretroviral drugs. The IQ for TPV is calculated by the formula IQ = TPV Ctrough / (3.75 x Z x fold change of the patients virus), where Z = wild type control IC50 IIIB.
Time frame: After 2 weeks of treatment until the end of trial
Population: The trial has been stopped due to a poor enrollment
Secondary
Occurrence of Tipranavir (TPV) Trough Concentration >120 μM
Patients with TPV trough above 120 μM are at high risk of developing a Grade 3 or 4 ALT or AST elevations. The risk of Grade 3 or greater transaminase elevations appeared to be uniform at TPV trough concentration below 120 μM. Hence, for this study the TPV trough should be maintained below 120 μM.
Time frame: After 2 weeks of treatment until the end of trial
Population: The trial has been stopped due to a poor enrollment
Secondary
Occurrence of Viral Load Less Than 400 Copies/mL at Each Visit
Patients with a viral load of less than 400 copies/mL at each visit as measured from a plasma sample.
Time frame: After 4 weeks of treatment until the end of the trial
Secondary
Occurrence of Viral Load Less Than 400 Copies/mL at Weeks 24 and 48
Patients with a viral load of less than 400 copies/mL at Weeks 24 and 48 as measured from a plasma sample.
Time frame: 24 and 48 weeks
Population: The trial has been stopped due to a poor enrollment
Secondary
Patients Adherence With Study Medication Based on Pill Count
number of pills actually taken divided by the planned number of pills the patient should take
Time frame: After 4 weeks of treatment until the end of the trial
Population: The trial has been stopped due to a poor enrollment
Secondary
Post-dose Tipranavir (TPV) and Ritonavir (RTV) Concentrations at Week 4
Post-dose Tipranavir (TPV) and Ritonavir (RTV) plasma concentrations at Week 4
Time frame: Week 4
Population: The trial has been stopped due to a poor enrollment
Secondary
Time to New AIDS or AIDS Related Progression Event or Death
Time to new AIDS or AIDS related progression event or death as defined by AIDS defining and/or AIDS-related illnesses.
Time frame: After Day 1 of treatment until the end of the trial
Population: The trial has been stopped due to a poor enrollment
Secondary
Time to Treatment Failure
For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL.
Time frame: After Day 1 of treatment until the end of the trial
Population: The trial has been stopped due to a poor enrollment
Secondary
Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
Tipranavir (TPV) and Ritonavir (RTV) trough concentrations from plasma samples at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48
Time frame: after 2 weeks of treatment till Week 48
Population: The trial has been stopped due to a poor enrollment
Secondary
Virologic Response Defined as Viral Load <50 Copies/mL at Each Visit
Virologic response defined as viral load less than 50 copies/mL
Time frame: After 4 weeks of treatment until the end of the trial
Population: The trial has been stopped due to a poor enrollment