Exploratory Study of Tipranavir and Ritonavir in Multiple Protease Inhibitor-experienced HIV Patients

Tipranavir Disodium: An Open-Label ExploratorySstudy of Tipranavir and Ritonavir in Combination With One Nucleoside Reverse Transcriptase Inhibitor and One Non-Nucleoside Reverse Transcriptase Inhibitor in Multiple Protease Inhibitor-Experienced HIV Patients

The primary objective was to evaluate the antiviral activity and safety of two regimens of tipranavir (500 mg BID or 1000 mg BID) plus ritonavir (100 mg BID) administered in combination with 1 new nucleoside reverse transcriptase inhibitor (NRTI) + efavirenz in multiple protease-inhibitor-experienced HIV-1 positive patients.

Inclusion Criteria:

• Multiple (two or more) PI-experience. Eligible patients must have had exposure to at least two antiretroviral regimens containing a single protease inhibitor or a regimen containing dual protease inhibitors
• In the investigator's opinion, the patient had adhered to PI-containing regimens
• Exposure of ≥ 3 months to the current PI therapy
• Exposure of ≥ 4 months to the prior PI therapy with single PI-containing regimens
• Stable PI-containing regimen for at least 2 months prior to study entry
• HIV-1-RNA ≥ 5,000 copies/mL
• Cluster of differentiation (CD)4+ cell count ≥ 50 cells/mm**3
• At least one new NRTI option available
• Age ≥ 13 years
• Acceptable screening laboratory values that indicated adequate baseline organ function at the time of screening. Laboratory values were considered acceptable if the severity was ≤ Grade 1 (AIDS Clinical Trial Group (ACTG) Grading Scale). Stable Grade 2 abnormalities were permitted if the values had been demonstrated and documented for at least ≥ 2 months.
• Acceptable medical history, physical examination, electrocardiogram, and chest X-ray prior to entry into the treatment phase of the study
• Agreement to use a barrier contraceptive method of birth control for at least 30 days prior to study drug administration, during the study, and 30 days after the end of the study
• Ability to swallow numerous tablets and capsules without difficulty
• Ability to understand and provide informed consent. Minors were required to have approval of a parent or legal guardian

Exclusion Criteria:

• Prior exposure, defined as > 7 treatment days, to nonnucleoside reverse transcriptase inhibitor (NNRTIs) including, but not limited to: nevirapine, efavirenz, delavirdine, atevirdine, MKC-442, loviride, and HBY-097
• Clinically significant active or acute (onset within the month previous to study entry) medical problems, including the following: opportunistic infections, such as active cryptococcosis, Pneumocystis carinii pneumonia, herpes zoster, histoplasmosis, or cytomegalovirus or nonopportunistic diseases, including, but not limited to, progressive multifocal leukoencephalopathy, lymphoma, or malignancy requiring systemic therapy
• Prior exposure (> 7 days) to tipranavir
• History of clinically significant nervous system or muscle diseases, seizure disorder, or psychiatric disorder that might impair adherence to the protocol
• Taking of any known P450 3A enzyme-inducing drugs within 30 days of study entry and including the following: rifabutin, rifampin, carbamazepine, dexamethasone, phenobarbital, phenytoin, sulfadimidine, sulfinpyrazone, or troleandomycin
• Hypersensitivity to tipranavir and/or ritonavir
• Use of interferons, interleukins, HIV vaccines, or any active immunizations within 30 days prior to study entry
• Taking of any investigational medication with the exception of adefovir dipivoxil (Preveon™) and amprenavir (Agenerase™) within 30 days of study entry
• Pregnancy or lactation (serum β-human chorionic gonadotrophin test had to have been negative within 14 days of study entry)
• Evidence of active substance abuse, which in the investigator's opinion, could affect compliance to the protocol
• In the investigator's judgment, inability to comply with the protocol requirements for reasons other than those specified