Tipranavir/Ritonavir vs. Genotypically Defined Protease Inhibitor/Ritonavir in HIV Patients (RESIST-2)

Randomized, Open-label, Comparative Safety and Efficacy Study of Tipranavir Boosted With Low Dose Ritonavir (TPV/RTV) Versus Genotypically-defined Protease Inhibitor/Ritonavir (PI/RTV) in Multiple Antiretroviral Drug-experienced Patients (RESIST 2: Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients With Tipranavir)

The objective of this study is to demonstrate the safety and efficacy of tipranavir/ritonavir versus an active control arm in highly treatment experienced Human immunodeficiency virus-1 infected patients. Patients must have a viral load > =1000 cells/mL, and genotype indicating at least one resistance conferring protease inhibitor-mutation as determined from a predefined panel of mutations. Any CD4+ count is acceptable.

Inclusion Criteria:

1. Signed informed consent prior to trial participation.

2. Human immunodeficiency virus-1 infected males or females >=18 years of age.

3. Screening genotypic resistance report indicating both of the following:

   • at least one primary protease mutation at the following sites 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V or 90M , and
   • no more than two protease mutations on codons 33, 82, 84, or 90.

4. At least 3 consecutive months experience taking antiretrovirals from each of the classes of Nucleoside reverse transcriptase inhibitor(s), Non-nucleoside reverse transcriptase inhibitor(s), and Protease inhibitor(s) at some point in treatment history,

   • with at least 2 Protease inhibitor-based regimens (minimum 3 months of exposure of each), one of which must be part of the current regimen, and
   • current Protease inhibitor-based antiretroviral medication regimen for at least 3 months prior to randomisation.

5. Human immunodeficiency virus-1 viral load >=1000 copies/mL at screening.

6. Acceptable screening laboratory values that indicate adequate baseline organ function. Laboratory values are considered to be acceptable if the following apply:

   • Total cholesterol <=400 mg/dl or 10,36 mm/L.
   • Total triglycerides <=750 mg/dl or 8,5 mm/L.
   • Alanine aminotransferase <=3x upper limit of normal and aspartate aminotransferase <=2.5x upper limit of normal.
   • Any Grade gamma-glutamyl transpeptidase is acceptable.
   • Any Grade creatinine kinase is acceptable as long as there is no concurrent myopathy.
   • All other laboratory test values <= Grade 1(Division of Acquired immune deficiency syndrome, National Institute of Health grading scale).

7. Acceptable medical history, as assessed by the investigator, with chest X-ray and electrocardiogram within 1 year of study participation.

8. Willingness to abstain from ingesting substances during the study which may alter plasma study drug levels by interaction with the cytochrome P450 system.

9. A prior Acquired immune deficiency syndrome-defining event is acceptable as long as it has resolved or the patient has been on stable treatment for at least 2 months (Acquired immune deficiency syndrome related complex is acceptable).

Exclusion Criteria:

1. Antiretroviral medication naïve.

2. Patients on recent drug holiday, defined as off antiretroviral medications for at least 7 consecutive days within the last 3 months.

3. Alanine aminotransferase >3x upper limit of normal and aspartate aminotransferase >2.5x upper limit of normal at either screening visit.

4. Female patients of child-bearing potential who:

   • have a positive serum pregnancy test at screening or during the study,
   • are breast feeding
   • are planning to become pregnant, or
   • are not willing to use a barrier method of contraception, or
   • require ethinyl estradiol administration

5. Prior tipranavir use.

6. Use of investigational medications within 30 days before study entry or during the trial. (T-20 [enfuvirtide] and Tenofovir (Viread), investigational at the time of writing of this protocol, will be allowed.)

7. Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g. interferon, cyclosporin, hydroxyurea, interleukin 2).

8. Inability to adhere to the requirements of the protocol, including active substance abuse as assessed by the investigator.

9. In the opinion of the investigator, likely survival of less than 12 months because of underlying disease.