Comparison of TPV/r to DRV/r in Triple Class Experienced Patient With Resistance to > 1 PI

A Prospective, Randomized, Open-labelled, Multi-centre Trial Comparing the Safety and Efficacy of Ritonavir-boosted Aptivus (Tipranavir, TPV/r) to That of Prezista® (Darunavir, DRV/r) in Three-class (NRTI, NNRTI, and PI) Treatment-experienced Patients With Resistance to More Than One PI. POTENT: PrOspecTive EvaluatioN of Tipranavir vs. Darunavir in Treatment Experienced Patients

The objective of this study is to compare the efficacy and safety of Tipranavir/ritonavir (TPV/r, 500mg/200mg twice daily) to the safety and efficacy of Darunavir/ritonavir (DRV/r 600 mg /100 mg twice daily) in combination with investigator selected optimised background regimens in patients who are three-class (Nucleoside reverse transcriptase inhibitors (NRTI), Nonnucleoside reverse transcriptase inhibitors (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 virtual phenotype resistance testing.

Inclusion Criteria:

1. Signed informed consent prior to trial participation.

2. HIV-1 infected male or female >18 years of age.

3. Three-class (NRTI, NNRTI, and PI) treatment-experienced patients (a minimum of 3-months duration for each class or documented class hypersensitivity/intolerance) with resistance (minimal or reduced response) to more than one PI on the screening virtual phenotype resistance testing. In the case of NNRTIs, NNRTI resistance in the absence of exposure is equivalent to being NNRTI treatment experienced.

4. Patient's optimized background regimen must contain one of the following ARV options:

   • A minimum of two genotypically active nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) reported as "maximal response" or "sensitive" on the screening virtual phenotype report.
   • A minimum of one genotypically active NRTI reported as "maximal response" or "sensitive" on the screening virtual phenotype report plus Enfuvirtide if not used previously.
   • A minimum of one genotypically active NRTI reported as "maximal response" or "sensitive" on the screening virtual phenotype report plus an integrase inhibitor if not used previously and if available through an expanded access program and allowed by local regulatory authorities.
   • A minimum of one genotypically active NRTI reported as "maximal response" or "sensitive" on the screening virtual phenotype report plus the CCR5 chemokine receptor antagonist Maraviroc if available through an expanded access program, not used previously and allowed by local regulatory authorities.
   • Zero or one genotypically active NRTI reported as "maximal response" or "sensitive" on the screening virtual phenotype report plus two of the following drugs, Enfuvirtide, an integrase inhibitor and Maraviroc if available, not used previously and allowed by local regulatory authorities.
   • Two genotypically partially active NRTIs (provided that they are not part of the current failing regimen) reported as "reduced response" on the screening virtual phenotype report plus one of the following drugs, Enfuvirtide, an integrase inhibitor or Maraviroc if available, not used previously and allowed by local regulatory authorities.

5. Patient has been on their current (failing) PI-containing regimen for at least 8 weeks prior to randomization.

6. Patient has on-going viral replication (defined as an HIV-1 viral load of ≥ 500 copies/mL) and a successful virtual phenotype obtained at screening.

7. Any baseline CD4 cell count will be allowed.

8. Karnofsky performance score of ≥ 70.

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

   • ALT ≤2.5 x ULN and AST ≤2.5 x ULN (≤DAIDS Grade 1, Appendix 10.1).
   • Any DAIDS grade cholesterol, triglycerides, GGT, CPK or LDH is acceptable.
   • All other laboratory test values must be ≤DAIDS Grade 2.

10. Willingness to initiate CD4+ cell count-guided chemoprophylaxis to prevent opportunistic infections.

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

Inclusion Criteria:

1. Previous use of Tipranavir (TPV) or Darunavir (DRV).

2. Full genotypic resistance (reported as minimal response) to Tipranavir (TPV) or Darunavir (DRV) on screening virtual phenotype:

3. Female patient of child-bearing potential who:

   has a positive serum pregnancy test at screening, is breast feeding, is planning to become pregnant, is not willing to use double-barrier methods (simultaneous use of two different methods such as diaphragm with spermicidal substance and condom) of contraception or requires ethinyl estradiol administration. Barrier methods of contraception include diaphragm with spermicidal substance, condom for females, cervical caps and condoms.

4. History of Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any malignancy.

5. Any AIDS defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at screening visit.

6. Use of immunomodulatory drugs (such as interferon, cyclosporin, hydroxyurea and interleukin 2) within 30 days prior to randomization.

7. Current use of systemic cytotoxic chemotherapy.

8. All contraindications listed in the product monographs of Aptivus, Prezista and Norvir.