Tipranavir superior to other PIs in detailed resistance analysis

In people with multiclass-resistant HIV, tipranavir/ritonavir-based therapy stifled viral replication better than treatment with any of 4 other ritonavir-boosted protease inhibitors (PIs), regardless of PI resistance pattern at study entry.

Detailing results of the combined RESIST trials at the 12^th Conference on Retroviruses and Opportunistic Infections in Boston, Massachusetts, Stanford University’s Jonathan Schapiro, MD, reported that 41.2% of people randomized to treatment including tipranavir/ritonavir met the protocol definition of 24-week virologic response compared with 18.9% of people randomised to one of the control PI arms. The control arms included ritonavir-boosted lopinavir, indinavir, saquinavir, or amprenavir.

Tipranavir/ritonavir also proved superior to comparison PIs in analyses focusing on 3 different sets of resistance mutations at study entry:

• All mutations representing a change from the consensus protease sequence
• Primary PI mutations at protease positions 30, 46, 48, 50, 82, 84, or 90
• Four protease mutations at positions 30, 82, 84, and 90, which were originally thought to impair response to tipranavir (also known as protease resistance associated mutations or PRAMS)

The RESIST studies recruited people with at least 3 months of nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), and PI experience, including at least 2 PI-based regimens. Participants had an HIV-1 RNA viral load above 1000 copies/mL, at least one primary PI mutation, and two or fewer PRAMs. Enrollees started new antiretroviral regimens picked by their clinicians (which could include enfuvirtide) plus either tipranavir/ritonavir (500/200 mg twice daily) or one of the control boosted PIs. Baseline PI mutation profiles were similar in the 582 people randomized to tipranavir/ritonavir and the 577 controls.

Among people with any PI mutation, the response to tipranavir/ritonavir proved significantly better than responses to other PIs, no matter how many of the PI mutations a person had when the study started:

The tipranavir/ritonavir-induced reduction in HIV-1 RNA viral load averaged 1.85 log₁₀ copies/mL for people with 12 or fewer mutations vs 0.44 log₁₀ copies/mL in the control group (P

• 13 to 15 mutations, -0.63 vs -0.42 log₁₀ copies/mL (P
• 16 to 18 mutations, -1.08 vs -0.16 log₁₀ copies/mL (P
• 19 or more mutations, -0.36 vs +0.2 log₁₀ copies/mL (P

Responses always favored tipranavir/ritonavir in people with one or more primary PI mutations or one or more PRAMs, although differences from the control group were not always statistically significant.

With tipranavir nearing licensing review, clinicians will probably soon be making mutation-based calls on whether to use this drug in treatment-experienced patients. Dr. Schapiro noted that the 4 PRAMs once thought most likely to imperil responses to tipranavir did not turn out to be particularly good predictors of response in the RESIST-1 and 2 trials. More detailed analysis disclosed 21 mutations likely to hobble tipranavir, although Dr. Schapiro rated that unwieldy list only a “starting point” for more practical practice guidelines.

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