Charles Hicks and colleagues presented data from the RESIST 1 trial, a study comparing the efficacy and safety of tipranavir (TPV), a new HIV-1 protease inhibitor (PI), combined with low-dose ritonavir (RTV, Norvir) and compared to other boosted PI regimens. Tipranavir was found to have activity against many forms of PI-resistant virus.

To be included in this study, patients had to meet the following requirements:

1. Be older than 18 years of age;

2. Have a viral load more than 1,000 copies/mL;

3. Have been on at least 2 different PI-containing regimens for at least 3 months;

4. Have at least one or more primary PI mutations; and

5. Have less than or equal to 2 PI mutations at codon 33, 82, 84 and 90 (which are the mutations known to confer tipranavir resistance).

There were no CD4+ cell count restrictions.

Patients were considered to have had a treatment response to tipranavir if their viral load decreased by >1 log₁₀ copies/mL by 24 weeks. Patients who were failing a PI-containing regimen had a genotype performed. An expert panel reviewed the genotype and then suggested an optimized background regimen.

Patients were then randomized to either tipranavir boosted with ritonavir (500 mg/200 mg) or a comparator PI (called a CPI) boosted with ritonavir, which could include one of the following PIs: lopinavir (LPV), amprenavir (APV, Agenerase), indinavir (IDV, Crixivan) or saquinavir (SQV, Fortovase, Invirase).

Any patient who failed the CPI arm after 8 weeks was allowed to switch to the tipranavir arm. Patients were allowed to use enfuvirtide (T-20, EFV, Fuzeon) and any other active antiretroviral agent.

In the end, 620 patients were recruited. The median number of PI mutations in this patient population was 15. The median age was 42, 90% were male and 77% were white. The median CD4+ cell count and viral load were 123 cells/mm³ and 4.8 log₁₀ copies/mL, respectively.

Enfuvirtide was added to the regimens of about one third of the patients. The percentage of patients started on the following CPI regimens were: lopinavir 61%, indinavir 4%, amprenavir 16% and saquinavir 21%. Baseline samples showed significant phenotypic resistance to all CPIs, but not to tipranavir.

All 610 patients in the study were given resistance tests and assigned to an optimized background regimen of 2 drugs. Three hundred eleven of the patients added tipranavir to this optimized regimen and 309 added a boosted CPI.

By week 24, 263 of the patients in the tipranavir arm remained on treatment and 48 discontinued; only 13 patients experienced virologic failure. In comparison, only 151 in the CPI arm were still on treatment and 139 had discontinued with 109 people experiencing virologic failure.

In an intent-to-treat (ITT) analysis, the following was found when comparing the tipranavir arm to the CPI arm:

When those patients who also started with enfuvirtide were considered separately:

However, toxicities such as nausea, diarrhea and increased serum levels of ALT, cholesterol and triglycerides were seen significantly more frequently in the tipranavir arm of this study than in the CPI arm.

From these 24-week results, the authors concluded that tipranavir demonstrates significant efficacy and safety in treatment-experienced patients who have significant PI mutations. When boosted with ritonavir, tipranavir shows significantly more activity in terms of viral load reduction or CD4+ cell increase compared to other ritonavir-boosted regimens.

The positive effect of tipranavir was clearly increased when drugs such as enfuvirtide were added to a regimen. Of concern was the significant amount of lipid abnormalities and gastrointestinal symptoms seen, which, although a consistent and expected finding with other ritonavir-boosted regimens, may limit tipranavir's use in some patients.

Tipranavir will be a welcome addition in those patients with limited treatment options as a result of PI-resistant virus. An expanded access program will soon be available for this medication. For information on currently enrolling trials of tipranavir, click here.