TMC114/Ritonavir Shows Considerable Antiviral Activity in Patients with Extensive Baseline PI Resistance and Is Active against Multi-PI-resistant HIV

Protease inhibitors (PIs) have reduced morbidity and mortality in patients with HIV infection. However, the emergence of resistance to these drugs has created a need for new PIs active against resistant viruses.

The experimental PI TMC 114 from Tibotec has a unique resistance profile that makes it an attractive candidate for use in HIV infection, especially in heavily treatment-experienced patients. In addition, the pharmacokinetics of TMC114 are enhanced by coadministration of low-dose ritonavir/RTV (Norvir).

The results of the current study were reported by HIV and Hepatitis.com in a review of presentations at the 12th International HIV Drug Resistance Workshop in 2003. The results of the study were published in the June 10, 2005 issue of AIDS, and are worth a second review.

This trial assessed the antiretroviral activity, safety, and tolerability of substituting TMC114/RTV for current PIs in a non-suppressive antiretroviral regimen (ART) in multiple-PI-experienced, HIV-1-infected patients. This was a randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs.

At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days. The time-averaged difference (DAVG) in HIV-1 RNA from baseline, change in HIV-1 RNA from baseline, proportions achieving plasma HIV-1 RNA < 400 copies/ml and >= 0.5 and >= 1.0 log10 copies/ml reductions in HIV-1 RNA, and safety were assessed.

Results

·         DAVG responses in all TMC114/RTV groups (range, -0.56 to -0.81 log10 copies/ml) were significantly greater (P < 0.001) than in the controls (-0.03 log10 copies/ml).

·         Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively.

·         A reduction of >= 0.5 and >= 1.0 log10 copies/ml was attained by 97% and 76% of patients, respectively, in all TMC114/RTV groups and by 25% and 17%, respectively, in the control group. HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group.

·         Most common reported adverse events were gastrointestinal and central nervous system disorders (mild to moderate severity).

·         No dose relationship was observed.

·         Biochemical, hematological and electrocardiographic parameters showed no significant changes.

In conclusion, the authors write, “TMC114/RTV demonstrated a potent antiretroviral effect over 14 days in multiple-PI-experienced patients and was generally well tolerated.”

Discussion

TMC114/RTV showed considerable antiviral activity in patients with extensive baseline PI resistance and was active against multi-PI-resistant HIV-1 as replacement for PIs in a non-suppressive regimen.

This efficacy is especially noteworthy since 80% of patients (54% for lopinavir/RTV) were receiving an RTV-boosted PI at study entry. It is unlikely that the efficacy of TMC114/RTV was influenced by differences in PI resistance among treatment groups; based on fold changes in EC₅₀, PI resistance was at least as common for virus from patients in the TMC114/RTV groups as for control patients.

The efficacy, safety, tolerability and durability of the antiretroviral effect of TMC114/RTV are currently being investigated in phase IIB clinical trials.

06/03/05

Reference
K Arasteh and others (for the TMC 114-C207 Study Team). TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. AIDS 19(9): 943-947, June 10, 2005.