Efficacy of the Protease Inhibitors Tipranavir plus Ritonavir in Treatment-Experienced Patients: 24-Week Analysis from the RESIST-1 Trial

Background . Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. Methods . Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of ⩾1 log10 less than the baseline level without treatment change at week 24. Results . Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a ⩾1-log10 reduction in the HIV-1 load (intent-to-treat population; P < .0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. Conclusions . TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection

Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis

TMC125-C223 is an open-label, partially blinded, randomized clinical trial to evaluate the efficacy and safety of two dosages of etravirine (TMC125), a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV-1.A total of 199 patients were randomly assigned 2: 2: 1 to twice-daily etravirine 400 mg, 800 mg and control groups, respectively. The primary endpoint was a change in viral load from baseline at week 24 in the intention-to-treat population.Patients had HIV-1 with genotypic resistance to approved NNRTIs and at least three primary protease inhibitor (PI) mutations. Etravirine groups received an optimized background of at least two approved antiretroviral agents [nucleoside reverse transcriptase inhibitors (NRTI) and/or lopinavir/ritonavir and/or enfuvirtide]. Control patients received optimized regimens of at least three antiretroviral agents (NRTIs or PIs and/or enfuvirtide).The mean change from baseline in HIV-1 RNA at week 24 was -1.04, -1.18 and -0.19 log10 copies/ml for etravirine 400 mg twice a day, 800 mg twice a day and the control group, respectively (P < 0.05 for both etravirine groups versus control). Etravirine showed no dose-related effects on safety and tolerability. No consistent pattern of neuropsychiatric symptoms was observed. There were few hepatic adverse events, and rashes were predominantly early onset and mild to moderate in severity.Etravirine plus an optimized background significantly reduced HIV-1-RNA levels from baseline after 24 weeks in patients with substantial NNRTI and PI resistance, and demonstrated a favorable safety profile compared with control

Maraviroc for previously treated patients with R5 HIV-1 infection

Background CC chemokine receptor 5 antagonists are a new class of antiretroviral agents.Methods We conducted two double- blind, placebo- controlled, phase 3 studies - Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment- Experienced Patients ( MOTIVATE) 1 and MOTIVATE 2 - with patients who had R5 human immunodeficiency virus type 1 ( HIV- 1) only. They had been treated with or had resistance to three antiretroviral- drug classes and had HIV- 1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy ( OBT) based on treatment history and drug- resistance testing. Safety and efficacy were assessed after 48 weeks.Results A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV- 1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV- 1 RNA from baseline was greater with maraviroc than with placebo: - 1.66 and - 1.82 log(10) copies per milliliter with the once- daily and twice- daily regimens, respectively, versus - 0.80 with placebo in MOTIVATE 1, and - 1.72 and - 1.87 log(10) copies per milliliter, respectively, versus - 0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV- 1 RNA levels of less than 50 copies per milliliter ( 42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P&lt; 0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo ( increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P&lt; 0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups.Conclusions Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV- 1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV- 1 who were receiving OBT. (ClinicalTrials. gov numbers, NCT00098306 and NCT00098722.)