IAS: Darunavir Noninferior to Lopinavir in TITAN trial

SYDNEY, July 27 -- HIV treatment with the newly approved protease inhibitor darunavir (Prezista) was noninferior to the standard-of-care treatment lopinavir/ritonavir (Kaletra) in a year-long trial."This is the first time that any drug has been shown to be superior to lopinavir," said Jose Valdez-Madruga, MD, director of clinical trials for the Sao Paulo AIDS Program in Brazil. "Patients with experienced HIV infection now have an option for treatment."
In a presentation at the International AIDS Society meeting, Dr. Valdez-Madruga said that after 48 weeks of treatment, 71% of HIV-infected participants who were taking darunavir, boosted with ritonavir, had undetectable viral loads, using the <50 copies/mL assay. In comparison, 60% of patients on lopinavir, boosted with ritonavir, achieved the undetectable level on that assay.
The 11% difference in being able to suppress the virus to undetectable levels reached statistical significance (P=.005), Dr. Valdez-Madruga said.
In the TITAN (TMC114/r in Treatment-Experienced patients Naïve to lopinavir) trial, investigators screened 785 patients before enrolling 595 into the group given either darunavir at 600 mg and ritonavir at 100 mg or lopinavir at 400 mg and ritonavir at 100 mg on a twice-daily dosing schedule.
In addition to the protease inhibitors, all patients received an optimized background regimen of at least two antiretrovirals from the nucleoside reverse transcriptase or non-nucleoside reverse transcriptase classes. The use of enfuvirtide (Fuzeon) was not allowed in the trial.
Dr. Valdez-Madruga said that the primary endpoint of the trial was to show that the darunavir regimen was non-inferior to the lopinavir regimen.
The researchers assigned 298 patients to darunavir and 297 were given lopinavir. At the start of the trial, the average viral load in each group was about 40,000 copies/mL. The participants had mean CD-4 positive cell counts of about 230. About 30% of patients in each group were naïve to protease inhibitors.
About 21% of patients in the darunavir arm did not finish the trail, but only four participants (1.3%) dropped out because of virological failure. About 29% of lopinavir patients dropped out, 34 because of virologic failure (11.4%).
The most common adverse event in the trial was diarrhea, reported by 31.8% of darunavir patients and 41.8% of lopinavir patients. Twice as many lopinavir patients had Grade 2-4 diarrhea than darunavir patients. About 16.1% of patients on darunavir reported any kind of rash, compared with 6.7% of patients on lopinavir.
"We also found that darunavir appears to protect the other drugs classes better than lopinavir," Dr. Valdez-Madruga said. He explained that fewer resistance mutations in the nucleoside reverse transcriptase class and in the protease inhibitor class appeared while patients were being treated with darunavir.
"The study shows that darunavir is a better drug than lopinavir," commented Robert Murphy, M.D., of Northwestern in Chicago.
"Whether this trial will change clinical practice, however, may not have anything to do with the science," Dr. Murphy said. He noted that lopinavir/ritonavir can be taken as one pill, but darunavir and ritonavir have to be taken separately. "That means patients have to fill two prescriptions and have two co-pays. Kaletra is a very good drug. I wouldn't switch a patient on the basis of this trial unless there was a reason for doing so."
Dr. Valdez-Madruga concurred. He said that if a patient was experiencing diarrhea on lopinavir, he would consider a switch because diarrhea was less frequent among darunavir patients. Primary source: Abstract Book 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention incorporating the 19th ASHM ConferenceASM ConferenceAJournal
Source reference: Jose Valdez-Madruga et al "TUAB101 - Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naïve, treatment-experienced patients: a randomised, controlled phase III trial (TITAN)," Abstract Book 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention incorporating the 19th ASHM Conference, 22-25 July 2007, Sydney, Australia; p 91.