icon- folder.gif   Conference Reports for NATAP  
 
  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
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Darunavir and Lopinavir Resistance Differences in TITAN
 
 
  4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
 
Mark Mascolini
 
Lancet, the esteemed British journal, scooped the IAS Conference in Sydney by publishing results of the TITAN trial demonstrating virologic superiority of darunavir/ritonavir over lopinavir/ritonavir in antiretroviral-experienced people who had yet to try lopinavir [1]. But TITAN investigators repeated their findings at the Sydney meeting [2] and offered further details on pretreatment resistance and how many new mutations emerged when one of the ritonavir-boosted protease inhibitors (PIs) faltered [3].
 
TITAN signed up 595 people who had taken two nucleosides plus a nonnucleoside and/or a PI for at least 12 weeks, but none had tried darunavir or lopinavir. Everyone had a viral load above 1000 copies while taking a stable antiretroviral regimen or had been off treatment for 4 weeks or more. Upon entering the study, enrollees averaged a CD4 count of 232 and a viral load of 4.3 log copies/mL. They began darunavir or lopinavir with a background regimen including nucleosides and sometimes also a nonnucleoside. No one could take enfuvirtide.
 
Almost one third of study participants (31.4%) had never taken antiretrovirals, and 81.8% had virus susceptible to four or more PIs. At study entry median phenotypic sensitivity score for the background regimen measured 2.0 in both study arms, and trial participants had a median (range) of 0 (0 to 6) primary PI mutations, 4 (0 to 17) primary or other PI mutations, 0 (0 to 5) darunavir-related mutations, 1 (0 to 11) lopinavir-related mutations, and 2 (0 to 8) nucleoside-related mutations.
 
Median (range) fold change in susceptibility measured 0.60 (0.1 to 43.8) for darunavir and 0.75 (0.3 to 74.5) for lopinavir. While 82.6% of enrollees had no darunavir-related mutations, only 3.9% had three or more such mutations. All told, then, study participants entered TITAN with virus somewhat more susceptible to darunavir than to lopinavir.
 
After 48 weeks a significantly higher proportion of people assigned to darunavir had a viral load below 400 or 50 copies (P < 0.01) (Table). Because the lower limit of the confidence interval for the 400-copy difference between darunavir and lopinavir did not exceed -12%, the TITAN team concluded that darunavir is noninferior to lopinavir in this study population. And because the confidence interval (2% to 17%) did not include 0, statisticians could conclude that darunavir is superior to lopinavir (P = 0.008). The less-than-50-copy response rate difference (Table) varied little when statisticians limited the analysis to people who started the trial with a lopinavir fold-change in susceptibility below 40 or below 10.
 

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Thirty-one people (10.4%) assigned to darunavir endured a virologic failure, compared with 65 (22%) randomized to lopinavir. Among people with virologic failure, proportionately fewer in the darunavir arm ended up with new mutations conferring resistance to darunavir or lopinavir, fewer with darunavir failure had new primary PI mutations (21% versus 36%), and fewer with darunavir failure had new nucleoside-related mutations (14% versus 27%).
 
People who had three or more darunavir-related mutations or 13 PI-related mutations of any kind when the study began had a diminished response to darunavir/ritonavir. Study participants with six or more lopinavir-related mutations or two darunavir-related mutations at study entry had a diminished response to lopinavir. But six baseline lopinavir mutations had no impact on response to darunavir.
 
Rates of toxicities affecting more than 12% of study participants were similar in the darunavir and lopinavir groups: 31.9% and 41.8% with diarrhea, 18.5% and 20.9% with nausea, and 12.4% and 11.1% with nasopharyngitis. A higher proportion taking darunavir than lopinavir had rash (16.1% versus 6.7%), but only 2 people dropped out of the study because of rash, and 1 of them was also taking nevirapine.
 
References
1. Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370:49-58.
 
2. Valdez-Madruga J, Berger DS, McMurchie M, et al. Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-na•ve, treatment-experienced patients: a randomised, controlled phase III trial (TITAN). 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUAB101.
 
3. De Meyer S, De Paepe E, Vangeneugden T, et al. Effect of baseline and on-treatment mutations on the antiretroviral activity of darunavir/ritonavir and lopinavir/ritonavir: results of a randomised, controlled, phase III study (TITAN). 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WEPEB038.