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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RNA Response, Coreceptor Swaps, and Cancers After 48 Weeks of Vicriviroc
 
 
  4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
 
Mark Mascolini
 
Vicriviroc, the CCR5 antagonist from Schering, held HIV in check through 48 weeks of ACTG 5211 in about one third of treatment-experienced people taking 10 or 15 mg of the drug with ritonavir and other antiretrovirals. Roy Gulick (Cornell University, New York) reported coreceptor switches in 7 of 60 people (12%) taking 10 or 15 mg of vicriviroc and two additional cancer diagnoses in the vicriviroc group.
 
ACTG investigators randomized 118 people taking a failing ritonavir-containing regimen to add 5, 10, or 15 mg of vicriviroc daily or placebo for 2 weeks. At that point everyone switched background regimen drugs based on resistance testing, but everyone continued taking 100 mg of ritonavir daily. Median pretreatment viral load stood at 36,380 copies and median CD4 count at 146. Most study participants were men, and two thirds were white. One third had already tried enfuvirtide.
 
A safety panel closed the 5-mg vicriviroc arm early, and treatment assignments were revealed after investigators noted 5 cases of cancer. (More malignancies developed later; see below.) People taking placebo were allowed to switch to vicriviroc if they suffered virologic failure, defined as less than a 10-fold drop in viral load at or after treatment week 16.
 
The two higher doses of vicriviroc were clearly superior to placebo, though median viral load drops and percentages of people with loads under 400 or 50 copies at week 48 proved slightly better with 10 mg than 15 mg. Among 20 people taking 10 or 15 mg of vicriviroc who had a viral load below 50 copies at week 24, 14 (70%) kept a sub-50 load through 48 weeks.

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The trial plan mandated that everyone have R5 virus when screened for the study. But when they actually started their study regimen, the coreceptor assays showed dual/mixed (R5/X4) virus in 12 people (10%). Time to virologic failure proved faster in people with dual/mixed virus when the study began than in those with R5-only virus, though this difference lacked statistical significance (P = 0.22), perhaps because of the small number of people analyzed.
 
During the study coreceptor use changed in 18 people, 3 in the placebo group (2 after a switch to vicriviroc) and 15 in vicriviroc arms (8 taking 5 mg, 4 taking 10 mg, and 3 taking 15 mg). Among 26 vicriviroc-treated people who had a virologic failure, 9 (35%) saw their virus change coreceptor preference from CCR5 to CXCR4 or dual/mixed tropism. After dual/mixed or X4-using virus emerged in people taking vicriviroc, viral loads and CD4 counts remained relatively stable through 48 weeks of follow-up.
 
As in trials of other new antiretrovirals, virologic response proved best among people who took enfuvirtide for the first time in their study regimen. The 12 enfuvirtide-naive people starting that drug with vicriviroc averaged nearly a 3-log (1000-fold) viral load plunge by week 48, compared with about a 2-log (100-fold) drop in 29 enfuvirtide-naive people who did not start the fusion inhibitor and about a 1-log (10-fold) drop in 19 people who already had enfuvirtide experience when the trial began.
 
Malignancies cropped up in 8 people taking vicriviroc, 2 more than the 6 reported at week 24. The first 6 cases were non-Hodgkin lymphoma in 2 people, Hodgkin disease in 2, one gastric adenocarcinoma, and one squamous cell carcinoma. The two new cases were basal cell carcinoma and recurrent Kaposi sarcoma. Squamous cell carcinoma developed in 2 people randomized to placebo, 1 of whom had switched to 10 mg of vicriviroc. Gulick concluded that "the relationship of vicriviroc to malignancy remains uncertain."
 
Reference
1. Gulick R, Su Z, Flexner C, et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment-experienced subjects: 48 week results. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract TUAB102.