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  18th CROI
Conference on Retroviruses
and Opportunistic Infections
Boston, MA
February 27 - March 2, 2011
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Viral Load and CD4 Changes With Ritonavir-Boosted and Unboosted Attachment Inhibitor
  18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Viral load fell by a median of 1.69 log copies/mL after 8 days of BMS-663068 alone or with a ritonavir boost in an open-label multiple-dose study [1]. The virologic effect did not seem proportional to the dose of this attachment inhibitor. Median CD4 counts rose in all five treatment groups, but CD4 results varied widely in this small study.
BMS-663068 is a prodrug for BMS-626529, which binds to the viral envelope protein gp120 and thus disrupts HIV attachment to the CD4 receptor. Previous single- and multiple-dose studies in 200 healthy volunteers and 50 people with HIV suggested that once- or twice-daily dosing may be feasible.
This trial randomized previously untreated adults or adults who had not been treated for at least 8 weeks to one of five doses of BMS-663068, with or without ritonavir, for 8 days. There were 10 people per dose group, and 6 or 7 in each group were naive to antiretrovirals. Everyone had HIV-1 subtype B, a pretreatment viral load above 5000 copies, and a pretreatment CD4 count above 200.
Group A: 600 mg of BMS-663068 every 12 hours plus 100 mg of ritonavir every 12 hours
Group B: 1200 mg of BMS-663068 at bedtime plus 100 mg of ritonavir at bedtime
Group C: 1200 mg of BMS-663068 every 12 hours plus 100 mg of ritonavir every 12 hours
Group D: 1200 mg of BMS-663068 every 12 hours plus 100 mg of ritonavir every morning
Group E: 1200 mg of BMS-663068 every 12 hours without ritonavir
All but 3 of the 50 study participants were men, and 16 people (32%) had antiretroviral experience. Age averaged 42 years. Median pretreatment viral load was 4.4 log (about 25,000 copies), and median pretreatment CD4 count was 432. Thirty-nine people completed dosing and had a pretreatment 50% inhibitory concentration (IC50) at or below 0.1 microM.
Median maximal viral load declines were similar in groups A through D and somewhat smaller in group E:
Group A: 1.64 log
Group B: 1.59 log
Group C: 1.78 log
Group D: 1.63 log
Group E: 1.22 log
When the investigators eliminated 3 group E participants with a pretreatment IC50 above 0.1 microM, median maximal response in that arm was 1.6 log. Overall median maximal response stood at 1.69 log.
CD4 changes were highly variable from person to person, falling through 8 days in some study participants. Doses A, B, and C produced the best median CD4 cell changes on day 8:
Group A: Median +53
Group B: Median +86
Group C: Median +106
Group D: Median +28
Group E: Median +33
Geometric mean day 8 area under the curve for BMS-626529 was highest in group C (60,624 ng x h/mL, coefficient of variation [CV] 27%), followed by group D (55,170 ng x h/mL, CV 36%), group E (42,589 ng x h/mL, CV 21%), group A (26,772 ng x h/mL, CV 49%), and group B (22,946 ng x h/mL, CV 44%).
Geometric mean day 8 minimum concentration was again highest in group C (749 ng/mL, CV 56%), followed by group D (613 ng/mL, CV 62%), group E (524 ng/mL, CV 57%), group A (436 ng/mL, CV 68%), and group B (55 ng/mL, CV 101%).
No deaths occurred during the study, and there were no serious adverse events or discontinuations due to adverse events. The researchers reported no clinically relevant changes in ECGs, laboratory values, vital signs, or physical exams. Overall, 33 people (66%) had adverse events judged to be treatment-related. Eighteen of 50 study participants (36%) complained of headache, and 8 of 50 (16%) had rash, but most headaches and rashes were mild.
A phase 2b study of BMS-663068 plus other antiretrovirals in treatment-experienced people is planned for 2011.
1. Nettles R, Schurmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: a potentially first-in-class HIV attachment inhibitor. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 49.