844
Vicriviroc Therapy and EBV Plasma Viral Loads in HIV-1-infected Treatment-experienced Subjects
Athe M.N. Tsibris*1,2, Athe M.N. Tsibris*1,2, R Paredes3,4, R Paredes3,4, Z Su5, C Flexner6, P Skolnik7, C Godfrey8, W Greaves9, M Hughes5, R Gulick10, D Kuritzkes1,3, and D Kuritzkes1,3
1Harvard Med Sch, Boston, MA, US; 2Massachusetts Gen Hosp, Boston, US; 3Brigham and Women's Hosp, Boston, MA, US; 4Fndn irsiCaixa, Badalona, Spain; 5Harvard Sch of Publ Hlth, Boston, MA, US; 6Johns Hopkins Univ, Baltimore, MD, US; 7Boston Med Ctr, MA, US; 8Div of AIDS, NIAID, NIH, Bethesda, MD, US; 9Schering Plough, Kenilworth, NJ, US; and 10Cornell Univ, New York, NY, US
Background: Lack of functional
CCR5 increases the severity of certain viral infections such as West Nile virus. The occurrence of 5 malignancies
(including 4 lymphomas—2 Hodgkin’s and 2 non-Hodgkin’s) among subjects
receiving the CCR5 inhibitor vicriviroc (VCV) in ACTG protocol A5211 prompted
us to determine whether CCR5 inhibition had any effect on plasma titers of
Epstein-Barr virus (EBV), which is associated with many AIDS-related
lymphomas.
Methods: HIV-1-infected,
triple-class experienced subjects with R5 virus and plasma HIV-1 RNA
≥5000 copies/mL on a failing ritonavir-boosted
protease inhibitor regimen were randomized to receive 1 of 3 doses of VCV (5,
10, 15 mg daily) or placebo plus optimized background therapy. Concentrations
of EBV DNA were measured by a quantitative real-time polymerase chain reaction
assay in plasma samples at entry and weeks 2, 16, and 48.
Results: Samples from 85
subjects were analyzed for EBV DNA; 3 of the 4 subjects who developed lymphomas
are included in this group. Of these, 76 subjects with mean plasma HIV-1 RNA of
4.57 (±0.71) log10 copies/mL and mean CD4 counts of
162 (±127) cells/mm3 at baseline had samples at both
baseline and follow-up, and are included in this analysis. Of the 76 subjects,
we randomized 10 to the placebo arm where they received VCV following virologic
failure. Of 76 subjects, 5 (7%), all from the VCV arms, had detectable EBV viremia (≥600 copies/mL) at
baseline; viremia decreased to <600 copies/mL in all but one by the last visit. Over the 48-week study
period, a smaller proportion of VCV-treated subjects developed detectable EBV
DNA than placebo subjects (8% vs 17%), although this
difference was not statistically significant (p = 0.36). No subjects
experienced sustained increases in plasma EBV load. Of the 3 lymphoma subjects,
2 tested had detectable plasma EBV DNA, but all EBV levels were <3200
copies/mL. EBV DNA was not detected in 2 placebo subjects with squamous cell carcinomas of the skin or in the VCV-treated
subject with gastric adenocarcinoma.
Conclusions: CCR5 blockade was
not associated with up-regulated EBV replication in HIV-1-infected subjects
with advanced disease receiving VCV plus optimized background therapy.
|
