Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS Clinical Trials Group A5211

Abstract

Background: Lack of functional CCR5 increases the severity of certain viral infections, including West Nile virus and tickborne encephalitis. In a phase II trial of the investigational CCR5 antagonist vicriviroc (AIDS Clinical Trials Group protocol A5211), 4 lymphomas occurred in study patients who received vicriviroc. Because of the known association between unregulated Epstein-Barr virus (EBV) replication and lymphoma in immunocompromised patients, we evaluated whether vicriviroc exposure was associated with lymphoma EBV antigen positivity and/or had an effect on plasma levels of EBV DNA.

Methods: Clinical findings for all 4 patients enrolled in the A5211 study who developed lymphoma (2 Hodgkin and 2 non-Hodgkin) were reviewed, and tumor specimens were assessed for evidence of ongoing EBV replication. Longitudinal plasma samples from 116 patients in the A5211 study were analyzed, and EBV DNA was quantified by real-time polymerase chain reaction.

Results: Plasma EBV DNA was not detected in the 2 patients with non-Hodgkin lymphoma; both patients with Hodgkin lymphoma who had samples tested had EBV DNA levels <3200 copies/mL. One patient with Hodgkin lymphoma had a lymph node core biopsy specimen that was strongly positive for EBV; the other 3 lymphomas were histochemically EBV negative. None of the 116 patients with available samples experienced sustained increases in plasma EBV levels.

Conclusions: CCR5 antagonism by vicriviroc treatment in treatment-experienced patients was not associated with reactivation of EBV infection.

Trial registration: ClinicalTrials.gov NCT00082498.

Conflict of interest statement

Potential conflicts of interest. M.D.H. has served as a paid member of data and safety monitoring boards for Boehringer-Ingelheim and Tibotec and as a consultant to Bristol-Myers Squibb. J.A.A. has served as a research investigator and/or advisory board member for Pfizer, Gilead, Tibotec, GlaxoSmithKline, Merck, Abbott, Bristol-Myers Squibb, and Boehringer-Ingelheim. J.S.C. has consulted or served on an advisory board for Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Pfizer, Tiobtec, and Merck; has served on Data Safety Monitoring Boards for Koronnis and Achillion; and her institution has received research grants from Schering-Plough, Merck, Tibotec, and Theratechnologies. W.L.G. is an employee of Schering-Plough Research Institute. C.F. served on a scientific advisory board for Schering-Plough. P.R.S. receives research grant support from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, Schering-Plough, and Tibotec. T.J.W. has received honoraria from Merck and Tibotec and receives research support from Tibotec. R.M.G. receives research grant support from Pfizer and Schering-Plough and has served as an ad-hoc consultant to Abbott, GlaxoSmithKline, Monogram, Pfizer, Roche-Trimeris, and Schering-Plough. D.R.K. has served as a consultant to and has received honoraria and/or research grant support from Abbott, Bayer, Monogram Biosciences, Pfizer, and Schering-Plough. All other authors: no conflicts.

Figures

Figure 1

Serial plasma viral loads, CD4 cell counts, and viral coreceptor use in 4 patients who developed lymphoma while receiving vicriviroc (VCV) during AIDS Clinical Trials Group A5211. A, Case 1 (Hodgkin lymphoma [HL]). B, Case 2 (non-Hodgkin lymphoma [NHL]). C, Case 3 (HL). D, Case 4 (NHL). HIV RNA levels are represented by closed circles, and CD4 cell counts are represented by open squares. Vertical arrows denote the time of lymphoma diagnosis. For patients 1 and 3, the lymphoma diagnosis occurred after the last available CD4 T cell count and plasma HIV-1 RNA load. Patient 1 had a screening coreceptor use assay (Trofile) performed 2 weeks prior to study entry that demonstrated CCR5-using virus only. At study entry and at all subsequent time points analyzed, however, dual-mixed virus was detected. Protocol-defined virologic failure was met when patients did not achieve a confirmed reduction in HIV-1 RNA load of ≥1 log10 copies/mL by week 16. DM, both CCR5- and CXCR4-using viruses detected; R5, CCR5-using virus only detected; rHL, recurrent HL.

Figure 2

Lymphoma histology and corresponding Epstein-Barr virus (EBV) immunohistochemistry of the 4 cases of lymphoma diagnosed in AIDS Clinical Trials Group A5211. A, Case 1 (Hodgkin lymphoma [HL]). B, Negative EBV stain findings in case 1, with the exception of Reed-Sternberg cells. C, Case 2 (diffuse large B cell non-Hodgkin lymphoma). D, Negative EBV stain findings in case 2, with the exception of Reed-Sternberg cells. E, Case 3 (HL). F, Strongly EBV-positive lymph node biopsy specimen from patient 3 (case 3). G, Case 4 (diffuse large B cell non-Hodgkin lymphoma. H, Negative EBV stain findings in case 4.