HIV VIRAL BURDEN (VB) DURING EPOCH CHEMOTHERAPY (CT) FOR HIV-RELATED LYMPHOMAS

Abstract

Half of patients (pts) with HIV-lymphomas die from complications of HIV. To assess the impact of CT on VB, a predictor of HIV progression, we serially measured HIV-RNA by PCR during and following EPOCH CT. Because of potential pharmacokinetic interactions and overlapping toxicities, pts did not receive antiretrovirals during CT. We developed EPOCH(mg/m2) letoposide (200), vincristine (1.6), and doxorubicin (40) by continuous infusion × 96-hrs on days 1-4; cyclophosphamide (0-750) day 6 and prednisone (60) days 1-6| based on experimental evidence that prolonged exposure to natural product derived drugs is more cytotoxic and better tolerated than bolus exposure. EPOCH was tested in 10 pts with previously untreated HIV-related lymphomas. Pt characteristics included male sex = 10 (100%); median (range) age = 37 (32-45), performance status = 1 (1-4) and CD4 = 42 cell/mm3 (9-474); LDH > nl = 8 (80%); Stage I/II = 5 (50%) and IV = 5 (50%); and histology-large cell = 7 (70%), small non-cleaved = 2 (20%) and unclassified = 1 (10%). Seven(70%) pts responded with 6 complete (CR) and 1 partial response. Median event-free and overall survival were each 5.6 months. One CR died in remission of AIDS, and 5 (50%) pts are event-free at 15-20 mos. Toxicity was evaluated in all pts over 41 cycles. Neutrophil and platelet nadirs <500 and <50,000 µL, respectively, occurred on 29% and 12%, and fever/neutropenia occurred on 7% of cycles. Two pts had prolonged hospitalizations for opportunistic infections present at diagnosis of lymphoma. VB was serially assessed in 8 pts on days 1, and 6 of each cycle, and 3 and 6 wks post-CT Median (range) VB RNA copies/µl plasma were: pre-CT = 19,365(0-730,000; n=8); 3 wks post-CT= 13,500 (0 - 28,000; n=5) and; 6 wks post-CT = 5100(0-15,000; n=5)(p<0.01 baseline vs either wk 3 or 6). Of interest, VB tended to decrease between days 1 and 6 of each cycle median of cycles (range) day 1 = 17,000 (0-730,000; n=29) and day 6= 8,150 (1000-47,000; n=23)(p<0.01). Over all cycles, median log 10 VB ranged from−.04 to +.77, and compared with baseline, median log 10 VB after CT was stable: 3 wks post-CT = +.4 and 6 wks post-CT = −.09. Among 4 pts with baseline VB < 5000, there was a small median increase in log 10 VB at 6 wks post-CT = +1.28 [median (range) 6 wks post-CT = 5100(0-15,000)], and among the 4 pts with baseline VB > 38,000, there was a median decrease in log 10 VB of −.7 in the last measured value(includes pts who died before completing CT)[median (range) = 10,450(0-99,000)]. Among the 5 pts in CR, the median (range) CD4 decreased from pre-CT = 317 (42 - 474) to 3 wks post-CT= 77 (57-229), and increased at 6 wks post-CT = 150 cells/µl (42-172)(p=0.01). Antiretroviral therapy was begun at 6 wks post-CT. EPOCH is active and well tolerated in HIV-related lymphoma. These results suggest that CT may not induce viral replication and, if confirmed, would indicate that the use of antiretrovirals during CT should be primarily guided by toxicity and potential pharmacokinetic interactions with CT