The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection

Background: Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been not ed after drug cessation, apparently associated with prior drug interruption s and autologous boosting of HIV-1 specific immune responses. We hypothesiz ed that cyclic structured treatment interruptions structured treatment inte rruptions (STI) could augment HIV-1 specific immune responses in chronic HI V-1 infection, which might help to control HIV-I replication off therapy. Methods: We initialed an STI pilot study in 10 antiretroviral treatment-nai ve HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 50 0 X 10(6) cells/l and plasma viral load > 5000 copies/ml who received highl y active antiretroviral therapy (HAART) for 1 year with good response (plas ma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed. Results: In all of the patients viral load rebounded, but doubling times in creased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before startin g HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and i n four it remained stable below 5000 copies/ml. Those subjects who controll ed viral replication developed significantly stronger HIV-I specific cellul ar immune responses than subjects lacking spontaneous decline (P < 0.05). D uring viral rebounds no genotypic or phenotypic changes conferring resistan ce to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was signifi cantly higher than the pre-treatment level (P = 0.004). Conclusions: Our findings suggest that STI in chronic HIV-1 infection might augment HIV-l-specific cellular immune responses associated with a spontan eous and sustained drop in plasma viral load in some subjects but at the po tential cost of lower CD4 T-cell counts. (C) 2001 Lippincott Williams & Wil kins.