The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection.
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 noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy.
                We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed.
                In all of the patients viral load rebounded, but doubling times increased 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 starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance 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 significantly higher than the pre-treatment level (P = 0.004).
                Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.
A limited number of studies were available to address this topic, and, of the two randomized trials identified, both were in abstract form only. Observational studies also were limited in number and were of lesser quality. Although the quality of the evidence varied from the randomized trials, ranging from very low to moderate, there appeared to be substantial benefits for key outcomes (e.g. mortality, AIDS-defining illness and mortality as a composite endpoint, and unnecessary switches) favoring both immunologic and clinical monitoring or virologic, immunologic, and clinical monitoring versus clinical monitoring alone. Very low-quality evidence from observational studies suggested that virologic, immunologic, and clinical monitoring led to more frequent switching, earlier switching, and switching at higher CD4 counts compared with immunologic and clinical monitoring. Further information on the studies currently reported in abstract form will provide insight. Ongoing studies addressing this topic likely will provide information to further clarify optimal monitoring strategies for guiding when to switch first-line therapy. Additionally, studies looking at different virologic monitoring frequencies and/or virologic monitoring at different times after ART initiation (e.g. after 2-3 years) would be informative. Finally, cost-analysis studies will lend further insights into the applicability of these findings to low-resource settings.