CD4 Cell Count--Guided Treatment Interruption: Be Smart and Wait for More Evidence

The striking improvement of HIV infec-tion–related morbidity and mortality after the introduction of HAART in the mid 1990s [1] was followed by the daunting realization that eradication of HIV infection is not possible with current antiret-rovirals and that prolonged HAART leads to substantial abnormalities in the metabolism of glucose and lipids, which may accelerate the progression of atheroscle-rosis. Indeed, several reports have linked the use of combination antiretroviral therapy to an increased risk of cardiovascular disease [2, 3]. In addition, changes in body appearance, such as lipoaccumulation and lipoatrophy, as a result of HAART may negatively impact quality of life and long-term adherence to anti-HIV therapy. These findings have driven the exploration of 2 major strategies of structured treatment interruptions (STIs) for chronically HIV-infected individuals receiving prolonged suppressive HAART: (1) dis-continuation of all antiretroviral drugs for a defined period of time, and (2) discon-tinuation of all antiretroviral drugs until the CD4 cell count drops below a predetermined level. By decreasing the duration of exposure to antiretroviral drugs, these strategies seek to prevent long-term toxicities, to improve quality of life, and to reduce the cost associated with continuous HAART. Achievement of these goals depends on the length of time of the HAART interruption while the integrity of the immune system is preserved. Lower CD4 cell count nadir [4], greater CD4 cell count increase after HAART is commenced , and older age [5] have been associated with a more rapid decline in CD4 cell count after interruption of therapy. Patients with these characteristics might expect planned CD4 cell count–guided interruptions to be shorter. Risks associated with the rebound in viremia after discontinuation of HAART include the progression of HIV disease as a result of an abrupt decline in the CD4 cell count, the emergence of antiretroviral drug resistance that may hinder future treatment options, the reseeding of viral reservoirs, the occurrence of acute retro-viral syndrome, the increased transmission of HIV, and decreased quality of life. HIV-1 resistance mutations may be ar-chived in the latent reservoirs of resistant viruses and reemerge after antiretroviral drugs are discontinued or may emerge under the selective pressure of repeated cycles of intermittent therapy. Simultaneous discontinuation of all components of a regimen containing antiretrovirals with different half-lives may select for resistant viruses during periods of exposure to " monotherapy " in patients without detectable plasma viremia. The non-nucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz and nevirapine and the nucleoside reverse-transcriptase …