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Trials That Matter: CD4+ T-Lymphocyte CountGuided Interruption of Antiretroviral Therapy in HIV-Infected Patients

Editor's Note: We are deeply sorry to report that Dr. Abrutyn died unexpectedly while preparing this editorial for publication. He was an associate editor of Annals for 29 years, which is just one of many accomplishments of a splendid life in medicine. An appreciation of his career appears elsewhere in this issue. Advances in antiretroviral chemotherapy have been remarkably successful in suppressing HIV replication, preventing or reversing much of the immunologic damage from HIV infection, reducing the incidence of clinical events and hospitalizations, and prolonging life (1). However, treatment is merely suppressive, not curative (2), and antiretroviral therapy is associated with clinical toxicity, emergence of drug resistance, substantial cost, and burdensome pill-taking. As a result, the concept of structured interruptions to treatment is attractive. Proponents of structured treatment interruption have had several theoretical goals, including providing pulse exposures of viral antigens as an autoimmunization strategy to boost anti-HIV immune responses (35); repopulating with drug-sensitive wild-type virus in persons with multidrug-resistant HIV (69); and reducing drug exposure and its adverse clinical, social, and economic consequences (1012). Current treatment guidelines recommend waiting until an AIDS-defining clinical event has occurred or the patient's CD4+ T-lymphocyte count (CD4 count) has fallen below 200 cells/mm3, signifying that the patient is substantially immunocompromised, before starting antiretroviral therapy (1, 13). These guidelines also encourage physicians to consider starting treatment when the CD4 count is between 200 and 350 cells/mm3 (1, 13). Whether therapy should then be continuous or could be intermittentas guided by the CD4 cell counthas been an open question. The Strategies for Management of Antiretroviral Therapy (SMART) study was designed to address this question for patients who begin treatment with a CD4 count greater than 350 cells/mm3 or who achieve this level after treatment (11). What Did This Trial Show? The multinational SMART study was an open-label, randomized trial of continuous versus intermittent antiretroviral therapy in HIV-infected patients with CD4 counts greater than 350 cells/mm3. The median CD4+ count at study entry was approximately 600 cells/mm3. Nearly all participants had taken antiretroviral drugs for a median of 6 years. Patients randomly assigned to the intermittent therapy group received no antiretroviral therapy until their CD4 count fell below 250 cells/mm3; treatment then continued until the count rose above 350 cells/mm3, at which time therapy was interrupted again. Patients assigned to the continuous therapy group received uninterrupted treatment. The primary end point was new or recurrent opportunistic disease or death from any cause. After 5472 of a planned 6000 patients had started the study, an independent data and safety monitoring board halted enrollment because the intermittent therapy group had a higher rate of the study end points, including opportunistic disease and death, than the continuous therapy group (3.3 vs. 1.3 events per 100 person-years; unadjusted hazard ratio, 2.6 [95% CI, 1.9 to 2.7]). After adjustment for the most recent CD4 cell count and HIV RNA level, the hazard ratio dropped to 1.5 (CI, 1.0 to 2.1). Of the 85 deaths in the study, only 8% were attributed to opportunistic disease, whereas 18% were caused by types of cancer other than those considered to be opportunistic. Notably, patients in the intermittent therapy group had more major cardiovascular, renal, or hepatic diseases than did those in the continuous therapy group (1.8 vs. 1.3 per 100 person-years; hazard ratio, 1.7 [CI, 1.1 to 2.5]). How Did This Trial Advance Knowledge? The SMART study showed that in antiretroviral-experienced persons with an average baseline CD4 count of nearly 600 cells/mm3, continuous antiretroviral therapy is superior to intermittent therapy that ceases treatment until the CD4 count falls to 250 cells/mm3 and then resumes treatment until the CD4 count again exceeds 350 cells/mm3. Lower CD4 cell counts and unsuppressed viremia accounted for mostbut not allof the increased risk for opportunistic disease or death in the treatment interruption group. The study had 2 surprising findings: the very low proportion of deaths due to opportunistic disease, and the increased probability that patients in the intermittent therapy group would develop serious cardiovascular and renal disease. Therefore, the study results raise important questions about the effects of uncontrolled HIV replication and a deteriorating immune system on organ systems. A variety of factors, such as immune activation associated with uncontrolled HIV infection, may be involved. We need to understand the pathophysiologic mechanisms that underlie the nonopportunistic causes of death in the SMART study. What Should Clinicians Do? The SMART study is a major blow to the concept of structured treatment interruptions guided by the CD4 count. It discourages allowing the CD4 count to fall to 250 cells/mm3 by intentionally interrupting therapy when the count exceeds 350 cells/mm3. The safety of a CD4 countguided strategy that maintains a count greater than 250 cells/mm3 is still open to question. The unfavorable results of this study have also prompted renewed interest in the vexing challenge of when to initiate antiretroviral therapy. Both of these decisionswhen to begin therapy and whether to interrupt itrequire adequately powered clinical trials to define effective treatment strategies that maximize the benefits while reducing the burdens of antiretroviral therapy. The SMART trial and another study (14) have shown that cardiovascular disease and nonopportunistic types of cancer are increasingly the cause of death in persons being treated for HIV infection. It now appears that cycling patients on and off therapy may further increase morbidity and mortality from these nonopportunistic diseases. The SMART study supports continuing treatment in most antiretroviral-experienced persons who have started therapy. It also reminds us to try our best to prevent organ disease and types of cancer that we do not usually think of as being associated with HIV but may in fact be caused by poorly understood consequences of HIV infection (15).