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The expense, inconvenience, and long-term toxicity of potent combination antiretroviral therapy have inspired sustained interest in intermittent treatment techniques. Some pilot studies have suggested that using CD4-cell counts to guide treatment interruptions is a reasonable way to minimize both drug toxicity and clinical HIV complications. However, results from a large international study (previously reported at the 13th Retrovirus Conference [ACC Mar 15 2006]) suggest otherwise.
More than 5000 HIV-infected participants were randomized to receive antiretroviral therapy either continuously or intermittently. In the latter group, all antiretrovirals were stopped when CD4-cell counts exceeded 350 cells/mm3 and were resumed if and when counts fell below 250 cells/mm3. Drugs could also be resumed for clinical AIDS-related problems at any CD4-cell count. Specific drug regimens were selected by the subjects' primary physicians.
After a mean 16-month follow-up, patients who received intermittent therapy had significantly higher rates of all-cause mortality (hazard ratio, 1.8) and AIDS-related opportunistic disease (HR, 6.6 for serious conditions and 3.6 for nonserious ones) than did patients who received continuous therapy. The combined endpoint of major cardiovascular, hepatic, or renal disease was also more common in the intermittent-therapy group, as were acute problems of the kind often ascribed to drug toxicity, even though drug exposure in this group was roughly one third that of the other. The study was stopped prematurely because of these results.
Subset analysis indicated that even among participants with nadir CD4 counts >300 cells/mm3, intermittent treatment carried a significantly higher risk for opportunistic disease or death than did continuous treatment. Of the 55 deaths in the intermittent-treatment arm, 40 were of known cause; only 4 of them were ascribed to opportunistic disease. The most frequent causes of death were non-HIV–related cancers in 11 patients and cardiovascular events in 7.
The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count–guided interruption of antiretroviral treatment. N Engl J Med 2006 Nov 30; 355:2283-96.
Currier JS and Baden LR. Getting smarter — The toxicity of undertreated HIV infection. N Engl J Med 2006 Nov 30; 355:2359-61.
Comment
This study, along with ANRS 1269 (Lancet 2006; 367:1981), has dashed hopes that intermittent treatment tuned to the CD4-cell count would prove to be the safest, most effective way of treating HIV infection. The results imply that even with “good” CD4-cell counts, patients who are not receiving treatment are still at risk for bad clinical events that may be abrogated by antiretroviral therapy, and these events are not necessarily limited to the usual AIDS-related opportunistic infections and malignancies.
As an editorialist notes, perhaps the only patients who can safely receive intermittent antiretroviral treatment are those who do not need treatment in the first place. Or perhaps differently configured intermittent techniques will still be successful — for example, those using other CD4-cell–count parameters for stopping and starting treatment, as some smaller studies have done (ACC Aug 21 2006), or those using yet-undiscovered surrogate markers that will correlate with clinical risk better than CD4-cell count does.