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More Evidence for Starting ART at 500 CD4 Cells

Starting antiretroviral treatment when CD4 count falls below 500 cells/mm3 reduces the risk of AIDS-defining illness -- but not death -- compared with a 350 cells/mm3 threshold.

Since the early years of effective antiretroviral therapy (ART), experts have debated the optimal time to start treatment. Starting early can preserve immune function and a growing body of evidence suggests it may prevent long-term problems related to chronic inflammation. On the other hand, early ART initiation involves greater expense and side effects related to long-term therapy.

While it has long been clear that starting ART before a person's CD4 T-cell count falls below 200 cells/mm3 reduces the likelihood of progression to AIDS or death, there has been less evidence regarding benefits and risks of starting at higher thresholds.

In December 2009, the U.S. antiretroviral treatment guidelines panel raised the recommended ART initiation threshold from 350 to 500 cells/mm3, with half the panel favoring even earlier therapy. European and World Health Organization thresholds stand at 350 cells/mm3.

As described in the April 19, 2011, Annals of Internal Medicine, investigators with the HIV-CAUSAL Collaboration compared combination ART initiation strategies, aiming to identify the optimal CD4 cell count at which treatment should be initiated, with a focus on developed or high-income countries.

This prospective observational study looked at nearly 21,000 treatment-naive patients at HIV clinics in Europe and the Veterans Administration health system in the U.S. enrolled between 1996 and 2009.

All participants entered the study with CD4 counts of at least 500 cells/mm3 (median 660 cells/mm3) and no prior AIDS-defining illnesses. A total of 390 people developed an AIDS-defining illness or died before their CD4 count fell below 500 cells/mm3, nearly 3000 started ART while their count was still above 500 cells/mm3, and approximately 9000 maintained this level without treatment.

The remaining 8392 participants had CD4 counts that fell into the 200-500 cells/mm3 range during follow-up; within this group, researchers compared outcomes among people who started ART at thresholds ranging from 200 to 500 cells/mm3.


  • People who started combination ART at 350 cells/mm3 had a similar risk of death due to all causes as those who started at 500 cells/mm3 (hazard ratio 1.01, or essentially no difference).
  • Those who started at 200 cells/mm3 had a somewhat increased risk of death compared with those who started at 500 cells/mm3 (hazard ratio 1.20, or 20% increased risk).
  • Looking at progression to AIDS-defining illness or death combined, people who started at 350 cells were at significantly greater risk than those who started at 500 cells/mm3 (hazard ratio 1.38, or 38% increase).
  • The difference in the combined endpoint was even greater for those who started at 200 compared with 500 cells/mm3 (hazard ratio 1.90, or nearly double the risk).
  • However, 5-year survival rates (98%) and AIDS-free survival rates (92%) were the same for people who started ART at 350 and 500 cells/mm3.

Based on these findings, approximately 48 patients would have to start ART at a threshold of 500 rather than 350 cells/mm3 to prevent 1 AIDS-defining illness or death over 5 years.

"Initiation of combination ART at a threshold CD4 count of [500 cells/mm3] increases AIDS-free survival," the study authors concluded. "However, mortality did not vary substantially with the use of CD4 thresholds between [300 and 500 cells/mm3]."

A limitation of this study is that it did not look at non-AIDS conditions such as cardiovascular, liver, and kidney disease, which account for a growing proportion of morbidity and mortality among people with HIV now that effective therapy has dramatically reduced rates of opportunistic illness and AIDS-related death.

In an accompanying editorial, Jason Baker and Keith Henry argued that, "the continuing HIV epidemic and tightening of resources requires that we clarify the absolute benefits, risks, and costs of expanding the indications for combination ART."

A large study called START is now underway to address this question, but it is expected to take several years to provide answers.

Investigator affiliations: Harvard School of Public Health, Boston, Massachusetts; University of Bristol, Bristol, United Kingdom; University College London Medical School and Medical Research Council, London, United Kingdom; Veterans Affairs Connecticut Healthcare System and Yale University School of Medicine, New Haven, Connecticut; University of Amsterdam, Amsterdam, the Netherlands; Universitätsspital Basel, Basel, Switzerland; University Hospital Zurich and University of Zurich, Zurich, Switzerland; Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Instituto de Salud Carlos III and Hospital Ramón y Cajal, Madrid, Spain; Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; Barcelona Center for International Health Research and Hospital Clinic, Barcelona, Spain; and INSERM U943, Université Pierre et Marie Curie, and Hôpital Pitié-Salpétrière, Paris, France.



HIV-CAUSAL Collaboration. When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries: An Observational Study. Annals of Internal Medicine 154(8):509-515 (abstract). April 19, 2011.

J Baker and K Henry. If we can't get what we want, can we get what we need? Optimizing use of antiretroviral therapy in the current era. Annals of Internal Medicine 154(8): 563-565. April 19, 2011.