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CASCADE Study Finds Benefit of ART Below CD4 Count of 500, But Not Above


Starting antiretroviral therapy (ART) at CD4 cell counts between 350 and 499 cells/mm3 predicted slower HIV disease progression among participants in the CASCADE cohort, investigators reported in the September 26, 2011, Archives of Internal Medicine. A similar benefit was not apparent, however, for those who started with 500-799 cells/mm3.

When to start antiretroviral treatment remains subject to debate. A growing body of evidence indicates that immune activation and inflammation related to chronic HIV infection can cause a host of problems well before a person's CD4 T-cell count falls to dangerous levels. But prolonged treatment may also lead to unknown long-term toxicities.

Current U.S. treatment guidelines call for starting therapy when the CD4 count falls below 500 cells/mm3, but above this level ART is considered optional and the risk/benefit balance is not clear. A large randomized, controlled trial called START is exploring this question, but final results will not be available for several years. Until then, researchers are looking for clues from observational studies.

Michele Jonsson Funk, Joseph Eron, and fellow investigators with the CASCADE  (Concerted Action on SeroConversion to AIDS and Death in Europe) Collaboration sought to estimate the clinical benefit of highly active ART (HAART) initiation compared with deferring therapy for HIV positive people with CD4 cell counts below 800 cells/mm3.

Between January 1996 and May 2009, the researchers constructed monthly sequential nested sub-cohorts that included all ART-eligible treatment-naive individuals without AIDS who had a CD4 count less than 800 cells/mm3. The primary outcome was time to AIDS diagnosis (e.g., < 200 cells/mm3 or opportunistic illness) or death among patients who initiated ART in a given month compared with those who did not do so.


  • The analysis included 9455 participants in 23 clinical cohorts in Europe, Australia, and Canada who contributed a total of 52,268 person-years of follow-up data.
  • Within this group, 812 (8.6%) developed AIDS and 544 (5.8%) died.
  • Risk of AIDS or death according to CD4 cell count strata at the time of ART initiation was as follows:

o      200-349 cells/mm3: adjusted hazard ratio (HR) 0.59, or about 40% risk reduction;

o      350-499 cells/mm3: adjusted HR 0.75, or about 25% reduction;

o      500-799 cells/mm3: adjusted HR 1.10, indicating no significant reduction (in fact, a slight increase).

  • Looking at all-cause mortality according to CD4 count at ART initiation, changes were as follows:

o      200-349 cells/mm3: adjusted HR 0.71, or about 30% risk reduction;

o      350-499 cells/mm3: adjusted HR 0.51, or nearly 50% reduction;

o      500-799 cells/mm3: adjusted HR 1.2, essentially no difference.

  • Looking at "number needed to treat" (NNT):

o      21 people would have to start ART with 200-349 cells/mm3 to prevent 1 AIDS diagnosis or death within 3 years;

o      34 people would have to start treatment with 350-499 cells/mm3 to prevent 1 case of AIDS or death.

Based on these findings, the study authors concluded, "Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500 [cells/mm3] (but not 500-799 [cells/mm3]) was associated with slower disease progression."

In an accompanying editorial, Daniel Kuritzkes from Brigham and Women's Hospital indicated that these results confirm the validity of the current guidelines threshold of 500 cells/mm3, but support continuing the START trial to get more definitive data about earlier treatment initiation.

Meanwhile, many experts think selected patients can benefit from starting therapy sooner, including people with comorbid conditions such as hepatitis B or C coinfection, those with rapidly falling CD4 counts, and perhaps people over age 50. Of note, while the CASCADE analysis included death from all causes, it did not look at serious non-AIDS-defining conditions such as cardiovascular disease.

Investigator affiliations: Department of Epidemiology, Gillings School of Global Public Health, and Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC; EpiQuest Sciences Inc, Libertyville, IL; Medical Research Council Clinical Trials Unit, London, UK; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Statistics, North Carolina State University, Raleigh, NC; Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN.



M Jonsson Funk, JS Fusco, SR Cole, JJ Eron, et al. (Writing Committee for the CASCADE Collaboration). Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Archives of Internal Medicine171(17): 1560-1569 (abstract). September 26, 2011.

DR Kuritzkes. HAARTfor HIV-1 Infection: Zeroing In on When to Start: Comment on "Timing of HAART Initiation and Clinical Outcomes in Human Immunodeficiency Virus Type 1 Seroconverters." Archives of Internal Medicine171(17): 1569-1570. September 26, 2011.