HAART initiated at higher CD4 count slowed disease progression

Writing Committee for the CASCADE Collaboration. Arch Intern Med. 2011;171:1560-1569.

Highly active antiretroviral therapy initiated at CD4 cell counts between 350 cells/mcL and 499 cells/mcL was associated with slower disease progression when compared with a deferral strategy, according to new findings published in the Archives of Internal Medicine.

“There is consensus among researchers and health care providers that HIV patients with CD4 counts below 350 cells/mcL should start ART,” Michele Jonsson Funk, PhD, research assistant professor at the UNC Gillings School of Global Public Health of the University of North Carolina at Chapel Hill, told Infectious Disease News. “However, there is still uncertainty regarding how much patients benefit — if at all — by starting treatment at higher CD4 counts. We designed this study to shed light on that unanswered question.”

Funk and colleagues evaluated 9,455 HIV-1 seroconverters enrolled in Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) between January 1996 and May 2009. Participants were followed for 52,268 person-years. The researchers compared disease progression and mortality between HAART initiation and HAART deferral strategies among groups of monthly, nested subcohorts of HAART-naive and AIDS-free patients with CD4 cell counts of less than 800 cells/mcL.

Primary outcome measure was a comparison of time to AIDS or mortality among those in the HAART initiation group vs. those in the deferral group. Overall, 8.6% of patients developed AIDS and 5.8% died.

HAART was protective at CD4 cell counts between 200 cells/mcL and 349 cells/mcL (adjusted HR=0.59; 95% CI, 0.43-0.81). When initiated between 350 cells/mcL and 499 cells/mcL, researchers observed a 25% reduction in the RR for AIDS or mortality (adjusted HR=0.75; 95% CI, 0.49-1.14). AIDS-free survival did not differ after adjusting for covariates between 500 cells/mcL and 799 cells/mcL (adjusted HR=1.10; 95% CI, 0.67-1.79).

Further, researchers observed a 49% reduction in the RR for mortality from all causes at CD4 cell counts between 350 cells/mcL and 499 cells/mcL (adjusted HR=0.51; 95% CI, 0.33-0.80). No benefit was observed when treatment was initiated between 500 cells/mcL and 799 cells/mcL (adjusted HR=1.02; 95% CI, 0.49-2.12).

“The bottom-line from these findings, taken together with other studies published during the past few years, is that initiating therapy when the patient’s CD4 count is between 350 cells/mcL and 500 cells/mcL appears to be beneficial over the long term,” Jonsson Funk said in a press release. “But, for patients with a CD4 count greater than 500 cells/mcL, the jury is still out.” – by Ashley DeNyse

Disclosure: This research was funded by grant R01 AI 066920 from the National Institute of Allergy and Infectious Diseases, NIH. Additional support was provided by the University of North Carolina Center for AIDS Research, funded by grant P30 AI 50410 from the NIAID, NIH. The research leading to these results has received funding from a grant from the European Union Seventh Framework Programme (FP7/2007- 2013) under EuroCoord grant agreement 260694.

This study provides additional evidence of the benefits of HAART in individuals with CD4+ T cell counts less than 500 cells/mm³, but did not suggest benefit at CD4+ T-cell counts greater than 500 cells/mm³. This finding is in agreement with several other large cohort studies, but inconsistent with the findings of the NA-ACCORD study, which reported a survival benefit to starting HAART in individuals with CD4+ T-cell counts greater than 500 cells/mm³. Whether differences in results of the two studies are due to differences in the populations studied or the statistical techniques used is unclear. A limitation of the present study is that the benefits of starting HAART earlier, particularly for those with high CD4+ T-cell counts, may not manifest for many years. Furthermore, the public health benefits of decreased HIV transmission to others are not accounted for in such an analysis. Importantly, a major limitation of all observational studies including this one is that regardless of the multitude of factors that are controlled for in statistical analyses, the possibility remains that other factors that have not been controlled for may influence the outcomes. Thus, data from a randomized controlled study are critical to truly determine the utility of initiation of HAART at high CD4+ T-cell counts. Fortunately, such data are expected to be available in March 2015 from the Strategic Timing of Anti-Retroviral Therapy (START) study, which is currently randomizing subjects throughout the world with greater than 500 CD4+ T-cells/mm³ to immediate HAART vs. initiation of HAART once CD4+ cells decrease to less than 350 cells/mm³.

– Elizabeth Connick, MD

Infectious Disease News Editorial Board member

Disclosure: Dr. Connick reports no relevant financial disclosures.

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