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AIDS 2012: Incomplete CD4 T-Cell Response to ART Raises Mortality Risk

Having fewer than 700 CD4 cells/mm³ and hepatitis C coinfection were associated with greater risk of death in a study of U.S. veterans, researchers reported at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC, suggesting that it may be beneficial to start antiretroviral treatment before CD4 counts fall to this level.

The recommended CD4 cell threshold for initiating antiretroviral therapy (ART) has increased in recent years, rising from 350 cells/mm³ to 500 cells/mm³ and finally to no upper limit in the latest U.S. DHHS treatment guidelines. Yet this recommendation remains controversial, as some patients and clinicians are concerned about toxicities related to long-term drug exposure before the immune system sustains much damage.

Henning Drechsler from the Dallas VA Medical Center looked at the association between CD4 cell levels and death rates after a first prescription of highly active antiretroviral therapy (HAART), or effective combination treatment, among U.S. veterans, using data from the Veterans Administration (VA) Clinical Case Registry. They focused on incomplete CD4 cell recovery, or failure to reach a near-normal level -- usually listed as 500-1500 cells/mm³, but averaging in the 700-1000 cells/mm³range. They also assessed other factors including ART adherence and hepatitis B or C coinfection.

Most participants (98%) were men, about half were black and half white, and the average age at HAART initiation was 48 years; 41% had hepatitis C virus (HCV) and 13% had hepatitis B virus (HBV) coinfection. At baseline the median CD4 count was 260 cells/mm³ and the median CD8 cell count was 1116 cells/mm³. Patients were prescribed HAART for at least 14 days, were followed for at least 18 months, and achieved viral suppression < 400 copies/mL within this period.

Results

• Overall mortality by year of HAART initiation progressively declined, from 29.6 per 100 person-years in 1996 to 14.1 per 100 person-years in 2008.
• Median CD4 cell count increased for the first 10 years on HAART, reaching about 600 cells/mm³.
• CD8 cell counts, however, remained elevated compared with normal levels (> 800 cells/mm³).
• Patients in the highest quintile (one-fifth) of CD4 counts -- or > 700 cells/mm³ -- had mortality rates similar to those of people of the same sex, race, and age in the HIV negative general population.
• The likelihood of reaching 700 cells/mm³ depended on baseline CD4 cell levels when starting HAART; fewer than half of patients who started with 350-499 cells/mm³ eventually reached this level.
• In a univariate analysis, mortality risk factors included older age, earlier year of HAART initiation, HBV or HCV coinfection, persistent low-level detectable viral load, and abnormal lymphocyte subset proportions, along with being in the lower 4 CD4 count quintiles.
• However, sex, race, history of clinical AIDS, and baseline viral load did not predict mortality.
• Good ART adherence was associated with lower risk of death.
• Use of stavudine (d4T; Zerit) was associated with higher mortality, while use of zidovudine (AZT; Retrovir), emtricitabine (Emtriva), tenofovir (Viread), efavirenz (Sustiva), and/or ritonavir (Norvir) had a protective effect.
• In a multivariate analysis, low-level viral load and lymphocyte subset proportions at baseline were no longer significant predictors of death.
• Poor adherence, earlier year of HAART initiation, HBV or HCV, recent (but not cumulative) stavudine use, and being in the lower CD4 count quintiles remained independent mortality risk factors.

CD4 cell "area under the curve" averages "defined a mortality gradient which included the low normal stratum of 510-699 cells[/mm³]," the researchers concluded. "Given that more than half of patients may progress to CD4 counts < 500/[cells/mm³] within a year after HIV seroconversion, our observations suggestion that immediate HAART initiation will likely translate into a mortality benefit by maintaining CD4 counts well above 700 cells/[mm3]."

"While intermittent low-level viremia (< 1000 copies/mL) was not associated with an increased risk of death, measured HAART adherence maintained a strong predictive effect...and is likely a superior surrogate for long-term stable interruption of viral replication than infrequently measured plasma viral loads," they continued. "Consistent with many other studies, hepatitis C coinfection was independently associated with a 66% increased risk of death."

8/21/12

Reference

H Drechsler, S Zhang, M Holodniy, and R Bedimo. Immune reconstitution on HAART defines survival in US veterans. XIX International AIDS Conference (AIDS 2012).  Washington, DC, July 22-27, 2012. Abstract MOPE113.