Starting HAART with a Higher CD4 Cell Count Improves Immune Recovery and Reduces the Risk of Disease Progression or Death

By Liz Highleyman

Current U.S. HIV treatment guidelines recommend starting antiretroviral therapy when the CD4 cell count falls within the 200-350 cells/mm3 range. However, recent studies suggest that earlier treatment may be more beneficial.

Effect of CD4 Count on Immune Recovery Study ACTG 384 compared 6 different HAART regimens consisting of efavirenz (Sustiva) or nelfinavir (Viramune) plus 2 different NRTI "backbones" in patients starting HAART for the first time.

As reported at the recent 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia (July 22-25, 2007), study investigators sought to determine whether reconstitution of T-cell subsets was affected by baseline CD4 cell count. They analyzed data from 978 ACTG 384 participants.

Using advanced flow cytometry, the researchers compared total CD4 T-cells, naive CD4 T-cells, memory CD4 T-cells, and CD8 T-cells during the 144 weeks of the study, then analyzed the results with respect to baseline CD4 count strata (the results below are reported in this order):

• <50 cells/mm3;
• 51-200 cells/mm3;
• 201-350 cells/mm3;
• 351-500 cells/mm3;
• >500 cells/mm3.

Results

• Absolute CD4 cell counts in the lower strata failed to catch up to those seen in the higher strata, even though CD4 cell increases were similar for all groups throughout the 144 weeks.

• Baseline CD4 naive-to-memory cell ratios (median 0.21, 0.45, 0.57, 0.66, and 0.81, respectively) were lower in the lower strata.

• This remained the case at weeks 48, 96, and 144 (median 0.43, 0.50, 0.68, and 0.80, 0.69, respectively, at the end of follow-up).

• T-cell subsets in patients with baseline CD4 counts greater than 350 cells/mm3 approached or were within the normal range for absolute CD4 cell, CD4 naive cell, and CD4 memory cell counts, and for CD4 naive-to-memory cell ratios.

• In contrast, patients who began HAART with 350 cells/mm3 or less generally failed to regain the normal values seen in the general population.

• HIV positive patients' median CD4-to-CD8 cell ratios at baseline (0.05, 0.18, 0.34, 0.49, and 0.64, respectively) were lower than those of HIV negative control subjects (2.02).

• CD4-to-CD8 cell ratios remained low at week 144, especially in subjects with baseline CD4 counts of 350 cells/mm3 or lower (0.40, 0.51, 0.69, 0.91, and 1.19, respectively).

Conclusion

"T-cell deficits were most notable for subjects in the lowest CD4 cell stratum, whose median CD4 naive-to-memory cell ratio after nearly 3 years remained below the baseline values of other strata," the study investigators reported. "Median CD4-to-CD8 ratios for all strata appeared to be lower than HIV-negative controls, especially those in the lower strata."

Based on these results, they concluded, "These data support consideration of earlier initiation of ART (>350 CD4 cells/mm3) to allow restoration of normal T-cell populations."

Massachusetts General Hospital, Harvard Medical School, Boston, MA; Harvard School of Public Health, Boston, MA; University of California-Davis Medical Center, Sacramento, CA; Case Western Reserve University School of Medicine, Cleveland, OH; Roger Williams Medical Center, Miriam Hospital ACTU, Providence, RI; Stanford University Medical Center, Stanford, CA.

Effect of CD4 Count on Disease Progression

In another study presented at the conference, Dutch researchers assessed changes in the rate of progression to AIDS or death after the Netherlands lowered its cut-off for starting HAART from 500 to 350 cells/mm3 in the year 2000.

The investigators analyzed data from more than 3000 patients from the ATHENA cohort who were diagnosed with HIV between 1998 and 2005 (77.2% diagnosed after 2000). Study participants had a CD4 count of at least 200 cells/mm3 and were treatment-naive.

Results

• During the follow-up period, 45 patients died and 165 progressed to either an AIDS diagnosis or death.

• The hazard ratio for AIDS or death was 1.8 for patients with a baseline CD4 cell count of 200-350 cells/mm3 and 1.2 for those with 350-500 cells/mm3, compared to those with 500 cells/mm3 or more.

• Patients with 200-350 cells/mm3 were about 50% more likely to progress to AIDS or death than those with more than 500 cells/mm3.

• However, CD4 counts were not associated with the risk of death alone.

• Patients with baseline CD4 counts of 200-350 cells/mm3 had a 55% lower risk of AIDS or death if they were diagnosed in the year 2000 or earlier.

• For 1032 subjects still undergoing follow-up, median CD4 cells counts after 192 weeks were:

- 505 cells/mm3 for those who started with 200-350 cell/mm3;

- 500 cells/mm3 for those who started with 350-500 cell/mm3;
573 cells/mm3 for those who started with more than 500 cell/mm3.

• The weekly CD4 cell increase was 8.2, 7.0, and 3.7 cells/mm3 less for each respective CD4 count category for patients diagnosed after 2000 compared to those diagnosed earlier.

Conclusions

"The risk of AIDS/death was higher when the recommended CD4 range for starting HAART was 200-350 [cells/mm3]," the researchers concluded. "As current HAART regimens are less toxic and easier to adhere to than before 2000, the CD4 threshold for starting HAART should be reconsidered."

These findings are consistent with those of another recent ATHENA cohort analysis*, which found that 73% of patients who started HAART with CD4 cell counts above 350 cells/mm3 reached a level of 800 cells/mm3 or more within 7 years. But the likelihood of attaining this normal level fell to 46% for those who started treatment with 200-350 cells/mm3 and 26% or less for those who started with fewer than 200 cells/mm3.

HIV Monitoring Foundation, Amsterdam, Netherlands; Leiden University Medical Centre, Leiden, Netherlands; Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands; Academic Medical Centre of the University of Amsterdam, Netherlands.

08/31/07

References

G Robbins, E Chan, J Spritzler, and others. Effect of baseline CD4 cell count on immune reconstitution during combination antiretroviral therapy in ACTG 384. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (4th IAS). Sydney, Australia, July 22-25, 2007. Abstract WEPEB080.

A van Sighem, L Gras, C Smit, and others (for the ATHENA study team). A CD4 threshold below 350 cells/mm3 for starting HAART is associated with a higher risk of disease progression. 4th IAS. Sydney, Australia, July 22-25, 2007. Abstract WEPEB016.

* L Gras, AM Kesselring, JT Griffin, and others. CD4 Cell Counts of 800 Cells/mm3 or Greater After 7 Years of Highly Active Antiretroviral Therapy Are Feasible in Most Patients Starting With 350 Cells/mm3 or Greater. JAIDS 45(2): 183-192. June 1, 2007.