No CD4 plateau found after 4 years on HAART in those with prior severe immune suppression

CD4 counts can continue to rise after four years in people on continuously successful HAART regardless of CD4 baseline, according to a study published in the September 5th issue of AIDS. Significantly, this is the first study to find no evidence of a plateau in CD4 gains in patients who began therapy with less than 200 CD4 cells/mm³, suggesting that the immune system is able to slowly and continuously restore itself even after advanced immune suppression - as long as HIV replication is kept below 1000 copies/ml.

Two studies published in AIDS last year (Kaufmann et al. and Valdez et al.), found that a plateau in CD4 gains was reached after only two or three years on suppressive HAART. However, the former study only followed half the participants for more than 45 months which could have led to an underestimation of true CD4 gains, and the latter included a smaller sample of participants and allowed for higher levels of viraemia which may have affected the outcome.

Here, a total of 423 patients (93% male, median age 40) from four US clinic-based cohorts who had initiated HAART prior to January 1998 and achieved a plasma HIV viral load below 1000 copies/ml were observed for up to four years, and their data included only if their viral load remained below 1000 copies/ml. Use of hydroxyurea, IL-2 or pregnancy during the first 48 weeks of HAART were reasons for exclusion. Baseline CD4 counts were as follows: 16% had below 50 cells/mm³; 33% had between 50-199 cells/mm³; 27% had between 200-349 cells/mm³; and 24% had 350 cells/mm³ or more.

Of the 153 patients who maintained a plasma viral load below 1000 copies/ml for four years, 38 began with less than 50 cells/mm³; 40 began with between 50-199 cells/mm³; 40 began with between 200-349 cells/mm³; and 35 began with 350 cells/mm³ or more.

The analysis did not appear to retain those patients who had experienced the best CD4 cell gains throughout the study, researchers said. When they compared the rate of CD4 cell gain at different time-points between those who still had viral load below 1000 copies/ml at year 4 and those who didn't, no difference was observed.

For those with baseline CD4 counts of 350 cells/mm³ or below there continued to be yearly statistically significant increases in CD4 counts. Statistically significant rises were only seen between month 3 and month 12, and between year 3 and 4, in those with baseline counts of 350 cells/mm³ or more.

The mean absolute changes in CD4 cell counts (in cells/mm³) from year 3 to 4 were as follows: 89 (p3; 86 (p3; 95 (p3; and 88 (p3 or more.

The authors found several factors independently associated with CD4 count changes from month 3 to year 4. Most significantly, every 100 cell/mm³ increase in baseline CD4 was associated with 63 fewer cells/mm³ gained during that time (p = 0.005). Being younger (60 less cells/mm³ gained for every 10 year age increase; p = 0.02) and being female (p = 0.005) were also associated with better CD4 increases.

Interestingly, those with a low frequency of viral load measurements between 50 and 1000 copies/ml (3 compared with those whose viral load remained consistently below 50 copies/ml. The authors speculate that higher CD4 rises drive, rather than depend upon, ‘blips’ since there is a larger pool of CD4 cells for HIV to infect.

Even though the authors note that after four years on suppressive HAART CD4 levels have not yet peaked - even in those with low CD4 counts at baseline - they do not recommend veering away from current guidelines which suggest that HAART should be initiated at between 200 and 350 cells/mm³, because other studies have shown that there is an increased risk of progression to AIDS when initiating HAART below CD4 counts below 200 cells/mm³. However, for those who have presented late, or who had no option but to begin HAART with a CD4 count below 200 cells/mm³, this study provides the first evidence that the immune system can continue to recover for at least four years despite prior advanced immune suppression .