CD4 cell counts are still increasing after seven years of antiretroviral therapy in patients whose baseline CD4 cell count was below 500 cells/mm3 when they started HIV therapy, delegates to the recent Conference on Opportunistic Infections and Retroviruses (CROI) learnt earlier this month. Other research presented to the conference also showed that, to stand the best chances of achieving an increase in CD4 cell count to normal levels, it is necessary to start treatment with a CD4 cell count above 350 cells/mm3, and that patients with ongoing immune activation and a large thymus have smaller gains in CD4 cell count. A small study in the United Kingdom also suggested a possible role for recombinant human growth hormone to 'kick-start' HIV-specific immune responses.
CD4 cell gains after seven years of anti-HIV therapy
CD4 cell counts are still increasing after seven years of potent antiretroviral therapy in patients who started treatment with a CD4 cell count below 500 cells/mm3, investigators from the Dutch ATHENA cohort reported to CROI.
A total of 840 individuals who were naïve to antiretroviral therapy and started treatment with a potent combination of anti-HIV drugs between 1997 and 1998 were included in the investigators’ analysis. Before treatment was initiated, median CD4 cell count was 260 cells/mm3 and median viral load was a little under 100,000 copies/ml.
Mean increases in CD4 cell count after seven years of treatment were approximately 390 cells/mm3 for patients who started therapy with a CD4 cell count below 350 cells/mm3. Smaller increases were observed in patients who started treatment with higher baseline CD4 cell counts, with a mean increase of 280 cells3 recorded in patients who started HIV therapy with a CD4 cell count between 351 – 500 cells/mm3 and a mean increase of 180 cells/mm3 was seen amongst patients who started treatment with a baseline CD4 cell count above 500 cells/mm3.
A lower baseline CD4 cell count predicted whether an individual would spend at least six and a half years on HIV treatment, with 82% of patients with a pre-treatment CD4 cell count below 50 cells/mm3 spending this amount of time or more on therapy compared to just 58% of patients with a CD4 cell count above 500 cells/mm3 prior to treatment.
Factors significantly associated with larger gains in CD4 cell count were lower baseline CD4 cell count and higher baseline viral load, and longer continuous use of antiretroviral therapy.
Amongst 505 continuously treated patients, CD4 cell count increased by a median of 70 cells/mm3 per year during the first three years of therapy. The increase slowed to 30 cells/mm3 per year during the next two years of antiretroviral therapy and to 10 cells/mm3 between years five and seven. When the investigators analysed these findings according to an individual’s baseline CD4 cell count, they found that patients who had a CD4 cell count below 500 cells/mm3 were still gaining a mean of 14 cells/mm3 per year during years five to seven of treatment, compared to a mean annual loss of 31 cells/mm3 amongst patients who started antiretroviral therapy with a CD4 cell count above 500 cells/mm3.
Baseline CD4 cell count and CD4 cell gain on treatment
Investigators from Johns Hopkins University presented data from 262 patients who had been taking anti-HIV therapy for five years showing that only individuals who started treatment with a baseline CD4 cell count above 350 cells/mm3 saw their CD4 cell counts increase to near normal levels.
Mean pre-treatment CD4 cell count was 234 cells/mm3) and the mean five year increase in CD4 cell count was 238 cells/mm3.
The investigators stratified their results according to patients’ baseline CD4 cell count. They found that after five years of treatment, the mean CD4 cell count was 423 cells/mm3 amongst patients who started treatment with a CD4 cell count of 200 cells/mm3 or less, 501 cells/mm3 for patients who started treatment with a CD4 cell count between 201 – 350 cells/mm3 and 681 cells/mm3 for patients who started treatment with a CD4 cell count above 351 cells/mm3.
Significant increases in CD4 cell count were seen every year for patients who started treatment with a CD4 cell count below 200 cells/mm3 (p 3. However, patients who started treatment with a CD4 cell count above 351 cells/mm3 there were no significant increases in CD4 cell count after the first year of antiretroviral treatment.
And the a role for thymus size
A second American study also found that CD8 cell activation has a negative impact on CD4 cell gain after 48 weeks of antiretroviral therapy, but only amongst patients with a large thymus at baseline. The study included 133 patients who had a median CD4 cell count of 304 cells/mm3 and a median viral load of 50,000 copies/ml prior to starting anti-HIV therapy.
Greater CD4 cell gains after 48 weeks of antiretroviral therapy were associated with lower CD8 activation (p = 0.004). The investigators also found that CD4 cell gains and reduction in CD8 activation was dependent upon thymic size. There was no association between CD4 cell gain and CD8 activation amongst patients with a small thymus (thymic score two or below), but there was a strong association amongst patients with a large thymus (p = 0.007).
The investigators conclude that their findings show “distinct mechanisms underlying T-cell regeneration according to thymic output.”
The role of immune activation
Immune activation is associated with the extent of CD4 cell count recovery during long-term antiretroviral therapy, according to American research presented to CROI.
The research included 623 individuals who had their CD4 cell count, viral load and markers of immune activation (HLA-DR co-expression on CD4 and CD8 cells) measured at weeks 24, 48, 72, 96, 120 and 144 of antiretroviral treatment.
Median baseline CD4 cell count was 280 cells/mm3 and median viral load was 75,000 copies/ml. Gains in CD4 cell count were strongly associated with the amount of time on treatment. However, at weeks 48 and 144 both CD4 and CD8 cell percentage were associated with the degree of immune activation a person had experienced.
In further analysis, the investigators found that each 10% decrease in CD8 activation at week 48 was associated with a 30% increase in the odds of achieving an increase of 100 cells/mm3 or more. The investigators concluded that reducing immune activation may be “an important independent determination of the immunologic outcome of highly active antiretroviral therapy.”
Recombinant human growth hormone to ‘kick-start’ HIV specific immune responses
A study conducted at the Chelsea and Westminster Hospital, the UK’s largest HIV treatment centre, demonstrated that daily injections with recombinant human growth hormone could increase HIV-specific CD4 and interferon-gamma producing CD8 cells.
The small randomised, double-blind, placebo controlled study involved twelve patients. All had chronic HIV infection, were taking stable antiretroviral therapy and had a CD4 cell count above 200 cells/mm3.
Significant increases in CD4 specific and CD8 cells were seen amongst individuals who received daily injections of 4mg recombinant human growth hormone. However, when the frequency of these injections was reduced to alternate days and then twice-weekly, the strength of these responses weakened.
“Immune based therapeutic strategies in treated chronic HIV infection may enable the induction of virus-specific CD4 T cells essential for the subsequent ‘kick-start’ and expansion of specific CD8 T cells”, conclude the investigators.
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Rodriguez B et al. T cell activation is inversely associated with CD4+ T cell increases after HAART, and predicts CD4 gains at 48 weeks after controlling for baseline CD4 count and plasma HIV RNA level. Thirteenth Conference on Retroviruses and Opportunistic Infections, abstract 528, Denver, 2006.
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