Investigators from one of the US’s leading HIV treatment centres suggest that anti-HIV therapy may need to be started earlier than is currently recommended to enable CD4 cell counts to return to normal levels. In a study published in the February 15th edition of Clinical Infectious Diseases, researchers from Johns Hopkins University in Baltimore established that after six years of HIV suppression with antiretroviral therapy, individuals who started HIV therapy with a CD4 cell count above 350 cells/mm3 were much more likely to experience a sustained increase in their CD4 cell count to normal, or near normal levels. The investigators also established that in all patients, regardless of their immune status at baseline, CD4 cell increases leveled off after four years of anti-HIV treatment.
“These data suggest that commencement of [HIV therapy] at a lower CD4 cell count will result in a CD4 cell count that does not return to normal levels; this may be a reason to consider starting [treatment for HIV] before the CD4 cell count decreases to 3”, write the investigators.
The aim of potent anti-HIV therapy is to achieve sustained suppression of HIV replication, which allows the recovery of the immune system. It is not yet clear if long-term use of HIV therapy will allow CD4 cell counts to return to normal levels. However, studies so far suggest that gains in CD4 cell counts may plateau within two years of treatment being commended, and only one study (which found increases up to seven years after treatment initiation) has looked at changes in CD4 cell count after five years of HIV therapy.
HIV treatment guidelines currently recommend that the initiation of HIV therapy should be delayed until CD4 cell counts have declined to 350 – 200 cells/mm3. Investigators at Johns Hopkins University wondered what the immunological outcome of six years of virologically effective HIV therapy would be, if it was commenced according to these guidelines: would CD4 cell counts would increase to normal levels, or would plateau at less-than-normal.
Their analysis included 655 patients who had sustained HIV suppression (a viral load below 400 copies/ml) after commencing HIV therapy. The patients were stratified according to their baseline CD4 cell counts (below 200 cells/mm3; 201 – 349 cells/mm3; and, above 350 cells/mm3) and annual changes in CD4 cell count were plotted for each group of patients. Analyses were also conducted to see if factors such as gender, race, age, HIV risk group, and hepatitis C coinfection status affected immune restoration during long-term HIV therapy.
The median age of the patients was 39 years, 69% were male, 70% were black, and injecting drug use was the commonest cause of HIV transmission (38%, followed by 31% sex between men, 22% heterosexual transmission).
After six years of HIV therapy, median CD4 cell count increased by a median of 274 cells/mm3, to a median of 544 cells/mm3.
Amongst patients whose baseline CD4 cell count was below 200 cells/mm3 median CD4 cell count increased to 493 cells/mm3. Patients who started HIV treatment with a baseline CD4 cell count between 201 – 349 cells/mm3 had a median CD4 cell count of 508 cells/mm3 after six years of potent HIV therapy, and individuals who initiated antiretroviral therapy with a CD4 cell count above 350 cells/mm3 had a median CD4 cell count of 829 cells/mm3 at the end of follow-up.
For all three groups of patients, there was a significant increase in CD4 cell count for the first four years of antiretroviral therapy (p
The investigators then looked to see what proportion of patients from each baseline strata achieved CD4 cell counts above 500 and 750 cells/mm3. They found that 42% of patients with a baseline count below 200 cells/mm3 had a CD4 cell count above 500 cells/mm3 after six years of HIV treatment, as did two-thirds of patients whose baseline CD4 cell count was between 201 – 349 cells/mm3 and 85% if individuals who had a baseline CD4 cell count above 350 cells/mm3.
When the investigators looked to see what percentage of patients achieved CD4 cell counts of above 750 cells/mm3 after six years of viral suppression with HIV therapy, it was revealed that 12% of patients with an initial CD4 cell count of below 200 cells/mm3, 21% of those with baseline counts between 201 – 349 cells/mm3, and 46% of individuals with a baseline CD4 cell count above 350 cells/mm3 achieved this outcome.
In multivariate anaylsis, a baseline CD4 cell count above 350 cells/mm3 was a significant predictor (p = 0.01) of greater CD4 cell gains with six years of suppressive HIV therapy. Older patients (above 45 years) experienced significantly lower gains in CD4 cell count (p = 0.03), as did individuals who had injecting drug use as their HIV risk activity (p = 0.001).
Choice of anti-HIV drug (protease inhibitor versus a non-nucleoside reverse transcriptase inhibitor) did not affect significantly affect CD4 cell gains, nor did coinfection with hepatitis C virus, gender or race.
“Among patients receiving [HIV therapy] who achieve durable suppression of HIV load to 3 had CD4 cell counts that returned to nearly normal levels.”
The investigators conclude, “we recommend that consideration be given to initiation of [HIV therapy] at a CD4 cell count above 350 cells/mm3 to achieve better immune recovery.”
Moore RD et al. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 44 (on-line edition), 2007.