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CD4 Cell Count Continue to Increase for at Least 3 years After Starting HAART & maintaining undetectable viral load: adherence is important
  Study title: ""The potential for CD4 cell increases in HIV-positive individuals who control viraemia with highly active antiretroviral therapy
Researchers including Colette Smith, Mike Youle, Margaret Johnson, and Andrew Phillips, from the Royal Free Medical School in London, UK reported in the current issue of the journal AIDS (2003; 17(7):963-969) on CD4 increases they observed from following treatment-naive patients for 3 years on HAART.
These results suggest that immune reconstitution can continue for prolonged periods of time in those maintaining virological suppression. There is evidence that CD4 cell counts could return to those seen in HIV-negative individuals.
The potential for immune reconstitution up to 2 years after commencing HAART therapy is well known. There is some evidence that the rate of immune recovery, as measured by the CD4 cell count, at 2 years after starting treatment is slower than that at earlier times. However, because of the relatively short time since HAART was introduced the behaviour of the immune system over longer periods of time is less well documented. It is not known whether or when this recovery will eventually stop, and whether the immune system will ultimately recover to and remain at levels comparable to those seen in HIV-negative individuals. One study has shown that the greatest increases in CD4 cell counts occurred in the first 2 years of therapy; however, this study had small numbers and not all participants were therapy naive.
We studied the potential recovery possible in the immune system as demonstrated by the CD4 cell count in a study of antiretroviral-naive patients treated with HAART with long periods of follow-up. As immune recovery is maximal when there is a suppression of plasma viral loads, our study examined the behaviour of CD4 cell counts in patients who sustained virological suppression while on HAART for prolonged periods of time. Of particular interest was whether CD4 cell counts continued to increase after 2 years of treatment, and to what extent the immune system could potentially recover under optimal circumstances.
The objective of this study is to explore the long-term CD4 cell responses to highly active antiretroviral therapy (HAART) in treatment-naive patients whose viral loads remained below 500 copies/ml for prolonged periods. A total of 237 patients whose viral loads remained below 500 copies/ml for one year or more. All individuals included in the study were patients at the Ian Charleson Clinic at the Royal Free Hospital, London. Median follow-up was 1.9 years. All patients studied thus had to have achieved undetectable plasma HIV-1-RNA levels (defined as less than 500 copies/ml) within 6 months of starting therapy, and had to have remained below this level until at least one year after starting HAART. "Blips" (transient episodes of detectable viraemia), defined as single viral load measurements that rose above 500 copies/ml but then returned to undetectable levels at the next reading, were allowed, as it has been shown that patients with single blips do not progress more quicklyCD4 cell counts were analysed to investigate long-term immunological response using mixed-effects models with the slope allowed to change after 1, 12 and 24 months of HAART.
The median baseline CD4 cell count was 175 cells/mm3. After an initial rapid increase in the first month after HAART (97.2 cells/mm3 a month), increases in CD4 cell counts continued less rapidly (11.6 cells/mm3 a month). This increase slowed by 2.4 cells/mm3 a month after one year. CD4 cell counts continued increasing after 2 years, but the rate of increase again slowed (estimated slope at 2 years 5.4 cells/mm3 a month; decrease in slope from year 2 compared with years 1-2 3.7 cell/mm3 a month). A total of 198 out of 211 patients (94%) with measurements at baseline and one year experienced an increase in CD4 cell counts in this interval; 81 and 67% had an increasing slope between 1 and 2 and 2 and 3 years, respectively. By the end of follow-up, CD4 cell counts had increased by 319 cells/mm3, and were more than 500 cells/mm3 in 40% of patients. The authors concluded that although the rate of immune recovery slowed after 2 years, CD4 cell counts rose in most and began to return to levels seen in HIV-negative individuals.
A summary of the change in CD4 cell count between years is shown in Table below. Of 211 subjects with measurements at both baseline and one year, 198 (93.8%) experienced an increase in CD4 cell count from baseline. Overall, CD4 cell counts increased by a median of 197 cells/mm3 (IQR 111-296) during the first year of follow up. One hundred and nine out of 134 participants with values at years 1 and 2 (81.3%) experienced an increase from their 1-year count at their 2-year reading. The CD4 cell counts of a further 51/76 participants (67.1%) increased at 3 years compared with their 2-year reading. Therefore, 32.9% experienced a decrease in their CD4 cell count. Comparing the lower limits of the range and IQR shows that 25% of those with a CD4 cell count at both 2 and 3 years experienced a decrease of between 311 and 19 cells/mm3 in this time interval.
  Author's discussion
The results from this study imply that in those starting HAART who manage to maintain virological suppression, the number of CD4 T lymphocytes will continue to increase for at least 3 years after starting HAART. After an initial biphasic effect, the CD4 cell count continues to rise at a steady rate but the rate of this increase slowed after 2 years. This is partly to do with the fact that some patients have started to reach 'normal' levels.
Of those who had a CD4 cell count taken at 2 and 3 years, approximately 35% experienced a decrease in their CD4 cell count. As this does not take into account the magnitude of the fall in CD4 cell count, these changes could be caused by random fluctuations. However, as 25% of those with a CD4 cell count at both 2 and 3 years experienced a decrease of between 311 and 19 cells/mm3, some of those who were maintaining virological suppression and so remaining adherent to therapy were no longer sustaining immunological reconstitution.
We have considered the potential for immune reconstitution in those who maintain virological suppression. Therefore, we have, by the nature of our analysis, chosen a very select and highly adherent population. Clearly, these results are unlikely to be generalizable to those who do not maintain an undetectable viral load, but they emphasize the importance of good adherence, and reinforce the need to provide support to enable patients to be able to tolerate their medications.
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