CD4 responses after viral suppression for more than 7 years on HAART

An important study published earlier this year, looking at long-term immunological responses after long-term HAART treatment, provided important quantitative data on the limits in CD4 responses experienced by a significant proportion of patients. Median follow-up in the study was 7.5 years (IQR 5.5-9.7) with over 20% patients followed for over 10 years. [1]

This was a study in five US clinic cohorts, that included 366 patients who had maintained viral suppression for at least four years (defined as viral load consistently <1000 copies/mL). Kaplan-Meier analyses were determined by baseline CD4 quartile, with the primary endpoint of time to immune restoration defined as >2 CD4 counts higher than 500 cells/mm³.

The median CD4 cell count at the time of starting treatment was 201 cells/mm³ (IQR 72344) with roughly 25% patients starting with very advanced HIV and 25% starting based on current guidelines (at 350 cells/mm³). The median age was 47 years and 17% were women.

The majority (71%) of patients initiated HAART with a protease inhibitorbased regimen. Approximately half of the cohort was treatment-naive when they started their first HAART regimen. Twelve percent of the population were coinfected with HCV.

Most patients responded well to treatment: the median CD4 cell count after four years of HAART was 560 cells/mm³ (IQR, 390-776).

However, 151 patients (41%) had a CD4 cell count that was less than 500 cells/mm³ at year 4, of whom 61 eventually had a confirmed increase to >500 cells/mm³. Many of the remaining patients remained below this threshold through 10 years of observation.

Results strongly correlated with baseline CD4 count: 95%, 75% and 56% of patients who started treatment at >300, 100200 and <100 cells/mm³ respectively, were able to achieve a CD4 cell count >500 cells/mm³. Baseline CD4 count also correlated with time to reaching CD4 >500 and inversely with magnitude of the changes in CD4 count.

In multivariate analysis, age was the only factor consistently associated with CD4 cell count increases, with younger patients having greater increases than older patients. HCV coinfection, sex, and pre-HAART nucleoside use were not statistically significant predictors of CD4 cell count increases.

Comment

One concern with this study was the use, largely for historical reasons, of a high virological cut-off for the definition of virological success (<1000 copies/mL). An analysis using a <50 copy/mL cut-off may show greater long-term benefits as it would be looking at patients with greater suppression, who are also closer to the current standard of care.

These data are nevertheless important at highlighting that baseline CD4 count is closely linked to immunological response. It also supports the widespread recommendation to start treatment prior to CD4 counts dropping <350 cells/mm³.

Although some patients starting at lower levels still achieve strong responses, a minimum CD4 threshold of 300 cells/mm³ optimised the chance of normalising CD4 counts. Many patients starting at <200 cells/mm³ did not achieve counts over 500 cells/mm³, even after 10 years sustained virological suppression on HAART.

Kelley CF et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis. 2009;48:787794. doi: 10.1086/597093.
http://www.journals.uchicago.edu/doi/abs/10.1086/597093