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87% of Persons Treated with HAART Will Eventually Achieve a CD4
T cell Count >/= 350 Cells that Likely Will Protect against Opportunistic
Infections
The key feature of untreated HIV infection is the progressive loss of CD4
T cells, the immune system white blood cells that
protect against a variety of opportunistic infections. The major achievement of potent HAART consists
of a durable suppression
of viral replication, a steep increase
in the CD4 T cell count, and a partial reversal of HIV-related immunological changes.
In
the present study, appearing in the August 1, 2005 issue of Clinical
Infectious Diseases, [1] researchers of the
Swiss
Cohort Study describe what factors determine incomplete CD4
T cell restoration and the clinical consequences
in their large cohort.
Prior
studies have shown that a complete and durable restoration
of the CD4 T cell count and, particularly,
of critical T cell subsets, such as naive
cells, can be best achieved by very early
initiation of ART, preferably during primary
HIV-1 infection [2,3].
In
chronic HIV-1 infection, the recovery of the
CD4 T cell count is hindered by residual viral
replication, impaired thymic function, advanced age, enhanced
T cell activation and apoptosis, and, possibly, viral coinfection
[with HCV or HBV].
As a consequence, a substantial proportion of treated individuals show incomplete or even poor CD4 T cell recovery.
In
some studies, CD4 T cell counts seemed to
reach a plateau after the first 2 3 years of ART, whereas other studies found that,
for selected groups of patients with a well-suppressed
HIV-1 RNA load, there were continuous, albeit
small increases in CD4 T cell counts even
after 34 years of ART. Thus, long-term CD4 T cell recovery,
including its modulating factors, needs further
evaluation.
Researchers
in the Swiss Cohort Study studied the determinants and the clinical relevance of incomplete CD4 T cell restoration.
Longitudinal
CD4 T cell count was analyzed in 293 participants
of the cohort who had had a plasma HIV-1 RNA
load <1000 copies/mL for  5 years.
CD4
T cell recovery was stratified by CD4 T cell
count 5 years after initiation of ART (500
cells/ L was defined as a complete response, and <500 cells/L
was defined as an incomplete response). Determinants of incomplete responses and clinical events were
evaluated using logistic regression and survival
analyses.
Results
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The
median CD4 T cell count increased from
180 cells/L
at baseline to 576 cells/L 5 years after antiretroviral therapy (ART) initiation.
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A
total of 35.8% of patients were incomplete
responders, of whom 47.6% reached a CD4 T
cell plateau <500 cells/L. |
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Centers
for Disease Control and Prevention HIV-1 disease
category B and/or C events occurred in 21%
of incomplete
responders and in 14.4% of complete
responders (P > .05). |
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Older
age, lower baseline CD4 T cell count,
and longer duration of HIV infection were
significantly associated with a CD4 T cell count
<500 cells/L
at 5 years. |
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The
median increases in CD4 T cell count after
36 months of ART were smaller in incomplete responders (P < .001) and predicted, in conjunction
with baseline CD4 T cell count and age,
incomplete response with 80% sensitivity and
72% specificity. |
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Discussion
In
this study, researchers first evaluated the capacity
of the immune system to replenish the depleted
pool of CD4 T cells in patients who had well-suppressed
virus levels during long-term ART. They noted that approximately two-thirds of patients had reached a CD4 T cell count >500 cells/L but that the remaining one-third showed impaired
CD4 T cell recovery.
Approximately one-half of patients with impaired CD4 T cell recovery had reached a CD4 T cell plateau, showing no evidence of further increases in CD4 T cell count.
Secondly,
they observed that a persistently low CD4 T cell
count was associated more frequently with HIV-related CDC category B and C clinical events, although the difference between complete and incomplete
responders was not statistically significant.
Third,
they developed a model that may be useful to
identify individuals with incomplete CD4 T cell recovery early after initiation of ART.
Incomplete
responders showed smaller CD4 T cell recovery
during the first 36
months of ART. On the basis of these smaller
changes, baseline CD4 T cell count, and age,
incomplete CD4 T cell responses could be predicted
with relatively high accuracy.
Mathematical
models for prediction of longitudinal CD4
T cell counts provided interesting estimations. These
models predicted a maximum CD4 T cell count
of 650 cells/L
51 months after ART initiation in this cohort.
“Furthermore,”
say the authors, “the model predicted that 87% of
treated persons will eventually achieve a CD4 T
cell count 350 cells/L,
which is likely to provide adequate protection against
opportunistic infections.”
Regarding
those with good virologic responses who commence ART
at similar baseline CD4 T cell counts, the
authors write, “A total of 70% will even achieve
a nearly normal CD4 T cell count 500
cells/L.
Individuals
with incomplete CD4 T cell recovery to <500
cells/L
had more advanced HIV-1 infection at baseline.
CD4 T cell changes during the first 36
months of ART already reflect the capacity
of the immune system to replenish depleted CD4
T lymphocytes.
Finally,
note the authors, “A limitation of the study was the
still relatively short follow-up period of
5 years. Only an extended observation time beyond
78
years will show whether predictions of the
model were correct.”
In
a jointly-written editorial [4] accompanying the present
article, the authors observe, “Early recognition of how
patients will respond to ART may result in
tailored drug regimens that improve outcome
and quality of life and reduce unnecessary drug
use and costs.”
“The
determinants of discordant response require further study, with the goal of developing new interventions.
However, true advances in tailoring therapy
will only be confirmed if they impact functional
immunocompetence by not only increasing CD4 T cell
counts but also decreasing HIV-associated morbidity
and death. “
07/11/05
References
1. G R Kaufmann
and others (The Swiss Cohort Study). Characteristics, Determinants, and Clinical Relevance of CD4 T Cell Recovery to <500 Cells/ microliter in HIV Type 1Infected Individuals Receiving Potent Antiretroviral Therapy. Clinical Infectious Diseases 41:361-372.
August 1, 2005.
2.
G Carcelain and others. T cell changes after combined nucleoside
analogue therapy in HIV primary infection. AIDS 13:10771081. 1999.
3.
G R Kaufmann and others. Rapid restoration of CD4 T cell subsets
in subjects receiving antiretroviral therapy during primary HIV-1
infection. AIDS 14: 2643-2651. 2000.
4. S
C Sasson, A D Kelleher and D A Cooper.
Characteristics, Determinants, and Clinical Relevance of CD4
T Cell Recovery to <500 Cells/ microliter in HIV Type 1Infected
Individuals Receiving Potent Antiretroviral Therapy. Clinical
Infectious Diseases 41: 373-365. August 1, 2005.
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