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An Increase in CD4+ Cell Count Predicts Clinical Benefits in Patients
with Advanced HIV Disease and Persistently Detectable Viral Load
Although combination antiretroviral
therapy has resulted in significantly improved survival rates
and a higher quality of life
in HIV patients, not all individuals treated with HAART achieve
a potent and durable response to therapy. In fact, studies show
that 50-60% of patients experience virologic failure
within 2 years of initiating HAART. This situation places them at
risk of disease progression, development of AIDS and possibly death
[1,2,3].
Yet there are many examples of patients
experiencing sustained CD4+ cell count increases in
spite of not achieving full virological suppression.
These patients experience similar rates of disease
progression and death
similar to those who achieve full virological suppression.
[4].
In the current study summarized below,
researchers conducted an analysis demonstrating a significant, graded
association between CD4 cell count increase after 12 months and
risk of progression
to AIDS or death
in patients with persistently detectable
HIV viral loads.
In the view of the study authors, this
is an important finding that can help to guide clinical decision
making regarding the use of HAART in patients who have advanced
disease and limited treatment options. The study was conducted by
Dr. Mona Loutfy and other members of the Terry Beirn Community Programs
for Clinical Research on AIDS and the Canada HIV Trials Networks.
Results of the study appear in the October 15, 2005 issue of The
Journal of Infectious Diseases [5]
The exact mechanism whereby
recovery of CD4+ cell counts occurs
in the presence of persistent viremia has not
been fully explained.
The magnitude of the CD4+
cell count increase that is necessary to bring
about clinical benefit has not been determined. In this
study, the investigators describe the relationship between 12-month
CD4+ cell count response and clinical
outcome in an HIV population who started HAART
and after 12 months of treatment, still exhibited detectable
HIV RNA. Twelve months after the start
of treatment was selected as the time point for
assessment, because the virologic and immunologic
response to a new antiretroviral regimen would
have occurred by this time.
The observed CD4+
cell count response at month 12 was divided
into 5 categories:
(1) a decrease or no change
in CD4+ cell count (the reference
group);
(2) an increase of 1—24 cells/mm3;
(3) an increase of 25—49
cells/mm3;
(4) an increase of 50—99 cells/mm3;
and (5) an increase of >100
cells/mm3.
The
end point of interest was the first occurrence of an AIDS-defining
event or death (whichever occurred first) after the first 12 months
of HAART.
Results
 |
Of
the 775 patients originally randomized, all but 228
were excluded; all the selected patients were treatment-experienced,
had not reached a clinical endpoint before 12 months, and had
an HIV viral load (VL)
> 400 copies/mL at 12 months; |
|
A
decrease or no change in CD4+ cell
count at month 12 relative to baseline
was observed in 65 (29%) and 2 (1%) patients,
respectively; these patients composed the reference
group. |
|
Of
the remaining patients, 34 (15%), 26 (11%),
39 (17%), and 62 (27%) had increases in
CD4+ cell count of 1 24, 2549, 5099, and >/=
100 cells/mm3 by 12 months, respectively. |
|
Overall,
the median changes in VL at 1, 4, 8, and
12 months were -1.08, -0.57, -0.20, and
-0.14 log10 copies/mL, respectively. |
|
After
month 12, patients were followed for a
median of 40 months. |
|
A
total of 81 patients (35.5%) developed AIDS
(n = 50) or died (n = 51)
during follow-up, with 20 patients reaching both
end points. |
|
A
further 18 patients (7.9%) were lost to follow-up. |
|
The
most common AIDS-defining events were espophageal candidiasis
(19 cases) and Pneumocystis
jiroveci pneumonia
(15 cases). |
|
The
cumulative percentages of patients who developed
AIDS or died during the first 2 years
of follow-up were 17.9%, 29.4%, 3.9%, 2.6%,
and 1.6% in patients with a decrease or
no change in CD4+ cell count or with increases
of 124, 2549, 5099, and >/=100
cells/mm3, respectively. |
|
After
3 years of follow-up, these percentages
were 39.2%, 47.1%, 19.7%, 13.1%, and 6.6%, respectively. |
|
For
comparison, among the 85 patients with
a VL >= 400 copies/mL at 12 months who
were consequently excluded from the main analysis,
the cumulative percentage progressing to AIDS
or death after 2 and 3 years of follow-up
were 3.5% and 9.5%, respectively. |
The
researchers’ analyses investigating the relationship between
12-month CD4+ cell count response and subsequent
AIDS-defining illness or death yielded similar
results. There was a lower risk of clinical
progression relative to the reference group for
each incremental increase in CD4+ cell count
response. [emphasis added—Ed]
The
adjusted hazard ratios (HRs) decreased from 0.83 (95%
confidence interval [CI], 0.45-1.55; P =
.57) for those with an increase of 1-24 cells/mm3,
to 0.47 (95% CI, 0.22-1.00; P = .05)
for those with an increase of 25-49 cells/mm3,
to 0.31 (95% CI, 0.15-0.67; P = .003)
for those with an increase of 50-99 cells/mm3,
and to 0.23 (95% CI, 0.11-0.50; P <
.0002) for those with an increase of >100
cells/mm3. When 12-month CD4+ cell
count response was analyzed as a continuous predictor
of an AIDS-defining event or death after 12
months, the adjusted HR was 0.79 (95% CI,
0.71-0.88; P < .0001) for each increase
of 25 cells/mm3.
Discussion
For HIV
patients, the primary goal of therapy is to
attain a VL below the limit of detection of
the currently available technology (<50 copies/mL)
[6]. However, this goal is not always attainable in treatment-experienced
patients, because of the development of drug
resistance. For these patients, the goals
of therapy are often shifted to a focus on
immunologic maintenance or recovery and delayed
disease progression.
Several
studies have supported this approach as being feasible
for periods of up to 5 years and have
found immunologic recovery to be correlated with
improved clinical outcomes even in the presence
of detectable viremia.
In
the present cohort of 228 HIV patients with
advanced immunosuppression who started a PI-containing
HAART regimen, an incremental decrease in the risk
of clinical progression with increasing 12-month CD4+
cell count responses was observed despite persistently
detectable viral load.
Thus,
the results indicate that, in cases where complete
VL suppression does not occur, the CD4+
cell count response is a very important predictor
of clinical outcome and that patients with discordant
responses to HAART may still experience a favorable
clinical outcome during the next first few years
of therapy.
These
findings have important implications for the management
of antiretroviral-experienced patients, according to the study authors.
“First,
for patients in whom complete virologic suppression
is unlikely or has not occurred, emphasis should
be placed on monitoring and maximizing CD4+
cell count increases.”
“Second,
our data provide support for maintaining patients
with discordant responses on their current regimen
as long as CD4+ cell count recovery is
maintained, thereby waiting for new
[anti-HIV] agents with which to construct
a potent regimen composed of as many virologically
active drugs as possible.”
In
summary, this study demonstrated a significant, graded
association between CD4+ cell count increase
after 12 months of treatment and risk of progression
to AIDS or death in patients with persistent
viremia.
A 25-cell/mm3 increase in CD4+ cell count
was associated with a 21% reduction in the
risk of an AIDS-defining event or death (P
< .0001) [emphasis added—Ed].
“This
finding,” write the authors, “could help to guide clinical
decision making with regard to the use of
antiretroviral therapy for patients with advanced
HIV disease and few treatment options.”
09/23/05
References
1.
F
J Palella and others. Declining morbidity and mortality among patients
with advanced human immunodeficiency virus infection. HIV Outpatient
Study Investigators. N Engl J Med 338:853-860. 1998.
2.
A
N Phillips and others. HIV viral load response to antiretroviral
therapy according to the baseline CD4 cell count and viral load.
JAMA 286:2560-2567. 2001.
3.
G M Lucas and others. Highly active antiretroviral
therapy in a large urban clinic: risk factors for virologic failure
and adverse drug reactions. Ann Intern Med 131:81-87. 1999.
4.
S
Grabar and others. Clinical outcome of patients with HIV-1 infection
according to immunologic and virologic response after 6 months of
highly active antiretroviral therapy. Ann Intern Med 133:401-410. 2000.
5.
M R Loutfy
and others (for the Terry Beirn
Community Programs for Clinical
Research on AIDS and
the Canada HIV Trials
Network).
CD4+ Cell Count
Increase Predicts Clinical Benefits
in Patients with Advanced
HIV Disease and Persistent
Viremia after 1 Year
of Combination Antiretroviral Therapy.
The Journal of Infectious Diseases 192(8):1407-1411.
October 15, 2005.
6. P
G Yeni and others. Treatment for adult HIV infection: 2004 recommendations
of the International AIDS Society-USA Panel. JAMA 292:251-265. 2004
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