Pre-treatment CD4
cell count is the most important factor in immune recovery following the
initiation of combination antiretroviral therapy (cART), according to the
results of a large observational and modelling study published in HIV Medicine. The 7600 people included in the analysis all had an
estimated date of seroconversion.
The average CD4 cell count five years post
cART initiation was approximately 500 cells/mm3 for people with a
baseline count of 200 cells/mm3 compared to 800 cells/mm3
for people with a baseline count of 500 cells/mm3. Surprisingly,
people with high baseline viral load (VL) also had stronger CD4 recovery. There
was also evidence that starting therapy soon after seroconversion was also
associated with more robust CD4 cell count gains.
“We found that the
most important predictors of recovery in CD4 counts in patients with
well-established dates of seroconversion following the initiation of cART are
the CD4 count and VL at time of treatment initiation,” comment the authors.
“The strong association of CD4 count at treatment initiation with the long-term
maximum of post-treatment recovery was expected given the findings of previous
research on this topic.”
Observational
studies have consistently found that starting HIV therapy at higher CD4 counts
is associated with greater long-term increases in CD4 count. But potential
limitations of these studies include uncertainty about the time of
seroconversion and reliance on a single pre-treatment CD4 count.
To overcome these
limitations, investigators from the CASCADE (Concerted Action on SeroConversion
to AIDS and Death in Europe) designed an observational study involving 7600
people, all of whom had an estimated date of HIV seroconversion. Their
analysis also included all pre- and post-treatment CD4 counts (39,255 vs 61,487,
respectively). Analyses were also conducted to see if other patient
characteristics influenced post-treatment immune recovery.
The people
received care between 2003 and 2014. The median calendar date of seroconversion
was May 2006. Three-quarters of participants were men who have sex with men (MSM), 5% were HCV (hepatitis C virus)-positive and
approximately two-thirds started cART a year or more after seroconversion.
Median viral load at the time of treatment initiation was approximately 70,000
copies/ml. Half of people started a cART regimen based on a ritonavir-boosted
protease inhibitor, with 39% taking a non-nucleoside reverse transcriptase inhibitor (NNRTI) and 6% an integrase inhibitor.
CD4 cell counts
improved rapidly in the first two to three months after the initiation of
treatment; most people experienced further subsequent increases for the next
five years.
Baseline CD4 count
was the single most important factor in long-term maximum CD4 count recovery
(five year count = 800 vs 700 vs 500 cells/mm3, respectively, for
baseline counts of 500 vs 350 vs 200 cells/mm3).
People who
started therapy within six months of seroconversion demonstrated a faster speed
of recovery compared to people who delayed therapy (p < 0.0001).
After taking into
account baseline CD4 cell count and time since seroconversion, higher viral
load at time of treatment initiation was also associated with stronger
long-term CD4 cell recovery.
“There is some
evidence that higher plasma VL levels are associated with sequestration of CD4
cells in lymphoid tissue, and it has been suggested that this is associated
with a more rapid increase in circulating CD4 cells following the initiation of
cART,” note the authors. “This may also imply that in cases with high
pre-treatment VL, the baseline level of circulating CD4 cells provides a
slightly pessimistic indicator of the underlying state of the immune system at
treatment initiation.”
Several other
factors had a small but nevertheless significant (p < 0.005) impact on CD4
count gains, including HIV risk group (MSM vs men infected via heterosexual
contact), younger age (under 20 years vs over 60 years), HCV infection status
(HCV negative vs HCV positive) and type of antiretroviral therapy (integrase
inhibitor vs NNRTI).
In a final
analysis, the investigators took into account uncertainty about the exact time
of seroconversion. This showed that CD4 count recovered more rapidly if therapy
was started within four months of seroconversion.
But the
investigators were unable to explain all the variance in CD4 count change after
treatment initiation and call for more research to fully identify the factors
affecting CD4 response to cART.
“These
finding…provide further supporting evidence for the initiation of cART soon
after HIV diagnosis, as now recommended in World Health Organization
guidelines,” conclude the authors.