Very Early ART and Persistent Inflammation in Treated HIV
CID
Very Early ART and Persistent Inflammation in Treated HIV
Peter W. Hunt 0
0 Department of Medicine, University of California-San Francisco
immune activation; HIV; antiretroviral therapy; acute HIV infection; inflammation
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There is unequivocal evidence that
earlier antiretroviral therapy (ART)
initiation, even among those with CD4+ T-cell
counts >500 cells/mm3, reduces morbidity
in human immunodeficiency virus (HIV)–
infected individuals. The Strategic Timing
of Antiretroviral Therapy (START) and
Temprano trials both demonstrated an
approximately 50% reduced risk of AIDS
or non-AIDS events in HIV-infected
individuals randomized to immediate ART
initiation compared to delayed ART
initiation [1, 2]. These unambiguous results
prompted changes to international
treatment guidelines, which now recommend
initiating ART in all HIV-infected
individuals regardless of CD4+ T-cell count.
Nevertheless, there was also a suggestion
from both of these trials that immediate
ART initiation failed to completely restore
normal health. For example, there was a 1%
risk of AIDS at 5 years even in the
immediate ART arm of START and a 5%–8%
incidence of serious morbidity and mortality
(largely from tuberculosis) at 30 months in
the Temprano trial, even among those who
initiated ART at a high CD4+ T-cell count.
These rates of infectious complications and
cancer are much higher than are observed
in the general population in these settings.
Thus, while very early ART initiation
clearly improves health, it may not completely
restore normal health.
The study by Sereti et al in this issue of
Clinical Infectious Diseases offers
important new insights into why very early ART
initiation improves but fails to normalize
health in HIV-infected individuals [3].
It is now well appreciated that immune
activation and inflammation persist at
abnormally high levels in many
HIVinfected individuals despite suppressive
ART, particularly when ART initiation is
delayed to more advanced disease stages.
This persistent inflammatory state has
been linked to an increased risk of
subsequent morbidity and mortality in several
studies and has emerged as an important
target for interventions in the modern
treatment era [4]. What has been less
clear is whether very early ART
initiation could prevent this persistent
inflammatory state. In their study, Sereti et al
characterized longitudinal changes in
immune activation among HIV-infected
Thai individuals who initiated ART
extremely early, that is, within the first
2–3 weeks of their infection. They found
that many markers of immune activation
and inflammation were already
abnormally elevated in these acutely
HIVinfected participants relative to a cohort
of at-risk but HIV-uninfected controls.
Furthermore, most markers declined
during suppressive antiretroviral therapy
to levels that were significantly lower than
observed in a cohort of HIV-infected
Thai individuals who initiated ART
during chronic HIV infection and at much
lower CD4+ T-cell counts. This provided
strong evidence that there is likely to be
a cost of delaying antiretroviral therapy
on the persistent inflammatory state once
ART-mediated viral suppression is
established and may at least partially explain
why early ART initiation in the START
and Temprano trials decreased
morbidity. On the other hand, many markers
of immune activation and inflammation
remained abnormally elevated in the
individuals with very early ART
initiation, even after 2 years of ART-mediated
viral suppression compared to at-risk
but HIV-uninfected controls. Abnormal
immune activation persisted even among
the subgroup of individuals who initiated
ART before HIV-specific antibodies were
even detectable by fourth generation
assays (typically <14 days of infection).
This important observation might
provide a reason why the risk of infectious
and neoplastic complications remained
abnormally high in the immediate ART
groups in the START and Temprano
trials relative to the general population.
While it certainly appears from the
study by Sereti et al that many markers of
immune activation fail to normalize even
when ART is initiated during the earliest
stages of acute HIV infection, there are
several caveats that need to be considered.
First, it is possible that the HIV-uninfected
control group had fewer coinfections and
other exposures (ie, smoking, alcohol, and
substance abuse) that contribute to
systemic immune activation than the acutely
HIV-infected group, even though they
were sampled from an at-risk population
of individuals who volunteered for HIV
vaccine studies. Thus, confounding by
coinfections and other exposures may have
contributed to the apparently abnormal
persistent inflammatory state in the acutely
treated HIV-infected individuals in this
study. Second, the acutely HIV-infected
individuals in this study were all treated
with efavirenz-based regimens. Recent
clinical trials suggest that efavirenz-based
ART results in greater levels of immune
activation (particularly as assessed by
soluble CD14) than integrase inhibitor–based
ART and other comparator regimens [5, 6].
So it remains to be seen whether abnormal
immune activation would persist if acutely
HIV-infected individuals were treated with
modern efavirenz-sparing regimens.
The study by Sereti et al is also
interesting for the biomarkers that did not decline
with very early ART initiation. Plasma
levels of intestinal fatty acid binding
protein (I-FABP), a marker of intestinal
epithelial cell turnover and/or death that has
been shown to predict increased
mortality in treated HIV infection [7], actually
increased within the first few weeks of ART
in their study and remained abnormally
high compared to the HIV-uninfected
control group even after 2 years of viral
suppression. The fact that efavirenz was
used by all participants is again
notable as efavirenz-based ART resulted in a
greater increase in plasma I-FABP levels
than lopinavir/ritonavir-based ART in a
recent randomized, controlled trial [8].
It remains unclear whether this reflects a
direct effect of efavirenz on the gut
epithelium. It also remains unclear whether the
early ART-mediated increases in I-FABP
in this study reflect increased gut barrier
dysfunction (and pathogenic microbial
translocation) or simply restoration of
normal gut epithelial cell proliferation
(coincident with a decline in microbial
translocation). These questions will need
to be addressed in future studies.
Lastly, the study by Sereti et al raises
important questions about the
relationship between persistent inflammation and
morbidity and mortality in treated HIV
infection. Notwithstanding the caveats
listed above, their study likely suggests that
early ART initiation can attenuate but not
fully abrogate the persistent inflammatory
state. If this were the case, one might have
expected immediate ART initiation in the
START and Temprano trials to decrease
but not completely abrogate the risk of
several morbidities that have previously
been linked to the inflammatory state in
treated HIV infection, including
cardiovascular, pulmonary, and
neurocognitive disease. On the contrary, immediate
ART failed to improve surrogate markers
of these morbidities in START. One
possibility is that the participants in START
and Temprano were too young to have a
significant enough risk for these
morbidities to measure a benefit of earlier ART.
Another possibility is that these
morbidities require much longer term exposure to
the HIV-associated inflammatory state to
observe. Alternatively, as we have recently
argued [4], the determinants of the
persistent inflammatory state in
individuals who initiated ART at more advanced
disease stages may be more diverse and
have a broader anatomic distribution (eg,
HIV reservoirs not just in T cells but also
tissue-based myeloid cells,
cytomegalovirus in vascular tissue, and uncontained
microbial translocation) than those that
persist in individuals who are treated early
(ie, HIV reservoirs primarily confined
to inductive lymphoid tissues). A more
limited anatomic distribution of the root
drivers of the inflammatory state in those
treated early might result in a narrower
spectrum of diseases, particularly those
most directly affected by adaptive immune
defects. Addressing these hypotheses in
future studies may well provide important
insights into the pathogenesis of
morbidity and mortality in treated HIV infection.
Note
Financial support. The author has received
institutional grant funding through the National
Institutes of Health (R01AI110271).
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