Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection
Clinical Infectious Diseases
Starting Antiretroviral Therapy in Acute HIV Infection
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1 aboratory of Immunoregulation, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, The Henry M. Jackson Foundation for the Advancement 6 7
2 IMnsotnitturétealo , fQMueebdeicca,lCSacniaednaces, US Army Medical Component, Bangkok , Thailand
3 ARCTh-rmonediciaitmedmHunIVeascutipvpartieosnsioan.d inflammation in treated HIV
4 DwOoIr:k1i0s.1w0r9i3tt/ecnid/bcyiw(a6)83US Government employee(s) and is in the public domain in the US
5 PDwuOobIrl:kishised by
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8 Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de
9 eUdiRceinsee , aDrcihvisPiaornk
INNriienctiaoSlnayesareCSthi.,oUmStahoyenltl,1y;0fJVo.ricKtthroeerbRVs,Val2c5No4u/iStrt,Ea6yAJaReCProHhma0en1u0Hp,.hRKaVikm3,0,43J,/4aS,bmEMAeRserCLlHi.nF0lLe1.3tRcaohnbedbr,,S3,B4EoANnRenClsiHeonS01lLi1.keMp,riocthoSacueotell,e3t,e4raDpmaosnrniePliCn.yDakoourenk,,2 JRionbtaenrattJA.Ona'Cnownonrealnl,i3c,4h,9,3A,4d,8a,amanRdupert, 1 7,a 3,4 8 8 3,4 3,4 5 Background. Serious non-AIDS events cause substantial death despite human immunodeficiency virus (HIV) supepnreds-soiorgnanwiethveanntsti.rWetreovairmaledthteoradpeyte(rAmRiTn)e. wBhioemthaerrkeArRsTofiinnifltdiiasmteioamsneadtaiunordnin,cgoacguutleatHioInVcainscfeacdteioanctwivoautilodna,tatenndufiabterocshisanpgresdiicnt these pression with antiretroviral therapy (ART). Biomarkers of inflammation, coagulation cascade activation, and fibrosis predict these ebniodm-oarrgkaenr leevveenlst.s. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these bioMmeatrhkoedrsl.evePlsl.asma samples were obtained from participants starting ART during acute or chronic HIV infection and from HIVtaenidnRe[fisIbu-FrlotAss.is (ChRyaPl,urToNniFc, ascILid-6[RH,AI-])FAwBerPe, msCeDas1u4r,edD-adtibmaseerl,inanedanHdAthlreovueglshw9e6reweleekvsatoefdAiRnTa.cute HIV infection. Early ART was BP]), lipopolysaccharide-induced monocyte activation (soluble CD14 [sCD14]), coagulation cascade activation [D-dimer], and fibrosis (hyaluronic acid [HA]) were measured at baseline and through 96 weeks of ART. assRoecsiautletds.witChRiPn,crTeNasFe,dsII-LF-A6BRP,Il-eFvAelsBbPu,tsCnoDr1m4a,lDiza-dtiiomneorf, TanNdF,HsIAL-l6eRve,lasnwdeDre-deimleveartleedveilns. aCcRuPte, sHCIDV14i n,afencdtiHonA. lEeavrellys dAeRcrTeawseads Results. CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was adsusroicnigatAedRwTitbhuitnrcermeaaseindeId-FeAleBvPatleedveclsombuptanroedrmwailtihzaHtioInV-oufnTiNnfFe,cstIeLd-6pRa,rtaincidpDan-tdsi.mHeirglheevrels.CCDR1P4,,sCRDP1,4a,nanddDH-dAi mleveerlsledveeclsrewaseerde associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased adsusroicnigatAedRwTitbhuhtirgehmeraipneerdipehlervaaltebdlocoodmmpoanreodnuwcilteharHcIeVll-aunndingfuetctiendtepgararteicdipHanIVts.DHNiAghleerveslCs.DD1e4c,rCeaRsePs, ianndsCDD-1d4imanerd lCevRePlslewveerles during ART but remained elevated compared with HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were awsesroecicaotrerdelwatiethd hwiigtheirnpcreeraipsheserianl CblDoo4dTm-coenllocnouucnletsa.r cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels weCreocnocrluresliaotneds. wiAthRiTncirneiatsiaetsediniCnDea4rlTy-caeclultceoHunIVts. infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute-pahttaesneuraetsep oinnflsea,menterocyte turnover, monocyte activation, and fibrosis biopmearrskoenrss wreitmhaHinIeVd ienlfeevcattieodn.. Additional interventions to mation may be needed to optimize clinical outcomes in perKsoeynwsowridths. HIaVcuitnefeHcItiVonin.Afedcdtiiotino;naanltiinretterrovveinratilotnhsertaopayt;teinnfluaamteminafltiaomn;mmaotinooncyte activation; sIL-6R. markers remained elevated. may be needed to optimize clinical outcomes in persons with HIV infection.
preBsasicokngrwouitnhda; ntiSretrriovuisranlotnh-eAraIpDyS(eAvRenTt)s; cBaiuosme asrukbesrtsanotfiainlfldaismeamseatainodn; dceoaathgudlaetsipointechauscmadane aimctmivautnioond; eafincdienficbyrovsiirsuspr(eHdIiVct)tshuepse-
of ART at high CD4 T-cell counts and/or within the first year
of seroconversion results in more robust immune restoration
and less chronic immune activation [1, 7], whereas lower
nadir CD4 T-cell counts are associated with higher risk of
serious non-AIDS events [8, 9]. However, whether ART initiation
during acute HIV infection could eliminate increased
inflammation in chronic HIV infection remains unknown.
We hypothesized that initiation of ART during the earliest
stages of acute HIV infection would normalize levels of
stages of acute HIV infection would normalize levels of
HIV/AIDS • CID • 1
biomarkers associated with disease and death in chronic HIV
infection. We evaluated biomarkers of inflammation and
coagulation at baseline and over the subsequent 96 weeks in
participants of an ongoing, prospective study of ART initiation
in acute HIV infection in Bangkok, Thailand (RV254/
Study Design and Participants
In RV254/SEARCH010 (NCT00796146), high-risk participants
presenting to voluntary testing and counseling centers at the
Thai Red Cross Anonymous Clinic were screened for acute
HIV infection in real time by means of pooled nucleic acid
testing (NAT) and sequential immunoassay (IA) . Participants
with nonreactive HIV immunoglobulin G (n = 78) were
enrolled and categorized as fourth-generation IA (4thG) stage 1
(4thG1; NAT positive, 4thG IA negative, and third-generation
[3rdG] IA negative), 4thG stage 2 (4thG2; NAT and 4thG IA
positive and 3rdG IA negative), and 4thG stage 3 (4thG3;
NAT, 4thG IA, and 3rdG IA positive; Western blot negative
or indeterminate) [10, 12]. Samples were collected before ART
(baseline) and over 96 weeks of ART. Thai HIV-uninfected
controls were prevaccinated age- and sex-matched participants
from RV114 (n = 99), an HIV vaccine trial , and RV304/
SEARCH013 (n = 29), a tissue sampling study
(NCT01397669) . Chronically infected Thai participants
were enrolled in SEARCH011, a study of neurocognitive
impairment in persons with varying monocyte proviral burden
(n = 27) , or the RV217 natural history cohort (n = 14)
. Individuals with unthawed samples were selected. Samples
were collected from SEARCH011 before ART and after 48
weeks of ART and from RV217 before ART. All participants
provided signed informed consent.
Intestinal fatty acid binding protein (I-FABP), soluble CD14
(sCD14) (R&D Biosystems), and hyaluronic acid (HA)
(Corgenix) were measured with enzyme-lined immunosorbent assay;
C-reactive protein (CRP) with electrochemiluminescence
assay (Meso Scale Discovery), and D-dimer with Enzyme
Linked Fluorescent Assay (bioMerieux). Tumor necrosis factor
(TNF), soluble interleukin 6 (IL-6) receptor (sIL-6R), soluble
gp130 (sgp130), and high-sensitivity IL-6 were measured
using the Luminex platform (Millipore). All biomarkers were
measured in samples from participants with acute HIV
infection, HIV-uninfected participants, and untreated participants
with untreated chronic HIV infection. sCD14, I-FABP,
Ddimer, HA, and CRP were measured in SEARCH011 samples,
and IL-6, TNF, sIL-6R, and sgp130 in RV217 samples. sCD14,
HA, CRP, and D-dimer were measured in available unthawed
samples from treated participants with chronic infection. All
biomarkers were performed in duplicate on cryopreserved
2 • CID • HIV/AIDS
acid citrate dextrose plasma according to the manufacturers’
instructions and for research purposes only. All assays were
performed after the first thaw except I-FABP (second thaw).
Total and Integrated HIV DNA Measurements
Sigmoid biopsies were performed in the RV254 cohort. The
frequencies of cells harboring total and integrated HIV DNA in
peripheral blood mononuclear cells (PBMCs) and sigmoid colon
gut biopsies were measured as described elsewhere [17, 18].
Data were reported as median (interquartile range) values.
Comparisons between 4thG groups were performed using the
Mann–Whitney U test for continuous variables and χ2 or Fisher
exact test for categorical variables. To account for differences
between acute and chronic infection, we used a linear regression
model adjusted by age and sex. Comparisons within groups
across time points were performed using the Wilcoxon signed
rank test. Biomarker levels were compared between participants
who received 48 weeks of ART starting during acute or chronic
HIV infection, and between participants who received 96 weeks
of ART and HIV-uninfected participants. The Spearman rank
test was used to determine correlations. Statistical tests were 2
sided and were differences were considered statistically
significant at P < .05. Analyses were performed using StataCorp 2013
(StataCorp) and Prism (version 6.0; GraphPad) software.
Acutely infected participants had a median age of 28 years
(interquartile range, 24–33 years) and were 92.3% male, compared
with 35 (30–42) years and 37.0% male for chronically infected
and 27 (22–37) years and 77.1% male for HIV-uninfected
(Table 1). The median CD4 T-cell count was 384 cells/mm3
and the median HIV RNA level 5.6 log10 copies/mL for
acutely infected participants, compared with 230 cells/mm3
and 4.7 log10 copies/mL for chronically infected participants.
For acutely infected participants, 14 were in 4thG1, 22 in
4thG2, and 42 in 4thG3. Age, sex, CD4 T-cell counts, and
HIV RNA levels did not differ significantly across stages. The
median time since self-reported HIV exposure was 12 days in
4thG1, 17 in 4thG2, and 18 in 4thG3. Sixty-one participants
(78.2%) had ≥3 symptoms of acute retroviral syndrome. The
median time to ART initiation was 2 days. Seventy-six
participants received tenofovir, emtricitabine, and efavirenz.
Fortyfour also received maraviroc and raltegravir (mega-HAART
[highly active ART]) . Two participants who opted not to
take ART were excluded from the longitudinal analysis. One
participant who reported nonadherence remained viremic and
was excluded from the longitudinal analysis at week 48.
Participants with blips were included in the analysis, including 5
participants at week 24 and 1 at week 48 (all with HIV RNA levels
<2.3 log10 copies/mL).
Table 1. Baseline Characteristics
Age, median (IQR), y
Male sex, No. (%)
Time from HIV exposure (per participant),
median (IQR), d
Antiretroviral syndrome, No. (%)d
CD4 T-cell count, median (IQR), cells/µL
Plasma HIV RNA, median (IQR), log10 copies/mL
Acute HIV Infectiona
5 (35.7) 17 (77.3)e 39 (92.9)e
494 (347–561)c 323 (265–443)c 386 (298–496)c
5.6 (4.9–6.4)c 5.6 (5.1–6.6)c 5.6 (5.2–6.2)c
Abbreviations: 4thG1, fourth-generation (4thG) stage 1; 4thG2, 4thG stage 2; 4thG3, 4thG stage 3; HIV, human immunodeficiency virus; IQR, interquartile range; NA, not available.
a For the 4thG acute HIV infection stages: 4thG1 was defined as nucleic acid testing (NAT) positive and 4thG and third-generation (3rdG) immunoassay (IA) negative; 4thG2, as NAT and 4thG IA
positive and 3rdG IA negative; and 4thG3, as NAT, 4thG IA, and 3rdG IA positive and Western blot negative or indeterminate.
b Before antiretroviral therapy.
c P < .05 (comparison with chronically HIV-infected population; before antiretroviral therapy or after 48 weeks).
d Antiretroviral syndrome was defined by ≥3 of the following: fever, adenopathy, headache, fatigue, myalgia, arthralgia, pharyngitis, oral ulcer, genital ulcer, weight loss, anorexia, nausea and
vomiting, diarrhea, odynophagia, rash, oral candidiasis, vaginal candidiasis, and neurologic symptoms.
e P < .05 (comparison with 4thG1; the difference between 4thG2 and 4thG3 was not significant).
Plasma levels of CRP, an acute-phase reactant associated with
cardiovascular events and death [3, 4, 19], were significantly
higher in HIV-infected participants from 4thG2 and 4thG3
than in HIV-uninfected participants (P < .001 for both) (Table 2;
Figure 1A; Supplementary Table 1). CRP levels were significantly
lower in 4thG1 than in 4thG2 (P = .006) or 4thG3 (P = .03).
Baseline plasma TNF levels were significantly higher in 4thG3
than in HIV-uninfected participants (P = .006; Figure 1B).
Plasma IL-6 levels, associated with increased morbidity and
mortality risk [3, 4, 19], were significantly higher in 4thG2
compared with 4thG1 (P = .04) but not compared with
HIV-uninfected participants (Figure 1C). Levels of sIL-6R, which
mediates IL-6 signaling in cells without IL-6R , were
significantly increased in 4thG3 compared with HIV-uninfected
participants (P < .001; Figure 1D) and 4thG1 (P = .02) but not
compared with 4thG2. Levels of sgp130, which inactivates the
IL-6/sIL-6R complex, did not differ significantly among
HIVinfected groups or compared with HIV-uninfected participants
(Figure 1E ).
Next, we evaluated the effects of ART on these biomarkers.
The median CRP level for all acutely HIV-infected participants
decreased after 2 weeks of ART (P < .001), driven by changes in
4thG2 and 4thG3 (Figure 1F ). CRP levels remained
significantly lower than in treated chronically HIV-infected
participants at week 48 (P < .001), even after adjustment for age and
sex (Supplementary Table 2), but they were elevated compared
with those in HIV-uninfected participants at week 96 (P = .04).
TNF levels increased after 48 weeks of ART (P < .001; Figure 1G)
but decreased by week 96 to levels similar to those in
Median IL-6 levels varied over time receiving ART (Figure 1H).
After 96 weeks of ART, IL-6 levels were similar in participants
treated during acute HIV infection and HIV-uninfected
participants. Levels of sIL-6R decreased significantly after 24 and 96
weeks of ART (P < .001 for both; Figure 1I), with decreases
primarily in the 4thG2 and 4thG3 groups. sIL-6R levels at 96
weeks were similar to those in HIV-uninfected participants,
regardless of stage at diagnosis. The sgp130 levels increased
significantly by week 24 (P < .001; Figure 1J) in all 4thG groups and
remained higher compared with baseline at 96 weeks (P < .001),
particularly in the 4thG3 group (P = .001). After 96 weeks
of ART, all groups had sgp130 levels comparable to those in
HIV-uninfected participants. Participants with lower sgp130 levels
at baseline were more likely to have persistently increased IL-6
levels (odds ratio, 4.0 [95% CI, 1.3–12.1] for sgp130 below vs
above the median; P = .01). Together, these data show that ART
started during very early acute HIV infection normalized TNF
and mediators of IL-6 signaling but not CRP levels.
Intestinal Permeability and Microbial Translocation
Intestinal damage and microbial translocation start in acute
infection . Plasma levels of I-FABP, a marker of enterocyte
turnover associated with death , were significantly higher
at baseline than in HIV-uninfected participants only in the
4thG3 group (P = .03) (Figure 2A). Plasma sCD14 levels,
reflecting monocyte activation and predictive of death , were
significantly higher at baseline in all HIV-infected groups compared
with HIV-uninfected participants (P < .001 for all; Figure 2B)
and did not differ among 4thG stages.
We evaluated biomarker changes after starting ART during
early acute HIV infection. I-FABP levels increased during the
first 2 weeks of ART (P < .001) before plateauing at levels
comparable to those in treated chronically HIV-infected
participants at 48 weeks, even after adjustment for age and sex
(Supplementary Table 2), and significantly higher than those
in HIV-uninfected participants after 96 weeks of ART
HIV/AIDS • CID • 3
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(P<.001) (Figure 2C). In contrast, sCD14 levels decreased after
4thG2 and 4thG3, and remained significantly lower through
week 96 compared with baseline (P<.001 for all; Figure 2D).
sCD14 levels were significantly lower in participants treated
during acute HIV infection after 48 weeks of ART than in
participants treated during chronic HIV infection (P<.001), even
after adjustment for age and sex (Supplementary Table 2).
Nonetheless, sCD14 levels remained significantly higher than
in HIV-uninfected participants after 96 weeks of ART
(P<.001). In summary, increased enterocyte turnover persisted
and monocyte activation decreased but did not normalize in
participants starting ART during acute HIV infection.
Coagulation and Fibrosis
Increased levels of D-dimer, reflecting coagulation cascade
activation, and HA, reflecting fibrosis, are also associated with
disease progression and death [3–5]. D-dimer levels were
significantly increased in the 4thG2 and 4thG3 groups
compared with HIV-uninfected participants (P< .001 for both;
tively). D-dimer levels in the 4thG1 group were comparable to
those in HIV-uninfected participants. Plasma HA levels were
increased in 4thG2 and 4thG3 groups compared with
HIVNext, we assessed the impact of ART initiation during acute
infection on these biomarkers. After 12 weeks, plasma
D-dimer levels decreased significantly compared with baseline
(P< .001) and then stabilized through 96 weeks of ART
(Figure 3C). Circulating D-dimer levels in participants treated
during acute HIV infection were significantly lower than in
treated chronically HIV-infected participants after 48 weeks
of ART (P<.001), even after adjustment for age and sex
(Supplementary Table 2). Compared with those in HIV-uninfected
96 weeks of ART. In contrast, after 2 weeks of ART, HA levels
lower than in treated chronically HIV-infected participants
after 48 weeks of ART (P<.001), even after adjustment for
age and sex (Supplementary Table 2) but remained higher
than in HIV-uninfected participants after 96 weeks (P<.001).
Thus, whereas coagulation biomarkers may normalize when
ART is started during acute HIV infection, a profibrotic state
Relationships Among CD4 T-Cell Counts, HIV Burden, and Biomarkers
To assess whether inflammation was associated with HIV
disease state, we performed correlation analyses of these
biomarkers with CD4 T-cell count and HIV burden in the acute HIV
cohort. We pooled all stages to encompass the breadth of
disease (Supplementary Table 3). As reported elsewhere, total
and integrated PBMC HIV DNA levels are higher at baseline
HIV/AIDS • CID • 5
in the later stages and decrease to 1 and 0.1 log10 copies/106
PBMCs, respectively, after 48 weeks of ART; the sigmoid
colon has a similar pattern . Among acutely infected
participants at baseline, higher plasma HIV RNA levels were
correlated with higher sIL-6R, I-FABP, sCD14, HA, and D-dimer levels.
A similar pattern was observed for total and integrated PBMC
HIV DNA levels (Supplementary Figure 1A–C). Higher
integrated HIV DNA levels in the gut were correlated with higher
baseline sCD14, CRP, and D-dimer levels. Low baseline
peripheral CD4 T-cell counts were correlated with high CRP levels,
but low sigmoid colon CD4 T-cell counts were associated
with high plasma HIV RNA, sCD14, and HA levels
(Supplementary Figure 1D–F ).
To determine whether improvement in inflammation was
associated with improvement in HIV disease state in the acute
infection cohort, we correlated changes in inflammatory
biomarkers with changes in CD4 T-cell count and HIV burden.
After 24 weeks of ART, the median CD4 T-cell count increased
to 600 cells/mm3. Increases in CD4 T-cell counts were
6 • CID • HIV/AIDS
associated with decreases in sCD14 and CRP levels
(Supplementary Figure 2A and 2B). Similarly, only fold decrease in
D-dimer levels correlated with fold-decrease in plasma HIV
RNA levels (r = 0.29; P = .01), total HIV DNA in PBMCs
(r = 0.33; P = .005), and intestinal total HIV DNA levels
(Supplementary Figure 2C). Together, these data suggest an
association of the coagulation cascade with HIV burden and of gut
damage and persistent inflammation with slow CD4 T-cell
Although inflammation persists with ART started during early
and chronic HIV infection, the effect of initiating ART during
early acute HIV infection on chronic inflammation is unknown.
Using age- and sex-matched controls from Bangkok, Thailand,
we found that (1) acute HIV infection is associated with
increased levels of biomarkers of intestinal damage, inflammation,
coagulation, and fibrosis and with suppressive ART initiated
during acute HIV infection; (2) the procoagulant state
normalizes after early ART; (3) enterocyte damage persists
during suppressive ART; (4) monocyte activation, systemic
inflammation, and fibrosis remain increased but lower than in
participants starting ART in chronic HIV infection; and (5)
increases in CD4 T-cell populations correlate with decreases in
sCD14 and CRP levels. These results show that some elements
of very early immune damage by HIV are durable and
potentially irreversible, CD4 T-cell reconstitution may be determined
by reduction in inflammation, and additional
immunomodulatory therapies during early infection may be necessary to avert
these long-term consequences.
The biomarkers reflect an inflammatory state at diagnosis,
consistent with previous data showing a cytokine storm during
acute HIV infection . HIV itself probably contributes to this
inflammation, because higher baseline plasma HIV RNA levels
and total and integrated PBMC HIV DNA were correlated with
higher sCD14, D-dimer, sIL-6R, and I-FABP levels. The
normalization of D-dimer levels with early ART in association
with decreased HIV burden suggests a reduced risk of
prothrombotic events, such as deep-vein thromboses and
pulmonary emboli. Conversely, the persistently elevated levels of
biomarkers of monocyte activation (sCD14), systemic
inflammation (CRP, IL-6, sIL-6R, TNF), and fibrosis (HA) during
ART indicate that drivers of inflammation other than HIV itself
persist even with early ART. The early differences in biomarker
levels across 4thG stages did not persist in chronic infection,
suggesting that starting ART even at the earliest stages of
infection may not normalize inflammation. Conversely, a few days’
delay in ART initiation may not adversely impact inflammation
during chronic HIV infection.
Intestinal damage, increased regulatory T-cell infiltration,
and lymph node collagen deposition occur within 1–2 weeks
of infection , therefore preceding ART initiation. Recently,
RV254 participants with acute HIV infection were shown to
have increased neutrophil infiltration, immune activation
(Ki67-positive cells), and inflammation (cells expressing TNF,
Mx1, and indoleamine 2,3-dioxygenase 1) in the sigmoid
colon. Despite decreasing intestinal inflammation, ART
initiated during acute infection did not decrease intestinal neutrophil
infiltration, a marker of gut damage . Similarly, in this
population, mucosal T-helper 17 cell depletion was demonstrated in
Fiebig stage III but not stage I. Early ART restored T-helper 17
presence but not polyfunctionality , suggesting persistent
immune and mucosal dysregulation, consistent with
persistently elevated I-FABP and sCD14 levels. Similarly, early
suppressive ART cannot halt the acute-phase reaction. The absence
of increases in IL-6 levels may reflect a lack of sensitivity of
the multiplex assay or the cross-sectional comparison.
Nonetheless, increased IL-6 transsignaling by sIL-6R, persistently
increased here, is associated with cardiac events in non-HIV
populations and animal models . The increased profibrotic
state based on HA levels, despite early ART, may perpetuate
fibrosis in lymphatic tissue, the liver, and other tissues .
However, the independent effect of ART on these biomarkers
is unclear [27, 28].
Notably, levels of biomarkers predictive of cardiovascular
events, such as sCD14, sIL-6R, and CRP, remain elevated
compared with those in HIV-uninfected Thai participants despite
ART initiation in acute infection, raising the question of
whether these patients remain at increased risk for non-AIDS events.
These biomarker levels, however, are lower than those observed
in many Western cohorts and lower than those associated with
end-organ disease, although variations in assays used and
patient populations (eg, age, coinfections) may contribute to
some differences [2, 4, 19, 29–32]. Thus, the clinical implications
of this persistent low-level elevation remain unclear.
Our study has several limitations. Our chronically
HIVinfected cohort was small and not matched for age or sex to
the acutely HIV-infected cohort, potentially resulting in higher
inflammatory marker levels. The acutely infected participants
were 15–20 years younger than participants in many studies
associating biomarkers with clinical outcomes and thus may have
less inflammation [2, 3, 5, 19]. No major end-organ events have
occurred to determine the clinical significance of our findings.
Nonetheless, this study provides important insight into the
evolution of inflammation in acute HIV infection and the potential
impact of early ART.
In conclusion, initiation of ART during acute HIV infection
is insufficient to resolve the chronic inflammation associated
with increased all-cause morbidity and mortality risk in treated
HIV infection. Initiating ART during acute infection, however,
attenuates inflammation more than initiating ART in chronic
HIV infection. These data are consistent with findings of the
Strategic Timing in AntiRetroviral Therapy (START) study,
which confirmed a decreased event rate in persons starting
ART with CD4 T-cell counts >500/µL . Whether persistent
residual inflammation will translate into increased end-organ
disease remains to be determined. If so, further interventions
to attenuate inflammation, even among patients treated during
acute HIV infection, may be necessary to optimize clinical
Supplementary materials are available at http://cid.oxfordjournals.org.
Consisting of data provided by the author to benefit the reader, the posted
materials are not copyedited and are the sole responsibility of the author, so
questions or comments should be addressed to the author.
Acknowledgements. The study team is grateful to the individuals who
volunteered to participate in this study and the staff at the Thai Red Cross
AIDS Research Centre and the Department of Retrovirology, US Army
Medical Component, Armed Forces Research Institute of Medical Sciences.
We thank Silvia Ratto-Kim for providing samples from the RV114 study,
and we also thank the RV254/SEARCH 010, RV304/SEARCH 013 and
SEARCH 011 Protocols team members that include from SEARCH/
TRCARC/HIV-NAT: Praphan Phanuphak, Nipat Teeratakulpisarn, Supanit
Pattanachaiwit, Thep Chalermchai, Mark de Souza, Eugene Kroon, Carlo
Sacdalan, Phillip Chan, Donn Colby, Duanghathai Sutthichom,
Somprartthana Rattanamanee, Peeriya Prueksakaew, Sasiwimol Ubolyam, Pacharin
Eamyoung, Naphassanant Laopraynak, Suwanna Puttamaswin, Nitiya
Chomchey, Putthachard Karnsomlap, Tarandeep Singh, Chattiya
Nitpolprasert; from Pharmongkut Klao Hospital: Pasiri Sithinamsuwan; from
AFRIMS: Sorachai Nitayaphan, Somchai Sriplienchan, Rapee Trichavaroj,
Alexandra Schuetz, Nicos Karasavvas, Sandhya Vasan, Yuwadee
PhuangNgern, Surt Jongrakthaitae, Werrawan Chuenaron, Rapee Trichavaroj,
Nantana Tantibul, Hathairat Savadsuk, Tanya Wansom, Siriwat Akapirat,
Bessara Nuntapinit; from MHRP: Trevor Crowell, Madelaine Ouellette,
Oratai Butterworth; from University of Montreal: Remi Fromentin.
Disclaimer. The content of this manuscript is solely the responsibility
of the authors and does not necessarily represent the official views of any of
the institutions mentioned above, the US Department of the Army, the US
Department of Defense, or the National Institutes of Health, nor does
mention of trade names, commercial products, or organizations imply
endorsement by the US government or the Thai Red Cross AIDS Research Centre.
Financial support. This work was supported by the Intramural
Research Program of the National Institutes of Health, National Institute of
Allergy and Infectious Diseases; by a cooperative agreement
(W81XWH11-2-0174) between The Henry M. Jackson Foundation for the
Advancement of Military Medicine and the US Department of Defense; and by
the National Institutes of Health (grants R01MH095613 and
R01NS061696 to SEARCH 010 and SEARCH 011, respectively). The
Government Pharmaceutical Organization (GPO), Thailand, Gilead, Merck and
ViiV Healthcare provided support for antiretroviral medications.
Potential conflicts of interest. N. C. is a board member of Theravectys.
V. V. has consulted for Merck and ViiV Healthcare. J. A. has received
honoraria from ViiV Healthcare, Merck, Gilead Sciences, and Roche
Pharmaceuticals for her participation in advisory meetings. N. S. U. has
consulted for Gilead Sciences, Entera Health, and Tobira Therapeutics
and has been compensated for her participation in advisory meetings. All
other authors report no potential conflicts. All authors have submitted the
ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that
the editors consider relevant to the content of the manuscript have been
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