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Initiation of antiretroviral therapy in early HIV infection
reduces but does not abrogate chronic residual inflammation
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".....Despite decreasing intestinal inflammation, ART initiated in acute infection did not decrease intestinal neutrophil infiltration, a marker of gut damage[.......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.....ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in people with HIV infection. ....Notably, biomarkers predictive of cardiovascular events, such as sCD14, sIL-6R, and CRP, remain elevated compared with HIV-uninfected Thai participants despite ART initiation in acute infection, raising the question of whether these patients remain at increased risk for non-AIDS.....the clinical implications of this persistent low-level elevation remain ......In conclusion, initiation of ART during acute HIV infection is insufficient to resolve the chronic inflammation associated with increased all-cause morbidity and mortality in treated HIV infection. Initiating ART during acute infection, however, attenuates inflammation to a greater extent than initiating ART in chronic HIV infection. These data are consistent with the Strategic Timing in AntiRetroviral Therapy (START) study which confirmed a decreased event rate in persons starting ART at CD4 counts >500 cells/μL[33]. Whether persistent residual inflammation will translate into increased end-organ disease remains to be determined.[from Jules: by then everyone will be disabled or dead, we have to conclude & its not a stretch at all that persistent inflammation will increase comorbidities risk & frailty!] If so, further interventions to attenuate inflammation even among patients treated in acute HIV infection may be necessary to optimize clinical outcomes"
Clinical Infectious Diseases Advance Access published October 12, 2016
Irini Sereti1, Shelly J. Krebs2,3, Nittaya Phanuphak4, James L. Fletcher4, Bonnie Slike2,3, Suteeraporn Pinyakorn2,3, Robert J. O'Connell2,3,5, Adam Rupert6, Nicolas Chomont7, Victor Valcour8, Jerome H. Kim2,3,9, Merlin L. Robb2,3, Nelson L. Michael2,3, Daniel C. Douek10, Jintanat Ananworanich2,3,4,*, and Netanya S. Utay11,*, for the RV254/SEARCH 010, RV304/SEARCH 013 and SEARCH 011 protocol teams
"we evaluated the effects of ART on these biomarkers. The median CRP level of all acute HIV-infected participants decreased after 2 weeks of ART (P=.0009), driven by changes in 4thG2 and 4thG3 (Figure 1F). CRP levels remained significantly lower than in chronic treated HIV-infected participants at week 48 (P<.0001), even after adjusting for age and sex (Supplementary Table 2), but elevated compared to HIV-uninfected participants at week 96 (P=.04). TNF levels increased after 48 weeks of ART (P=.0008; Figure 1G) but decreased by week 96 to levels similar to HIV-uninfected participants.....these data show that ART started during very early acute HIV infection normalized TNF and mediators of IL-6 signaling but not CRP levels.....sCD14 levels remained significantly higher compared to HIV-uninfected participants after 96 weeks of ART (P<.0001). In summary, increased enterocyte turnover persisted and monocyte activation decreased but did not normalize in participants starting ART during acute HIV infection.....Intestinal damage and microbial translocation start in acute infection[21]. Plasma levels of I-FABP, a marker of enterocyte turnover associated with mortality[19], were significantly higher at baseline in the 4thG3 group only compared to HIV-uninfected participants (P=.03) .....I-FABP levels increased during the first two weeks of ART (P<.0001) before plateauing at levels comparable to those of chronic treated HIV-infected participants at 48 weeks, even after adjusting for age and sex (Supplementary Table 2), and significantly higher than HIV-uninfected participants after 96 weeks of ART (P<.0001) (Figure 2C).....after 2 weeks of ART, HA levels decreased significantly (P=.003; Figure 3D). HA levels were lower than in chronic treated HIV-infected participants after 48 weeks of ART (P<.0001), even after adjusting for age and sex (Supplementary Table 2) but remained higher than in HIV-uninfected participants after 96 weeks (P=.0009). Thus, whereas coagulation biomarkers may normalize when ART is started during acute HIV infection, a pro-fibrotic state persists. .....these data suggest an association of the coagulation cascade with HIV burden and of gut damage and persistent inflammation with slow CD4 T-cell recovery. "
Discussion
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[22]. HIV itself likely contributes to this inflammation, as higher baseline plasma HIV RNA levels and total and integrated PBMC HIV DNA 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[23], therefore preceding ART initiation. Recently, RV254 participants with acute HIV infection were shown to have increased neutrophil infiltration, immune activation (Ki67+ cells), and inflammation (TNF+, Mx1+, and indoleamine 2,3- dioxygenase-1+ cells) in the sigmoid colon. Despite decreasing intestinal inflammation, ART initiated in acute infection did not decrease intestinal neutrophil infiltration, a marker of gut damage[24]. Similarly, in this population, mucosal Th17 cell depletion was demonstrated in Fiebig Stage III but not Stage I. Early ART restored Th17 presence but not polyfunctionality[14], 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[25]. The increased pro-fibrotic state based on HA levels, despite early ART, may perpetuate fibrosis in lymphatic tissue, the liver, and other tissues[26]. However, the independent effect of ART on these biomarkers is unclear[27, 28].
Notably, biomarkers preictive of cardiovascular events, such as sCD14, sIL-6R, and CRP, remain elevated compared with HIV-uninfected Thai participants despite ART initiation in acute infection, raising the question of whether these patients remain at increased risk for non-AIDS
Figure 1. Inflammatory biomarker levels in HIV-uninfected participants from Thailand (black dots); in participants with acute HIV infection diagnosed in stage 4thG1 (blue), 4thG2 (green), or 4thG3 (red); and in participants with chronic untreated HIV infection (purple). (A-E) Plasma biomarker levels at study entry before starting ART. A) CRP; B) TNF; C) IL-6; D) soluble IL-6 receptor (sIL-6R); E) soluble gp130 (sgp130). Horizontal bars indicate median values. (F-J) Changes in plasma biomarker levels over 96 weeks of ART initiated during acute HIV infection. F) CRP; G) TNF; H) IL-6; I) sIL-6R; J) sgp130. Purple dashed line indicates median biomarker level in participants during treated chronic HIV infection, and black dotted line indicates median biomarker level in HIV-uninfected participants from Thailand. + indicates difference statistically significant from treated chronic HIV-infected participants (P < .05). * indicates difference statistically significant from HIV-uninfected participants (P < .05). Median values with IQR bars are illustrated.
Abstract
Background. Serious non-AIDS events cause substantial morbidity and mortality despite HIV suppression with antiretroviral therapy (ART). Biomarkers of inflammation, coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels.
Methods. Plasma samples were obtained from participants starting ART during acute HIV infection, chronic HIV infection, and HIV-uninfected participants, from Bangkok, Thailand. Biomarkers of inflammation (C-reactive protein [CRP], interleukin 6 [IL-6], soluble IL-6 receptor [sIL-6R], soluble gp130 [sgp130], TNF), enterocyte turnover (intestinal fatty acid binding protein [I-FABP]), 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.
Results. CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased during ART, but remained elevated compared to HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels correlated with increases in CD4 T-cell counts.
Conclusions. ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in people with HIV infection.
Excerpts
Of acutely infected participants, 14 were in 4thG1, 22 in 4thG2, and 42 in 4thG3. Age, sex, CD4 T-cell counts, and HIV RNA levels were not significantly different across stages. 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. Median time to ART initiation was 2 days. Seventy-six participants received tenofovir, emtricitabine, and efavirenz. Forty-four also received maraviroc and raltegravir ("megaHAART")[10]. Two participants who opted not to take ART were excluded from the longitudinal analysis. At week 48, one participant who reported non-adherence remained viremic and was excluded from the longitudinal analysis. Participants with blips were included in the analysis, including five participants at week 24 and one at week 48 (all HIV RNA <2.3 log10 copies/ml).
Intestinal permeability and microbial translocation
Intestinal damage and microbial translocation start in acute infection[21]. Plasma levels of I-FABP, a marker of enterocyte turnover associated with mortality[19], were significantly higher at baseline in the 4thG3 group only compared to HIV-uninfected participants (P=.03) (Figure 2A). Plasma sCD14 levels, reflecting monocyte activation and predictive of mortality[2], were significantly higher at baseline in all HIV-infected groups compared to HIV-uninfected participants (P<.0001 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 two weeks of ART (P<.0001) before plateauing at levels comparable to those of chronic treated HIV-infected participants at 48 weeks, even after adjusting for age and sex (Supplementary Table 2), and significantly higher than HIV-uninfected participants after 96 weeks of ART (P<.0001) (Figure 2C). In contrast, sCD14 levels decreased after two weeks of ART (P=.005), primarily driven by changes in 4thG2 and 4thG3, and remained significantly lower through week 96 compared to baseline (P<.0001 for all; Figure 2D). Soluble CD14 levels were significantly lower in participants treated during acute HIV infection after 48 weeks of ART compared to participants treated in chronic HIV infection (P<.0001), even after adjustment for age and sex (Supplementary Table 2). Nonetheless, sCD14 levels remained significantly higher compared to HIV-uninfected participants after 96 weeks of ART (P<.0001). In summary, increased enterocyte turnover persisted and monocyte activation decreased but did not normalize in participants starting ART during acute HIV infection.
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