Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Inflammatory Markers During Early Treatment of Seroconverters in a Randomized Placebo-Controlled Trial of PrEP (ANRS-IPERGAY)

Inflammatory Markers During Early Treatment of Seroconverters in a Randomized Placebo-Controlled... Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 applyparastyle “fig//caption/p[1]” parastyle “FigCapt” Open Forum Infectious Diseases BRIEF REPORT e effic Th acy of pre-exposure prophylaxis (PrEP) to prevent Inflammatory Markers During Early HIV infection is particularly established in men who have sex Treatment of Seroconverters in a with men (MSM) [9–12]. In case of PrEP failure, HIV-1 diag- nosis and ART initiation can occur very early on during the Randomized Placebo-Controlled Trial course of infection owing to bimonthly or quarterly repeated of PrEP (ANRS-IPERGAY) screening. 1,3, 4 1,3 4 5 Sylvain Chawki, Isabelle Charreau, Audrey Gabassi, Diane Carette, Eric Cua, To our knowledge, the evolution of the inflammatory profile 6 7 2 4 Laurent Cotte, Gilles Pialoux, Claire Pintado, Laurence Meyer, 1,3 1,3,a 2,3,a of people with HIV compared with their inflammatory profile Marie-Laure Chaix, Constance Delaugerre, and Jean-Michel Molina before the primary infection has not yet been reported. Department of Virology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France, Maladies Infectieuses, Hôpital Saint-Louis, Assistance Publique Hôpitaux Here, we longitudinally assessed the inflammation profile of 3 4 de Paris, Paris, France, INSERM U944, Paris University, Paris, France, INSERM 5 HIV seroconverters participating in a PrEP trial before HIV in- SC10-US19, Villejuif, France, Maladies Infectieuses, Hôpital L’Archet, Nice, France, Maladies Infectieuses, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France, fection, at the time of primary infection, and during the first and Maladies Infectieuses, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, year of ART. France HIV-related inflammation is associated with poor outcomes. METHODS We describe inflammatory biomarkers in 17 participants in a Participants pre-exposure prophylaxis trial who seroconverted with very The ANRS IPERGAY study was a double-blinded randomized early initiation of antiretroviral therapy. Inflammation peaked trial of PrEP for seronegative highly exposed MSM that took at the time of HIV infection and returned to baseline within place between February 2012 and June 2016 [11, 12]. The study 6–12  months. Starting antiretroviral therapy very early could protocol allowed for sampling plasma, stored at –80°C at each help mitigate long-lasting HIV-related inflammation. Keywords. CRP; D-dimers; early antiretroviral therapy; study trial visit: baseline, months 1 and 2, and subsequently HIV; IL6; PrEP; sCD14. every 2  months for all participants. For people with break- through HIV infections, blood collection was also performed at the time of HIV diagnosis before starting ART (M0) and Early initiation of antiretroviral therapy (ART) for the treat- 6 months (M6) and 12 months (M12) after ART initiation. ment of HIV infection is associated with improved long-term All participants with an HIV diagnosis, by means of plasma clinical outcome, reduced immune deficiency, limited viral HIV-1-RNA or fourth-generation enzyme-linked immu- reservoir constitution, and limited HIV transmission [1–3]. nosorbent (EIA-4G) serological assay, were included in this Primary HIV infection is associated with marked inflamma- substudy. tion (elevated soluble CD14 [sCD14], tumor necrosis factor [TNF]–alpha, interleukin [IL]-6) [1, 4]. It is generally accepted Patient Consent Statement that people treated during symptomatic primary HIV infection The study was carried out in accordance with Good Clinical have persistent HIV-related inflammation, with inflammatory Practices, the ANRS Ethical Chart for Research, and the biomarkers decreasing over time but never returning to normal Declaration of Helsinki. The protocol was approved by national levels (TNF-alpha, C-reactive protein [CRP], sCD14, and hy- ethics committees in France (Comité de Protection des aluronic acid) [1, 5]. HIV-related inflammation is associated Personnes de Paris Ile-de-France I). All participants provided with poor cardiovascular outcome, metabolic changes, and written informed consent. overall shorter life expectancy, making inflammation the target of innovative therapeutic strategies [6–8]. Inflammatory Biomarkers Inflammatory biomarkers were measured on plasma when available at the last visit before HIV diagnosis, at the time of Received 1 December 2020; editorial decision 12 February 2021; accepted 19 February 2021. HIV diagnosis before starting ART (M0), and at M6 and M12 Co-last authors, contributed equally  Correspondence: Sylvain Chawki, M.D.; MSc, Maladies Infectieuses, Hôpital Saint Louis, 1 of ART. avenue Claude Vellefaux, 75010 Paris, France (sylvain.chawki@gmail.com). CRP levels were measured with the Cobas third-generation Open Forum Infectious Diseases 2021 immunoassay (limit of quantification [LOQ] 0.6  mg/L, © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons interassay variability coefficient at LOQ 30%), and IL-6 levels Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted were measured using IL-6 Elecsys Immunoassay kits (LOQ reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/ofid/ofab085 1.5 pg/mL, variability coefficient 3.1%) with an automated BRIEF REPORT • ofid • 1 Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 COBAS Modular platform (Roche Diagnostics, Meylan, Treatment of HIV infection was at the discretion of the primary France). D-dimers were quantified using the LIATEST DdiPlus care physician. STA kit (LOQ 270 ng/mL, variability coefficient 7.31%) with Immunologic and virologic screening and follow-up test re- a STA-R coagulation analyzer (Stago Diagnostica, Asnières- sults are presented in Supplementary Table 1. The median viral sur-Seine, France). Human sCD14 (hCD14) was measured load (IQR) was initially elevated at 6.3 (4.4–7.0) log copies/ with the hCD14 Quantikine ELISA kit (LOQ 250 pg/mL, mL and then was suppressed to <20 cp/mL in 75% and 93% variability coefficient 7.4%, R&D Systems, Minneapolis, MN, of patients aer M6 a ft nd M12 of treatment, respectively. e Th 3 3 USA). Biomarkers were quantified using consistent reagent median CD4 count (IQR) was 543/mm (390–770/mm ) at lots to eliminate lot-to-lot variability. For CRP, IL-6, and the time of diagnosis and increased during ART to 846/mm 3 3 3 D-dimer, analyses were performed consecutively for each (613–975/mm ) and 964/mm (760–1078/mm ) at M6 and plasma sample after 1 single freeze-thaw cycle. For sCD14, M12, respectively. however, all samples were analyzed during 1 single run on the Inflammatory Biomarkers same plate. The evolution of biomarkers (CRP, D-dimers, IL-6, and sCD14) Statistical Analysis is summarized in Figure 1. Inflammatory biomarkers were described at each visit as me- At the visit before diagnosis, a median (IQR) of 59 (49–66) dian and interquartile range for continuous variables and as days prior, 6 patients had an elevated CRP (defined by a value numbers and percentages for qualitative variables and were >2  mg/L), including 3 with a current symptomatic sexually compared between visits using a Wilcoxon signed rank test. transmitted infection (STI; 1 with gonorrhea, 1 with gonorrhea All P values and confidence intervals were 2-sided. All analyses and chlamydia, and 1 with chlamydia and syphilis). Two pa- were conducted with SAS, version 9.4 (SAS Institute Inc., Cary, tients had elevated D-dimers (>500  ng/mL) at the visit before NC, USA). All values below the lower limit of quantification diagnosis, including 1 with a diagnosis of syphilis and concom- were set to 0. itant chlamydia infection. Fifteen patients had elevated IL-6 levels (>1.5 pg/mL), including 8 with a current symptomatic RESULTS STI (3 chlamydia and 6 gonorrhea, including 1 with both). All patients had elevated sCD14 (>250  ng/mL), including 8 with Patients a current symptomatic STI (3 chlamydia and 6 gonorrhea, in- HIV-1 infection occurred in 31 participants during the cluding 1 with both). IPERGAY trial [11, 12]. Plasma samples were available for 17 In the 3 weeks leading up to and aer HIV di ft agnosis, 8 STIs participants for at least the visit before the diagnosis (n = 17) were diagnosed in 5 different participants: 1 oral gonorrhea 1 and 2 other visits among the following: the visit at the time of week before HIV diagnosis, 1 syphilis on the same day as HIV HIV diagnosis before ART (M0; n = 17), the visit during fol- diagnosis, 1 anal chlamydia, 3 anal gonorrhea, and 2 pharyn- low-up at 6 months (M6; n = 14), and/or the visit 12 months geal gonorrhea in 3 other participants 4, 5, and 8 days aer ft HIV (M12; n = 11) after ART initiation. Fourteen patients were in diagnosis. the placebo arm, and 3 were on PrEP [11, 12]. The 3 partici- e e Th volution of CRP and D-dimer levels showed no time ef- pants in the PrEP arm were self-reportedly not adherent to fect (Figure 1). IL-6 and sCD14 levels were significantly higher the PrEP regimen, and no resistance mutation was detected at M0 than before HIV diagnosis (P = .03 and .003, respectively) at HIV diagnosis [11, 12]. All were men with a median age and tended to return to baseline levels at M6 and M12. Individual (interquartile range [IQR]) of 34 (27–44) years. Fiebig stages inflammatory profiles are presented in Supplementary Figure 1. at diagnosis were I  (n  =  1; 6%), II (n  =  7; 41%), III (n  =  3; Immuno-virological evolution is presented in Supplementary 18%), IV (n  =  3; 18%), V (n  =  2; 12%), and VI (n  =  1; 6%). Table 1. Ten patients presented with symptomatic primary infection (9 fever and/or flu syndrome, 5 cephalalgia, 2 rashes, and 1 sore DISCUSSION throat). Time between HIV diagnosis and start of ART ranged from HIV primary infection led to high levels of inflammation [6]. 2 to 63 days with a median (IQR) of 6 (3–8) days. Patients were Even with early initiation of ART, people with symptomatic HIV treated with a backbone of TDF and FTC and a third agent primary infection tend to have higher chronic levels of inflamma- including a protease inhibitor in 7 cases (41%); an integrase tory biomarkers than non-HIV-infected people up to 36 months inhibitor in 8 cases (47%). Two patients (12%) were treated after ART initiation [1]. Here, we present the results of a study with a combination of 4 drugs: TDF, FTC, and a protease in- that analyzed the evolution of the inflammatory biomarkers in hibitor associated with an integrase inhibitor in 1 case and a the setting of very early initiation of ART compared with baseline non-nucleoside reverse transcriptase inhibitor in the other. inflammatory biomarker levels before HIV infection. 2 • ofid • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 P = 1.00 P = .63 12.5 P = .17 P = .55 10.5 7.5 5.0 2.5 0.0 Before Before M6 of ART M12 of ART Before Before M6 of ART M12 of ART diagnosis ART diagnosis ART Min-max 0 to 13.5 0 to 5.7 0 to 13.1 0 to 5.4 Min-max 0 to 2020 0 to 2450 0 to 2270 0 to 410 Median (IQR) 0 (0 – 2.3) 0 (0 – 3.1) 0 (0 – 0) 0 (0 – 0) Median (IQR) 0 (0 – 290) 350 (0 – 590.0) 140 (0 – 320) 280 (0 – 330) CRP>2 mg/L 6/17 (35%) 5/17 (29%) 3/14 (21%) 1/10 (10%) DDIM>270 ng/mL 6/17 (35%) 10/17 (59%) 7/14 (50%) 6/11 (55%) P = .28 P = .65 P = .003** P = .03* Before Before M6 of ART M12 of ART Before Before M6 of ART M12 of ART diagnosis ART diagnosis ART Min-max 0.0 to 4.8 0 to 7.1 0 to 5.1 0 to 3.5 Min-max 1387 to 2715 1681 to 3747 1282 to 3357 1263 to 2555 Median (IQR) 2002 (1773 – 2315) 2395 (2114 – 3160) 2393 (1866 – 2654) 1676 (1543 – 1981) Median (IQR) 1.9 (1.6 – 3.3) 3.5 (2.9 – 3.9) 2.0 (1.8 – 3.1) 1.7 (1.5 – 2.7) SCD>14>250 ng/mL 17/17 (100%) 17/17 (100%) 14/14 (100%) 11/11 (100%) IL-6>1.5 pg/mL 15/16 (94%) 16/17 (94%) 11/13 (85%) 8/10 (80%) Figure 1. Evolution of inflammatory biomarkers before and after HIV and antiretroviral therapy. The mean for each visit is represented by the red plus sign and the median by the horizontal line across the boxes. All values below the lower limit of quantification were set to 0. The visit “Before diagnosis” happened a median (IQR) of 59 (49–66) days before the following visit. Abbreviations: ART, antiretroviral therapy; CRP, C-reactive protein; DDIM, D-dimer; IL-6, interleukin-6; IQR, interquartile range; sCD14, soluble CD14. We report that in this cohort of high-risk MSM, HIV pri- time point before HIV infection, and a high proportion of par- mary infection was frequently symptomatic and associated ticipants with CRP or D-dimer levels below the limit of quan- with a marked elevation in inflammatory biomarkers. We also tification. Five participants were diagnosed with STIs around noted ~50% elevated inflammatory biomarker levels even be- the time of HIV diagnosis; this should not ae ff ct the overall re- fore HIV infection. Our study showed that very early treatment sults of the inflammatory biomarkers presented here due to the of HIV infection (median of 6  days aer HIV di ft agnosis in a wide temporal spread of these infections from HIV diagnosis cohort with 41% FIEBIG stage II) could allow a return to pre- and the relatively small number of events. The test/P value for infection levels of specific inflammatory biomarkers (IL-6 and each biomarker at baseline was compared with the time of HIV sCD14) when CRP and D-dimer levels did not seem to change diagnosis and month 12 and was not adjusted for multiple com- throughout the course of infection. parisons because of the limited number of observations. This Our analyses of individual data for inflammatory biomarkers analysis was exploratory and centered on a controlled and care- highlight 2 main patterns: (i) elevated baseline inflammation fully selected number of conditions. Additionally, due to signif- that appears not to be significantly ae ff cted by HIV infection icant missing data at month 12, bars and raw medians between followed by a decrease in levels to lower than the individual baseline and month 12 should not be compared in Figure 1. baseline, hinting toward potential confounders; (ii) inflamma- Measuring ultrasensitive CRP levels might increase sensi- tion peaking at the time of HIV infection followed by a slow tivity and uncover fluctuating inflammation for all participants return to baseline levels. with a value <2 mg/L. Our study is limited by the small sample size, the retrospective Overall, in a context of elevated HIV-related inflammation, nature of the data, the lack of available CD4 T-cell counts at the very early treatment leads to a rapid decrease in inflammatory BRIEF REPORT • ofid • 3 CRP, mg/L IL-6, pg/mL D-dimer, ng/mL IL-6, pg/mL Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 2. Achhra  AC, Phillips  A, Emery  S, et  al; International Network for Strategic biomarkers and might allow a return to pre-infection levels. Initiatives in Global HIV Trials (INSIGHT) Strategic Management of This decrease might in turn lead to better long-term outcomes. Antiretroviral Therapy (SMART) and Flexible Initial Retrovirus Suppressive Our study reinforces the recommendation of early treatment Therapies (FIRST) study groups. Pre-therapy inflammation and coagulation ac- tivation and long-term CD4 count responses to the initiation of antiretroviral for people who seroconvert while taking PrEP. Future larger therapy. HIV Med 2015; 16:449–54. studies should consider prospectively monitoring inflamma- 3. Cohen  MS, Chen  YQ, McCauley  M, et  al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; tory biomarkers in people who seroconvert while on PrEP and 365:493–505. in those with STIs to confirm these results. 4. Stacey AR, Norris PJ, Qin L, et al. Induction of a striking systemic cytokine cas- cade prior to peak viremia in acute human immunodeficiency virus type 1 infec- tion, in contrast to more modest and delayed responses in acute hepatitis B and C Supplementary Data virus infections. J Virol 2009; 83:3719–33. Supplementary materials are available at Open Forum Infectious Diseases 5. Sereti I, Krebs SJ, Phanuphak N, et al; RV254/SEARCH 010, RV304/SEARCH 013 online. Consisting of data provided by the authors to benefit the reader, and SEARCH 011 protocol teams. Persistent, albeit reduced, chronic inflamma- the posted materials are not copyedited and are the sole responsibility tion in persons starting antiretroviral therapy in acute HIV infection. Clin Infect of the authors, so questions or comments should be addressed to the Dis 2017; 64:124–31. corresponding author. 6. Krastinova  E, Lecuroux  C, Leroy  C, et  al; ANRS PRIMO Cohort. High soluble CD14 levels at primary HIV-1 infection predict more rapid disease progression. J Infect Dis 2015; 212:909–13. Acknowledgments 7. Grund B, Baker JV, Deeks SG, et al; INSIGHT SMART/ESPRIT/SILCAAT Study Financial support. This work was supported by the National Agency Group. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity of Research on AIDS and Viral Hepatitis (ANRS) and the Bill & Melinda and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS Gates Foundation as part of the IPERGAY trial (ClinicalTrials.gov number, One 2016; 11:e0155100. 8. Ghislain  M, Bastard  JP, Meyer  L, et  al; ANRS-COPANA Cohort Study Group. NCT01473472). Late antiretroviral therapy (ART) initiation is associated with long-term persist- Potential coni fl cts of interest. We declare that there are no conflicts of ence of systemic inflammation and metabolic abnormalities. PLoS One 2015; interest in relation to the submitted work. All authors have submitted the 10:e0144317. ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that 9. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemo- the editors consider relevant to the content of the manuscript have been prophylaxis for HIV prevention in men who have sex with men. N Engl J Med disclosed. 2010; 363:2587–99. Author contributions. Designed the study: C.D., J.M.M., M.L.C. 10. McCormack  S, Dunn  DT, Desai  M, et  al. Pre-exposure prophylaxis to pre- Managed the participants’ care: E.C., L.C., G.P., C.P., J.M.M. Performed vent the acquisition of HIV-1 infection (PROUD): effectiveness results from the measurements: A.G., S.C. Analyzed the data: I.C., L.M., D.C. Wrote the the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53–60. paper: S.C., C.D., and J.M.M. All authors provided critical review and feed- 11. Molina JM, Capitant C, Spire B, et al; ANRS IPERGAY Study Group. On-demand back of the manuscript. preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015; 373:2237–46. References 12. Molina  JM, Charreau  I, Spire  B, et  al; ANRS IPERGAY Study Group. Efficacy, 1. Novelli S, Lécuroux C, Avettand-Fenoel V, et al. Long-term therapeutic impact of safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for the timing of antiretroviral therapy in patients diagnosed with primary human HIV in men who have sex with men: an observational cohort study. Lancet HIV immunodeficiency virus type 1 infection. Clin Infect Dis 2018; 66:1519–27. 2017; 4:e402–10. 4 • ofid • BRIEF REPORT http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Inflammatory Markers During Early Treatment of Seroconverters in a Randomized Placebo-Controlled Trial of PrEP (ANRS-IPERGAY)

Download PDF
4 pages

Loading next page...
 
/lp/oxford-university-press/inflammatory-markers-during-early-treatment-of-seroconverters-in-a-EqoXqCCF5O

References (25)

Publisher
Oxford University Press
Copyright
Copyright © 2021 Infectious Diseases Society of America
eISSN
2328-8957
DOI
10.1093/ofid/ofab085
Publisher site
See Article on Publisher Site

Abstract

Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 applyparastyle “fig//caption/p[1]” parastyle “FigCapt” Open Forum Infectious Diseases BRIEF REPORT e effic Th acy of pre-exposure prophylaxis (PrEP) to prevent Inflammatory Markers During Early HIV infection is particularly established in men who have sex Treatment of Seroconverters in a with men (MSM) [9–12]. In case of PrEP failure, HIV-1 diag- nosis and ART initiation can occur very early on during the Randomized Placebo-Controlled Trial course of infection owing to bimonthly or quarterly repeated of PrEP (ANRS-IPERGAY) screening. 1,3, 4 1,3 4 5 Sylvain Chawki, Isabelle Charreau, Audrey Gabassi, Diane Carette, Eric Cua, To our knowledge, the evolution of the inflammatory profile 6 7 2 4 Laurent Cotte, Gilles Pialoux, Claire Pintado, Laurence Meyer, 1,3 1,3,a 2,3,a of people with HIV compared with their inflammatory profile Marie-Laure Chaix, Constance Delaugerre, and Jean-Michel Molina before the primary infection has not yet been reported. Department of Virology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France, Maladies Infectieuses, Hôpital Saint-Louis, Assistance Publique Hôpitaux Here, we longitudinally assessed the inflammation profile of 3 4 de Paris, Paris, France, INSERM U944, Paris University, Paris, France, INSERM 5 HIV seroconverters participating in a PrEP trial before HIV in- SC10-US19, Villejuif, France, Maladies Infectieuses, Hôpital L’Archet, Nice, France, Maladies Infectieuses, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France, fection, at the time of primary infection, and during the first and Maladies Infectieuses, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, year of ART. France HIV-related inflammation is associated with poor outcomes. METHODS We describe inflammatory biomarkers in 17 participants in a Participants pre-exposure prophylaxis trial who seroconverted with very The ANRS IPERGAY study was a double-blinded randomized early initiation of antiretroviral therapy. Inflammation peaked trial of PrEP for seronegative highly exposed MSM that took at the time of HIV infection and returned to baseline within place between February 2012 and June 2016 [11, 12]. The study 6–12  months. Starting antiretroviral therapy very early could protocol allowed for sampling plasma, stored at –80°C at each help mitigate long-lasting HIV-related inflammation. Keywords. CRP; D-dimers; early antiretroviral therapy; study trial visit: baseline, months 1 and 2, and subsequently HIV; IL6; PrEP; sCD14. every 2  months for all participants. For people with break- through HIV infections, blood collection was also performed at the time of HIV diagnosis before starting ART (M0) and Early initiation of antiretroviral therapy (ART) for the treat- 6 months (M6) and 12 months (M12) after ART initiation. ment of HIV infection is associated with improved long-term All participants with an HIV diagnosis, by means of plasma clinical outcome, reduced immune deficiency, limited viral HIV-1-RNA or fourth-generation enzyme-linked immu- reservoir constitution, and limited HIV transmission [1–3]. nosorbent (EIA-4G) serological assay, were included in this Primary HIV infection is associated with marked inflamma- substudy. tion (elevated soluble CD14 [sCD14], tumor necrosis factor [TNF]–alpha, interleukin [IL]-6) [1, 4]. It is generally accepted Patient Consent Statement that people treated during symptomatic primary HIV infection The study was carried out in accordance with Good Clinical have persistent HIV-related inflammation, with inflammatory Practices, the ANRS Ethical Chart for Research, and the biomarkers decreasing over time but never returning to normal Declaration of Helsinki. The protocol was approved by national levels (TNF-alpha, C-reactive protein [CRP], sCD14, and hy- ethics committees in France (Comité de Protection des aluronic acid) [1, 5]. HIV-related inflammation is associated Personnes de Paris Ile-de-France I). All participants provided with poor cardiovascular outcome, metabolic changes, and written informed consent. overall shorter life expectancy, making inflammation the target of innovative therapeutic strategies [6–8]. Inflammatory Biomarkers Inflammatory biomarkers were measured on plasma when available at the last visit before HIV diagnosis, at the time of Received 1 December 2020; editorial decision 12 February 2021; accepted 19 February 2021. HIV diagnosis before starting ART (M0), and at M6 and M12 Co-last authors, contributed equally  Correspondence: Sylvain Chawki, M.D.; MSc, Maladies Infectieuses, Hôpital Saint Louis, 1 of ART. avenue Claude Vellefaux, 75010 Paris, France (sylvain.chawki@gmail.com). CRP levels were measured with the Cobas third-generation Open Forum Infectious Diseases 2021 immunoassay (limit of quantification [LOQ] 0.6  mg/L, © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons interassay variability coefficient at LOQ 30%), and IL-6 levels Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted were measured using IL-6 Elecsys Immunoassay kits (LOQ reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/ofid/ofab085 1.5 pg/mL, variability coefficient 3.1%) with an automated BRIEF REPORT • ofid • 1 Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 COBAS Modular platform (Roche Diagnostics, Meylan, Treatment of HIV infection was at the discretion of the primary France). D-dimers were quantified using the LIATEST DdiPlus care physician. STA kit (LOQ 270 ng/mL, variability coefficient 7.31%) with Immunologic and virologic screening and follow-up test re- a STA-R coagulation analyzer (Stago Diagnostica, Asnières- sults are presented in Supplementary Table 1. The median viral sur-Seine, France). Human sCD14 (hCD14) was measured load (IQR) was initially elevated at 6.3 (4.4–7.0) log copies/ with the hCD14 Quantikine ELISA kit (LOQ 250 pg/mL, mL and then was suppressed to <20 cp/mL in 75% and 93% variability coefficient 7.4%, R&D Systems, Minneapolis, MN, of patients aer M6 a ft nd M12 of treatment, respectively. e Th 3 3 USA). Biomarkers were quantified using consistent reagent median CD4 count (IQR) was 543/mm (390–770/mm ) at lots to eliminate lot-to-lot variability. For CRP, IL-6, and the time of diagnosis and increased during ART to 846/mm 3 3 3 D-dimer, analyses were performed consecutively for each (613–975/mm ) and 964/mm (760–1078/mm ) at M6 and plasma sample after 1 single freeze-thaw cycle. For sCD14, M12, respectively. however, all samples were analyzed during 1 single run on the Inflammatory Biomarkers same plate. The evolution of biomarkers (CRP, D-dimers, IL-6, and sCD14) Statistical Analysis is summarized in Figure 1. Inflammatory biomarkers were described at each visit as me- At the visit before diagnosis, a median (IQR) of 59 (49–66) dian and interquartile range for continuous variables and as days prior, 6 patients had an elevated CRP (defined by a value numbers and percentages for qualitative variables and were >2  mg/L), including 3 with a current symptomatic sexually compared between visits using a Wilcoxon signed rank test. transmitted infection (STI; 1 with gonorrhea, 1 with gonorrhea All P values and confidence intervals were 2-sided. All analyses and chlamydia, and 1 with chlamydia and syphilis). Two pa- were conducted with SAS, version 9.4 (SAS Institute Inc., Cary, tients had elevated D-dimers (>500  ng/mL) at the visit before NC, USA). All values below the lower limit of quantification diagnosis, including 1 with a diagnosis of syphilis and concom- were set to 0. itant chlamydia infection. Fifteen patients had elevated IL-6 levels (>1.5 pg/mL), including 8 with a current symptomatic RESULTS STI (3 chlamydia and 6 gonorrhea, including 1 with both). All patients had elevated sCD14 (>250  ng/mL), including 8 with Patients a current symptomatic STI (3 chlamydia and 6 gonorrhea, in- HIV-1 infection occurred in 31 participants during the cluding 1 with both). IPERGAY trial [11, 12]. Plasma samples were available for 17 In the 3 weeks leading up to and aer HIV di ft agnosis, 8 STIs participants for at least the visit before the diagnosis (n = 17) were diagnosed in 5 different participants: 1 oral gonorrhea 1 and 2 other visits among the following: the visit at the time of week before HIV diagnosis, 1 syphilis on the same day as HIV HIV diagnosis before ART (M0; n = 17), the visit during fol- diagnosis, 1 anal chlamydia, 3 anal gonorrhea, and 2 pharyn- low-up at 6 months (M6; n = 14), and/or the visit 12 months geal gonorrhea in 3 other participants 4, 5, and 8 days aer ft HIV (M12; n = 11) after ART initiation. Fourteen patients were in diagnosis. the placebo arm, and 3 were on PrEP [11, 12]. The 3 partici- e e Th volution of CRP and D-dimer levels showed no time ef- pants in the PrEP arm were self-reportedly not adherent to fect (Figure 1). IL-6 and sCD14 levels were significantly higher the PrEP regimen, and no resistance mutation was detected at M0 than before HIV diagnosis (P = .03 and .003, respectively) at HIV diagnosis [11, 12]. All were men with a median age and tended to return to baseline levels at M6 and M12. Individual (interquartile range [IQR]) of 34 (27–44) years. Fiebig stages inflammatory profiles are presented in Supplementary Figure 1. at diagnosis were I  (n  =  1; 6%), II (n  =  7; 41%), III (n  =  3; Immuno-virological evolution is presented in Supplementary 18%), IV (n  =  3; 18%), V (n  =  2; 12%), and VI (n  =  1; 6%). Table 1. Ten patients presented with symptomatic primary infection (9 fever and/or flu syndrome, 5 cephalalgia, 2 rashes, and 1 sore DISCUSSION throat). Time between HIV diagnosis and start of ART ranged from HIV primary infection led to high levels of inflammation [6]. 2 to 63 days with a median (IQR) of 6 (3–8) days. Patients were Even with early initiation of ART, people with symptomatic HIV treated with a backbone of TDF and FTC and a third agent primary infection tend to have higher chronic levels of inflamma- including a protease inhibitor in 7 cases (41%); an integrase tory biomarkers than non-HIV-infected people up to 36 months inhibitor in 8 cases (47%). Two patients (12%) were treated after ART initiation [1]. Here, we present the results of a study with a combination of 4 drugs: TDF, FTC, and a protease in- that analyzed the evolution of the inflammatory biomarkers in hibitor associated with an integrase inhibitor in 1 case and a the setting of very early initiation of ART compared with baseline non-nucleoside reverse transcriptase inhibitor in the other. inflammatory biomarker levels before HIV infection. 2 • ofid • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 P = 1.00 P = .63 12.5 P = .17 P = .55 10.5 7.5 5.0 2.5 0.0 Before Before M6 of ART M12 of ART Before Before M6 of ART M12 of ART diagnosis ART diagnosis ART Min-max 0 to 13.5 0 to 5.7 0 to 13.1 0 to 5.4 Min-max 0 to 2020 0 to 2450 0 to 2270 0 to 410 Median (IQR) 0 (0 – 2.3) 0 (0 – 3.1) 0 (0 – 0) 0 (0 – 0) Median (IQR) 0 (0 – 290) 350 (0 – 590.0) 140 (0 – 320) 280 (0 – 330) CRP>2 mg/L 6/17 (35%) 5/17 (29%) 3/14 (21%) 1/10 (10%) DDIM>270 ng/mL 6/17 (35%) 10/17 (59%) 7/14 (50%) 6/11 (55%) P = .28 P = .65 P = .003** P = .03* Before Before M6 of ART M12 of ART Before Before M6 of ART M12 of ART diagnosis ART diagnosis ART Min-max 0.0 to 4.8 0 to 7.1 0 to 5.1 0 to 3.5 Min-max 1387 to 2715 1681 to 3747 1282 to 3357 1263 to 2555 Median (IQR) 2002 (1773 – 2315) 2395 (2114 – 3160) 2393 (1866 – 2654) 1676 (1543 – 1981) Median (IQR) 1.9 (1.6 – 3.3) 3.5 (2.9 – 3.9) 2.0 (1.8 – 3.1) 1.7 (1.5 – 2.7) SCD>14>250 ng/mL 17/17 (100%) 17/17 (100%) 14/14 (100%) 11/11 (100%) IL-6>1.5 pg/mL 15/16 (94%) 16/17 (94%) 11/13 (85%) 8/10 (80%) Figure 1. Evolution of inflammatory biomarkers before and after HIV and antiretroviral therapy. The mean for each visit is represented by the red plus sign and the median by the horizontal line across the boxes. All values below the lower limit of quantification were set to 0. The visit “Before diagnosis” happened a median (IQR) of 59 (49–66) days before the following visit. Abbreviations: ART, antiretroviral therapy; CRP, C-reactive protein; DDIM, D-dimer; IL-6, interleukin-6; IQR, interquartile range; sCD14, soluble CD14. We report that in this cohort of high-risk MSM, HIV pri- time point before HIV infection, and a high proportion of par- mary infection was frequently symptomatic and associated ticipants with CRP or D-dimer levels below the limit of quan- with a marked elevation in inflammatory biomarkers. We also tification. Five participants were diagnosed with STIs around noted ~50% elevated inflammatory biomarker levels even be- the time of HIV diagnosis; this should not ae ff ct the overall re- fore HIV infection. Our study showed that very early treatment sults of the inflammatory biomarkers presented here due to the of HIV infection (median of 6  days aer HIV di ft agnosis in a wide temporal spread of these infections from HIV diagnosis cohort with 41% FIEBIG stage II) could allow a return to pre- and the relatively small number of events. The test/P value for infection levels of specific inflammatory biomarkers (IL-6 and each biomarker at baseline was compared with the time of HIV sCD14) when CRP and D-dimer levels did not seem to change diagnosis and month 12 and was not adjusted for multiple com- throughout the course of infection. parisons because of the limited number of observations. This Our analyses of individual data for inflammatory biomarkers analysis was exploratory and centered on a controlled and care- highlight 2 main patterns: (i) elevated baseline inflammation fully selected number of conditions. Additionally, due to signif- that appears not to be significantly ae ff cted by HIV infection icant missing data at month 12, bars and raw medians between followed by a decrease in levels to lower than the individual baseline and month 12 should not be compared in Figure 1. baseline, hinting toward potential confounders; (ii) inflamma- Measuring ultrasensitive CRP levels might increase sensi- tion peaking at the time of HIV infection followed by a slow tivity and uncover fluctuating inflammation for all participants return to baseline levels. with a value <2 mg/L. Our study is limited by the small sample size, the retrospective Overall, in a context of elevated HIV-related inflammation, nature of the data, the lack of available CD4 T-cell counts at the very early treatment leads to a rapid decrease in inflammatory BRIEF REPORT • ofid • 3 CRP, mg/L IL-6, pg/mL D-dimer, ng/mL IL-6, pg/mL Downloaded from https://academic.oup.com/ofid/article/8/3/ofab085/6179257 by DeepDyve user on 25 March 2021 2. Achhra  AC, Phillips  A, Emery  S, et  al; International Network for Strategic biomarkers and might allow a return to pre-infection levels. Initiatives in Global HIV Trials (INSIGHT) Strategic Management of This decrease might in turn lead to better long-term outcomes. Antiretroviral Therapy (SMART) and Flexible Initial Retrovirus Suppressive Our study reinforces the recommendation of early treatment Therapies (FIRST) study groups. Pre-therapy inflammation and coagulation ac- tivation and long-term CD4 count responses to the initiation of antiretroviral for people who seroconvert while taking PrEP. Future larger therapy. HIV Med 2015; 16:449–54. studies should consider prospectively monitoring inflamma- 3. Cohen  MS, Chen  YQ, McCauley  M, et  al; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; tory biomarkers in people who seroconvert while on PrEP and 365:493–505. in those with STIs to confirm these results. 4. Stacey AR, Norris PJ, Qin L, et al. Induction of a striking systemic cytokine cas- cade prior to peak viremia in acute human immunodeficiency virus type 1 infec- tion, in contrast to more modest and delayed responses in acute hepatitis B and C Supplementary Data virus infections. J Virol 2009; 83:3719–33. Supplementary materials are available at Open Forum Infectious Diseases 5. Sereti I, Krebs SJ, Phanuphak N, et al; RV254/SEARCH 010, RV304/SEARCH 013 online. Consisting of data provided by the authors to benefit the reader, and SEARCH 011 protocol teams. Persistent, albeit reduced, chronic inflamma- the posted materials are not copyedited and are the sole responsibility tion in persons starting antiretroviral therapy in acute HIV infection. Clin Infect of the authors, so questions or comments should be addressed to the Dis 2017; 64:124–31. corresponding author. 6. Krastinova  E, Lecuroux  C, Leroy  C, et  al; ANRS PRIMO Cohort. High soluble CD14 levels at primary HIV-1 infection predict more rapid disease progression. J Infect Dis 2015; 212:909–13. Acknowledgments 7. Grund B, Baker JV, Deeks SG, et al; INSIGHT SMART/ESPRIT/SILCAAT Study Financial support. This work was supported by the National Agency Group. Relevance of interleukin-6 and D-dimer for serious non-AIDS morbidity of Research on AIDS and Viral Hepatitis (ANRS) and the Bill & Melinda and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS Gates Foundation as part of the IPERGAY trial (ClinicalTrials.gov number, One 2016; 11:e0155100. 8. Ghislain  M, Bastard  JP, Meyer  L, et  al; ANRS-COPANA Cohort Study Group. NCT01473472). Late antiretroviral therapy (ART) initiation is associated with long-term persist- Potential coni fl cts of interest. We declare that there are no conflicts of ence of systemic inflammation and metabolic abnormalities. PLoS One 2015; interest in relation to the submitted work. All authors have submitted the 10:e0144317. ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that 9. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemo- the editors consider relevant to the content of the manuscript have been prophylaxis for HIV prevention in men who have sex with men. N Engl J Med disclosed. 2010; 363:2587–99. Author contributions. Designed the study: C.D., J.M.M., M.L.C. 10. McCormack  S, Dunn  DT, Desai  M, et  al. Pre-exposure prophylaxis to pre- Managed the participants’ care: E.C., L.C., G.P., C.P., J.M.M. Performed vent the acquisition of HIV-1 infection (PROUD): effectiveness results from the measurements: A.G., S.C. Analyzed the data: I.C., L.M., D.C. Wrote the the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:53–60. paper: S.C., C.D., and J.M.M. All authors provided critical review and feed- 11. Molina JM, Capitant C, Spire B, et al; ANRS IPERGAY Study Group. On-demand back of the manuscript. preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015; 373:2237–46. References 12. Molina  JM, Charreau  I, Spire  B, et  al; ANRS IPERGAY Study Group. Efficacy, 1. Novelli S, Lécuroux C, Avettand-Fenoel V, et al. Long-term therapeutic impact of safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for the timing of antiretroviral therapy in patients diagnosed with primary human HIV in men who have sex with men: an observational cohort study. Lancet HIV immunodeficiency virus type 1 infection. Clin Infect Dis 2018; 66:1519–27. 2017; 4:e402–10. 4 • ofid • BRIEF REPORT

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Mar 1, 2021

Keywords: hiv; inflammatory markers; inflammation; hiv infections; anti-retroviral agents; pre-exposure prophylaxis; fibrin fragment d substance; interleukin-6

There are no references for this article.