Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Drugs
Published in: Drugs 5/2016

01-04-2016 | Leading Article

Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection

Authors: Denise C. Hsu, Irini Sereti

Published in: Drugs | Issue 5/2016

Login to get access

Abstract

In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available.
Literature
1.
van Sighem A, Danner S, Ghani AC, Gras L, Anderson RM, de Wolf F. Mortality in patients with successful initial response to highly active antiretroviral therapy is still higher than in non-HIV-infected individuals. J Acquir Immune Defic Syndr. 2005;40(2):212–8.PubMedCrossRef
2.
3.
4.
5.
Causes of death in. HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis Off Publ Infect Dis Soc Am. 2010;50(10):1387–96. doi:10.​1086/​652283.CrossRef
6.
7.
8.
9.
10.
11.
12.
13.
Guiguet M, Boue F, Cadranel J, Lang JM, Rosenthal E, Costagliola D, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. 2009;10(12):1152–9. doi:10.​1016/​S1470-2045(09)70282-7.PubMedCrossRef
14.
15.
16.
17.
18.
Giordano TP, Kramer JR, Souchek J, Richardson P, El-Serag HB. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: a cohort study, 1992–2001. Arch Intern Med. 2004;164(21):2349–54. doi:10.​1001/​archinte.​164.​21.​2349.PubMedCrossRef
19.
Chen TY, Ding EL, Seage Iii GR, Kim AY. Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis Off Publ Infect Dis Soc Am. 2009;49(10):1605–15. doi:10.​1086/​644771.CrossRef
20.
Saves M, Chene G, Ducimetiere P, Leport C, Le Moal G, Amouyel P, et al. Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;37(2):292–8. doi:10.​1086/​375844.CrossRef
21.
22.
23.
Althoff KN, McGinnis KA, Wyatt CM, Freiberg MS, Gilbert C, Oursler KK, et al. Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults. Clin Infect Dis Off Publ Infect Dis Soc Am. 2015;60(4):627–38. doi:10.​1093/​cid/​ciu869.CrossRef
24.
Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759–71. doi:10.​1038/​nrc3611.PubMedCrossRef
25.
26.
27.
28.
29.
30.
Il’yasova D, Colbert LH, Harris TB, Newman AB, Bauer DC, Satterfield S, et al. Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomark Prev. 2005;14(10):2413–8. doi:10.​1158/​1055-9965.​EPI-05-0316.CrossRef
31.
Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, Uitterlinden AG, et al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol. 2006;24(33):5216–22. doi:10.​1200/​JCO.​2006.​07.​1381.PubMedCrossRef
32.
Heikkila K, Harris R, Lowe G, Rumley A, Yarnell J, Gallacher J, et al. Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control. 2009;20(1):15–26. doi:10.​1007/​s10552-008-9212-z.PubMedCrossRef
33.
Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–40. doi:10.​1016/​S0140-6736(09)61717-7.PubMedCrossRef
34.
Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. Circulation. 2001;103(19):2323–7.PubMedCrossRef
35.
Danesh J, Lewington S, Thompson SG, Lowe GD, Collins R, Kostis JB, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005;294(14):1799–809. doi:10.​1001/​jama.​294.​14.​1799.PubMed
36.
37.
Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106(5):506–12 (pii: S0002934399000662).PubMedCrossRef
38.
Cohen HJ, Harris T, Pieper CF. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am J Med. 2003;114(3):180–7 (pii: S0002934302014845).PubMedCrossRef
39.
Suzuki T, Voeks J, Zakai NA, Jenny NS, Brown TM, Safford MM, et al. Metabolic syndrome, C-reactive protein, and mortality in US Blacks and Whites: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Diabetes Care. 2014;37(8):2284–90. doi:10.​2337/​dc13-2059.PubMedPubMedCentralCrossRef
40.
41.
Borges AH, Silverberg MJ, Wentworth D, Grulich AE, Fatkenheuer G, Mitsuyasu R, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS. 2013;27(9):1433–41.PubMedPubMedCentralCrossRef
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
Ho HN, Hultin LE, Mitsuyasu RT, Matud JL, Hausner MA, Bockstoce D, et al. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol. 1993;150(7):3070–9.PubMed
52.
53.
54.
55.
56.
Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005;434(7037):1148–52. doi:10.​1038/​nature03513.PubMed
57.
Veazey RS, Tham IC, Mansfield KG, DeMaria M, Forand AE, Shvetz DE, et al. Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vivo. J Virol. 2000;74(1):57–64.PubMedPubMedCentralCrossRef
58.
59.
60.
61.
62.
Gori A, Tincati C, Rizzardini G, Torti C, Quirino T, Haarman M, et al. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J Clin Microbiol. 2008;46(2):757–8. doi:10.​1128/​JCM.​01729-07.PubMedPubMedCentralCrossRef
63.
64.
65.
Novati S, Sacchi P, Cima S, Zuccaro V, Columpsi P, Pagani L, et al. General issues on microbial translocation in HIV-infected patients. Eur Rev Med Pharmacol Sci. 2015;19(5):866–78.PubMed
66.
67.
Bas S, Gauthier BR, Spenato U, Stingelin S, Gabay C. CD14 is an acute-phase protein. J Immunol. 2004;172(7):4470–9.PubMedCrossRef
68.
Perkins MR, Bartha I, Timmer JK, Liebner JC, Wollinsky D, Gunthard HF, et al. The interplay between host genetic variation, viral replication, and microbial translocation in untreated HIV-infected individuals. J Infect Dis. 2015;212(4):578–84. doi:10.​1093/​infdis/​jiv089.PubMedCrossRef
69.
70.
Romero-Sanchez M, Gonzalez-Serna A, Pacheco YM, Ferrando-Martinez S, Machmach K, Garcia-Garcia M, et al. Different biological significance of sCD14 and LPS in HIV-infection: importance of the immunovirology stage and association with HIV-disease progression markers. J Infect. 2012;65(5):431–8. doi:10.​1016/​j.​jinf.​2012.​06.​008.PubMedCrossRef
71.
72.
Gonzalez VD, Falconer K, Blom KG, Reichard O, Morn B, Laursen AL, et al. High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol. 2009;83(21):11407–11. doi:10.​1128/​JVI.​01211-09.PubMedPubMedCentralCrossRef
73.
74.
75.
Deayton JR, Prof Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet. 2004;363(9427):2116–21. doi:10.​1016/​S0140-6736(04)16500-8.
76.
77.
Ling PD, Vilchez RA, Keitel WA, Poston DG, Peng RS, White ZS, et al. Epstein-Barr virus DNA loads in adult human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;37(9):1244–9. doi:10.​1086/​378808.CrossRef
78.
79.
Wittkop L, Bitard J, Lazaro E, Neau D, Bonnet F, Mercie P, et al. Effect of cytomegalovirus-induced immune response, self antigen-induced immune response, and microbial translocation on chronic immune activation in successfully treated HIV type 1-infected patients: the ANRS CO3 Aquitaine Cohort. J Infect Dis. 2013;207(4):622–7. doi:10.​1093/​infdis/​jis732.PubMedCrossRef
80.
Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001;7(1):73–9. doi:10.​1038/​83381.PubMedCrossRef
81.
82.
Vanderford TH, Adamski J, Silvestri G. HIV-associated chronic immune activation: current understandings and therapeutic intervention. HIV Ther. 2010;4(2):161–77.CrossRef
83.
Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992;175(2):331–40.PubMedCrossRef
84.
Muro-Cacho CA, Pantaleo G, Fauci AS. Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J Immunol. 1995;154(10):5555–66.PubMed
85.
Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, et al. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med. 1998;4(2):215–21.PubMedCrossRef
86.
Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, Schacker T, et al. Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis. 2006;193(5):703–12. doi:10.​1086/​500368.PubMedCrossRef
87.
88.
89.
90.
91.
92.
Dock JN, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis. 2011;2(5):382–97.PubMedPubMedCentral
93.
94.
95.
Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101(7):2711–20. doi:10.​1182/​blood-2002-07-2103.PubMedCrossRef
96.
97.
98.
Nakajima T, Schulte S, Warrington KJ, Kopecky SL, Frye RL, Goronzy JJ, et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002;105(5):570–5.PubMedCrossRef
99.
Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011;53(11):1120–6. doi:10.​1093/​cid/​cir627.CrossRef
100.
Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St Clair M, et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis. 1998;178(1):70–9.PubMedCrossRef
101.
Bisset LR, Cone RW, Huber W, Battegay M, Vernazza PL, Weber R, et al. Highly active antiretroviral therapy during early HIV infection reverses T-cell activation and maturation abnormalities. Swiss HIV Cohort Study. AIDS. 1998;12(16):2115–23.PubMedCrossRef
102.
103.
104.
Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187(10):1534–43. doi:10.​1086/​374786.PubMedCrossRef
105.
Mendez-Lagares G, Romero-Sanchez MC, Ruiz-Mateos E, Genebat M, Ferrando-Martinez S, Munoz-Fernandez MA, et al. Long-term suppressive combined antiretroviral treatment does not normalize the serum level of soluble CD14. J Infect Dis. 2013;207(8):1221–5. doi:10.​1093/​infdis/​jit025.PubMedCrossRef
106.
Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12(7):F51–8.PubMedCrossRef
107.
Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999;354(9184):1112–5. doi:10.​1016/​S0140-6736(99)06102-4.PubMedCrossRef
108.
109.
Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr. 2000;25(4):312–21.PubMedCrossRef
110.
111.
112.
113.
114.
De Wit S, Sabin CA, Weber R, Worm SW, Reiss P, Cazanave C, et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care. 2008;31(6):1224–9. doi:10.​2337/​dc07-2013.PubMedPubMedCentralCrossRef
115.
116.
117.
118.
119.
120.
121.
Nou E, Lu MT, Looby SE, Fitch KV, Kim EA, Lee H, et al. Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV. AIDS. 2015. doi:10.​1097/​QAD.​0000000000000946​.
122.
Strategies for Management of Antiretroviral Therapy Study G, El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. doi:10.​1056/​NEJMoa062360.CrossRef
123.
124.
Siedner MJ, Ng CK, Bassett IV, Katz IT, Bangsberg DR, Tsai AC. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002–2013: a meta-analysis. Clin Infect Dis Off Publ Infect Dis Soc Am. 2015;60(7):1120–7. doi:10.​1093/​cid/​ciu1137.
125.
126.
Helleberg M, Afzal S, Kronborg G, Larsen CS, Pedersen G, Pedersen C, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013;56(5):727–34. doi:10.​1093/​cid/​cis933.CrossRef
127.
Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;58(1):e1–34. doi:10.​1093/​cid/​cit665.CrossRef
128.
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934. doi:10.​1016/​j.​jacc.​2013.​11.​002.
129.
Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33(13):1635–701. doi:10.​1093/​eurheartj/​ehs092.PubMedCrossRef
130.
Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. The Lancet. 2015.
131.
Cholesterol Treatment Trialists C, Fulcher J, O’Connell R, Voysey M, Emberson J, Blackwell L, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397–405. doi:10.​1016/​S0140-6736(14)61368-4.CrossRef
132.
Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141(6):421–31.PubMedCrossRef
133.
134.
Martin A, Smith DE, Carr A, Ringland C, Amin J, Emery S, et al. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS. 2004;18(7):1029–36.PubMedCrossRef
135.
136.
Madruga JR, Cassetti I, Suleiman JM, Etzel A, Zhong L, Holmes CB, et al. The safety and efficacy of switching stavudine to tenofovir df in combination with lamivudine and efavirenz in HIV-1-infected patients: three-year follow-up after switching therapy. HIV Clin Trials. 2007;8(6):381–90. doi:10.​1310/​hct0806-381.PubMedCrossRef
137.
Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77–85. doi:10.​1097/​QAI.​0b013e31828ace69​.PubMedCrossRef
138.
Eron JJ, Young B, Cooper DA, Youle M, Dejesus E, Andrade-Villanueva J, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet. 2010;375(9712):396–407. doi:10.​1016/​S0140-6736(09)62041-9.PubMedCrossRef
139.
MacInnes A, Lazzarin A, Di Perri G, Sierra-Madero JG, Aberg J, Heera J, et al. Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial. HIV Clin Trials. 2011;12(1):24–36. doi:10.​1310/​hct1201-24.PubMedCrossRef
140.
Ucciferri C, Falasca K, Vignale F, Di Nicola M, Pizzigallo E, Vecchiet J. Improved metabolic profile after switch to darunavir/ritonavir in HIV positive patients previously on protease inhibitor therapy. J Med Virol. 2013;85(5):755–9. doi:10.​1002/​jmv.​23543.PubMedCrossRef
141.
142.
143.
Edgeworth A, Treacy MP, Hurst TP. Thiazolidinediones in the treatment of HIV/HAART-associated lipodystrophy syndrome. AIDS Rev. 2013;15(3):171–80.PubMed
144.
145.
Slama L, Lanoy E, Valantin MA, Bastard JP, Chermak A, Boutekatjirt A, et al. Effect of pioglitazone on HIV-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (ANRS 113). Antivir Ther. 2008;13(1):67–76.PubMed
146.
Nagy GS, Tsiodras S, Martin LD, Avihingsanon A, Gavrila A, Hsu WC, et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;36(6):795–802. doi:10.​1086/​367859.CrossRef
147.
148.
Lee JH, Chan JL, Sourlas E, Raptopoulos V, Mantzoros CS. Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. J Clin Endocrinol Metab. 2006;91(7):2605–11. doi:10.​1210/​jc.​2005-1545.PubMedCrossRef
149.
Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW, et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab. 2009;94(4):1137–44. doi:10.​1210/​jc.​2008-1588.PubMedPubMedCentralCrossRef
150.
Havlir DV, Bassett R, Levitan D, Gilbert P, Tebas P, Collier AC, et al. Prevalence and predictive value of intermittent viremia with combination hiv therapy. JAMA. 2001;286(2):171–9 (pii: joc01773).PubMedCrossRef
151.
152.
Armah KA, McGinnis K, Baker J, Gibert C, Butt AA, Bryant KJ, et al. HIV status, burden of comorbid disease, and biomarkers of inflammation, altered coagulation, and monocyte activation. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012;55(1):126–36. doi:10.​1093/​cid/​cis406.CrossRef
153.
154.
Ostrowski SR, Katzenstein TL, Pedersen BK, Gerstoft J, Ullum H. Residual viraemia in HIV-1-infected patients with plasma viral load <or=20 copies/ml is associated with increased blood levels of soluble immune activation markers. Scand J Immunol. 2008;68(6):652–60. doi:10.​1111/​j.​1365-3083.​2008.​02184.​x.PubMedCrossRef
155.
Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010;7(8). doi:10.​1371/​journal.​pmed.​1000321.
156.
Hatano H, Hayes TL, Dahl V, Sinclair E, Lee TH, Hoh R, et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis. 2011;203(7):960–8. doi:10.​1093/​infdis/​jiq138.PubMedPubMedCentralCrossRef
157.
158.
Dahl V, Lee E, Peterson J, Spudich SS, Leppla I, Sinclair E, et al. Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis. 2011;204(12):1936–45. doi:10.​1093/​infdis/​jir667.PubMedPubMedCentralCrossRef
159.
Llibre JM, Buzon MJ, Massanella M, Esteve A, Dahl V, Puertas MC, et al. Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study. Antivir Ther. 2012;17(2):355–64. doi:10.​3851/​IMP1917.PubMedCrossRef
160.
Vallejo A, Gutierrez C, Hernandez-Novoa B, Diaz L, Madrid N, Abad-Fernandez M, et al. The effect of intensification with raltegravir on the HIV-1 reservoir of latently infected memory CD4 T cells in suppressed patients. AIDS. 2012;26(15):1885–94. doi:10.​1097/​QAD.​0b013e3283584521​.PubMedCrossRef
161.
Byakwaga H, Kelly M, Purcell DF, French MA, Amin J, Lewin SR, et al. Intensification of antiretroviral therapy with raltegravir or addition of hyperimmune bovine colostrum in HIV-infected patients with suboptimal CD4+ T-cell response: a randomized controlled trial. J Infect Dis. 2011;204(10):1532–40. doi:10.​1093/​infdis/​jir559.PubMedCrossRef
162.
163.
Hatano H, Strain MC, Scherzer R, Bacchetti P, Wentworth D, Hoh R, et al. Increase in 2-LTR circles and decrease in D-dimer after raltegravir intensification in treated HIV-infected patients: a randomized, Placebo-Controlled Trial. J Infect Dis. 2013. doi:10.​1093/​infdis/​jit453.
164.
Massanella M, Negredo E, Puig J, Puertas MC, Buzon MJ, Perez-Alvarez N, et al. Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV-infected HAART-suppressed individuals with poor CD4 T-cell recovery. AIDS. 2012;26(18):2285–93. doi:10.​1097/​QAD.​0b013e328359f20f​.PubMedCrossRef
165.
Buzon MJ, Massanella M, Llibre JM, Esteve A, Dahl V, Puertas MC, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16(4):460–5. doi:10.​1038/​nm.​2111.PubMedCrossRef
166.
Cuzin L, Trabelsi S, Delobel P, Barbuat C, Reynes J, Allavena C, et al. Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with poor immune restoration: MARIMUNO-ANRS 145 study. J Acquir Immune Defic Syndr. 2012;61(5):557–64. doi:10.​1097/​QAI.​0b013e318273015f​.PubMedCrossRef
167.
Wilkin TJ, Lalama CM, McKinnon J, Gandhi RT, Lin N, Landay A, et al. A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4(+) T-cell recovery despite sustained virologic suppression: ACTG A5256. J Infect Dis. 2012;206(4):534–42. doi:10.​1093/​infdis/​jis376.PubMedPubMedCentralCrossRef
168.
169.
170.
171.
172.
Chew KW, Hua L, Bhattacharya D, Butt AA, Bornfleth L, Chung RT, et al. The effect of hepatitis C virologic clearance on cardiovascular disease biomarkers in human immunodeficiency virus/hepatitis C virus coinfection. Open Forum Infect Dis. 2014;1(3):ofu104. doi:10.​1093/​ofid/​ofu104.PubMedPubMedCentralCrossRef
173.
Berenguer J, Alvarez-Pellicer J, Martin PM, Lopez-Aldeguer J, Von-Wichmann MA, Quereda C, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology. 2009;50(2):407–13. doi:10.​1002/​hep.​23020.PubMedCrossRef
174.
Berenguer J, Rodriguez E, Miralles P, Von Wichmann MA, Lopez-Aldeguer J, Mallolas J, et al. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012;55(5):728–36. doi:10.​1093/​cid/​cis500.CrossRef
175.
Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, Stephan C, et al. Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study. Lancet. 2015;385(9973):1098–106. doi:10.​1016/​S0140-6736(14)62483-1.PubMedCrossRef
176.
177.
178.
179.
180.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–78. doi:10.​1016/​S0140-6736(05)67394-1.PubMedCrossRef
181.
182.
Funderburg NT, Jiang Y, Debanne SM, Storer N, Labbato D, Clagett B, et al. Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013. doi:10.​1093/​cid/​cit748.
183.
Funderburg NT, Jiang Y, Debanne SM, Labbato D, Juchnowski S, Ferrari B, et al. Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;68(4):396–404. doi:10.​1097/​QAI.​0000000000000478​.PubMedCrossRef
184.
Aslangul E, Fellahi S, Assoumou LK, Bastard JP, Capeau J, Costagliola D. High-sensitivity C-reactive protein levels fall during statin therapy in HIV-infected patients receiving ritonavir-boosted protease inhibitors. AIDS. 2011;25(8):1128–31. doi:10.​1097/​QAD.​0b013e328346be29​.PubMedCrossRef
185.
186.
Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015;2(2):e52–63.PubMedCrossRef
187.
188.
189.
190.
Savarino A, Gennero L, Sperber K, Boelaert JR. The anti-HIV-1 activity of chloroquine. J Clin Virol. 2001;20(3):131–5 (pii: S1386-6532(00)00139-6).PubMedCrossRef
191.
Sperber K, Chiang G, Chen H, Ross W, Chusid E, Gonchar M, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1. Clin Ther. 1997;19(5):913–23 (pii: S0149-2918(97)80045-8).PubMedCrossRef
192.
Piconi S, Parisotto S, Rizzardini G, Passerini S, Terzi R, Argenteri B, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood. 2011;118(12):3263–72. doi:10.​1182/​blood-2011-01-329060.PubMedCrossRef
193.
Routy JP, Angel JB, Patel M, Kanagaratham C, Radzioch D, Kema I, et al. Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy. HIV Med. 2015;16(1):48–56. doi:10.​1111/​hiv.​12171.PubMedCrossRef
194.
Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–60. doi:10.​1016/​S0140-6736(09)60503-1.PubMedCrossRef
195.
196.
Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol. 2002;23(3):144–50 (pii: S1471490601021548).PubMedCrossRef
197.
Pettersen FO, Torheim EA, Dahm AE, Aaberge IS, Lind A, Holm M, et al. An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J Virol. 2011;85(13):6557–66. doi:10.​1128/​JVI.​00073-11.PubMedPubMedCentralCrossRef
198.
199.
200.
McComsey GA, Whalen CC, Mawhorter SD, Asaad R, Valdez H, Patki AH, et al. Placebo-controlled trial of prednisone in advanced HIV-1 infection. AIDS. 2001;15(3):321–7.PubMedCrossRef
201.
Wallis RS, Kalayjian R, Jacobson JM, Fox L, Purdue L, Shikuma CM, et al. A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm(-3). J Acquir Immune Defic Syndr. 2003;32(3):281–6.PubMedCrossRef
202.
203.
Miller KD, Masur H, Jones EC, Joe GO, Rick ME, Kelly GG, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med. 2002;137(1):17–25.PubMedCrossRef
204.
Cassol E, Malfeld S, Mahasha P, van der Merwe S, Cassol S, Seebregts C, et al. Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy. J Infect Dis. 2010;202(5):723–33. doi:10.​1086/​655229.PubMedCrossRef
205.
Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis. 2009;199(8):1177–85. doi:10.​1086/​597476.PubMedPubMedCentralCrossRef
206.
Martin DM, Boys CW, Ruf W. Tissue factor: molecular recognition and cofactor function. FASEB J. 1995;9(10):852–9.PubMed
207.
Roberfroid M. Prebiotics: the concept revisited. J Nutr. 2007;137(3 Suppl 2):830S–7S (pii: 137/3/830S).PubMed
208.
209.
Gori A, Rizzardini G, Van’t Land B, Amor KB, van Schaik J, Torti C, et al. Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the “COPA” pilot randomized trial. Mucosal Immunol. 2011;4(5):554–63. doi:10.​1038/​mi.​2011.​15.PubMedPubMedCentralCrossRef
210.
Villar-Garcia J, Hernandez JJ, Guerri-Fernandez R, Gonzalez A, Lerma E, Guelar A, et al. Effect of probiotics (Saccharomyces boulardii) on microbial translocation and inflammation in HIV-treated patients: a double-blind, randomized, placebo-controlled trial. J Acquir Immune Defic Syndr. 2015;68(3):256–63. doi:10.​1097/​QAI.​0000000000000468​.PubMedCrossRef
211.
212.
213.
Plettenberg A, Stoehr A, Stellbrink HJ, Albrecht H, Meigel W. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clin Investig. 1993;71(1):42–5.PubMedCrossRef
214.
Rump JA, Arndt R, Arnold A, Bendick C, Dichtelmuller H, Franke M, et al. Treatment of diarrhoea in human immunodeficiency virus-infected patients with immunoglobulins from bovine colostrum. Clin Investig. 1992;70(7):588–94.PubMedCrossRef
215.
216.
Festi D, Mazzella G, Orsini M, Sottili S, Sangermano A, Li Bassi S, et al. Rifaximin in the treatment of chronic hepatic encephalopathy; results of a multicenter study of efficacy and safety. Curr Ther Res. 1993;54(5):598–609.CrossRef
217.
218.
Tenorio AR, Chan ES, Bosch RJ, Macatangay BJ, Read SW, Yesmin S, et al. Rifaximin has a marginal impact on microbial translocation, T-cell activation and inflammation in HIV-positive immune non-responders to antiretroviral therapy—ACTG A5286. J Infect Dis. 2015;211(5):780–90. doi:10.​1093/​infdis/​jiu515.PubMedPubMedCentralCrossRef
219.
220.
Stinghen AE, Goncalves SM, Bucharles S, Branco FS, Gruber B, Hauser AB, et al. Sevelamer decreases systemic inflammation in parallel to a reduction in endotoxemia. Blood Purif. 2010;29(4):352–6. doi:10.​1159/​000302723.PubMedCrossRef
221.
Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Donate-Correa J, Cazana-Perez V, Garcia-Perez J. Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. Clin J Am Soc Nephrol. 2011;6(9):2272–9. doi:10.​2215/​CJN.​01650211.
222.
223.
Sandler NG, Zhang X, Bosch RJ, Funderburg NT, Choi AI, Robinson JK, et al. Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection. J Infect Dis. 2014;210(10):1549–54. doi:10.​1093/​infdis/​jiu305.PubMedPubMedCentralCrossRef
224.
225.
Moeser AJ, Nighot PK, Engelke KJ, Ueno R, Blikslager AT. Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol. 2007;292(2):G647–56. doi:10.​1152/​ajpgi.​00183.​2006.PubMedCrossRef
226.
227.
228.
Sereti I, Anthony KB, Martinez-Wilson H, Lempicki R, Adelsberger J, Metcalf JA, et al. IL-2-induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation. Blood. 2004;104(3):775–80. doi:10.​1182/​blood-2003-12-4355.PubMedCrossRef
229.
230.
231.
232.
Levy Y, Sereti I, Tambussi G, Routy JP, Lelievre JD, Delfraissy JF, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012;55(2):291–300. doi:10.​1093/​cid/​cis383.CrossRef
233.
234.
Tabb B, Morcock DR, Trubey CM, Quinones OA, Hao XP, Smedley J, et al. Reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti-tumor necrosis factor treatment during primary simian immunodeficiency virus infection. J Infect Dis. 2013;207(6):880–92. doi:10.​1093/​infdis/​jis643.PubMedPubMedCentralCrossRef
235.
Solovic I, Sester M, Gomez-Reino JJ, Rieder HL, Ehlers S, Milburn HJ, et al. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J. 2010;36(5):1185–206. doi:10.​1183/​09031936.​00028510.PubMedCrossRef
236.
237.
238.
Estes JD, Reilly C, Trubey CM, Fletcher CV, Cory TJ, Piatak M Jr, et al. Antifibrotic therapy in simian immunodeficiency virus infection preserves CD4+ T-cell populations and improves immune reconstitution with antiretroviral therapy. J Infect Dis. 2015;211(5):744–54. doi:10.​1093/​infdis/​jiu519.PubMedPubMedCentralCrossRef
239.
Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52(1):11–34.PubMed
240.
241.
Metadata
Title
Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection
Authors
Denise C. Hsu
Irini Sereti
Publication date
01-04-2016
Publisher
Springer International Publishing
Published in
Drugs / Issue 5/2016
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-016-0546-7

Other articles of this Issue 5/2016

Drugs 5/2016 Go to the issue

AdisInsight Report

Elbasvir/Grazoprevir: First Global Approval

Review Article

Review of Eravacycline, a Novel Fluorocycline Antibacterial Agent

Adis Drug Evaluation

Cobimetinib Plus Vemurafenib: A Review in BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma

Therapy in Practice

The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions

Current Opinion

Two-Drug Treatment Approaches in HIV: Finally Getting Somewhere?

Letter to the Editor

Comment on: “Therapies to Preserve β-Cell Function in Type 1 Diabetes”