Indian Journal of Sexually Transmitted Diseases and AIDS
REVIEW ARTICLE
Year
: 2016  |  Volume : 37  |  Issue : 2  |  Page : 123--128

Role of high-sensitivity C-reactive protein measurements in HIV patients


Arun Vishwanath, Saif Quaiser, Ruhi Khan 
 Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Correspondence Address:
Ruhi Khan
Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh - 202 002, Uttar Pradesh
India

Abstract

As we herald into the 21st century, the quality of life and the repertoire of highly active antiretroviral therapy (HAART) have considerably improved. However, considerable work is still needed to educate the population about primary and secondary prevention modalities. Moreover, regular monitoring of immune response with patients on HAART with conventional biomarkers is still a problem in low resource settings which needs to be addressed. We aim to review high-sensitivity C-reactive protein as a potential biomarker in this regard.



How to cite this article:
Vishwanath A, Quaiser S, Khan R. Role of high-sensitivity C-reactive protein measurements in HIV patients.Indian J Sex Transm Dis 2016;37:123-128


How to cite this URL:
Vishwanath A, Quaiser S, Khan R. Role of high-sensitivity C-reactive protein measurements in HIV patients. Indian J Sex Transm Dis [serial online] 2016 [cited 2017 Mar 28 ];37:123-128
Available from: http://www.ijstd.org/text.asp?2016/37/2/123/192127


Full Text

 Introduction



Over the past two decades with the advent of highly active antiretroviral therapy (HAART), there is a substantial increase in the life span of HIV patients. Hence, the focus has now shifted to managing long-term complication of HIV infection and improving the quality of life of HIV patients, especially in developed nations. On the other hand, in developing nations, the ever-growing incidence of HIV infection has placed a huge burden on their frail economy, so there is a growing need for simplifying HIV treatment protocols and for having cheaper alternatives for monitoring disease activity.

High-sensitivity C-reactive protein (hsCRP) has been touted as a potential solution for both these problems. First, hsCRP is considered to be a potential biomarker for predicting long-term disease progression and cardiovascular disease (CVD) risk, which is one of the major long-term complications in HIV patients. Second, it is also considered to be a marker for predicting mortality and as a tool for routine monitoring of disease activity with a potential to replace traditional costlier measures such as CD4 count and HIV RNA load. This review highlights the results of some promising studies conducted till now in this regard.

 C-Reactive Protein – An Inflammatory Biomarker



CRP was first identified by Tillett and Francis in 1930 as a substance in the serum of patients with acute inflammation that reacted with the C-polysaccharide of pneumococcus (hence the name).[1] Later, it was found to be an acute phase reactant with a pentameric structure that remains stable for a sufficiently long time, allowing measurements of 1000s of stored serum samples.[2] Most CRP is produced from liver apart from vascular endothelium in response to interleukin-6 produced from macrophages and adipocytes.[3],[4] Traditional CRP assays have been available for decades, but these assays are not sensitive at a lower concentration of CRP. However, with the advent of newer hsCRP assays such as ELISA, immunoturbidimetric assay, and laser nephelometry, it is now possible to detect low range differences in CRP levels and has thus become the main focus of research in vascular inflammation.

 High-Sensitivity C-Reactive Protein-Marker of HIV Disease Progression



Immune activation has been demonstrated to be a significant contributor to HIV disease progression in multiple studies.[5],[6],[7],[8] It was observed that this immune activation was associated with increased levels of bacterial components in blood, which was hypothesized to be due to increased microbial translocation from the gastrointestinal tract of patients and this microbial translocation was hypothesized to contribute for HIV disease progression.[9],[10] Naturally, CRP being an acute phase reactant should increase in patients with HIV disease progression if it is associated with microbial translocation and immune activation as hypothesized in these studies.[3],[11],[12],[13] This theory was tested by Andrew et al. in Rakai, Uganda [14] in a longitudinal study, where study population was divided into three population – long-term nonprogressor (i.e., CD4 >600 cells/µl at >7 years after seroconversion), standard progressors (i.e., death >5 but <9 years after seroconversion), and rapid progressors (i.e., death within 4 years after seroconversion). The results of this study concluded that there is a significant association of immune activation as measured by hsCRP levels with HIV disease progression. However, there was no association of CRP levels with markers of microbial translocation (namely lipopolysaccharide [LPS], endotoxin antibody, LPS-binding protein, and soluble CD14) thus disproving the hypothesis that microbial translocation is responsible for immune activation associated with HIV disease progression.

 High-Sensitivity C-Reactive Protein- predictor of HIV-Related Outcomes



Higher CRP concentrations have been associated with lower CD4 counts and higher HIV viral RNA load among HIV-infected individuals.[11] Results from studies evaluating serum CRP as a predictor of HIV-related mortality yielded mixed results in resource-rich settings. Some studies have reported significant associations between increased CRP concentration and faster progression to AIDS and greater risk of mortality but did not use clinically established CRP cutoff concentration.[11],[13],[15] Some studies found that a clinically elevated CRP concentration was associated with significantly reduced mortality risk.[16]

Drain et al. studied CRP levels as a marker of maternal disease progression and child mortality in HIV-infected mothers from Tanzania.[17] They found out that high CRP concentration was better than either low CD4 count <200/µl and high viral load ≥50,000 copies/ml for predicting maternal disease progression to AIDS. While CRP was not better than CD4 count or viral load in predicting maternal mortality outcomes, they remained a very strong and almost comparable predictor. These findings could be supported by the fact that the HIV patients are prone to opportunistic infection (mostly bacterial). More the infection, higher will be their CRP level (as it is an acute phase reactant) and higher is their chances of progression to AIDS. The exception to this argument is that when the CD4 count is very low (<50), it was found that the ability to mount a CRP response to pneumocystis pneumonia infection is substantially small,[18] while there is a significant risk of death despite low levels of CRP. The second finding that supports the results of this study is that HIV infection is regarded as a generalized inflammatory state that leads to depletion of vitamins and minerals. Deficiencies of vitamins and minerals have been found to be associated with disease progression and mortality among HIV-positive patients.[19],[20],[21] Moreover, high CRP levels were found to be associated with depleted stores of vitamins and minerals among HIV-positive [19],[22] and HIV-negative [23],[24],[25],[26] adults. This indirectly supports the finding that high CRP was associated with greater risk of disease progression and mortality.

In addition, Drain et al. also found that high maternal CRP was a better marker than viral load in predicting child mortality <2 years of age independent of maternal anthropometric measurements, CD4 count, viral RNA load, and breastfeeding status at the time of CRP measurement. This finding was supported by the fact that high maternal CRP may be a marker or cause of disease progression in mother, leading to deficient transfer of passive immunity, and nutrients to the child making them prone for infection and subsequent higher risk of mortality.[27],[28] Poor caring practice due to maternal morbidity or death is also a plausible social explanation for poor child outcomes.

 High-Sensitivity C-Reactive Protein as A Cardiovascular Disease Risk Predictor in HIV Patients



HIV-infected patients are at higher risk of CVD than uninfected general population.[29],[30] This is believed to be due to modification of traditional CVD risk factors [31] and pathogenic pathways of atherosclerosis and CVD [29],[32],[33],[34],[35],[36] by HIV infection and cART (combination ART). A study by De Luca et al. found a significant association between elevated hsCRP and CVD risk in HIV-positive patients receiving cART. There was 8-fold increase in CVD risk in patients with CRP levels >3.3 mg/L than those with <0.9 mg/L. A key finding of this study was that the effect of CRP on CVD risk was independent of traditional risk factors (like deranged lipid profile) and potential confounders (such as BMI, renal function, and use of statins). There was a strong but crude association of this marker with short-term CVD risk, but it was found to be a useful marker to predict the medium to long-term risk of experiencing CVD events. This study also identified 3.3 mg/ L as a potential threshold associated with significant risk of CVD in HIV-infected patients.[37] However, in disagreement with these findings, Ford et al. showed no association between hsCRP and CVD events in treated HIV patients.[38] While hsCRP was found to be elevated in patients with low risk of CVD events in a study by Boger et al.[39]

 Change in High-Sensitivity C-Reactive Protein Levels with Assisted Reproductive Technologies



Several studies have suggested a positive association between assisted reproductive technologies (ART) and CVD risk.[29],[40],[41] Theoretically hsCRP being a marker of CVD risk should increase with ART. On the contrary, there is also evidence that ART may improve endothelial function and protect against atherosclerosis thereby reducing CVD risk.[42],[43] Considering these associations, the impact of ARV therapy on CRP levels is of significant interest. In the ACTG 5056s study, with the introduction of indinavir CRP levels remained stable or decreased slightly over an average of 42 months.[44] A similar slight decline was seen in the HEAT study over 96 weeks following initiation of lopinavir/ritonavir.[45] Both these findings were noted only in men. In a study by Shikuma et al., a durably suppressive therapy with efavirenz did not improve hsCRP levels over a 96 week period but was associated with significantly increased levels of CRP in women and slight statistically nonsignificant increase in men. This study also showed that randomization to abacavir had no significant effect on changes in CRP levels.[46]

 C-Reactive Protein Levels in HIV/Hepatitis C Virus Coinfection



Both HIV and hepatitis C virus (HCV) being a chronic infection, activates immune system and results in proinflammatory state.[47],[48],[49],[50],[51] CRP being a marker of immune activation should increase in both the infection. However, very few studies are available in this regard. Reingold et al. reported that HIV/HCV coinfection was associated with a 50% lower adjusted CRP levels when compared with HIV-monoinfected men and women. It was proposed that HCV infection decreases CRP production from the liver.[52] This concept is supported by in vitro studies of expression of HCV proteins in cultured hepatocytes, which causes inhibition of secretion of other liver proteins like apoB-100.[53]

 Cost-Effectiveness and Feasibility of High-Sensitivity C-Reactive Protein Assay



hsCRP assays include ELISA, immunoturbidimetric assay, and laser nephelometry methods. Apart from the laser nephelometry method, the other two assays are cheaper and easy to perform, with nearly same sensitivity as laser nephelometry. In the Indian market, cd4 estimation costs around 1000 Rs. per sample, while hsCRP estimation costs around 300 Rs. per sample. As shown in the study by Drain et al., internationally cd4 count and HIV viral load estimation cost approximately US$10 and US$40, respectively, while hsCRP by immunoturbidimetry method costs around US$2 per sample. Thus, it is approximately one-fifth the cost of a CD4 cell count and one-twentieth the cost of an HIV viral load.[17]

Regarding feasibility, HIV diagnosis is initially made by ELISA method. hsCRP measurement can be made using the same method, thus requiring the same equipment and workforce. Immunoturbidimetry employs the same technique as that of commonly used latex agglutination method.[54],[55]

 Conclusion



From the studies conducted till date it can be safely concluded that hsCRP is an excellent predictor of CVD risk in HIV patients. The importance of evaluating, preventing, and managing CVD in patients with HIV is recognized in guidelines for the use of antiretroviral agents in HIV-infected adults.[56] Because hsCRP is cheap to measure and easily available, it may become a clinically useful tool to monitor CVD risk in HIV-positive patients. However, additional studies are required to analyze the influence of the addition of this marker to the cardiovascular risk scores before implementing routine measurement of hsCRP.

In a large international study, the baseline levels of CRP were independently associated with CVD events, including myocardial infarction, stroke, coronary revascularization, congestive heart failure, CVD death, and peripheral artery disease.[57] Hence, we propose that hsCRP should be measured in all HIV patients at greatest risk of cardiovascular morbidity and at least 6 monthly thereafter or at least as frequent as CD4 counts to monitor patients CVD risk profile.

hsCRP in HIV-infected patients is associated with traditional cardiovascular risk factors, principally in HAART-treated patients. hsCRP levels are not associated with CD4 cell counts and HIV-viral load and may constitute a marker for cardiovascular risk related to HIV infection and HAART;[58] therefore the additional cost of doing a hsCRP assay in all newly detected patients would be justifiable.

For a marker of risk to be valid, it must have:

A plausible biological mechanismApplicability to both gendersAbility to enhance our current risk estimationApplicability to populations in various geographic localities.

In case of hsCRP, not only all these criteria are met but the risk factor can also be modified.[2]

hsCRP is also a reliable marker of disease progression and a cheaper alternative for routine disease monitoring and predicting HIV-related outcomes, especially in a resource-poor setting. Further studies are required to understand the changes in hsCRP levels after HAART therapy and in HIV/HCV coinfection as the currently available data are either contradictory or insufficient.[SUPPORTING:1]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1930;52:561-71.
2Deron SJ. C-reactive protein: An inflammatory biomarker in clinical practice. J Lanc Gen Hosp 2007;2:63-8.
3Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111:1805-12.
4Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: Molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol 2005;288:H2031-41.
5Bentwich Z, Kalinkovich A, Weisman Z. Immune activation is a dominant factor in the pathogenesis of African AIDS. Immunol Today 1995;16:187-91.
6Rizzardini G, Piconi S, Ruzzante S, Fusi ML, Lukwiya M, Declich S, et al. Immunological activation markers in the serum of African and European HIV-seropositive and seronegative individuals. AIDS 1996;10:1535-42.
7McCune JM. The dynamics of CD4+T-cell depletion in HIV disease. Nature 2001;410:974-9.
8Douek DC. Disrupting T-cell homeostasis: How HIV-1 infection causes disease. AIDS Rev 2003;5:172-7.
9Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365-71.
10Brenchley JM, Price DA, Douek DC. HIV disease: Fallout from a mucosal catastrophe? Nat Immunol 2006;7:235-9.
11Lau B, Sharrett AR, Kingsley LA, Post W, Palella FJ, Visscher B, et al. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med 2006;166:64-70.
12Zulu I, Hassan G, Njobvu RN, Dhaliwal W, Sianongo S, Kelly P. Cytokine activation is predictive of mortality in Zambian patients with AIDS-related diarrhoea. BMC Infect Dis 2008;8:156.
13Melchior JC, Niyongabo T, Henzel D, Durack-Bown I, Henri SC, Boulier A. Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV-infected patients. Nutrition 1999;15:865-9.
14Redd AD, Eaton KP, Kong X, Laeyendecker O, Lutalo T, Wawer MJ, et al. C-reactive protein levels increase during HIV-1 disease progression in Rakai, Uganda, despite the absence of microbial translocation. J Acquir Immune Defic Syndr 2010;54:556-9.
15Feldman JG, Goldwasser P, Holman S, DeHovitz J, Minkoff H. C-reactive protein is an independent predictor of mortality in women with HIV-1 infection. J Acquir Immune Defic Syndr 2003;32:210-4.
16Grützmeier S, Sandström E. C-reactive protein levels in HIV complicated by opportunistic infections and infections with common bacterial pathogens. Scand J Infect Dis 1999;31:229-34.
17Drain PK, Kupka R, Msamanga GI, Urassa W, Mugusi F, Fawzi WW. C-reactive protein independently predicts HIV-related outcomes among women and children in a resource-poor setting. AIDS 2007;21:2067-75.
18Storgaard M, Laursen AL, Andersen PL. The C-reactive protein responses in HIV-infected patients with pneumonia. Scand J Infect Dis 1993;25:305-9.
19Look MP, Rockstroh JK, Rao GS, Kreuzer KA, Spengler U, Sauerbruch T. Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection. Biol Trace Elem Res 1997;56:31-41.
20Semba RD, Tang AM. Micronutrients and the pathogenesis of human immunodeficiency virus infection. Br J Nutr 1999;81:181-9.
21Kupka R, Fawzi W. Zinc nutrition and HIV infection. Nutr Rev 2002;60:69-79.
22Baeten JM, McClelland RS, Richardson BA, Bankson DD, Lavreys L, Wener MH, et al. Vitamin A deficiency and the acute phase response among HIV-1-infected and-uninfected women in Kenya. J Acquir Immune Defic Syndr 2002;31:243-9.
23Ford ES, Liu S, Mannino DM, Giles WH, Smith SJ. C-reactive protein concentration and concentrations of blood vitamins, carotenoids, and selenium among United States adults. Eur J Clin Nutr 2003;57:1157-63.
24Maehira F, Luyo GA, Miyagi I, Oshiro M, Yamane N, Kuba M, et al. Alterations of serum selenium concentrations in the acute phase of pathological conditions. Clin Chim Acta 2002;316:137-46.
25Ghayour-Mobarhan M, Taylor A, New SA, Lamb DJ, Ferns GA. Determinants of serum copper, zinc and selenium in healthy subjects. Ann Clin Biochem 2005;42(Pt 5):364-75.
26Koyanagi A, Kuffó D, Gresely L, Shenkin A, Cuevas LE. Relationships between serum concentrations of C-reactive protein and micronutrients, in patients with tuberculosis. Ann Trop Med Parasitol 2004;98:391-9.
27Pitt J, Henrard D, FitzGerald G, Mofenson L, Lew J, Hillyer G, et al. Human immunodeficiency virus (HIV) type 1 antibodies in perinatal HIV-1 infection: Association with human HIV-1 transmission, infection, and disease progression. For the Women and Infants Transmission Study. J Infect Dis 2000;182:1243-6.
28Fawzi WW, Msamanga GI, Wei R, Spiegelman D, Antelman G, Villamor E, et al. Effect of providing vitamin supplements to human immunodeficiency virus-infected, lactating mothers on the child's morbidity and CD4+ cell counts. Clin Infect Dis 2003;36:1053-62.
29Currier JS, Lundgren JD, Carr A, Klein D, Sabin CA, Sax PE, et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008;118:e29-35.
30Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 2007;92:2506-12.
31Law MG, Friis-Møller N, El-Sadr WM, Weber R, Reiss P, D'Arminio Monforte A, et al. The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: Comparison with observed events in the D: A: D Study. HIV Med 2006;7:218-30.
32Maggi P, Quirino T, Ricci E, De Socio GV, Gadaleta A, Ingrassia F, et al. Cardiovascular risk assessment in antiretroviral-naïve HIV patients. AIDS Patient Care STDS 2009;23:809-13.
33Teitel JM, Shore A, Read SE, Schiavone A. Immune function of vascular endothelial cells is impaired by HIV. J Infect Dis 1989;160:551-2.
34Zietz C, Hotz B, Stürzl M, Rauch E, Penning R, Löhrs U. Aortic endothelium in HIV-1 infection: Chronic injury, activation, and increased leukocyte adherence. Am J Pathol 1996;149:1887-98.
35de Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: Current perspectives. Lancet Infect Dis 2004;4:213-22.
36de Gaetano Donati K, Rabagliati R, Tumbarello M, Tacconelli E, Amore C, Cauda R, et al. Increased soluble markers of endothelial dysfunction in HIV-positive patients under highly active antiretroviral therapy. AIDS 2003;17:765-8.
37De Luca A, de Gaetano Donati K, Colafigli M, Cozzi-Lepri A, De Curtis A, Gori A, et al. The association of high-sensitivity c-reactive protein and other biomarkers with cardiovascular disease in patients treated for HIV: A nested case-control study. BMC Infect Dis 2013;13:414.
38Ford ES, Greenwald JH, Richterman AG, Rupert A, Dutcher L, Badralmaa Y, et al. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS 2010;24:1509-17.
39Boger MS, Shintani A, Redhage LA, Mitchell V, Haas DW, Morrow JD, et al. Highly sensitive C-reactive protein, body mass index, and serum lipids in HIV-infected persons receiving antiretroviral therapy: A longitudinal study. J Acquir Immune Defic Syndr 2009;52:480-7.
40Currier JS, Taylor A, Boyd F, Dezii CM, Kawabata H, Burtcel B, et al. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 2003;33:506-12.
41Bergersen BM. Cardiovascular risk in patients with HIV Infection: Impact of antiretroviral therapy. Drugs 2006;66:1971-87.
42Wolf K, Tsakiris DA, Weber R, Erb P, Battegay M; Swiss HIV Cohort Study. Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. J Infect Dis 2002;185:456-62.
43Torriani FJ, Komarow L, Parker RA, Cotter BR, Currier JS, Dubé MP, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol 2008;52:569-76.
44Henry K, Kitch D, Dube M, Zackin R, Parker RA, Sprecher D, et al. C-Reactive protein levels over time and cardiovascular risk in HIV-infected individuals suppressed on an indinavir-based regimen: AIDS Clinical Trials Group 5056s. AIDS 2004;18:2434-7.
45McComsey GA, Smith KY, Patel P, Bellos NC, Sloan L, Lackey P, et al. Similar Reductions in Markers of Inflammation and Endothelial Activation after Initiation of Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) in the HEAT Study. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada; 2009.
46Shikuma CM, Ribaudo HJ, Zheng Y, Gulick RM, Meyer WA, Tashima KT, et al. Change in high-sensitivity c-reactive protein levels following initiation of efavirenz-based antiretroviral regimens in HIV-infected individuals. AIDS Res Hum Retroviruses 2011;27:461-8.
47Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124:654-63.
48Abbate I, Romano M, Longo R, Cappiello G, Lo Iacono O, Di Marco V, et al. Endogenous levels of mRNA for IFNs and IFN-related genes in hepatic biopsies of chronic HCV-infected and non-alcoholic steatohepatitis patients. J Med Virol 2003;70:581-7.
49Rimaniol AC, Zylberberg H, Zavala F, Viard JP. Inflammatory cytokines and inhibitors in HIV infection: Correlation between interleukin-1 receptor antagonist and weight loss. AIDS 1996;10:1349-56.
50Stephensen CB, Marquis GS, Douglas SD, Wilson CM. Immune activation and oxidative damage in HIV-positive and HIV-negative adolescents. J Acquir Immune Defic Syndr 2005;38:180-90.
51Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: Mechanisms and consequences to the host. J Lipid Res 2004;45:1169-96.
52Reingold J, Wanke C, Kotler D, Lewis C, Tracy R, Heymsfield S, et al. Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: The fat redistribution and metabolic change in HIV infection (FRAM) study. J Acquir Immune Defic Syndr 2008;48:142-8.
53Domitrovich AM, Felmlee DJ, Siddiqui A. Hepatitis C virus nonstructural proteins inhibit apolipoprotein B100 secretion. J Biol Chem 2005;280:39802-8.
54Passing H, Bablok W. A new biometrical procedure for testing the equality of measurements from two different analytical methods. Application of linear regression procedures for method comparison studies in clinical chemistry, Part I. J Clin Chem Clin Biochem 1983;21:709 20.
55Sonderdruck Aus BL. DG Clinical Chemistry Releases 1995;26:207-24.
56Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. [Last accessed on 2013 Jan 11; Last updated on 2012 Mar 27].
57Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012;7:e44454.
58Guimarães MM, Greco DB, Figueiredo SM, Fóscolo RB, Oliveira AR Jr., Machado LJ. High-sensitivity C-reactive protein levels in HIV-infected patients treated or not with antiretroviral drugs and their correlation with factors related to cardiovascular risk and HIV infection. Atherosclerosis 2008;201:434-9.