2001 status nutrisi tnf viral load

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Infection 29 · 2001 · No. 5 © URBAN & VOGEL 257 Nutritional Status Impairments in HIV-Infected Patients Are Associated with Increased TNF- and IL-6 Serum Levels but Not with Viral Load M.C.G. Galhardo, M.G.C. de Carvalho, I. Georg, M. Perez, M.G. Morgado, L.M.S. de Azevedo, E.P. Sampaio, E.N. Sarno Abstract Background: Cytokines may alter metabolic pathways and contribute to malnutrition among human immunodefiency virus (HIV)-positive individuals. Patients and Methods: Tumor necrosis factor- (TNF-), interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2R), 2 - microglobulin serum levels and plasma viral load of 45 HIV- positive patients were determined and correlated to nutritional status impairment. Patients were grouped by CD4 counts into categories I (< 200/μl), II (200–499/μl), III (500/μl). There were 15 healthy controls. A nutritional grading system, based on anthropometric and laboratory data, was devised. Scores ranged from 0 to 5 (eutrophic to malnutrition). Results: AIDS patients’ cytokines and immune marker levels were significantly higher than those of the controls, but not always higher than those of other categories. AIDS patients had higher nutritional deficit grades than category III (p < 0.05) or the controls (p < 0.02) which, except for viral load, correlated with the parameters studied. Conclusion: Nutritional status impairments in HIV-positive individuals were associated with immune activation but not with viral load. Key Words HIV · Tumor necrosis factor- · Interleukin-6 · Malnutrition · Viral load Infection 2001; 29: 257-261 DOI 10.1007/s15010-001-1074-1 Introduction HIV infection leads to an activation of the immune system and triggers immune responses to HIV and/or other pathogens.At the same time, however, certain components of this general state of immune activation, particularly cy- tokines, may be detrimental and contribute to HIV patho- genesis and disease progression [1]. The interaction between cytokines and nutritional status has been well documented. Cytokines may lead to an alter- ation of metabolic pathways and might thereby play a major role in malnutrition among HIV-positive individuals. Some studies have reported that the presence of IL-6 [2], IL-1 [3], and, of special relevance, elevated levels of TNF- [4] and sol- uble TNF receptors [5, 6] in the sera were associated with pa- rameters of malnutrition in these patients.Therapeutic inter- ventions to block the action of TNF- (with thalidomide) [7, 8] and IL-6 (along with the administration of anti-IL-6 mono- clonal antibody) [9] were able to revert the wasting syndrome. Malnutrition may, in fact, contribute to a hastening of death of AIDS patients and may shorten life expectancy, insofar as cause of death has been specifically related to the loss of lean body mass [10] regardless of the CD4 lymphocyte count [11, 12]. Although the amount of information available with re- spect to the enormous impact of malnutrition on HIV infec- tion has progressively increased throughout the past decade, the immune mechanisms involved in the impairment of nu- tritional status continue to require further study. The objec- tive of this study was to correlate immunological parameters to the viral load and the nutritional status impairments found in a group of 45 Brazilian HIV-positive individuals. Patients and Methods Patients 45 HIV-positive patients (27 male and 18 female, mean age 37.17 ± 6.58 years, range 25–50 years) from the Evandro Chagas Hospital were selected at random to participate in this cross-sec- Infection Clinical and Epidemiological Study M.C.G. Galhardo (corresponding author), M.G.C. de Carvalho, I. Georg Centro de Pesquisa Hospital Evandro Chagas, Fundação Oswaldo Cruz, Avenida Brasil 4365, Rio de Janeiro, 22045-900 Brazil; Fax: (+55/21) 5909988, e-mail: [email protected] M. Perez Departamento de Medicina Preventiva, Núcleo de Estudos em Saúde Coletiva Universidade Federal do Rio de Janeiro, Brazil Mariza G. Morgado Laboratório de AIDS & Imunologia Molecular-Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil Lúcia M.S. de Azevedo Serviço de Dermatologia, Hospital Universitário Clementino Fraga Filho/Universidade Federal do Rio de Janeiro, Brazil Elizabeth P. Sampaio, Euzenir N. Sarno Laboratório de Hanseníase-Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Brazil Received: June 27, 2000 • Revision accepted: June 30, 2001

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Page 1: 2001 Status Nutrisi Tnf Viral Load

Infection 29 · 2001 · No. 5 © URBAN & VOGEL 257

Nutritional Status Impairments in HIV-InfectedPatients Are Associated with Increased TNF-� and

IL-6 Serum Levels but Not with Viral LoadM.C.G. Galhardo, M.G.C. de Carvalho, I. Georg, M. Perez, M.G. Morgado, L.M.S. de Azevedo,

E.P. Sampaio, E.N. Sarno

AbstractBackground: Cytokines may alter metabolic pathways andcontribute to malnutrition among human immunodefiencyvirus (HIV)-positive individuals.Patients and Methods: Tumor necrosis factor-� (TNF-�),interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2R), �2-microglobulin serum levels and plasma viral load of 45 HIV-positive patients were determined and correlated tonutritional status impairment. Patients were grouped by CD4counts into categories I (< 200/µl), II (200–499/µl),III (≥ 500/µl). There were 15 healthy controls. A nutritionalgrading system, based on anthropometric and laboratorydata, was devised. Scores ranged from 0 to 5 (eutrophic tomalnutrition).Results: AIDS patients’ cytokines and immune marker levelswere significantly higher than those of the controls, but notalways higher than those of other categories. AIDS patientshad higher nutritional deficit grades than category III (p <0.05) or the controls (p < 0.02) which, except for viral load,correlated with the parameters studied.Conclusion: Nutritional status impairments in HIV-positiveindividuals were associated with immune activation but notwith viral load.

Key WordsHIV · Tumor necrosis factor-� · Interleukin-6 · Malnutrition ·Viral load

Infection 2001; 29: 257-261DOI 10.1007/s15010-001-1074-1

IntroductionHIV infection leads to an activation of the immune systemand triggers immune responses to HIV and/or otherpathogens.At the same time, however, certain componentsof this general state of immune activation, particularly cy-tokines, may be detrimental and contribute to HIV patho-genesis and disease progression [1].

The interaction between cytokines and nutritional statushas been well documented. Cytokines may lead to an alter-ation of metabolic pathways and might thereby play a major

role in malnutrition among HIV-positive individuals. Somestudies have reported that the presence of IL-6 [2], IL-1� [3],and,of special relevance,elevated levels of TNF-� [4] and sol-uble TNF receptors [5, 6] in the sera were associated with pa-rameters of malnutrition in these patients.Therapeutic inter-ventions to block the action of TNF-� (with thalidomide) [7,8] and IL-6 (along with the administration of anti-IL-6 mono-clonal antibody) [9] were able to revert the wasting syndrome.Malnutrition may, in fact, contribute to a hastening of deathof AIDS patients and may shorten life expectancy, insofar ascause of death has been specifically related to the loss of leanbody mass [10] regardless of the CD4 lymphocyte count [11,12]. Although the amount of information available with re-spect to the enormous impact of malnutrition on HIV infec-tion has progressively increased throughout the past decade,the immune mechanisms involved in the impairment of nu-tritional status continue to require further study. The objec-tive of this study was to correlate immunological parametersto the viral load and the nutritional status impairments foundin a group of 45 Brazilian HIV-positive individuals.

Patients and MethodsPatients

45 HIV-positive patients (27 male and 18 female, mean age37.17 ± 6.58 years, range 25–50 years) from the Evandro ChagasHospital were selected at random to participate in this cross-sec-

Infection Clinical and Epidemiological Study

M.C.G. Galhardo (corresponding author), M.G.C. de Carvalho, I. GeorgCentro de Pesquisa Hospital Evandro Chagas, Fundação Oswaldo Cruz,Avenida Brasil 4365, Rio de Janeiro, 22045-900 Brazil; Fax: (+55/21)5909988, e-mail: [email protected]. PerezDepartamento de Medicina Preventiva, Núcleo de Estudos em SaúdeColetiva Universidade Federal do Rio de Janeiro, BrazilMariza G. MorgadoLaboratório de AIDS & Imunologia Molecular-Instituto Oswaldo Cruz,Fundação Oswaldo Cruz, BrazilLúcia M.S. de AzevedoServiço de Dermatologia, Hospital Universitário Clementino FragaFilho/Universidade Federal do Rio de Janeiro, BrazilElizabeth P. Sampaio, Euzenir N. SarnoLaboratório de Hanseníase-Instituto Oswaldo Cruz, Fundação OswaldoCruz, Brazil

Received: June 27, 2000 • Revision accepted: June 30, 2001

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tional study subsequent to their informed consent. None were tak-ing glucorticoid, thalidomide, pentoxifylline, megestrol acetateand/or testosterone.The patients at different stages of disease wereclassified on the basis of CD4+ cell counts, as follows: < 200 /µl(category 1 [AIDS patients], n=15), 200–499/µl (category 2, n=15)and ≥ 500/µl (category 3, n=15). 31 (68%) patients were taking an-tiretroviral agents at the time; 15 were receiving two drugs (meantime 7.8 months, range 2–14 months), 15 were on triple drug ther-apy (mean time 6.3 months, range 1–10 months); and one was re-ceiving quadruple drug therapy (1 month). The drugs comprisedthe nucleoside reverse transcriptase inibitors (NRTI) zidovidine,didanosine and dideoxycytidine in addition to lamivudine and theprotease inhibitors (PI) saquinavir and ritonavir, used in a varietyof combinations. During the study, three patients had tuberculosisand one had an atypical mycobacterial infection.The control groupincluded 15 healthy individuals (eight males and seven females,mean age 35.4 ± 7.4 years, range 20–42 years).

Laboratory StudiesCommercial ELISAs were utilized to quantify TNF-� serum levels(Innogenetics N.V. Zwijndrecht, Belgium), IL-6 (R&D system, Inc.,Minneapolis, USA), sIL-2R (Immunotech, Coulter Company, Mar-seille, France) and �2-microglobulin (bioMérieux s.a, Marcy-l'E-toile, France). HIV-1 RNA was determined by quantitative nucleicacid sequence based amplification (Organon, Technika), with de-tection limits of > 400 copies/ml. CD4 lymphocyte counts were de-termined by four-color (CD45, CD3, CD4, CD8) standard flow cy-tometry. Serum concentration levels of albumin, transferrin and he-moglobin were measured using standard procedures to evaluate nu-tritional status.Anthropometric measurements were carried out byan experienced investigator and included height, body weight, mid-arm muscle circumference, triceps skin-fold thickness, body massindex (BMI) and percentage of weight loss in relation to each pa-tient’s normal weight over the previous 6-month period. Skin-foldthickness (mm) measurements were done three times with aHoltain calliper according to international standards.Mid-arm mus-cle circumference (cm) was calculated with the mid-upper arm cir-cumference (MAC) formula minus 3.14 � triceps skin-fold thick-

ness. BMI was calculated according to the height and weight of theindividual (subject’s weight kg/height [m2]) as an indicator of bodysize.Alterations in anthropometric measurements were determinedby the loss of ≥ 10% of body weight and decreases in mid-arm mus-cle circumference, triceps skin-fold thickness and BMI. All the pa-tients and the control group (60 in total) were then graded from 0to 5 on the nutritional status impairment scale devised specificallyfor this study. This scale was based on the number of altered an-thropometric measurements and/or combined laboratory data(serum concentration levels of albumin, transferrin, and hemoglo-bin) found for each individual, which, in turn, would correspond tohis/her nutritional status diagnosis: 0 = no alterations in either an-thropometric measurements or laboratory data (euthropic); 1 = de-pletion of fat reserves (lower triceps skin-fold thickness); 2 = de-pletion of protein reserve: a) a decrease in two proteins measuredin the blood; or b) lowered mid-arm muscle circumference togetherwith a decrease in at least one protein measured in the blood; 3 =depletion of fat-protein reserves (a combination of numbers 1 and2); 4 = depletion of fat-protein reserves: a) lowered triceps skin-foldthickness and a decrease in three proteins measured in the blood,or: b) lowered triceps skin-fold thickness plus lowered mid-armmuscle circumference together with a decrease in two proteins mea-sured in the blood; and 5 = malnutrition, as indicated by: a) a de-crease in three anthropometric measurements together with a de-crease in two of the proteins measured in the blood, or: b) a lower-ing of four anthropometric measurements in conjunction with alowering of one of the proteins measured in the blood.

StatisticsNonparametric tests (Mann Whitney, Kruskall Wallis, Spearmanrank correlation) and parametric tests (ANOVA, Pearson corre-lation) were used for statistical analyses.

ResultsThe immunologic and virologic profile means of the cate-gories and control group are shown in table 1. Category 1(AIDS patients) individuals presented high mean TNF-�

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258 Infection 29 · 2001 · No. 5 © URBAN & VOGEL

Category 1a Category 2 Category 3 Control groupCD4 < 200/µl CD4 200–499/µl CD4 ≥ 500/µl

(n = 15) (n = 15) (n = 15) (n = 15)

CD4 /µl 96.66 (± 58.4 ) 344 (± 76.6) 756.33 (± 238.8) 809.86 (± 201.83)

HIV-1 RNA (log copies/ml) 4.72 (± 0.69) 3.9 (± 0.85) 4.4 (± 0.65) Not done

TNF-� pg/ml 41.8 (± 11.9 ) 35 (± 14.1) 37.5 (± 5) < 25

IL-6 pg/ml 8.77 (± 11.67) 3.08 (± 2.31) 1.94 (± 0.61)b 1.4 (± 0.65)

sIL-2R pg/ml 2,604 (± 1,398.12) 1,570.8 (± 521.64)c 1,769.6 (± 846.4) 957.6 (± 325.4)

�2-microglobulin mg/ml 3.703 (± 1.39) 2.21 (± 1.08)d 2.36 (± 1.02)e 1.435 (± 0.42)

Data are shown as mean ± SD values; TNF: tumor necrosis factor; IL: interleukin; sIL-2R: soluble interleukin 2 receptors;a the means of the AIDS patients' parameters were consistently higher than those of the controls, b indicates a significant difference alsowhen compared to category 3 (p < 0.0015), c indicates a significant difference also when compared to category 2 (p < 0.0021), d indicatesa significant difference also when compared to category 2 (p < 0.003), e indicates a significant difference also when compared to category3 (p < 0.01)

Table 1Immunologic and virologic profile.

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levels. In relation to the other three categories studied, cat-egory 1 presented high mean TNF-� levels which were sta-tistically higher only when compared to the control group(ANOVA, p < 0.004). The AIDS group also evidenced sig-nificantly higher IL-6 values (ANOVA, versus category 3p < 0.028; vs the control group p < 0.015).The other immuneactivation markers were again significantly higher amongAIDS patients (Table 1), while no significant difference inthe mean HIV-1 RNA levels in the plasma was found whencomparing the three categories with each other. The nutri-tional status data of the table 2 participants show that 28individuals, including controls, presented some degree ofnutrition depletion. Category 1 patients were less eutrophicthan the others; the four (8.9%) malnourished patients pre-sented opportunistic infections at the time of the study.TheAIDS patients were graded much higher on the nutritionaldeficit scale than either the category 3 (ANOVA, p < 0.05)or control group (ANOVA, p < 0.02).The parameter levelsof the 45 HIV-positive individuals were correlated by wayof linear regression (Table 3). TNF-�, sIL-2R and �2-mi-croglobulin levels correlated positively with all the para-meters studied (but not with viral load and IL-6 levels). Nu-tritional status grades also correlated positively with mostof the parameters studied aside from viral load and CD4counts. Significant values were found for CD4 and gradesonly when patients were categorized into groups (Table 1).

Moreover, except for viral load, there was an inverse cor-relation between CD4 counts and all the parameters stud-ied.

When the four AIDS patients with opportunistic in-fections were excluded from the analysis to eliminate anypotential bias that immune activation might have on thosepatients who were free of opportunistic infections, AIDSpatients maintained significantly higher mean IL-6 levels(ANOVA, 5.06 ± 3.72, vs category 3 p < 0.05; vs the controlgroup p < 0.01) and mean �2-microglobulin levels(ANOVA, 3.63 ± 1.57 vs category 2 p < 0.05; vs category 3p < 0.04; vs the control group p < 0.001). However, the meanTNF-� levels (20 ± 24.8) and mean sIL-2R levels (2,363 ±1,454.9) of category 1 were higher only when compared tothe control group (ANOVA, p < 0.02 and p < 0.01, respec-tively). It is noteworthy that aside from the AIDS patientswithout opportunistic infections, the nutritional statusgrades of category 1 individuals were similar in statisticalterms to those found in all the other groups (2.36 ± 1.4).

DiscussionThe results of this study confirm a correlation between highdegrees of immune activation and parameters of malnutri-tion in AIDS patients. Notwithstanding the administrationof antiretroviral treatment, increases in viral load were de-tected in most of the patients, indicating not only that the

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Infection 29 · 2001 · No. 5 © URBAN & VOGEL 259

n=15 Euthrophic Caloric depletion Protein depletion Caloric protein depletion Malnutrition Grades a

Category 1 4 4 1 2 4 3.3 bCategory 2 8 2 3 2 0 1.93Category 3 10 3 2 0 0 1.40Control group 10 0 3 2 0 1.67

a nutritional status impairment grades were based on the number of altered anthropometric measurements and/or laboratory data found;b AIDS patients had significantly higher grades than category 3 (p < 0.05) or the control group (p < 0.02)

Table 2Diagnosis of nutritional status and respective nutritional impairment grades.

HIV-RNA TNF-� IL-6 sIL-2R �2-microglobulin CD4r p-value r p-value r p-value r p-value r p-value r p-value

TNF-� 0.52 (0.001)IL-6 0.31 (0.4) 0.417 (0.0008)sIL-2R 0.36 (0.002) 0.70 (0.001) 0.417 (0.0001)�2-microglobulin 0.50 (0.001) 0.71 (0.001) 0.34 (0.004) 0.70 (0.001)CD4 /�l 0.19 (0.239) 0.39 (0.002) 0.35 (0.0048) 0.47 (0.003) 0.51 (0.0001)Grades 4 (0.219) 0.47 (0.0001) 0.41 (0.0008) 0.42 (0.0007) 0.49 (0.01) 0.197 (0.23)

Regression analyses were performed on data from 45 HIV-positive individuals. Results are expressed as: r values (correlation coefficients)and p-values (< 0.05 were considered statistically significant);TNF: tumor necrosis factor; IL: interleukin; sIL-2R: soluble interleukin 2 receptors

Table 3Correlations among viral load and serum levels of cytokine/immune activation markers, CD4 counts and nutritional status impairmentgrading in HIV-positive individuals.

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treatment failed to be suppressive but also confirming thebelief that persistent viral replication induces a state ofchronic immune activation, which, in turn, provokes cy-tokine production and the formation of a self-regulatingmechanism leading to HIV replication [1, 13]. Sustained cy-tokine activation in HIV infection was further demon-strated by Auskrust et al. [14]; despite significant decreasesin TNF levels during the course of highly active antiretro-viral therapy (HAART), complete normalization of im-munological status (TNF) was not achieved. In the presentstudy the findings regarding IL-6 were of particular inter-est in that the results pointed to the absence of correlationbetween IL-6 and viral load, corroborating a previous re-port indicating that drug-induced IL-6 blockades neglectedto significantly decrease HIV load [15] in contrast to in vitrostudies demonstrating HIV replication being stimulated byIL-6 [16]. As opposed to TNF, IL-6 might not significantlycontribute to HIV replication in vivo. On the other hand,opportunistic infections, such as those dealt with in thisstudy (category 1, four patients), were also seen to triggeran immune activation state [17, 18], which probably con-tributed to the higher mean cytokine levels among AIDSpatients. The higher sIL-2R levels found in category 1 maylikely reflect the immune activation state typically observedas seen in a variety of other studies [19].

The nutritional status impairment grading scaleadopted for the purposes of this study correlated positivelywith TNF-�, IL-6 and the other immune activation para-meters. TNF-� is the cytokine most commonly implicatedas a potential mediator of cachexia [20]. Elevated IL-6 lev-els have also been correlated with degrees of cachexia inexperimental cancer [21].TNF-�, a potent IL-6 stimulator,is a major hepatocyte-stimulating cytokine that elicitsacute-phase protein synthesis while decreasing the rate ofalbumin synthesis [22]. However, hypoalbuminemia inAIDS patients was not found here (data not shown). InHIV infection, the maladaptive blockage of lipid oxidationresults in weight loss together with a relatively greater lossof lean body mass than of fat.

In recent years, the Brazilian Ministry of Health hasbeen able to maintain antiretroviral drug distribution toHIV patients, most probably one of the main reasons whynone of the 45 patients studied presented HIV-inducedwasting syndrome. The most severely malnourished pa-tients were found to have tuberculosis, whose adverse ef-fects on the nutritional status of HIV-positive patients havebeen well documented [23]. Nevertheless, none of these re-sults in any way negate the assumption that wasting syn-drome continues to have an impact on HIV. In fact, it is im-portant to point out that wasting syndrome has consistentlybeen found to be the most frequent AIDS indicator condi-tion in Brazil and the second most important indicator inthe United States [24, 25]. Moreover, with the exception ofthe malnourished patients and contrary to expectations, thedecrease in lean body mass was not a prominent charac-teristic nor was any difference found in nutritional status

impairment grading when the four groups were compared.Surprisingly enough, however, there was also no correla-tion between nutritional status impairment grading and vi-ral load, which could clearly be attributed to the provenbeneficial effects of antiretroviral treatments on the nutri-tional status of HIV-positive patients [26, 27].

In conclusion, this study was able to demonstrate thatthe immune activation correlated to changes in body com-position throughout the stages of HIV infection and thatantiretroviral therapy has a significant impact on nutritionalstatus since extreme degrees of impairment (malnutrition)were shown to be the result of opportunistic infections andnot of HIV itself. Even so, the nutritional benefits ofHAART have to be weighed against the risks of lipodis-trophy [28].

AcknowledgementsThe authors wish to thank Liane Braga, Solange Alves, Luci Alves,Sonilde Melo Ivo Gomes de Carvalho, Luciano Pinho and GlícioBatista da Silva for their technical assistance, as well Valéria Rollafor her helpful hints.

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