Metabolic Changes Associated with Antiretroviral Therapy in Hiv-positive Patients

Alterações metabólicas associadas à terapia anti-retroviral em pacientes HIV-positivos ABSTRACT OBJECTIVE: To evaluate metabolic changes associated with highly active antiretroviral therapy (HAART) in HIV-positive patients, and to identify risk factors associated. METHODS: Retrospective study that included 110 HIV-positive patients who where on HAART in the city of Porto Alegre (Southern Brazil) between January 2003 and March 2004. Data on demographic variables, cigarette smoking, diabetes mellitus, cholesterol and triglyceride levels, stage of HIV infection, antiretroviral therapy and HCV coinfection were collected. General linear models procedure for repeated measures was used to test the interaction between HAART and HCV coinfection or protease inhibitor treatment. RESULTS: Total cholesterol, triglycerides, and glucose levels signifi cantly increased after receiving HAART (p<0.001 for all variables), but no interaction with protease inhibitors was seen for total cholesterol, glucose and triglyceride levels (interaction treatment*protease inhibitors p=0.741, p=0.784, and p=0.081, respectively). An association between total cholesterol levels and HCV coinfection was found both at baseline and follow-up (effect of HCV coinfection, p=0.011). Glucose levels were increased by HAART (treatment effect, p=0.036), but the effect was associated to HCV coinfection (treatment*HCV effect, p=0.018). Gender, smoking habit, intravenous drug use and age were not signifi cantly associated with cholesterol, triglyceride and glucose changes. CONCLUSIONS: HCV-infected patients at baseline were signifi cantly less likely to develop hypercholesterolemia. The results provide further evidence of the role of HAART for the development of metabolic disturbances. 284 Metabolic changes and antriretroviral drugs Almeida SEM et al Adverse drug reactions are one of the important factors associated with reduced quality of life among HIV-infected patients taking highly active antiretroviral therapy (HAART). 18 Abnormalities in lipid metabolism make HIV-positive patients subject to high risk for the development of coronary heart disease. 2 The mechanisms responsible for metabolic changes of anti-HIV drugs are not fully understood. Increases in serum triglycerides, low-density lipoproteins (LDL), and total cholesterol have been reported as well as the development of insulin resistance. 5 Lipid disturbances in HIV patients receiving protease inhibitor (PI) treatment are more evident. 13 Deeks et al 7 (1997), in a 32-week study, identifi ed persistent elevations in cholesterol of 30%–40% from baseline and in triglycerides of 200%–300% from baseline. It has been reported that ritonavir increases the production of very low-density lipoprotein cholesterol (VLDL), trig-RESUMO OBJETIVO: Avaliar as alterações metabólicas associadas à terapia anti-retroviral potente em pacientes HIV-positivos e identifi car fatores de risco associados. CONCLUSÕES: Pacientes infectados pelo …

Adverse drug reactions are one of the important factors associated with reduced quality of life among HIVinfected patients taking highly active antiretroviral therapy (HAART). 18Abnormalities in lipid metabolism make HIV-positive patients subject to high risk for the development of coronary heart disease. 2 The mechanisms responsible for metabolic changes of anti-HIV drugs are not fully understood.Increases in serum triglycerides, low-density lipoproteins (LDL), and total cholesterol have been reported as well as the development of insulin resistance. 5pid disturbances in HIV patients receiving protease inhibitor (PI) treatment are more evident. 13Deeks et al 7 (1997), in a 32-week study, identifi ed persistent elevations in cholesterol of 30%-40% from baseline and in triglycerides of 200%-300% from baseline.It has been reported that ritonavir increases the production of very low-density lipoprotein cholesterol (VLDL), trig-RESUMO OBJETIVO: Avaliar as alterações metabólicas associadas à terapia anti-retroviral potente em pacientes HIV-positivos e identifi car fatores de risco associados.

INTRODUCTION
lycerides, and apolipoprotein (apo) B in HIV-negative subjects indicating that treatment with this protease inhibitor in the absence of HIV infection can cause dyslipidemia. 19These observations have motivated researchers to investigate whether it is safe to switch patients with a PI-based regimen and optimal viral suppression to a simplifi ed maintenance therapy (SMT) to reduce side effects and metabolic disturbances. 4e objective of the present study was to describe both metabolic changes associated with HAART and risk factors associated in HIV-positive patients.

METHODS
A retrospective cohort study was conducted including 110 HIV-positive subjects who were on HAART at a reference laboratory in the city of Porto Alegre, Southern Brazil.Of all 200 subjects, we selected all subjects with at least one follow-up lipid profi le between January 2003 and March 2004.Data (drug treatments, symptoms, HAART duration, time of HIV exposure or HIV diagnosis, laboratory results, and patient demographics) were collected through local database search.Data for hepatitis C virus (HCV) and tuberculosis coinfection were identifi ed by laboratory testing.The diagnoses of diabetes and hypertension were defi ned as specifi c guidelines. 20,21Further exclusion criteria were secondary hyperlipidemia due to renal, hepatic or thyroid disease, and diabetes or fasting blood glucose levels above 110 mg/dL.Individuals that were on lipid-lowering medications were also excluded.Disease classifi cation was based on the National Sexually Transmitted Diseases (STD) and AIDS Program of the Brazilian Ministry of Health.a Continuous variables were expressed as mean (standard deviation, SD) or median (interquartile range) when no normal distribution was assumed.A general linear models procedure for repeated measures using type III sums of squares statistics was used to test the interaction between HAART and HCV coinfection or PI treatment.This sum of squares applies to unbalanced study designs and measures the effect of an independent variable (HCV coinfection or PI treatment) after adjustment for all other covariables included in the model.To test the interaction between HAART and HCV coinfection or PI treatment two different multivariate models were applied.Age, gender, CD4 levels, HIV-RNA measurements, HAART duration were included in both models as covariables.HCV coinfection was included as a covariable to test the interaction between HAART and PI treatment and PI treatment was included as a covariable to test the interaction between HAART and HCV coinfection.A 5% signifi cance level was set.All statistical analyses were performed using the SPSS package v. 13.0.
The study was approved by the Ethics Committee of Fundação Estadual de Produção e Pesquisa em Saúde (nº 2004-373H).Written informed consent was obtained from all subjects.

RESULTS
Table 1 shows the demographic characteristics, concomitant diseases and lipid, glucose, CD4 and HIV-RNA measurements of HIV-positive subjects taking non-nucleoside reverse transcriptase inhibitors Details on the antiretroviral drugs used in the study are given in Table 2.The NNRTI-containing regimen including zidovudine, lamivudine and efavirenz was the most frequently prescribed (62.8%).For PI-containing regimens, the most common combination was zidovudine, lamivudine, and nelfi navir (41.7%).
Total cholesterol >200 mg/dL was seen only in 7.2% of subjects at baseline, and in 25.5% of subjects on HAART.Similar results were found for triglyceride and glucose levels.Triglyceride levels >150 mg/dL were seen in 20.9% of subjects at baseline and in 32.7% during follow-up.Eight percent and 20.0% of subjects were hyperglycemic (glucose >110 mg/dL) at baseline and during follow-up, respectively.There were no risk differences between PI and NNRTI treatments for the development of hypercholesterolemia (RR=0.78,95% CI = 0.33;1.83),hyperglycemia (RR=1.05,95% CI = 0.43;2.56)or hypertriglyceridemia (RR=1.37,95% CI = 0.78;2.44)during follow-up.Similar results were found for HCV coinfection (Table 3).
Table 4 and the Figure provide adjusted lipid and glucose levels at baseline and follow-up for PI treatment and HCV coinfection.There were signifi cant increases in total cholesterol, triglyceride and glucose levels after receiving HAART (effect of treatment, p<0.001 for all variables), but no interaction with PI treatment was seen for total cholesterol (interaction treatment*PI p=0.741, Figure 1A), glucose (interaction treatment*PI p=0.784, Figure 1B) or triglyceride levels (interaction treatment*PI p=0.081, Figure 1C).mg/dL, respectively), showing an effect of HCV coinfection on total cholesterol levels regardless of HAART (Figure 1D).Glucose levels were increased by HAART (treatment effect p=0.036), but the effect was associated to HCV coinfection.HCV-negative subjects showed an increase of 10.4% in glucose levels, whereas HCV-positive subjects had similar glucose levels regardless of HAART (effect of HCV coinfection*treatment = 0.018, Figure 1E).No effect of HCV coinfection was seen for triglyceride levels (effect of HCV coinfection = 0.732, effect of HCV coinfection*treatment = 0.397, Figure 1F).

DISCUSSION
Data about the effect of HAART on metabolic changes in Brazilian HIV-positive patients are scarce.Data for other populations showed that multidrug antiretroviral therapy, including the use of protease inhibitors, is associated with dyslipidemia, [2][3][4][5][6][7][8][9][10][11][12]15 a well-recognized risk factor for the development of coronary artery disease. 10 revious studies indicated a broad variation in hypercholesterolemia and hypertriglyceridemia rates among HIV-positive patients on diverse highly-active antiretroviral therapy regimens.Lipid disorders are frequently associated with protease inhibitor treatment. 11owever, emerging evidences indicated an association between NNRTI-containing regimens and dyslipidemia and other metabolic changes.11 Hypercholesterolemia has been seen in almost 30% of PI-treated subjects and 23% of NNRTI users, while hypertriglyceridemia has been seen in 40% and 32% of patients, respectively.In our study both PI-containing and NNRTI-containing HAART increased total cholesterol, triglyceride and glucose levels compared to baseline, regardless of PI-containing HAART.In our study nelfi navir was the most frequent PI used (50% of PI-containing regimens).A recent clinical trial comparing atazanavir with nelfi navir showed that the latter was more strongly associated to increases in total cholesterol, LDL-cholesterol and triglycerides.16 The role of HCV coinfection in the development of metabolic complications or in the response to antiretroviral treatment in HIV-positive patients remains incompletely understood. Inour data, total cholesterol levels were signifi cantly lower in HIV-HCV coinfected patients on antiretroviral therapy.Previous investigations reported that patients infected with hepatitis C at baseline were signifi cantly less likely to develop hyperlipidemia.6,5,17 Interestingly, the presence of HCV coinfection during HIV treatment was also associated to higher insulin resistance, activated platelets, endothelial perturbation 8 and lipodystrophy.6,9 Moreover, HCV coinfection was associated to treatment discontinuation and interruption.1,3,14 The mechanism underlying the protective effect of hepatitis C in the risk of developing hyperlipidemia is not known, but might refl ect an impaired total cholesterol synthesis in the liver or total cholesterol hypercatabolism.
The limitations of our study include the retrospective cohort design (with high rates of missing data), disproportionately smaller number of patients in the PI-group, and absence of HIV-negative controls.In addition, data concerning other risk factors for coronary heart disease were not obtained in our study, including genetic factors, body mass index, plasma HDL and LDL levels, physical activity, and diet.To elucidate how antiretroviral therapy is associated to metabolic disturbances and could contribute to premature cardiovascular disease is of major importance.Therefore further research with larger sample size and detailed information regarding additional risk factors for coronary heart disease are necessary to better understand the effects of HAART.
In conclusion, our results provide further evidence of the role of HAART in lipid disorder development and emphasize the importance of analyzing the effect of antiretroviral therapy in different populations.In Brazil, the treatment of HIV-infected patients is provided by the government.Thus evidences found in our study may be useful to propose new guidelines for managing the metabolic changes during antiretroviral therapy.Moreover, our study found a signifi cant relationship between HIV-HCV coinfection and HAART effects on total cholesterol and glucose levels.In this regard, further studies are needed to clarify the exact role of HCV infection in the induction of such abnormalities.

Figure .
Figure.Adjusted marginal means for total cholesterol, glucose, and triglyceride levels (mg/dL) in antiretroviral-naïve subjects treated with HAART by PI treatment (A, B and C) and HCV coinfection (D, E and F).Porto Alegre, SouthernBrazil, 2003-2004.
a Relative risk (95% confi dence interval) TC: total cholesterol TG: triglycerides PI: protease inhibitor HCV: hepatitis C virus These results show a HAART effect on metabolic changes regardless of the antiretroviral regimen used.The same approaches were applied to investigate the effects of HCV coinfection on lipid and glucose parameters.For HCV coinfection, after controlling for age, gender, CD4 levels, HIV-RNA measurements, HAART duration and PI treatment, signifi cant increases in total cholesterol, triglyceride and glucose levels after receiving HAART (effect of treatment, coinfection was seen both at baseline and follow-up (effect of HCV coinfection p=0.011).At baseline, HCV-positive subjects had lower total cholesterol levels (141.7±33.2mg/dL) than HCV-negative subjects (156.6±37.4mg/dL).The same results were found during follow-up (157.3 ± 31.8 mg/dL and 183.0±38.5

Table 4 .
Estimated marginal means for total cholesterol, glucose and triglyceride levels analyzed by general linear models procedure for repeated measures.Porto Alegre, SouthernBrazil, 2003-2004.