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Hypertriglyceridemia and Hypercholesterolemia in Human Immunodeficiency Virus-1-Infected Children Treated with Protease Inhibitors
Archives of Medical Research 37 (2006) 129–132
ORIGINAL ARTICLE
Hypertriglyceridemia and Hypercholesterolemia in Human Immunodeficiency Virus-1-Infected Children Treated with Protease Inhibitors Fortino Solo´rzano Santos,a Laura G. Gochicoa Rangel,b Gerardo Palacios Saucedo,a Guillermo Va´zquez Rosales,a and Marı´a Guadalupe Miranda Novalesa a
Infectious Diseases Department, bPediatrics Department, Hospital de Pediatrı´a, Centro Me´dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Me´xico, D.F., Me´xico Received for publication September 27, 2004; accepted May 6, 2005 (ARCMED-D-04-00095).
Background. Adverse effects associated with highly active antiretroviral therapy (HAART), particularly protease inhibitors (PIs), have been identified in adult and pediatric patients. In this study, we monitored, for cholesterol and triglyceride levels, a cohort of HIV-1-infected children receiving a HAART regimen. Methods. HIV-infected patients !17 years old belonging to a cohort that has been followed since 1997 were enrolled in the study. Patients were receiving either a three- or four-drug antiretroviral regimen that included two nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine) combined with one or two PIs (ritonavir and/or saquinavir). Cholesterol and triglyceride levels were measured on fasting serum samples drawn at the time of enrollment and every 3 months thereafter. Clinical evaluation was performed on a monthly basis. Results. Twenty four patients were included. Median age at HIV infection diagnosis was 15 months. Twenty one patients received a four-drug antiretroviral regimen, while three patients received ritonavir plus zidovudine and lamivudine. Median follow-up was 27 months; 62.5% of patients had hypercholesterolemia and 79.2% had hypertriglyceridemia, most typically after 15 months of treatment. None of the patients had physical changes in body fat distribution suggesting lipodystrophy. Conclusions. Hyperlipidemia is a frequent complication in HIV-1-infected children undergoing antiretroviral treatment that includes PIs. Additional studies with larger cohorts and a longer follow-up are needed to propose a rationale and alternatives for patients who develop dyslipidemia while receiving PIs. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: HIV-infected children, Dyslipidemia and protease inhibitors, Hypercholesterolemia in HIV-infected children, Hypercholesterolemia and hypertriglyceridemia and HIV-infected patients.
Introduction The addition of protease inhibitors (PIs) to antiretroviral treatment (highly active antiretroviral therapy, or HAART) has allowed a sustained suppression of HIV replication and a reduction in morbidity and mortality in patients with
Address reprint requests to: Fortino Solo´rzano Santos, M.D., Av. Cuauhte´moc 330, Col. Doctores, Me´xico D.F., CP 06720, Mexico; E-mail: [email protected]
advanced HIV infection. The prognosis of HIV infection in pediatrics has also been modified with HAART, significantly reducing the incidence of opportunistic infections and improving the growth and neurodevelopment of infected children (1–3). A number of adverse effects associated with HAART, and particularly with PIs, such as lipodystrophic syndrome, hyperlipidemia, and peripheral insulin resistance, have been identified in adult and pediatric patients. The association has been higher among adult patients receiving ritonavir
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.05.013
130
Solo´rzano Santos et al./ Archives of Medical Research 37 (2006) 129–132
(RTV) (4–7). These metabolic disorders have led to concerns about increased cardiovascular risk in treated HIV-positive patients. Other side effects reported in adult patients include arteriosclerosis, acute myocardial infarction, and pancreatitis (8,9). Despite the unknown pathogenesis of these complications, they seem to be associated with a number of factors including interaction of genetic factors, HIV infection, and antiretroviral treatment (10). Some case reports and short cross-sectional studies have evaluated these metabolic complications of HAART in children (11–14). In the present study, a cohort of HIV-1 infected children receiving a HAART regimen that included PIs (RTV and/or saquinavir) was followed monitoring cholesterol and triglyceride serum levels.
Materials and Methods Study Design and Patient Sample HIV-1-infected children !17 years old from the AIDS clinic of a tertiary care facility pediatric hospital in Mexico City were enrolled in the study. These patients belong to a cohort that has been followed at the hospital since 1997 (15). Only patients who completed at least 24 months of follow-up were included. Diagnosis of HIV-1 infection was established according to the international criteria for pediatric patients (16). The children in this study were classified according to 1994 CDC criteria (16).
Antiretroviral Treatment and Drug Dosing Patients in the cohort were receiving a three- or four-drug antiretroviral regimen that included two nucleoside reverse transcriptase inhibitors (NRTIs)dlamivudine (3TC) and zidovudine (AZT)dcombined with one or two PIs, RTV and/or saquinavir (SQV). Antiretroviral treatment began at the time of diagnosis of HIV infection, independently of the patient’s age, symptoms, viral load (VL), and immune status. Dosages of antiretroviral drugs were SQV in hardgel capsules (SQVhgc) at 1200–1500 mg/m2 per day q8h (maximum of 600 mg t.i.d.), RTV 300–400 mg/m2 b.i.d. (maximum of 600 mg b.i.d.), ZDV 90–180 mg/m2 q6h (maximum of 200 mg t.i.d.), and 3TC 4 mg/kg b.i.d. (maximum of 150 mg b.i.d.). RTV was begun at 250 mg/m2 b.i.d., and parents or legal guardians were instructed to increase it every other day to achieve therapeutic dosage. Chocolate, yogurt, milk, or other fat-containing foods or beverages were used before RTV administration to mask the unpleasant taste and improve tolerance and absorption. Prophylaxis for Pneumocystis carinii pneumonia was administered when appropriate.
Laboratory Monitoring and Clinical Evaluation Cholesterol and triglyceride levels were measured on fasting serum samples drawn at the time of enrollment and every 3 months thereafter using an automated clinical chemistry analyzer (Dade Behring Dimension System, Dade Behring, Deerfield, IL). Total cholesterol levels !170 mg/dL were considered as normal, 170–199 mg/dL as borderline, and O200 mg/dL as abnormally high (17). Serum triglyceride levels were considered normal according to the values shown in Table 1 (18,19). In those children with abnormal total cholesterol and triglyceride levels, glucose, low-density-lipoprotein (LDL) and high-densitylipoprotein (HDL) levels were also determined. Clinical evaluation was performed monthly. In addition to demographic information, family history of dyslipidemia or premature coronary artery disease and the presence of symptoms attributed to hypertriglyceridemia and/or hypercholesterolemia were recorded. Given the absence of a consensus definiton of lipodystrophy syndrome in children, only the description of fat redistribution in the population was evaluated during the follow-up. Results Twenty four patients were included in the study, 14 males (58%) and 10 females (42%). Most patients (21 patients or 87.5%) acquired HIV infection vertically, whereas the remaining three acquired HIV infection by blood transfusion (12.5%). Median age at HIV infection diagnosis was 15 months (range, 1 month to 15 years). Seven patients were classified in clinical-immune category C3, six in category A2, three in category A1, three in A3, two in B3, and three patients in categories N1, N2, and B2, with one patient in each, respectively. When the patients began receiving PIs, 12 were !24 months of age (range, 1 month to 22 months), five were between 25 months and 4 years, and seven were between 6 and 15 years old. Three patients received RTV plus two NRTIs (AZT 1 3TC), while the other 21 received SQV plus RTV associated with 2 NRTIs (AZT 1 3TC). Patients were followed-up for a median time of 28 months (24–58 months). During the follow-up, 15/24 patients (62.5%) had hypercholesterolemia, of which 13 had normal cholesterol baseline levels and 2 had baseline levels that were borderline Table 1. Normal serum triglyceride levels according to gender and age Normal triglyceride levels (mg/dL) Age (years) 0–5 6–11 12–15 16–19
Male
Female
30–86 31–108 36–138 40–163
32–99 35–114 41–138 40–128
Protease Inhibitors and Hyperlipidemia in Children
Percent of patients
100 80 60 40
Hypercholesterolemia Hypertriglyceridemia
20 0 0
3
6
9
12
15
18
21
24
27
Months on treatment Figure 1. Accumulated frequency of hypercholesterolemia and hypertriglyceridemia in 24 HIV-infected pediatric patients under treatment with ritonavir and/or saquinavir, zidovudine, and lamivudine.
80 70
Without malnutrition
60
Grade I malnutrition
50
%
values. The other nine patients had normal cholesterol baseline levels, of which six had increased but not to abnormal levels during the follow-up (24 months). The children with hypercholesterolemia had no family history of dyslipidemia or premature coronary artery disease. Median serum cholesterol level for the cohort overall was 185 mg/dL (range, 21–444 mg/dL). Among those with high cholesterol levels the median was 234 mg/dL (202–444 mg/dL), median LDL was 98 mg/dL (63–144 mg/dL), median HDL was 30 mg/dL (12–64 mg/dL), and median glucose level was 89 mg/dL (39–143 mg/dL). The highest cholesterol level (444 mg/dL) was observed in a child of 21 months of age with 170 mg/dL of cholesterol at baseline, 264 mg/dL after 6 months of PI treatment, and 444 mg/dL at 12 months of treatment. Time elapsed from the beginning of PIs to the detection of borderline cholesterol levels was 7 months (2–25 months) and for detection of abnormally high cholesterol levels 10 months (2–18 months). The median serum triglyceride level for the cohort overall was 176 mg/dL (range, 16–1110 mg/dL). In 19/24 patients (79.2%), triglycerides were higher than 138 mg/dL (median 249 mg/dL; range, 141–1110 mg/dL), and 12 also had hypercholesterolemia. Time elapsed from the beginning of PIs to the detection of hypertriglyceridemia was 5 months (3–18 months). One patient had a high triglyceride level at baseline that increased during HAART. This patient did not have a family history of dyslipidemia, and his parents’ cholesterol and triglyceride levels were normal. The highest triglyceride level observed during the followup in the cohort was 1110 mg/dL in an 11-year-old boy who also had hypercholesterolemia but no family history of dyslipidemia. After 15 months of HAART most patients had both hypercholesterolemia and hypertriglyceridemia (Figure 1). In 7/19 patients with high level of triglycerides, glucose levels were O110 mg/dL. At enrollment 78% of the patients were malnourished. During the follow-up, all patients experienced improvement in their nutritional status (Figure 2). When the study was completed, none of the patients had physical changes in
131
40
Grade II malnutrition
30
Grade III malnutrition
20 10 0 0
3
6
9
12
15
18
21
24
Months Figure 2. Nutritional status of 24 HIV-1-infected children under HAART. 0 represents nutritional status at enrollment. Points along the curves represent percentages of patients in each category at time of follow-up evaluation.
body fat distribution suggesting lipodystrophy or complications associated with hyperlipidemia or hypercholesterolemia.
Discussion Treatment of HIV-infected patients with PIs has been associated with a number of metabolic disorders and an abnormal deposit of body fat (4–7,11,12). A number of possible causes for these complications have been proposed (4,10). In the present study, more than 60% of children had increased cholesterol and/or triglycerides 9–12 months after the beginning of treatment with PIs. This increase was observed at an earlier stage for triglycerides, and the levels were higher than those reported in adult patients (7,20). Although risk for micro- and macrovascular damage exists, the consequences of these changes are unknown. After 2 years of treatment with PIs in the present cohort, we did not detect consequences associated with hyperlipidemia such as cholelithiasis, acute pancreatitis, or premature coronary artery disease. Nevertheless, because these types of complications can occur long after beginning PIs, it is necessary to be aware of such complications in patients receiving this type of drug. The frequency of hypertriglyceridemia in the present cohort was higher than that reported by Amaya et al. (14) in a pediatric cohort from Houston, TX (79.2 vs. 28%). This difference could be attributed to dietary differences between the two populations. Although Amaya et al. did not find a relationship between hyperlipidemia and a particular antiretroviral treatment, the number of patients in their group was too small. Most patients in our cohort received RTV or the RTV plus SQV combination as part of their HAART regimen. RTV has been associated with a higher rate of hypertriglyceridemia (6,21,22) in comparison with other PIs, and the SQV-RTV combination seems to intensify this effect (4,10). There was no relationship between a high
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Solo´rzano Santos et al./ Archives of Medical Research 37 (2006) 129–132
ritonavir dose/hypertriglyceridemia, as patients received standard doses during the follow-up. At the present time we do not have a definite recommendation for prophylaxis or an effective treatment for dyslipidemia associated with PI usage in pediatrics. A possible strategy is to give nutritional advice aimed at reducing the intake of saturated fatty acids. Although the impact of modifying fat intake has not been evaluated, it would probably be negligible, considering the mechanism involved in the physiopathogenesis of hyperlipidemia linked to PI treatment. It has been suggested that the potential roles of RTV in lipid metabolism are related to a reduction of lipoprotein depuration during the postprandial period or by increasing lipid synthesis via liver enzymes. It has also been proposed that PIs inhibit proteins participating in lipid metabolism and adipocyte differentiation (23–25). Hypolipidemic therapy is not recommended for these patients because of potential drug interactions with PIs. At this time there is insufficient evidence to support recommendations for prevention and therapy in HIV-infected children who develop dyslipidemia while receiving PIs. Additional studies with larger cohorts and a longer follow-up to document complications associated with altered lipid metabolism are needed to propose rationales and alternatives. References 1. Rhone SA, Hogg RS, Yip B, Sherlock C, Conway B, Schechter MT, O’Shaughnessy MV, Montaner JS. The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study. AIDS 1998;12:619–624. 2. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Morb Mortal Wkly Rep 1998;47(RR–5):43–82. 3. Saez-Llorens X, Ramilo O. Early experience with protease inhibitors in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1998;17:728–738. 4. Mauss S, Stechel J, Willers R, Schmutz G, Berger F, Richter WO. Differentiating hyperlipidemia associated with antiretroviral therapy. AIDS 2003;17:189–194. 5. Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Korner T, Stoll M, Schmidt RE. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patient under treatment with protease inhibitors. AIDS 1999;13:F63–F70. 6. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 2000;160:2050–2056. 7. Sullivan AK, Gazzard N, Gazzard BG. Marked hypertriglyceridemia associated with ritonavir therapy. AIDS 1998;2:1393–1394.
8. Eriksson U, Opravil M, Amann FW, Schaffner A. Is treatment with ritonavir a risk factor for myocardial infarction in HIV-infected patients? AIDS 1998;12:2079–2080. 9. Behrens G, Schmidt H, Meyer D, Stoll M, Schmidt RE. Vascular complications associated with use of HIV protease inhibitors. Lancet 1998;351:1958–1960. 10. Green ML. Evaluation and management of dyslipidemia in patients with HIV infection. J Gen Intern Med 2002;17:797–810. 11. Arpadi S, Cuff PA, Horlick M, Kotler DP. Visceral obesity, hypertriglyceridemia, and hypercortisolism in a boy with perinatally acquired HIV infection receiving protease inhibitor-containing antiviral treatment. AIDS 1999;13:2312–2313. 12. Jaquet D, Levine M, Ortega RE, Faye A, Polak M, Vilmer E, Levy-Marchal C. Clinical and metabolic presentation of lipodystrophic syndrome in HIV-infected children. AIDS 2000;14: 2123–2128. 13. Babl FE, Reagan AM, Pelton SI. Abnormal body fat distribution in HIV-1 infected children on antiretrovirals. Lancet 1999;353:1243– 1244. 14. Amaya RA, Kozinetz CA, McMeans A, Schwarzwald H, Kline MW. Lipodystrophy syndrome in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2002;21:405–410. ´ lvarez MMT, Va´zquez G, Miranda G, 15. Palacios GC, Palafox VL, A Mun˜oz O, Solo´rzano F. Response to two consecutive protease inhibitors combination therapy regimens in a cohort of HIV-1-infected children. Scand J Infect Dis 2002;34:41–44. 16. Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children !13 years of age. MMWR 1994;43(RR12):1–19. 17. Starc T, Deckelbaum R. Evaluation of hypercholesterolemia in childhood. Pediatr Rev 1996;17:94–97. 18. Siberry G, Iannone R. The Harriet Lane Handbook. St. Louis, MO: Mosby;2000. 19. Bahar A, Sevgican U, Karademir F, Gocmen I. Serum cholesterol, triglyceride, VLDL-c, LDL-c and HDL-c levels in healthy children. Tohoku J Exp Med 2003;201:75–80. 20. Echevarria KL, Hardin TC, Smith JA. Hyperlipidemia associated with protease inhibitor therapy. Ann Pharmacother 1999;33:859– 863. 21. Manfredi R, Chiodo F. Disorders of lipid metabolism in patients with HIV disease treated with antiretroviral agents: frequency, relationship with administered drugs, and role of hypolipidaemic therapy with bezafibrate. J Infect 2001;42:181–188. 22. Roge BT, Katzenstein TL, Gerstoft J. Comparison of P-triglyceride levels among patients with human immunodeficiency virus on randomized treatment with ritonavir, indinavir or ritonavir/saquinavir. Scand J Infect Dis 2001;33:306–311. 23. Lenhard JM, Croom DK, Weiel JE, Winegar DA. HIV protease inhibitors stimulate hepatic triglyceride synthesis. Arterioscler Thromb Vasc Biol 2000;20:2625–2629. 24. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS 1999;13:2493–2505. 25. Mooser V, Carr A. Antiretroviral therapy-associated hyperlipidemia in HIV disease. Curr Opin Lipidol 2001;12:313–319.
ORIGINAL ARTICLE
Hypertriglyceridemia and Hypercholesterolemia in Human Immunodeficiency Virus-1-Infected Children Treated with Protease Inhibitors Fortino Solo´rzano Santos,a Laura G. Gochicoa Rangel,b Gerardo Palacios Saucedo,a Guillermo Va´zquez Rosales,a and Marı´a Guadalupe Miranda Novalesa a
Infectious Diseases Department, bPediatrics Department, Hospital de Pediatrı´a, Centro Me´dico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Me´xico, D.F., Me´xico Received for publication September 27, 2004; accepted May 6, 2005 (ARCMED-D-04-00095).
Background. Adverse effects associated with highly active antiretroviral therapy (HAART), particularly protease inhibitors (PIs), have been identified in adult and pediatric patients. In this study, we monitored, for cholesterol and triglyceride levels, a cohort of HIV-1-infected children receiving a HAART regimen. Methods. HIV-infected patients !17 years old belonging to a cohort that has been followed since 1997 were enrolled in the study. Patients were receiving either a three- or four-drug antiretroviral regimen that included two nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine) combined with one or two PIs (ritonavir and/or saquinavir). Cholesterol and triglyceride levels were measured on fasting serum samples drawn at the time of enrollment and every 3 months thereafter. Clinical evaluation was performed on a monthly basis. Results. Twenty four patients were included. Median age at HIV infection diagnosis was 15 months. Twenty one patients received a four-drug antiretroviral regimen, while three patients received ritonavir plus zidovudine and lamivudine. Median follow-up was 27 months; 62.5% of patients had hypercholesterolemia and 79.2% had hypertriglyceridemia, most typically after 15 months of treatment. None of the patients had physical changes in body fat distribution suggesting lipodystrophy. Conclusions. Hyperlipidemia is a frequent complication in HIV-1-infected children undergoing antiretroviral treatment that includes PIs. Additional studies with larger cohorts and a longer follow-up are needed to propose a rationale and alternatives for patients who develop dyslipidemia while receiving PIs. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: HIV-infected children, Dyslipidemia and protease inhibitors, Hypercholesterolemia in HIV-infected children, Hypercholesterolemia and hypertriglyceridemia and HIV-infected patients.
Introduction The addition of protease inhibitors (PIs) to antiretroviral treatment (highly active antiretroviral therapy, or HAART) has allowed a sustained suppression of HIV replication and a reduction in morbidity and mortality in patients with
Address reprint requests to: Fortino Solo´rzano Santos, M.D., Av. Cuauhte´moc 330, Col. Doctores, Me´xico D.F., CP 06720, Mexico; E-mail: [email protected]
advanced HIV infection. The prognosis of HIV infection in pediatrics has also been modified with HAART, significantly reducing the incidence of opportunistic infections and improving the growth and neurodevelopment of infected children (1–3). A number of adverse effects associated with HAART, and particularly with PIs, such as lipodystrophic syndrome, hyperlipidemia, and peripheral insulin resistance, have been identified in adult and pediatric patients. The association has been higher among adult patients receiving ritonavir
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.05.013
130
Solo´rzano Santos et al./ Archives of Medical Research 37 (2006) 129–132
(RTV) (4–7). These metabolic disorders have led to concerns about increased cardiovascular risk in treated HIV-positive patients. Other side effects reported in adult patients include arteriosclerosis, acute myocardial infarction, and pancreatitis (8,9). Despite the unknown pathogenesis of these complications, they seem to be associated with a number of factors including interaction of genetic factors, HIV infection, and antiretroviral treatment (10). Some case reports and short cross-sectional studies have evaluated these metabolic complications of HAART in children (11–14). In the present study, a cohort of HIV-1 infected children receiving a HAART regimen that included PIs (RTV and/or saquinavir) was followed monitoring cholesterol and triglyceride serum levels.
Materials and Methods Study Design and Patient Sample HIV-1-infected children !17 years old from the AIDS clinic of a tertiary care facility pediatric hospital in Mexico City were enrolled in the study. These patients belong to a cohort that has been followed at the hospital since 1997 (15). Only patients who completed at least 24 months of follow-up were included. Diagnosis of HIV-1 infection was established according to the international criteria for pediatric patients (16). The children in this study were classified according to 1994 CDC criteria (16).
Antiretroviral Treatment and Drug Dosing Patients in the cohort were receiving a three- or four-drug antiretroviral regimen that included two nucleoside reverse transcriptase inhibitors (NRTIs)dlamivudine (3TC) and zidovudine (AZT)dcombined with one or two PIs, RTV and/or saquinavir (SQV). Antiretroviral treatment began at the time of diagnosis of HIV infection, independently of the patient’s age, symptoms, viral load (VL), and immune status. Dosages of antiretroviral drugs were SQV in hardgel capsules (SQVhgc) at 1200–1500 mg/m2 per day q8h (maximum of 600 mg t.i.d.), RTV 300–400 mg/m2 b.i.d. (maximum of 600 mg b.i.d.), ZDV 90–180 mg/m2 q6h (maximum of 200 mg t.i.d.), and 3TC 4 mg/kg b.i.d. (maximum of 150 mg b.i.d.). RTV was begun at 250 mg/m2 b.i.d., and parents or legal guardians were instructed to increase it every other day to achieve therapeutic dosage. Chocolate, yogurt, milk, or other fat-containing foods or beverages were used before RTV administration to mask the unpleasant taste and improve tolerance and absorption. Prophylaxis for Pneumocystis carinii pneumonia was administered when appropriate.
Laboratory Monitoring and Clinical Evaluation Cholesterol and triglyceride levels were measured on fasting serum samples drawn at the time of enrollment and every 3 months thereafter using an automated clinical chemistry analyzer (Dade Behring Dimension System, Dade Behring, Deerfield, IL). Total cholesterol levels !170 mg/dL were considered as normal, 170–199 mg/dL as borderline, and O200 mg/dL as abnormally high (17). Serum triglyceride levels were considered normal according to the values shown in Table 1 (18,19). In those children with abnormal total cholesterol and triglyceride levels, glucose, low-density-lipoprotein (LDL) and high-densitylipoprotein (HDL) levels were also determined. Clinical evaluation was performed monthly. In addition to demographic information, family history of dyslipidemia or premature coronary artery disease and the presence of symptoms attributed to hypertriglyceridemia and/or hypercholesterolemia were recorded. Given the absence of a consensus definiton of lipodystrophy syndrome in children, only the description of fat redistribution in the population was evaluated during the follow-up. Results Twenty four patients were included in the study, 14 males (58%) and 10 females (42%). Most patients (21 patients or 87.5%) acquired HIV infection vertically, whereas the remaining three acquired HIV infection by blood transfusion (12.5%). Median age at HIV infection diagnosis was 15 months (range, 1 month to 15 years). Seven patients were classified in clinical-immune category C3, six in category A2, three in category A1, three in A3, two in B3, and three patients in categories N1, N2, and B2, with one patient in each, respectively. When the patients began receiving PIs, 12 were !24 months of age (range, 1 month to 22 months), five were between 25 months and 4 years, and seven were between 6 and 15 years old. Three patients received RTV plus two NRTIs (AZT 1 3TC), while the other 21 received SQV plus RTV associated with 2 NRTIs (AZT 1 3TC). Patients were followed-up for a median time of 28 months (24–58 months). During the follow-up, 15/24 patients (62.5%) had hypercholesterolemia, of which 13 had normal cholesterol baseline levels and 2 had baseline levels that were borderline Table 1. Normal serum triglyceride levels according to gender and age Normal triglyceride levels (mg/dL) Age (years) 0–5 6–11 12–15 16–19
Male
Female
30–86 31–108 36–138 40–163
32–99 35–114 41–138 40–128
Protease Inhibitors and Hyperlipidemia in Children
Percent of patients
100 80 60 40
Hypercholesterolemia Hypertriglyceridemia
20 0 0
3
6
9
12
15
18
21
24
27
Months on treatment Figure 1. Accumulated frequency of hypercholesterolemia and hypertriglyceridemia in 24 HIV-infected pediatric patients under treatment with ritonavir and/or saquinavir, zidovudine, and lamivudine.
80 70
Without malnutrition
60
Grade I malnutrition
50
%
values. The other nine patients had normal cholesterol baseline levels, of which six had increased but not to abnormal levels during the follow-up (24 months). The children with hypercholesterolemia had no family history of dyslipidemia or premature coronary artery disease. Median serum cholesterol level for the cohort overall was 185 mg/dL (range, 21–444 mg/dL). Among those with high cholesterol levels the median was 234 mg/dL (202–444 mg/dL), median LDL was 98 mg/dL (63–144 mg/dL), median HDL was 30 mg/dL (12–64 mg/dL), and median glucose level was 89 mg/dL (39–143 mg/dL). The highest cholesterol level (444 mg/dL) was observed in a child of 21 months of age with 170 mg/dL of cholesterol at baseline, 264 mg/dL after 6 months of PI treatment, and 444 mg/dL at 12 months of treatment. Time elapsed from the beginning of PIs to the detection of borderline cholesterol levels was 7 months (2–25 months) and for detection of abnormally high cholesterol levels 10 months (2–18 months). The median serum triglyceride level for the cohort overall was 176 mg/dL (range, 16–1110 mg/dL). In 19/24 patients (79.2%), triglycerides were higher than 138 mg/dL (median 249 mg/dL; range, 141–1110 mg/dL), and 12 also had hypercholesterolemia. Time elapsed from the beginning of PIs to the detection of hypertriglyceridemia was 5 months (3–18 months). One patient had a high triglyceride level at baseline that increased during HAART. This patient did not have a family history of dyslipidemia, and his parents’ cholesterol and triglyceride levels were normal. The highest triglyceride level observed during the followup in the cohort was 1110 mg/dL in an 11-year-old boy who also had hypercholesterolemia but no family history of dyslipidemia. After 15 months of HAART most patients had both hypercholesterolemia and hypertriglyceridemia (Figure 1). In 7/19 patients with high level of triglycerides, glucose levels were O110 mg/dL. At enrollment 78% of the patients were malnourished. During the follow-up, all patients experienced improvement in their nutritional status (Figure 2). When the study was completed, none of the patients had physical changes in
131
40
Grade II malnutrition
30
Grade III malnutrition
20 10 0 0
3
6
9
12
15
18
21
24
Months Figure 2. Nutritional status of 24 HIV-1-infected children under HAART. 0 represents nutritional status at enrollment. Points along the curves represent percentages of patients in each category at time of follow-up evaluation.
body fat distribution suggesting lipodystrophy or complications associated with hyperlipidemia or hypercholesterolemia.
Discussion Treatment of HIV-infected patients with PIs has been associated with a number of metabolic disorders and an abnormal deposit of body fat (4–7,11,12). A number of possible causes for these complications have been proposed (4,10). In the present study, more than 60% of children had increased cholesterol and/or triglycerides 9–12 months after the beginning of treatment with PIs. This increase was observed at an earlier stage for triglycerides, and the levels were higher than those reported in adult patients (7,20). Although risk for micro- and macrovascular damage exists, the consequences of these changes are unknown. After 2 years of treatment with PIs in the present cohort, we did not detect consequences associated with hyperlipidemia such as cholelithiasis, acute pancreatitis, or premature coronary artery disease. Nevertheless, because these types of complications can occur long after beginning PIs, it is necessary to be aware of such complications in patients receiving this type of drug. The frequency of hypertriglyceridemia in the present cohort was higher than that reported by Amaya et al. (14) in a pediatric cohort from Houston, TX (79.2 vs. 28%). This difference could be attributed to dietary differences between the two populations. Although Amaya et al. did not find a relationship between hyperlipidemia and a particular antiretroviral treatment, the number of patients in their group was too small. Most patients in our cohort received RTV or the RTV plus SQV combination as part of their HAART regimen. RTV has been associated with a higher rate of hypertriglyceridemia (6,21,22) in comparison with other PIs, and the SQV-RTV combination seems to intensify this effect (4,10). There was no relationship between a high
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ritonavir dose/hypertriglyceridemia, as patients received standard doses during the follow-up. At the present time we do not have a definite recommendation for prophylaxis or an effective treatment for dyslipidemia associated with PI usage in pediatrics. A possible strategy is to give nutritional advice aimed at reducing the intake of saturated fatty acids. Although the impact of modifying fat intake has not been evaluated, it would probably be negligible, considering the mechanism involved in the physiopathogenesis of hyperlipidemia linked to PI treatment. It has been suggested that the potential roles of RTV in lipid metabolism are related to a reduction of lipoprotein depuration during the postprandial period or by increasing lipid synthesis via liver enzymes. It has also been proposed that PIs inhibit proteins participating in lipid metabolism and adipocyte differentiation (23–25). Hypolipidemic therapy is not recommended for these patients because of potential drug interactions with PIs. At this time there is insufficient evidence to support recommendations for prevention and therapy in HIV-infected children who develop dyslipidemia while receiving PIs. Additional studies with larger cohorts and a longer follow-up to document complications associated with altered lipid metabolism are needed to propose rationales and alternatives. References 1. Rhone SA, Hogg RS, Yip B, Sherlock C, Conway B, Schechter MT, O’Shaughnessy MV, Montaner JS. The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study. AIDS 1998;12:619–624. 2. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Morb Mortal Wkly Rep 1998;47(RR–5):43–82. 3. Saez-Llorens X, Ramilo O. Early experience with protease inhibitors in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1998;17:728–738. 4. Mauss S, Stechel J, Willers R, Schmutz G, Berger F, Richter WO. Differentiating hyperlipidemia associated with antiretroviral therapy. AIDS 2003;17:189–194. 5. Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Korner T, Stoll M, Schmidt RE. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patient under treatment with protease inhibitors. AIDS 1999;13:F63–F70. 6. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 2000;160:2050–2056. 7. Sullivan AK, Gazzard N, Gazzard BG. Marked hypertriglyceridemia associated with ritonavir therapy. AIDS 1998;2:1393–1394.
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