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HCV/HIV Coinfection & Lipid Abnormalities
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"The Influence of Hepatitis C Virus Coinfection on the Risk of Lipid Abnormalities in a Cohort of HIV-1-Infected Patients After Initiation of Highly Active Antiretroviral Therapy"
Letters To The Editor. JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 36(1) 1 May 2004
Di Giambenedetto, Simona MD; Baldini, Francesco MD*; Cingolani, Antonella MD; Tamburrini, Enrica MD; Cauda, Roberto MD; De Luca, Andrea MD
Istituto di Clinica delle Malattie Infettive, Università Cattolica del Sacro Cuore, and *Istituto Nazionale delle Malattie Infettive-IRCCS Lazzaro Spallanzani, Rome, Italy. Supported by Istituto Superiore di Sanità, Ministero della Salute, IV Progetto Nazionale AIDS, Patologia, Clinica e Terapia dell'AIDS, grant nr 30.D.16.
Note from Jules Levin: following successful HCV therapy (Sustained Viral Response) status of lipids may be changed. Cholesterol and triglycerides may be higher due to improved liver function. This may need to be addressed by medical care providers and should be considered and studied.
To the Editor:
Highly active antiretroviral therapy (HAART) has significantly reduced AIDS-related morbidity and mortality. 1 The improved survival made possible by HAART has brought to light the potential long-term complications of drug therapy, including the risk of cardiovascular disease. 2 Several metabolic disorders such as dyslipidemia, diabetes, and alteration of body fat composition 2-4 can develop or worsen in patients during HIV therapy. Dyslipidemias in drug antiretroviral therapy include increases in total serum cholesterol, particularly an increase in the atherogenic non-high density lipoprotein (non-HDL) cholesterol and trigycerides. 5 HIV-infected patients may exhibit multiple known risk factors for cardiovascular disease. Of specific concern is the fact that treatment with essential components of HAART, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), particularly when both are used in combination, is associated with a lipid profile known to increase the risk of coronary heart disease, particularly among older subjects with increased CD4 cell counts and suppressed HIV replication. 5 In the large DAD multicohort study, hypercholesterolemia and hypertriglyceridemia have been recently shown to be independent predictors of myocardial infarction in HIV-infected patients on HAART. 2 While several risk factors for dyslipidemia during antiretroviral therapy have been identified, the roles of hepatitis virus coinfections and liver function have been only preliminarily investigated in this regard. In a Spanish cohort, patients coinfected with hepatitis C virus (HCV) had considerably lower rates of hyperlipidemia than those without HCV, and this effect was particularly evident in those treated with HAART. 6 A second study showed that HCV-coinfected patients starting HAART had lower cholesterol levels over time but identical triglycerides. 7
With the aim of evaluating the effect of HCV infection on the risk of reaching clinically significant serum lipid levels after beginning antiretroviral therapy, in the context of other relevant risk factors for hyperlipidemia, we analyzed the observational cohort database from a tertiary care center for infectious diseases in Rome, Italy, from 1996-2003. We selected HIV-1-infected patients beginning HAART, defined as any combination of >=3 drugs including at least one PI or NNRTI, with known baseline hepatitis B virus (HBV) and HCV serostatus, and with CD4, HIV RNA, and fasting serum lipids available at baseline and during follow-up, indicated as the first available result in the database. Logistic regression was employed to analyze predictors of categorical outcomes.
Of 907 patients beginning HAART, 225 meeting the above-mentioned criteria were selected for the analysis. At baseline, mean age was 37 years (95% CI, 36-38); 142 (63%) were males; 90 (40%) were injection drug users; 76 (34%) started an NNRTI-based HAART, 145 (64%) a PI-based HAART, while 4 (2%) started a combination of PI plus NNRTI. Mean CD4 cell counts were 314/mL (95% CI 299-350); mean HIV RNA 4.3 log copies/mL (95% CI 4.15-4.36); mean fasting total cholesterol was 6 mM (177 mg/dL); mean fasting triglycerides 1.4 mM (123 mg/dL); mean alanine aminotransferase (ALT) 32 IU/L; 108 (48%) patients were anti-HCV positive and 21 (9%) were positive for the hepatitis B surface antigen.
After starting HAART, by intention-to-treat analysis, 149 (66%) patients reached HIV RNA <500 copies/mL within week 32. At the first available follow-up (mean 13 weeks, 95% CI 12-15), the National Cholesterol Education Program (NCEP)-defined cutoffs for clinically meaningful dyslipidemia 8 were overcome in the following numbers: 39 patients (17%) reached total cholesterol >6.2 mM (>240 mg/dL), 63 (28%) had HDL <0.9 mM (35 mg/dL), and 81 (36%) had triglycerides >2.3 mM (200 mg/dL).
At univariate analysis, the following variables were found to be associated with the risk of total cholesterol >6.2 mM: age (for 1 year more, odds ratio [OR] 1.04; 95% CI 1.00-1.10), anti-HCV-positive status (OR 0.22; 95% CI 0.09-10.53), baseline total cholesterol (each 1 mg/dL higher, OR 1.03; 95% CI 1.01-11.05), while age, gender, HBV serostatus, baseline ALT, HIV RNA, and type of therapy were not associated. At multivariate analysis, independent predictors of total cholesterol >6.2 mM were older age and anti-HCV-positive status. Univariate predictors of HDL <0.9 mM were NNRTI-based HAART (OR 0.44; 0.22-10.88) and female sex (OR 0.19; 0.09-10.40) but not hepatitis virus serostatus; both variables remained independent predictors of elevated HDL at multivariate analysis. Variables associated with triglyceride levels >2.3 mM were older age (OR 1.03; 95% CI 1.00-1.07), female sex (OR 0.36; 95% CI 0.20-0.66), NNRTI-based HAART (OR 0.45; 0.25-0.84), and PI-based HAART (OR 1.95; 1.05-1.60), while hepatitis virus serostatus, baseline ALT and triglyceride levels, and viral load did not show significant associations. Virologic response showed a borderline association with triglycerides above NCEP cutoff (OR 1.88; 0.88-4.00). At multivariate analysis, factors showing an independent negative association with hypertriglyceridemia were female sex and the use of NNRTI-based HAART.
This observational cohort study showed in HIV-infected individuals an independent association of HCV coinfection with a reduced risk of clinically relevant elevations of total cholesterol. Older age, male gender, and PI-based HAART as compared with NNRTI-based HAART were other significant predictors of an atherogenic lipid profile. Our findings confirm and extend previous observations that coinfection with HCV is associated with a lower probability of total cholesterol elevations after HAART initiation. In particular, in HIV/HCV-coinfected patients, 3 months after HAART initiation, we detected a mean 80% reduction in the adjusted risk of total cholesterol elevations judged clinically relevant by NCEP guidelines. Given that HCV did not show associations with HDL cholesterol levels in this study, it can be indirectly deduced that the lower risk of total cholesterol elevation is related to the non-HDL cholesterol component. While HCV had no influence on triglyceride elevations, NNRTI-based regimens as compared with PI-based as well as female sex showed a reduced probability of low HDL cholesterol and high triglyceride levels: these variables may therefore be associated with a lower cardiovascular risk. Although lipid levels represent only surrogate markers of the cardiovascular risk, factors associated with its elevations should be taken into account when choosing treatment regimens in the individual patient.
Simona Di Giambenedetto, MD
Francesco Baldini, MD*
Antonella Cingolani, MD
Enrica Tamburrini, MD
Roberto Cauda, MD
Andrea De Luca, MD
Istituto di Clinica delle Malattie Infettive, Università Cattolica del Sacro Cuore, and *Istituto Nazionale delle Malattie Infettive-IRCCS Lazzaro Spallanzani, Rome, Italy
REFERENCES
1. Palella F, Delaney K, Moorman A, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:853-860.
2. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;20;349:2065-2067.
3. Carr A, Samaras K, Chisholm D, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;352:1881-1883.
4. Duong M, Petit JM, Piroth L, et al. Association between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27:245-250.
5. Friis-Moller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients: association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179-1193.
6. Collazos J, Mayo J, Ibarra S, et al. Hyperlipidaemia in HIV-infected patients: the protective effect of hepatitis C virus co-infection. AIDS. 2003;17:927-929.
7. Torti C, Patroni A, Tinelli C, et al. Influence of hepatitis C virus coinfection on lipid abnormalities in HIV-positive patients after highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;29:315-316.
8. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA. 1993;269:3015-3023.
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