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Insulin Resistance (25%) Is Associated With Advanced Liver Fibrosis and High Body Mass Index in HIV/HCV-Coinfected Patients
[Letters to the Editor]
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JAIDS Journal of Acquired Immune Deficiency Syndromes:Volume 50(1)1 January 2009pp 109-110
Ryan, Pablo MD*; Berenguer, Juan MD, PhD*; Michelaud, Dariela MD, PhD; Miralles, Pilar MD*; Bellon, J M MsC; Alvarez, Emilio MD, PhD; Catalan, Pilar PharmD_; Sanchez-Conde, Matilde MD*; Resino, Salvador PhD
*Department of Infectious Diseases; Biomedical Research Foundation; Molecular Immunobiology Laboratory; Department of Pathology; and _Department of Microbiology Hospital Gregorio Maranon Madrid, Spain The Research Unit Instituto de Salud Carlos III Majadahonda, Madrid, Spain
Supported by Grants from Fondo de Investigacion Sanitaria from the Spanish Health Ministry (Ref. PI05/2411, Ref. PI07/90201, Ref. ISCIII-RETIC RD06/006), Fundacion para la Investigacion y la Prevencion del SIDA en Espana (Ref. 36650/07, Ref. 36443/03), and the Post-MIR grant from the Gregorio Maranon Biomedical Research Foundation.
Presented at the 43rd Annual Meeting of the European Association for the Study of the Liver, April 23-27, 2008, Milan, Italy. Abstract 753.
"In conclusion, we found that approximately a quarter of HIV/HCV-coinfected patients who underwent a liver biopsy to assess their suitability for anti-HCV therapy had IR. We also found that IR was associated with advanced liver fibrosis and a high BMI."
To the Editor:
In hepatitis C virus (HCV)-monoinfected patients, insulin resistance (IR) has been identified as a factor that promotes steatosis and fibrosis progression1 and as an independent predictor of the response to peginterferon plus ribavirin.2 Unlike the results in HCV-monoinfected patients, the association of IR with the severity of liver fibrosis in HIV/HCV-coinfected patients has not been clearly elucidated.
The aims of this study were to determine the prevalence of IR, identify associated factors, and evaluate the relationship between IR and liver fibrosis in HIV/HCV-coinfected patients.
METHODS
Subjects were selected from the HIV outpatient clinic of our institution. They all had documented HIV/HCV coinfection and underwent liver biopsy before therapy with interferon and ribavirin between May 2000 and 2007. The eligibility criteria for anti-HCV therapy in our institution included absence of previous hepatic decompensation, CD4+ lymphocyte count higher than 200 cells per microliter, stable antiretroviral therapy or no need for antiretroviral therapy, and absence of active opportunistic infections and active drug or alcohol addiction. We excluded patients with diabetes mellitus.
On the day of the liver biopsy, the following information was obtained from the medical record: age, sex, risk category, weight, height, Centers for Disease Control and Prevention clinical category, prior antiretroviral therapy, plasma HIV RNA level and CD4+ T-cell count at the time of the biopsy, and nadir CD4+ T-cell count. After an overnight fast and before liver biopsy was performed, a blood sample was taken for complete blood counts, liver panel, basic metabolic panel, and coagulation tests. A serum sample was immediately stored and frozen at -70C for further assays.
HIV infection was documented in all patients by enzyme-linked immunosorbent assay and a Western blot assay. All patients tested positive for specific HCV antibodies and had detectable serum HCV RNA assessed by polymerase chain reaction. The HCV viral load was measured by polymerase chain reaction (Cobas Amplicor HCV Monitor Test; Roche Molecular Systems, Inc., Branchburg, NJ).
For each patient, the degree of IR was estimated using the homeostatic model assessment (HOMA) method described by Matthews.3 As in other studies, IR was considered altered when the HOMA score was 3.8 or higher. In our study, glucose and insulin were measured from an overnight fasting blood sample taken before liver biopsy. Insulin was measured using the Multiplex kit (LINCOplex; LINCO Research, Saint Charles, MO). Liver biopsy was performed on an outpatient basis following the recommendations of the Patient Care Committee of the American Gastroenterological Association.4 Grading and staging of the liver biopsy followed the criteria established by the METAVIR Cooperative Study Group.5 Data were analyzed using the SPSS software version 15.0 (SPSS Inc., Chicago, IL) 15.0 software.
RESULTS
The study cohort included 201 patients whose characteristics at the time of liver biopsy are shown in Table 1. The distribution of liver fibrosis in our cohort according to the METAVIR fibrosis stage score was 0 (8%) (no fibrosis), 1 (34%) (portal fibrosis), 2 (26%) (periportal fibrosis), 3 (20%) (bridging fibrosis), and 4 (11%) (cirrhosis). Liver steatosis was observed in liver biopsies from 108 (54%) patients. The median HOMA value was 2.47, and 54 (26.8%) patients were classified as having IR. When clinical and laboratory parameters for patients with and without IR were compared, no differences were found with respect to sex, age, HIV transmission category, Centers for Disease Control and Prevention clinical category, or HIV and HCV virological parameters. However, patients with IR had a higher body mass index (BMI), lower nadir CD4+ T-cell counts, and higher liver fibrosis scores than those without IR (Table 1). In a multivariate logistic regression analysis adjusted for age, alcohol abuse, nadir CD4 cell count, HCV viral load, HCV genotype, antiretroviral drugs, and liver steatosis, the variables independently associated with IR were advanced liver fibrosis (odds ratio, 4.0; 95% confidence interval, 1.2 to 12.4; P = 0.01) and BMI (odds ratio, 1.4; 95% confidence interval, 1.1 to 1.8; P = 0.006).
DISCUSSION
In this cross-sectional study carried out in 201 HIV/HCV-coinfected patients, the prevalence of IR measured by HOMA was 27%. The factors independently associated with IR were higher BMI and advanced liver fibrosis.
In HCV-monoinfected patients, IR has been identified as a factor associated with fibrosis progression. Interestingly, it has been found that hyperinsulinemia and hyperglycemia can activate hepatic stellate cells, which are the main extracellular matrix-producing cells in liver fibrogenesis.6 Little is known about the prevalence and associated factors of IR in HIV/HCV-coinfected patients. In a study, with 79 subjects, that used the same HOMA-IR cutoff value as ours, the authors found a 29.1% prevalence of IR.7 Unlike our study, no association was found between IR and liver fibrosis assessed by biopsy.
The association between BMI and IR is not a new finding. Inflammatory cytokines such as tumor necrosis factor alpha, leptin, and free fatty acids produced by adipose tissue play a regulatory role in glucose homeostasis and are implicated in the etiology of obesity-induced IR.8 In patients who are monoinfected by HCV, an increased BMI has been found to be associated with liver steatosis and progression of fibrosis.9 However, we found that BMI was not associated with liver fibrosis but with liver steatosis only in HCV genotype 1 infections (data not shown).
In conclusion, we found that approximately a quarter of HIV/HCV-coinfected patients who underwent a liver biopsy to assess their suitability for anti-HCV therapy had IR. We also found that IR was associated with advanced liver fibrosis and a high BMI. Further work must be done to assess the implications of these findings for practice and in particular how they relate to response to therapy with pegylated interferon plus ribavirin.
Pablo Ryan, MD*
Juan Berenguer, MD, PhD*
Dariela Michelaud, MD, PhD
Pilar Miralles, MD*
J. M. Bellon, MsC
Emilio Alvarez, MD, PhD
Pilar Catalan, PharmD_
Matilde Sanchez-Conde, MD*
Salvador Resino, PhD
*Department of Infectious Diseases; Biomedical Research Foundation; Molecular
Immunobiology Laboratory;
Department of Pathology; and _Department of Microbiology
Hospital Gregorio Maranon
Madrid, Spain
The Research Unit
Instituto de Salud Carlos III
Majadahonda, Madrid, Spain
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