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Lipid Protective Effect of HCV Coinfection
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"Lipid abnormalities in HIV/hepatitis C virus-coinfected patients"
HIV Medicine
Volume 7 Issue 8 Page 530 - November 2006
R Bedimo1,2, R Ghurani1, M Nsuami3, D Turner2, M-B Kvanli2, G Brown1,2 and D Margolis1,2
"....our findings are in accordance with published data showing that TC and TG levels were significantly lower in coinfected patients.....apparent protective effect of HCV infection on the development of dyslipidaemia...."
Note from Jules Levin: my personal experience was that after I eradicated HCV through 18 months of peginterferon plus ribavirin, my lipids went through the roof and were not very controllable with statin therapy. I managed to get control after a switch to Reyataz.
Background
Among HIV-infected patients, hepatitis C virus (HCV) coinfection is associated with increased rates of lipodystrophy and insulin resistance. Its impact on HIV-associated dyslipidaemia is less clear.
Methods
The lipid profiles of all HIV-infected patients and a subset of HCV-infected patients seen at the VA Medical Center in Dallas from January 2003 to March 2004 were analysed. Demographic data, HCV serostatus, and HIV treatment history were recorded. Lipid profiles of HIV/HCV-coinfected patients were compared with those of HIV-monoinfected and HCV-monoinfected patients.
Results
A total of 359 HIV-infected patients, 91 (25.3%) of whom were HCV coinfected, and 112 HCV-infected patients were included in the analysis. Among the HIV-infected patients, HCV coinfection was associated with a reduced risk of hypercholesterolaemia [9.9% vs 24.8%; relative risk (RR)=0.333; 95% confidence interval (CI)=0.158-0.699; P<0.001] and hypertriglyceridaemia (48.4% vs 60.3%; RR=0.616; 95% CI=0.382-0.994; P=0.031).
After controlling for duration of protease inhibitor (PI) therapy, race, alanine aminotransferase (ALT) concentration and platelet count, HCV remained an independent predictor of hypercholesterolaemia (RR=0.369; P=0.01) and any dyslipidaemia (RR=0.531; P=0.019). In addition, the rate of dyslipidaemias was lower among HCV-monoinfected than HIV/HCV-coinfected patients (29.5% vs 50.5; P=0.002). White race was also an independent predictor of dyslipidaemia (73.8% vs 50.7%; RR=2.32; 95% CI=1.44-3.76; P=0.001).
Conclusions
HCV coinfection independently predicted lower rates of dyslipidaemia among HIV-infected patients. An analysis of lipid kinetics among mono- and coinfected patients may elucidate the mechanisms of the apparent protective effect of HCV infection.
Introduction
The introduction of highly active antiretroviral therapy (HAART) has been associated with a significant decline in morbidity and mortality among HIV-infected patients [1]. As a consequence of the resulting increased patient survival, chronic complications including metabolic abnormalities and chronic liver disease [2-4], which frequently coexist in the same patient, are of growing importance.
A significant proportion of HIV-infected patients on HAART develop a cluster of metabolic abnormalities characterized by triglyceride-rich dyslipidaemia and insulin resistance often associated with fat redistribution or lipodystrophy [5-7]. A dysregulation of fatty acid metabolism leading to increased lipolysis has been implicated as the metabolic basis of HIV-lipodystrophy syndrome [8,9].
Also, the prevalence of hepatitis C virus (HCV) coinfection is very high among HIV-infected patients [3,4] and is a strong predictor of morbidity and mortality in the HAART era [10-12]. Among HIV-infected patients, while HCV coinfection appears to be associated with higher rates of lipodystrophy and glucose intolerance [13,14], its impact on the development of lipid abnormalities has still not been clearly elucidated. In a series by Duong et al. [13], insulin resistance was found to be significantly more frequent, and dyslipidaemia significantly less prevalent, in HIV/HCV-coinfected patients compared with HIV-monoinfected patients. Three other retrospective analyses [15-17] and one prospective cohort study [18] suggested that HCV coinfection is an independent factor preventing the emergence of treatment-limiting total cholesterol increases on HAART, possibly reflecting impaired total cholesterol synthesis in the liver or total cholesterol hypercatabolism. Finally, together with hypertension, depression and opportunistic infections, HCV infection was negatively associated with a diagnosis of dyslipidaemia in a retrospective cohort study [19].
As coinfection with HCV appears to decrease the prevalence of dyslipidaemia in HIV infection, lower rates of dyslipidaemia would be expected in HCV-monoinfected patients. None of the previous studies, however, compared rates of dyslipidaemia among HIV-monoinfected, HCV-monoinfected and HIV/HCV-coinfected patients. In addition, the small numbers of patients enrolled in these studies prevented the analyses of potentially contributing factors such as age and duration of HAART therapy.
To determine the impact of HCV coinfection on patients' lipid profiles, we have compared rates of hypercholesterolemia and hypertriglyceridemia among patients at the Dallas VA Medical Center with HIV monoinfection, HCV monoinfection and HIV/HCV coinfection.
Materials and methods
Setting and study design
The VA Medical Center in Dallas, Texas, operates both HIV and HCV out-patient clinics. All HIV-infected patients seen in HIV out-patient clinics between March 2003 and July 2004 and all HCV-infected patients seen in HCV out-patient clinics during the last 3 months of the previous observation period, and who had at least one measurement of lipid profile during the study period, were enrolled in the study. The HIV and HCV clinics see patients with similar demographic characteristics: over 95% of the clinic attendees are male and they have a median age of about 50 years.
Data on fasting lipid profiles, including concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL) and triglycerides (TG), were obtained. LDL was estimated by the laboratory using the following formula: LDL=TC-HDL-TG/5. As this formula is inaccurate at higher TG levels, no LDL level was reported for patients with TG≥400mg/dL. For patients with more than one measurement of lipid profile during the study period, the measurement with the highest levels of total cholesterol and TG was used, regardless of lipid-lowering therapy history. Although lipid profiles were always ordered - and were supposed to be collected - in the fasted state, this could not always be verified because of the retrospective nature of the data collection. The diagnosis of lipodystrophy was made by the clinic provider if the patient exhibited prominent peripheral and facial subcutaneous fat wasting (lipoatrophy) or central fat accumulation (lipohypertrophy) according to previously defined criteria [20].
In addition to patient demographic characteristics, other data obtained for all patients included serum transaminase, platelet and fasting blood sugar levels. For HIV- and HIV/HCV-infected patients, the nature and duration of antiretroviral therapy, and virological and immunological characteristics were obtained. For HIV-infected patients with more than one CD4 cell count and plasma HIV-1 RNA assay during the study period, the highest CD4 count and the lowest viral RNA measurement were recorded.
Data analysis
The total study population was divided into three groups: (1) patients with HIV infection only, (2) patients with HIV and HCV coinfection, and (3) patients with HCV infection only. To determine the potential impact of HCV infection and other factors on dyslipidaemias, mean levels of TC, HDL, LDL and TG were compared among the study groups. Also, the percentages of patients in each group with hypercholesterolaemia (defined as TC ≥240 mg/dL) and hypertriglyceridaemia (defined as serum TG ≥200 mg/dL) were compared. Platelet count was used in this analysis as a surrogate marker for severe liver dysfunction.
Data were analysed as categorical or continuous variables as appropriate. For categorical variables, χ2 and Fisher's exact tests were used to test for differences between groups. For continuous variables, nonparametric Wilcoxon rank sum tests were used. Univariate logistic regression models were fitted to identify factors associated with hypercholesterolaemia and hypertriglyceridaemia. Factors that were significant (P<0.05) in univariate analysis were then considered in a multivariable model. Nonsignificant variables (P≥0.05) were removed, beginning with the least significant variables, until the final full model was determined. Statistical analyses were performed using SPSS Version 11.0.2 for Mac OS X (SPSS Inc., Chicago, IL, USA).
Results
Patient characteristics
Four hundred and seventy-one patients seen in our HIV and HCV clinics during the study periods, and who had lipid profile measurements, were included in the analysis. Of the 359 HIV-positive patients, 91 (25.3%) were HCV- positive. One hundred and twelve patients had HCV infection but not HIV infection.
The median age of the study population was 51 years (range 30-76 years). Overall, 98.1% were male and 52.8% were white. Other demographic characteristics of the study population are presented in Table 1.
The HIV-monoinfected and HIV/HCV-coinfected groups were comparable in every respect except race distribution and mean alanine aminotransferase (ALT) concentration. HCV-only patients also had a significantly higher mean body mass index (BMI) (28.3) than HIV-only patients (26.1) and HIV/HCV-coinfected patients (26.1; P<0.0001).
Lipid profiles and lipodystrophy rates in HIV-monoinfected vs HIV/HCV-coinfected patients
In univariate analysis, HIV/HCV coinfection was associated with a significantly reduced risk of hypercholesterolaemia [9.9% vs 24.8%; relative risk (RR)=0.333; 95% confidence interval (CI)=0.158-0.699; P<0.001] and hypertriglyceridaemia (48.4% vs 60.3%; RR=0.616; 95% CI=0.382-0.994; P=0.031).
HIV/HCV-coinfected patients had lower mean TG (331 vs 240 mg/dL; P<0.0001) TC (183 vs 212 mg/dL; P<0.001) and LDL (95 vs 120 mg/dL; P<0.001) and higher HDL (44 vs 48 mg/dL; P=0.015) than HIV-monoinfected patients. In logistic regression analysis controlling for HAART therapy, gender and race, HCV infection remained independently associated with a reduced risk of hypercholesterolaemia, but not hypertriglyceridaemia.
Another analysis was performed to account for the fact that some previously dyslipidaemic patients could have normalized lipid profiles during the period of observation because they were receiving lipid-lowering medications. We therefore combined patients with dyslipidaemia (hypercholesterolaemia and/or hypertriglyceridaemia) with those on lipid-lowering therapy. Again, HIV/HCV-coinfected patients were significantly less likely to have dyslipidaemia or to be on lipid-lowering therapy than HIV-monoinfected patients (50.5% vs 68.4%; P=0.002).
The HIV-monoinfected group had a significantly higher rate of lipodystrophy than the HIV/HCV-coinfected group (28.4% vs 16.5%; P=0.015).
Lipid profiles of HCV-monoinfected vs HIV/HCV-coinfected patients
HCV-monoinfected patients had a significantly lower mean serum TG than HIV/HCV-coinfected patients (see Fig. 1 and Table 2). There was no statistically significant difference in mean TC, LDL or HDL between HCV-monoinfected and HIV/HCV-coinfected patients. While the percentage of patients with hypercholesterolaemia was comparable between the two groups (8.0% vs 9.9%, respectively; P=0.413), there were significantly fewer HCV-monoinfected patients than HIV/HCV-coinfected patients with hypertriglyceridaemia (16.1% vs 48.4%; P<0.0001) and with HDL<35 mg/dL (11.6% vs 24.2%; P=0.015). Also, fewer HCV-monoinfected than HIV/HCV-coinfected patients either had dyslipidaemia or were on lipid-lowering therapy (29.5% vs 50.5%; P=0.002).
Stratified analyses
Among all HIV-infected patients, comparison of lipid profiles between racial groups showed that mean serum TG (204 vs 323 mg/dL, respectively; P<0.0001), TC (189 vs 202 mg/dL; P=0.006) and LDL (102 vs 113 mg/dL; P=0.005) were significantly less elevated and HDL was significantly higher (53 vs 44 mg/dL; P<0.0001) in African-Americans than in Caucasians. Conversely, black patients were significantly less likely to have lipodystrophy than white patients (11.4% vs 35.4%; P<0.0001). The differences in mean TG and LDL levels remained statistically significant on multivariable analysis after controlling for HCV coinfection status, age, protease inhibitor (PI) duration, platelet count, and ALT level (Tables 3 and 4).
As HCV coinfection was more prevalent in African-Americans, and African-Americans had significantly lower rates of dyslipidaemia and HCV coinfection was significantly more prevalent among black patients than white patients (37.6% vs 16.1%, respectively; P<0.0001), it was probable that the previously reported protective effect of HCV coinfection on dyslipidaemia could be accounted for only by racial differences in rates of HCV coinfection. We therefore conducted stratified analyses among African-Americans only and Caucasians only. These analyses showed hypercholesterolaemia and hypertriglyceridaemia both to be significantly more prevalent among HIV-monoinfected than HIV/HCV-coinfected patients within each racial group.
Discussion
Our data show that HCV coinfection was an independent predictor of lower rates of dyslipidaemia in general, and hypercholesterolaemia in particular, among HIV-infected patients. Although HCV coinfection predicted lower rates of hypertriglyeridaemia in univariate analysis, this did not remain in multivariate analysis controlling for age, race, platelet count and ALT. Our results therefore add to a growing body of evidence that HCV coinfection is associated with the development of dyslipidaemia among HIV-infected patients [14-19,21].
HCV did not independently predict rates of lipodystrophy among HIV-infected patients and we did not have enough fasting blood sugar data to evaluate the effect of HCV on glucose intolerance in our study population. Previous studies showed that lipodystrophy and insulin resistance were significantly more frequent in HIV/HCV-coinfected patients [13,14]. Factors that independently predicted lipodystrophy in our cohort included longer duration of PI therapy, older age and white race. These findings are in accordance with previously published observations [7,19,22-24].
Regarding the impact of race on lipid abnormalities, our findings are again consistent with previous observations of lower rates of dyslipidaemia among African-Americans than Caucasians, both in HIV-infected populations [19,25] and in the general population [26]. As HCV infection is also more prevalent among African-Americans, both in our cohort and in previously published US data [4], it might be inferred that the lower rates of dyslipidaemia among HCV-coinfected patients is mainly a result of the higher proportion of African-Americans with HCV coinfection. However, both the sensitivity analyses comparing rates of dyslipidaemia in mono- and coinfected patients within each racial group separately and multivariate analyses controlling for race showed that HCV coinfection remained an independent predictor of lower rates of dyslipidaemia.
In summary, our findings are in accordance with published data showing that TC and TG levels were significantly lower in coinfected patients. Although the findings of one study did not support these findings [14], that study did not control for age, race, PI duration and degree of liver dysfunction.
Consistent with previously published data, we found that rates of hypercholesterolaemia and hypertriglyceridaemia among HIV/HCV-coinfected patients were also higher than those in HCV-monoinfected patients with similar demographics and severity of liver disease. This finding, together with recent comparisons of lipid profiles among HCV-infected patients and uninfected controls [27], significantly strengthens the hypothesis of an apparent protective effect of HCV infection on the development of dyslipidaemia.
Our cohort was larger than those reported in previous studies. However, these findings should be confirmed in a larger study on patients drawn from more diverse clinic populations. Our retrospective study could not control for confounding factors such as the impact of food intake in the measurement of serum TG levels. Despite instructions, patients did not always fast prior to lipid measurements. Serum TG levels among both mono- and coinfected patients might therefore be artifactually increased, blunting the apparent effect of HCV.
Another potential limitation is the subjective assessment of lipodystrophy. Finally, the stage of liver disease among HCV-coinfected or even HIV-monoinfected patients is likely to have a significant impact on lipid abnormalities. The stage of liver disease was not ascertained because our patients did not have liver biopsies. However, we have used platelet count, a surrogate marker for extent of liver dysfunction, and this variable was entered in all multivariate analyses.
We conclude from our data that:
1. HCV infection is associated with lower rates of dyslipidaemia among HIV-infected patients;
2. HCV infection does not appear to independently affect the rate of HIV-associated lipodystrophy in multivariable analysis, and
3. although HCV infection is significantly more prevalent in African-Americans, black race and HCV were both independently associated with lower rates of dyslipidaemia among HIV-infected patients.
Understanding the cause of the apparent protective effect of HCV coinfection might help shed light on the metabolic basis of HIV-associated dyslipidaemia, which has not been completely elucidated. One possibility is that HCV occupies LDL receptors, limiting the entry of LDL into cells. Indeed, HCV particles bind to LDL receptors in vitro and are present in the low-density fractions of plasma from infected patients, suggesting an association of the virus with lipoproteins and the use of lipoprotein receptors for cell entry [28]. Perhaps a more likely possibility is that HCV interferes with an HIV-induced dysregulation of lipoprotein metabolism. Recent evidence suggests that impairment of adipocyte differentiation, cytokine dysregulation and mitochondrial toxicity play a role in development of lipodystrophy and dyslipidaemias [8,9,23]. Studies of the lipid kinetics of HIV-infected patients with lipodystrophy have shown increased rates of lipolysis compared with non-HIV-infected patients. As this release of free fatty acids is not accompanied by an equivalent increase in fatty acid oxidation, there is increased free fatty acid availability for transfer to the liver and incorporation into lipoprotein triglycerides, which are secreted, and to the skeletal muscle where they impair normal insulin signalling [8,9]. There was a positive correlation between the rate of hepatic re-esterification and fasting plasma triglyceride concentration in HIV-infected patients without lipodystrophy, but not in patients with lipodystrophy.
Measurement of lipoprotein subfractions and lipid kinetics in HCV-coinfected and HIV- and HCV-monoinfected patients, using stable isotope tracer techniques, might help to elucidate these mechanisms.
As metabolic complications and chronic liver disease become the dominant factors in HIV-associated morbidity and mortality, studying their concurrent effects in HIV-infected patients might suggest better strategies for prevention of these complications.
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