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Hyperlipidemia in HIV-infected patients: the protective effect of hepatitis C virus co-infection

Collazos, Julio; Mayo, José; Ibarra, Sofía; Cazallas, Juan

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Section of Infectious Diseases, Hospital de Galdakao, Vizcaya, Spain.

Received: 9 May 2002; revised: 11 October 2002; accepted: 21 October 2002.

The prevalence of hyperlipidemia and factors related to it have been studied in a large sample of patients. We found a significant association between hyperlipidemia and the duration of antiretroviral therapy, serum cortisol levels, the presence of lipodystrophy, certain antiretroviral regimens and, especially, the absence of hepatitis C virus (HCV) infection. Patients co-infected with HCV had considerably lower rates of hyperlipidemia than non-infected patients, and this effect was particularly evident in patients treated with antiretroviral drugs.

The presence of hyperlipidemia in patients taking protease inhibitors (PI) compared with PI-naive patients or HIV-negative controls has been reported as a part of the lipodystrophy syndrome [1–4], as well as improvements in lipid abnormalities after switching from PI-based to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens [5].

The present study was carried out to evaluate the prevalence of hyperlipidemia in a large group of HIV-infected patients attending an outpatient clinic, and the factors associated with this disturbance.

The data were extracted from a database of HIV-infected men, most of whom were past intravenous drug users. The study group was composed of 197 patients, who underwent a total of 368 clinical and laboratory evaluations. The number of determinations per patient ranged from one to four, each separated by a mean interval of 27.4 weeks. All patients were clinically stable and did not have any acute severe illness at the time of sampling. All samples were obtained at between 8.00 and 8.30 a.m. after an overnight fast. Hyperlipidemia was defined as total cholesterol or triglyceride levels greater than 200 mg/dl.

Differences between groups were assessed using the Mann–Whitney U test and the chi-square test as appropriate. A stepwise logistic regression analysis was used to identify the independent association of the studied variables with the presence of hyperlipidemia. A P value of less than 0.05 for a two-sided test was considered statistically significant.

The mean age of the patients was 36.8 years, the mean CD4 cell count was 452.1 × 106/l, and 64% had an undetectable viral load. Hyperlipidemia was observed in 59 of the 197 patients (29.9%) and in 112 of the 368 determinations (30.4%). Hyperlipidemic patients were receiving antiretroviral therapy for longer periods (mean 26.7 versus 24.4 months, P = 0.049), and had higher serum cortisol levels (mean 618 versus 552 nmol/l, P = 0.002) than patients without hyperlipidemia. We did not find significant differences with respect to age, testosterone, 17β-estradiol, thyroid hormones, CD4 cell count, viral load, or a previous diagnosis of AIDS. Regarding other metabolic complications, we found that 38.8% of the lipodystrophic patients had hyperlipidemia compared with 27.7% of the non-lipodystrophic patients (P = 0.049). There were no differences regarding the existence of diabetes mellitus (P = 0.8). When patients with other metabolic disturbances such as lipodystrophy and diabetes were excluded, we also found an association of hyperlipidemia with longer periods of antiretroviral therapy (mean 26.7 versus 23.3 months, P = 0.007), and higher cortisol values (mean 618 versus 555 nmol/l, P = 0.004).

Table 1 shows the comparison of patients with hyperlipidemia with those without hyperlipidemia or without other metabolic complications according to the antiretroviral therapy and hepatitis C virus (HCV) status. Patients treated with efavirenz had higher rates of hyperlipidemia than patients treated with nevirapine (49 versus 20.7%, respectively, P = 0.002) and than patients treated with PI (31.5%, P = 0.02), differences that were also observed when other metabolic disturbances were excluded (64.1 versus 24.5%, P = 0.0002, and versus 39.2%, P = 0.007, respectively).

Table 1
Table 1
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Sequential evaluations of hyperlipidemia over time did not reveal significant differences (29.9, 31.5, 33.3, and 25%, respectively, P = 0.9). A logistic regression analysis of all variables studied selected absence of infection with HCV [odds ratio (OR) 0.24, 95% confidence interval (CI) 0.13–0.44, P < 0.001], serum cortisol (OR 1.05, 95% CI 1.01–1.09, P = 0.01), lipodystrophy (OR 1.96, 95% CI 1.06–3.61, P = 0.03) and duration of highly active antiretroviral therapy (HAART; OR 1.03, 95% CI 1.01–1.05, P = 0.02) as the only variables independently associated with hyperlipidemia. Only when the latter was excluded, were NNRTI (OR 2.29, 95% CI 1.31–3.98, P = 0.004) and PI treatment (OR 2.04, 95% CI 1.16–3.57, P = 0.01), in addition to the other three variables, selected as predictors of hyperlipidemia.

Some studies have also found that hyperlipidemia is associated with lipodystrophic changes [1,2,6,7], although others failed to find differences in PI-treated patients [8]. We also found that the period of treatment was a predictor of hyperlipidemia. In fact, antiretroviral drugs were associated with hyperlipidemia only when this factor was removed from the logistic regression analysis. Duration of therapy is considered a risk factor for lipodystrophy [1,2,8]. Although we are unaware of any study reporting a similar relationship with hyperlipidemia, our results are not unexpected.

We also found higher rates of hyperlipidemia in patients treated with efavirenz than those treated with nevirapine or PI, an aspect important when planning a change in the antiretroviral regimen and an association of hyperlipidemia with higher cortisol levels. Although hypercortisolemia, a known cause of insulin resistance, might contribute to the lipid disorders in these patients, its role is probably minor.

More interesting is our finding that patients co-infected with HCV had an appreciably lower rate of hyperlipidemia than HCV-negative individuals. These differences cannot be ascribed to different adherence to therapy because the rate of undetectable viral load in treated patients was very similar (66.4 versus 67.9%, respectively, P = 0.8). Lower cholesterol and triglyceride levels were also observed in a small group of HIV/HCV-co-infected patients despite increased insulin resistance [9]. Considering that up to 80% of HCV infections progress to chronic hepatitis, this feature probably relates to HCV-induced hepatic dysfunction. In a study [10], cholesterol levels were lower in patients with chronic active hepatitis than in healthy controls, and in cirrhotic patients than in patients with chronic active hepatitis and control individuals. However, differences in the lipid composition depending on the viral agent of chronic hepatitis have been reported [11], cholesterol values being significantly lower in patients with chronic HCV infection than in patients with chronic hepatitis B virus infection. Similarly, we found remarkable differences between these two aetiologies, also suggesting a specific role of the viral agent.

Finally, it is noteworthy that the beneficial effect of HCV infection on hyperlipidemia was non-existent in the absence of HAART, but was very marked when HAART was present. Consequently, the interactions of HAART on lipidic metabolism seem to be neutralized by the HCV infection. Interestingly, we found the opposite regarding lipodystrophy in HAART-treated patients, because HCV-infected individuals had higher rates of lipodystrophy than HCV-negative patients (27.0 versus 11.8%, respectively, P = 0.007), a finding supported by others in a small group of patients [9]. Therefore, our results suggest that antiretroviral therapy does not seem to affect the lipidic profile of HCV-co-infected patients negatively, which may contribute to alleviate the safety concerns in this population.

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References

1.Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998, 12:F51–F58.

2.Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis,is,is,is, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999, 353: 2093–2099.

3.Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Körner T, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 1999, 13:F63–F70.

4.Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS 1999, 13:2493–2505.

5.Martínez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 1999, 13:805–810.

6.Van der Valk M, Gisolf EH, Reiss P, Wit FWNM, Japour A, Weverling GJ, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS 2001, 15:847–855.

7.Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 2001, 32:130–139.

8.Gervasoni C, Ridolfo AL, Trifirò G, Santambrogio S, Norbiato G, Musicco M, et al. Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 1999, 13:465–471.

9.Duong M, Petit JM, Piroth L, Grappin M, Buisson M, Chavanet P, 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.

10.Cicognani C, Malavolti M, Morselli-Labate AM, Zamboni L, Sama C, Barbara L. Serum lipid and lipoprotein patterns in patients with liver cirrhosis and chronic active hepatitis. Arch Intern Med 1997, 157:792–796.

11.Fabris C, Federico E, Soardo G, Falleti E, Pirisi M. Blood lipids of patients with chronic hepatitis: differences related to viral etiology. Clin Chim Acta 1997, 261:159–165.

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