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Baseline serum low-density lipoprotein cholesterol levels predict response to hepatitis C virus therapy in HIV/hepatitis C virus coinfected patients

del Valle, Joséa,b,*; Mira, José Aa,b,*; de los Santos, Ignacioc; López-Cortés, Luis Fd,*; Merino, Dolorese,*; Rivero, Antoniof,*; Girón, José Ag,*; Ríos-Villegas, María Jh,*; González-Serrano, Mercedesi,*; Collado, Antonioj,*; García-García, José Aa,b*; Pineda, Juan Aa,*

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doi: 10.1097/QAD.0b013e3282ff8ad3
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Abstract

Introduction

Currently, therapy with pegylated interferon and ribavirin eradicates hepatitis C virus (HCV) only in 27–49% of human immunodeficiency virus (HIV)/HCV coinfected patients [1–8]. Because of this, strategies aimed to improve this rate of response need to be investigated, as untreated hepatitis C is at present one of the leading causes of morbidity and mortality among coinfected patients in areas where antiretroviral therapy is easily accessible [9–11]. One of these strategies consists of identifying predictors of response other than the well known ones, such as HCV genotype, plasma HCV-RNA load or therapy adherence. Predictors that are potentially modifiable are of the greatest interest, as they may allow us to implement HCV therapy in the most advantageous scenario.

A number of previous studies have highlighted the influence of baseline lipid values on the response to pegylated interferon and ribavirin therapy in HCV-monoinfected patients [12–15]. Namely, higher low-density lipoprotein (LDL) cholesterol and total cholesterol levels prior to HCV therapy correlated with higher rates of sustained virologic response (SVR) in these studies. These findings agree with those of in-vitro investigations, which showed that LDL may inhibit competitively the binding of HCV to the LDL receptor (LDL-r), which has been reported to function as a cellular receptor for HCV [16,17]. This competitive blockade would hamper the infection of hepatocytes with HCV [18]. The impact of lipid levels on the SVR may be particularly relevant in the setting of HIV/HCV coinfection, as dyslipidemia is very common in these patients [19]. However, it has not been determined to date whether the lipid profile also has a significant role in the response to pegylated interferon and ribavirin in HIV/HCV-coinfected patients. Therefore, studies are needed to clarify this issue.

The objective of the present study was to assess the relationship between baseline lipid levels and the response to pegylated interferon and ribavirin treatment in HIV/HCV-coinfected patients.

Patients and methods

Study population and follow-up

From October 2001 to February 2005, a cohort of 3564 HIV/HCV-coinfected patients older than 16 years was followed in 10 tertiary care hospitals in Spain. Of these, 339 (10%) received an anti-HCV therapy based on pegylated interferon and ribavirin at some time during the follow-up. All individuals were evaluated every 4 weeks during the first 24 weeks of therapy and every 8–12 weeks thereafter, while they were receiving anti-HCV treatment. Clinical, biochemical and hematological assessments were carried out at every visit. Plasma HCV RNA was assessed at least at weeks 12, 24 and 48 during treatment and at week 24 after completion of the treatment.

To accomplish the objective of the study, we retrospectively analyzed all HIV/HCV-coinfected patients belonging to the above-mentioned cohort who fulfilled the following criteria: to have an available serum lipid profile obtained in the month prior to anti-HCV treatment beginning, including at least total and high-density lipoprotein (HDL) cholesterol, as well as triglyceride levels; to be naïve for HCV therapy when started on pegylated interferon and ribavirin; not to have used lipid-lowering drugs in the previous 3 months. Patients who required lipid-lowering agents during the course of therapy against HCV were excluded from the study.

Treatment modalities

All patients received the combination of subcutaneous pegylated interferon α-2a (180 μg/week) or pegylated interferon α-2b (1.5 μg/kg per week) and oral ribavirin (800–1200 mg/day). In patients with HCV genotype 3, the treatment duration was 24 or 48 weeks, according to the decision of the treating physician. The length of the treatment was 48 weeks in all HCV genotype 1 or 4 carriers. Therapy was discontinued in patients who were nonresponders at week 12 or 24.

Assessment of efficacy

The main outcome variable was SVR, defined as undetectable plasma HCV-RNA 24 weeks after completion of treatment. The end of treatment response (ETR) was defined as undetectable plasma HCV-RNA when pegylated interferon and ribavirin treatment was permanently discontinued. A patient was considered to have developed early virologic response (EVR) when HCV-RNA levels had declined at least 2 log10 or had become undetectable at week 12. The efficacy was estimated according to the principle of intention to treat, considering all missing values as failures. A patient was considered as nonresponder if a reduction of at least 2 log10 in HCV-RNA levels was not reached at week 12 or when plasma HCV-RNA was still detectable at week 24. A relapse was defined as a lack of SRV after an ETR.

Laboratory methods

HCV genotype was determined by line-probe assay (INNOLiPA HCV, Innogenetics, Ghent, Belgium). Measurements of plasma HCV-RNA load were performed using a quantitative PCR assay (Cobas Amplicor HCV Monitor; Roche Diagnostic Systems Inc., Branchburg, New Jersey, USA – detection limit 600 IU/ml – or Cobas AmpliPrep-Cobas TaqMan; Roche Diagnostic Systems Inc., Meylan, France – detection limit 50 IU/ml, according to the available technique at each participating institution).

Total serum cholesterol, HDL cholesterol and triglyceride levels were measured in blood taken after a 12-h fast. Colorimetric enzymatic methods on a Hitachi analyzer with standard reagents (Roche Diagnostic) were used to carry out these measurements. The level of LDL cholesterol was estimated using the following equation:

In patients with serum triglyceride level equal or higher than 400 mg/dl, this equation was considered inaccurate, and the level of LDL cholesterol was not estimated.

Statistical analysis

Continuous variables are expressed as median (Q1–Q3). Categorical variables are expressed as number of cases (percentage). The associations between SVR and lipids levels were analyzed. For categorizing lipoprotein levels, the cut-off value that showed the highest predictive value to predict response to pegylated interferon and ribavirin in receiving operating characteristic (ROC) curves was chosen. Likewise, we also appraised the relationship between SVR and the following covariates: age, sex, BMI, antiretroviral treatment, HCV viral load, baseline CD4+ cell counts, HCV genotype, liver fibrosis degree according to the Scheuer's scoring system [20], exposure to the planned anti-HCV therapy, type of pegylated interferon and the daily dose of ribavirin. In the bivariate analysis, the comparisons between continuous variables were done using the Student's t-test if they followed a normal distribution or the Mann–Whitney U-test if they did not. Frequencies were compared using the χ2-test or applying Fisher's test when there were cells with expected frequencies lower than five. The two-tailed P value was selected in all cases and those less than 0.05 were considered significant. Variables associated with SVR with a P value less or equal to 0.2 in the bivariate analysis were included in a multivariate stepwise logistic regression analysis in which SVR was the dependent variable. Data were analyzed using the SPSS statistical software package release 14.0 (SPSS Inc., Chicago, Illinois, USA).

Ethical aspects

The study was designed and performed according to the Helsinki declaration and was approved by the Ethics Committee of the Hospital Universitario de Valme.

Results

Features of the study population

Two hundred and seventy-eight patients met the inclusion criteria. Twelve (4%) subjects showed triglyceride levels higher than 400 mg/dl, which led to LDL cholesterol levels being unable to be estimated. Six further patients required lipid-lowering treatment while on pegylated interferon and ribavirin therapy. Therefore, 260 individuals were included in the analysis. The most relevant characteristics of the patients included in the study appear in Table 1. Forty-six out of 101 (46%) subjects carrying HCV genotype 2 or 3 received a RBV dose of 1000 mg/day, whereas the remainder was treated with a dose of 800 mg/day. In the subgroup of 159 subjects with HCV genotype 1 or 4, 47 (30%) were treated with a RBV dose of 800 mg/day and 45 (70%) received a dose of 1000 or 1200 mg/day. Two hundred and twenty-seven patients (87%) patients received a ribavirin dose equal or greater than 10.6 mg/kg. Thirty (30%) individuals harboring HCV genotype 2 or 3 were treated for 24 weeks. All the remaining participants received therapy during 48 weeks. Antiretroviral therapy was used concomitantly with pegylated interferon and ribavirin in 218 (84%) individuals.

Table 1
Table 1:
Characteristics of the population (n = 260).

Response to pegylated interferon and ribavirin

One hundred and eighteen (45%) patients achieved ETR. SVR was observed in 102 (39%) subjects. At week 12 of treatment, 160 (62%) patients had developed EVR. All individuals who achieved SVR had previously EVR. Anti-HCV therapy had to be permanently discontinued because of adverse events in 34 (13%) patients. Twenty-three (9%) further subjects stopped therapy by their own decision.

No statistically significant association between SVR and the use of different antiretroviral drugs or drug families was observed (Table 2). HCV genotype 2 or 3, baseline plasma HCV-RNA load lower than 600 000 IU/ml, exposure to the planned therapy equal or greater than 80%, and lack of concomitant antiretroviral therapy predicted independently SVR (Table 3). Twenty-three (77%) patients with HCV genotype 2 or 3 treated during 24 weeks achieved SVR compared with 40 (57%) of those who received therapy for 48 weeks (P = 0.064).

Table 2
Table 2:
Antiretroviral drugs taken by the patients and rate of sustained virologic response according to its use (n = 218).
Table 3
Table 3:
Predictors of sustained virologic response (SVR).

Impact of baseline lipid levels on the response to treatment

The median (Q1–Q3) baseline values of triglycerides, total cholesterol, LDL cholesterol and HDL cholesterol among patients who did not achieved SVR were, respectively, 129 (101–178) mg/dl, 165 (138–196) mg/dl, 90 (65–116) mg/dl and 44 (35–56) mg/dl. The corresponding figures among patients who reached SVR were 124 (72–179) mg/dl, 168 (147–194) mg/dl, 93 (71–119) mg/dl and 44 (34–53) mg/dl, respectively. The differences in all the former parameters between both groups were not significant in the statistical analysis.

The frequencies of EVR, ETR and SVR according to the baseline level of lipids are shown in Table 4. EVR, ETR and SVR tended to be more common among patients with baseline LDL cholesterol equal or higher than 100 mg/dl. This level of LDL cholesterol was chosen because it was the best predictor of response to HCV therapy in ROC curves. There was no association between the rates of response and the levels of other lipids. Among HCV genotype 1 or 4 carriers, 22 (47%) of those who had LDL cholesterol levels lower than 100 mg/dl were treated with a dose of 800 mg/day compared with 25 (53%) of those who showed LDL cholesterol equal or higher than 100 mg/dl (P = 0.4). In the multivariate analysis LDL cholesterol levels equal or higher than 100 mg/dl were significantly associated with SVR (Table 3).

Table 4
Table 4:
Relationship between baseline lipid levels (mg/dl) and response to therapy.

The level of total cholesterol was higher among patients with genotype 1 or 4 than among those with genotype 2 or 3 [174 (148–208) vs. 155 (130–181) mg/dl, respectively, P < 0.001]. Similarly, patients with genotype 2 or 3 showed lower serum LDL cholesterol concentrations [85 (64–107) vs. 94 (72–123) mg/dl, P = 0.002]. The association between baseline LDL cholesterol levels higher than 100 mg/dl and SVR was observed in the subpopulation of patients harboring HCV genotype 1 or 4, both in the bivariate and in the multivariate analysis (Table 5). Among HCV genotype 2 or 3 carriers, 35 (58%) of those who had LDL cholesterol levels lower than 100 mg/dl achieved SVR compared with 25 (73%) of those who showed LDL cholesterol equal or higher than 100 mg/dl (P = 0.131). A multivariate analysis restricted to patients with HCV genotype 2 or 3, including the same variables as in the whole analysis, except for the genotype, showed an almost statistically significant association between LDL cholesterol level and SVR in this subpopulation as well (Table 5).

Table 5
Table 5:
Relationship between baseline low-density lipoprotein cholesterol levels and sustained virologic response (SVR) according to hepatitis C virus (HCV) genotype.

Discussion

In this study, higher serum LDL cholesterol levels have been shown to be a predictor of SVR to pegylated interferon and ribavirin in HCV/HIV-coinfected patients, as it had been previously reported in HCV-monoinfected patients [12–15]. Indeed, the rate of SVR was clearly higher in carriers of HCV genotype 1 or 4 with baseline LDL cholesterol equal or greater than 100 mg/dl than that found in patients with these genotypes and lower LDL cholesterol (31 vs. 17%). Similarly, patients with genotype 2 or 3 and LDL cholesterol higher than 100 mg/dl tended to show a rate of SVR greater than the remaining individuals harboring such genotypes (73 vs. 58%). The effect of the LDL cholesterol was independent of other predictors of response such as genotype, HCV-RNA load, adherence to the therapy, CD4 cell count or lack of concomitant antiretroviral therapy.

The main limitation of this study is its retrospective design. This might have led to unnoticed biases. Nevertheless, the rates of response and the predictors thereof found in this study were comparable with those previously reported in clinical trials and cohort studies conducted in HIV/HCV-coinfected patients [1–8]. These facts suggest that the potential biases were not relevant.

Total and LDL cholesterol decline as the severity of liver disease progresses [21]. Advanced fibrosis, particularly cirrhosis, is a factor that may reduce the tolerability of therapy with pegylated interferon and ribavirin, decreasing the rate of SVR [22]. Owing to these facts, LDL cholesterol might have been a confounder, which would reflect merely the presence of advanced liver disease. However, in this study, the rate of SVR in patients with cirrhosis was similar to that found in individuals having fibrosis F0 to F3. This is in keeping with the results of most clinical trials and cohort studies carried out in HIV/HCV-coinfected patients, where no relationship was found between the degree of liver fibrosis and the rate of SVR [1,2,4,6]. These facts support that LDL cholesterol level is actually a predictor of SVR.

The mechanism whereby high levels of serum LDL cholesterol enhance the response to pegylated interferon and ribavirin is unclear. On the one hand, HCV is believed to partially circulate bound to LDL in the bloodstream [23]. HCV may enter into the cell through CD81 and LDL-r [16,17,24]. As a consequence of this, LDL competes with binding and endocytosis of HCV in vitro[17]. Accordingly, the serum level of HCV antigen has been found to negatively correlate with the serum concentrations of betalipoproteins [18]. In this study, the rate of responses tended to be higher in patients with LDL cholesterol higher than 100 mg/dl from the first weeks of treatment. This is consistent with the interference in the replicative cycle of HCV having an impact on the early clearance of the virus rather than with an effect on the late clearance or on the relapses. On the other hand, other possible in-vitro mechanisms have been reported, such as HCV RNA replication control via cholesterol–biosynthetic pathway by regulating the geranylgeranylation of cellular proteins and downregulation of LDL receptor due to lowering of interleukin-1 in relation to interferon treatment [12,25].

Higher LDL cholesterol levels prior to treatment could be related to a better outcome only in genotype 1 or 2, but not genotype 3, carriers in the setting of HCV monoinfection [12]. In HIV/HCV-coinfected patients, as it has been shown in this study, the effect of LDL cholesterol seems to involve all HCV genotypes. Indeed, the level of statistical significance of the association between LDL cholesterol levels and SVR in patients with genotype 2 or 3 (all but one with genotype 3) was lower than those with genotype 1 or 4. However, there are two causes that may have accounted for this finding. First, the size of the population harboring genotype 2 or 3 was lower, thus leading to a less statistical power in this population. Second, the proportion of patients with LDL cholesterol higher than 100 mg/dl was lower among patients infected with genotype 2 or 3, due probably to the alterations in the lipoproteins metabolism induced by genotype 3. In fact, HCV genotype 3 interferes with the synthesis of cholesterol in hepatocytes, lowering its concentration in serum [12,26]. As a consequence of this, differences between patients with HCV genotype 3 and LDL cholesterol equal to or higher than 100 mg/dl and those with lower levels are more difficult to prove, as these populations are more unbalanced than among HCV genotype 1 or 4 carriers.

The predictors of SVR other than LDL cholesterol level found in this study were not unexpected, as they have been previously found to be associated with the outcome of pegylated interferon and ribavirin therapy [1–8]. Concomitant antiretroviral therapy can be a factor leading to a lower efficacy of HCV therapy in HIV/HCV-coinfected patients [6]. Some antiretroviral drugs such as didanosine, stavudine, zidovudine and abacavir may decrease the tolerability of pegylated interferon and ribavirin due to different interactions and toxicities, reducing its tolerability and the chance of achieving SVR [6,27]. On the contrary, some specific antiretroviral combinations might provide beneficial effects on the outcome of therapy against HCV. Thus, protease inhibitor-based combinations increase the levels of LDL cholesterol to a larger extent than other regimens [19,28,29]. Accordingly, and as the results of this study, we can hypothesize that protease inhibitor-based regimens might contribute to enhance the rate of SVR in HIV-coinfected patients receiving concomitantly antiretroviral therapy and pegylated interferon and ribavirin. In this study, no relationship between SVR and individual antiretroviral drugs and drug families was found. Nevertheless, the limited sample size of each therapy group and the high number of antiretroviral combinations used in this study precluded finding statistically significant differences. Studies on this topic should consider each protease inhibitor separately, as the effects of the drugs of this family on the lipid metabolism are different [30]. On the contrary, we have to consider that some protease inhibitors may increase insulin resistance [31], which could counterbalance the effect of high LDL cholesterol level, as insulin resistance has been found to be a predictor of poor response to therapy with pegylated interferon and ribavirin in HCV-monoinfected patients [32]. Nevertheless, in a recent study, there was no significant association between SVR and insulin resistance in HIV/HCV-coinfected patients, which suggests that this factor is not a relevant predictor of response to pegylated interferon and ribavirin therapy in this population [33].

In summary, this study shows for the first time that higher serum LDL cholesterol levels prior to therapy with pegylated interferon and ribavirin are associated with SVR in HIV/HCV-coinfected patients, as in HCV monoinfection. As this is a retrospective study, these results should be confirmed in prospective studies. Given that LDL cholesterol levels may be influenced by antiretroviral therapy, it is conceivable that specific combinations could contribute to improve the rate of SVR in these patients. Further studies should be undertaken in order to assess this issue. Finally, the results of this study, along with those found in HCV-monoinfected patients [12–15], support the idea that the interference with HCV entry via blockade of LDL-r may play a role in the therapy of HCV infection.

Acknowledgements

The authors thank Juan Macías, Raquel Carrillo, Bárbara Valera-Bestard, Nicolás Merchante, Salvador Vergara, Eva Recio, Laila Abdel-Kader, Ana Arizcorreta, Ángela Camacho, Julián Torre-Cisneros and Josefa Ruiz-Morales their collaboration in this work.

Sponsorship: This study has been partly supported by grants from the Consejería de Salud of the Junta de Andalucía (Reference 44/05), the Fondo de Investigaciones Sanitarias (FIS) (Reference PI051546) and the ISCIII-RETIC RD06/006.

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Keywords:

antiretroviral therapy; hepatitis C virus; lipoproteins; pegylated interferon

© 2008 Lippincott Williams & Wilkins, Inc.