Baseline serum low-density lipoprotein cholesterol levels predict response to hepatitis C virus therapy in HIV/hepatitis C virus coinfected patients Jose´ del Vallea,b,M, Jose´ A. Miraa,b,M, Ignacio de los Santosc, Luis F. Lo´pez-Corte´sd,M, Dolores Merinoe,M, Antonio Riverof,M, Jose´ A. Giro´ng,M, Marı´a J. Rı´os-Villegash,M, Mercedes Gonza´lez-Serranoi,M, Antonio Colladoj,M, Jose´ A. Garcı´a-Garcı´aa,b,M and Juan A. Pinedaa,M Background: High levels of serum low-density lipoprotein cholesterol are associated with better response to pegylated interferon and ribavirin in hepatitis C virus monoinfected patients. There are no data concerning this topic in HIV/hepatitis C virus coinfected patients in whom lipid disorders are particularly common. Objective: To assess the association between baseline lipid levels and sustained virologic response to pegylated interferon and ribavirin in coinfected patients. Methods: A total of 260 HIV/hepatitis C virus coinfected patients under treatment with pegylated interferon and ribavirin and who had a baseline serum lipid profile were included in this retrospective study. Results: Thirty-eight (24%) patients with genotypes 1–4 and 64 (63%) with genotypes 2–3 achieved sustained virologic response. Forty-nine (44%) patients with serum lowdensity lipoprotein cholesterol levels 100 mg/dl or more showed sustained virologic response compared with 53 (36%) with lower values [adjusted odds ratio: 2.51; 95% confidence interval: 1.40–4.87; P ¼ 0.003]. This association was independent of the remaining predictors of sustained virologic response which were genotypes 2–3, plasma hepatitis C virus RNA 600 000 IU/ml or less, exposure to at least 80% of the planned therapy and lack of concomitant antiretroviral therapy. The rate of sustained virologic response in patients with genotype 1 and low-density lipoprotein cholesterol at least 100 mg/ml was 31% compared with 17% in those with lower values (adjusted odds ratio: 2.19; 95% confidence interval: 1.04–4.66; P ¼ 0.040). The corresponding figures in subjects with genotypes 2–3 were 73 and 58% [2.71 (0.99–7.46); P ¼ 0.054]. No other lipid was associated with response. Conclusion: Higher low-density lipoprotein cholesterol levels predict sustained virologic response to pegylated interferon and ribavirin in HIV/hepatitis C virus

From the aInfectious Diseases Unit, Hospital Universitario de Valme, Sevilla, the bInternal Medicine Department, Hospital Universitario de Valme, Sevilla, the cInternal Medicine-Infectious Diseases Department, Hospital Universitario de La Princesa, Madrid, the dInfectious Diseases Deparment, Hospital Universitario Virgen del Rocı´o, Sevilla, the eInternal Medicine Department, Hospital Juan Ramo´n Jime´nez, Huelva, the fInfectious Diseases Section, Hospital Universitario Reina Sofı´a, Co´rdoba, the g Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta del Mar, Ca´diz, the hInfectious Diseases Unit, Internal Medicine Department, Hospital Universitario Virgen Macarena, Sevilla, the iInfectious Diseases Unit, Internal Medicine Department, Hospital Universitario Virgen de la Victoria, Ma´laga, and the jInternal Medicine Department, Hospital Torreca´rdenas, Almerı´a, Spain. Correspondence to Professor Juan A. Pineda, Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Avda. de Bellavista, 41014 Sevilla, Spain. E-mail: [email protected]
For the Grupo para el Estudio de las Hepatitis Vı´ricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). Received: 28 November 2007; revised: 6 February 2008; accepted: 21 February 2008.

ISSN 0269-9370 Q 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

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AIDS

2008, Vol 22 No 8 coinfected patients. This might be used to improve the rate of sustained virologic ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins response in this setting.

AIDS 2008, 22:923–930 Keywords: antiretroviral therapy, hepatitis C virus, lipoproteins, pegylated interferon

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 HCVmonoinfected patients [12–15]. Namely, higher lowdensity 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 antiHCV 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 highdensity lipoprotein (HDL) cholesterol, as well as triglyceride levels; to be naı¨ve 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 a-2a (180 mg/week) or pegylated interferon a-2b (1.5 mg/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

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Low-density lipoprotein predicts sustained virologic response del Valle et al.

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: LDL cholesterol ¼ total cholesterol  ðtriglycerides=5Þ  HDL cholesterol

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 CD4þ 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 x2-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%) Table 1. Characteristics of the population (n U 260). Parameter

Value

Age (years)a 40 (37–43) Male sex [n (%)] 207 (80) 23 (21–26) BMIa Former IDU [n (%)] 226 (87) HCV genotype [n (%)] 1 137 (53) 2 1 (0.4) 3 100 (39) 4 21 (8) Not available 1 (0.4) 5.80 (5.49–6.15) HCV-RNA load (log, IU/ml)a 88 (56–134) Serum alanine aminotransferase (IU/l)a Fibrosis stageb [n (%)] 2 93 (55) 3 77 (45) 29 (17) Cirrhosisb Type of pegylated interferon [n (%)] Alfa-2a 177 (68) Alfa-2b 83 (32) 13.90 (12.50–15.15) Ribavirin dose/weight (mg/kg)a Exposure to HCV therapy 80% or more [n (%)] 220 (85) HBsAg positive [n (%)] 7 (3) 80 (