JAC Advance Access originally published online on October 14, 2007
Journal of Antimicrobial Chemotherapy 2007 60(6):1347-1354; doi:10.1093/jac/dkm373
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Influence of concomitant antiretroviral therapy on the rate of sustained virological response to pegylated interferon plus ribavirin in hepatitis C virus/HIV-coinfected patients
1 Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla, Spain 2 Servicio de Medicina Interna, Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla, Spain 3 Servicio de Medicina Interna-Infecciosas, Hospital Universitario de la Princesa, Madrid, Spain 4 Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocío, Sevilla, Spain 5 Unidad de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Córdoba, Spain 6 Servicio de Medicina Interna, Hospital Juan Ramón Jiménez, Huelva, Spain 7 Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Puerta del Mar, Cádiz, Spain 8 Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen Macarena, Sevilla, Spain 9 Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario Virgen de la Victoria, Málaga, Spain 10 Servicio de Medicina Interna, Hospital Torrecárdenas, Almería, Spain
* Corresponding author. Tel: +34-955015864; Fax: +34-955015787; E-mail: japineda{at}telefonica.net
Received 9 May 2007; returned 27 June 2007; revised 2 September 2007; accepted 4 September 2007
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Abstract |
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Objectives: To investigate whether concomitant antiretroviral therapy (ART) is a predictor of sustained virological response (SVR) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients treated with pegylated interferon plus ribavirin.
Methods: Three hundred and ten HIV/HCV-coinfected patients on pegylated interferon plus ribavirin treatment, 258 of them with concurrent ART, were included in this retrospective multicentre study. The predictors of SVR were evaluated.
Results: SVR was shown by 114 (37%) subjects. HCV genotype 2 or 3, plasma HCV-RNA load lower than 600 000 IU/mL, an exposure to the therapy against HCV infection 
80% of the planned dose and baseline CD4 cell counts higher than or equal to 300/mm3 were predictors of SVR. Likewise, patients without ART and those receiving a combination including tenofovir or stavudine plus lamivudine plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) showed a higher SVR rate than the subjects who were on other ART strategies at baseline [44%, 44% and 29%, respectively; adjusted odd ratio (95% CI) for no ART = 1.96 (1.07–4.76), P = 0.025, and for ART including tenofovir or stavudine plus lamivudine plus a PI or a NNRTI = 2.08 (1.16–3.70), P = 0.014].
Conclusions: The ART strategy on starting therapy with pegylated interferon plus ribavirin is a predictor of SVR in HIV/HCV-coinfected patients. Subjects without ART and those receiving combinations of a PI or a NNRTI with a nucleos(t)ide backbone of tenofovir or stavudine plus lamivudine respond better than those who receive other regimens.
Keywords: tenofovir , stavudine , abacavir
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Introduction |
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The rate of sustained virological response (SVR) to therapy with pegylated interferon plus ribavirin in hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected patients seems to be lower than that achieved in HCV-monoinfected patients. Although no studies directly comparing both populations have been carried out, clinical trials performed in monoinfected and coinfected subjects separately have shown quite different results.1–7 Moreover, the rates found in cohort studies in coinfected patients are near to the lowest end of the range reported in clinical trials.8–10 Little is known about the causes of this lower efficacy of HCV therapy in coinfected patients. Lesser adherence, more frequent adverse effects, poorer immune response against HCV, higher levels of plasma HCV-RNA load, higher degrees of hepatic steatosis and more advanced liver fibrosis in HIV-coinfected individuals may account for these differences,11 but the precise contribution of each of these factors remains to be clarified.
Most coinfected patients undergoing therapy against chronic hepatitis C also require antiretroviral therapy (ART).8–10 Concomitant ART could be a factor leading to a lower rate of SVR in coinfected patients. Indeed, combined HIV and HCV therapy increases the daily number of pills and makes the treatment more complex. On the other hand, the simultaneous administration of ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) increases the risk of mitochondrial toxicity associated with the latter.12 Besides, other toxicities of antiretroviral drugs and HCV therapy may be additive or synergistic. Owing to these reasons, ART may decrease the tolerability of pegylated interferon and ribavirin, reducing the rate of success of such a therapy. However, there is little information about how ART or specific drugs or combinations influence the rate of SVR associated with pegylated interferon plus ribavirin in HIV/HCV-coinfected patients. It is critical to clarify this topic, in order to choose the ART strategies associated with better HCV therapy results.
The objective of this study was to find out whether concomitant ART is a factor associated with the rate of SVR in HIV/HCV-coinfected patients receiving treatment with pegylated interferon and ribavirin in daily clinical practice.
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Patients and methods |
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Patients and follow-up
From October 2001 to February 2005, a cohort of 3564 HIV/HCV-coinfected patients was followed in 10 tertiary care centres from Spain. The patients from this cohort who fulfilled the following criteria were included in this retrospective study: (i) older than 16 years; (ii) diagnosed with chronic hepatitis C, with persistently detectable HCV-RNA in plasma; (iii) previously naive for therapy against HCV infection; and (iv) started treatment against HCV infection with pegylated interferon alfa-2a or alfa-2b plus ribavirin. For the first 24 weeks of therapy patients were seen no less than every 4 weeks, and every 8–12 weeks during the remainder of the treatment course. Clinical, biochemical and haematological assessments were carried out at every visit. Plasma HCV-RNA was measured at least 12, 24 and 48 weeks after starting therapy. Likewise, all patients had a HCV-RNA determination 6 months after stopping HCV therapy. Plasma HCV-RNA was measured by PCR (Cobas Amplicor HCV Monitor, version 2.0, Roche Diagnostic System Inc., Branchburg, NJ, USA or Cobas AmpliPrep-Cobas Taqman, Roche Diagnostic System Inc., Meylan, France).
All patients were given therapy with subcutaneous pegylated interferon alfa-2a 180 µg every week or pegylated interferon alfa-2b 1.5 µg/kg every week plus oral ribavirin 500–1500 mg daily. Patients harbouring HCV genotype 1 or 4 were treated for 48 weeks, whereas those infected with genotype 2 or 3 received therapy for 24 or 48 weeks, according to the decision of the caring physician.
All patients received highly active antiretroviral therapy (HAART), according to the drugs available and the recommendations that were in force at the time of prescription. Specifically, the guidelines of the Department of Health and Human Services of the USA (http://AIDSinfo.nih.gov) and of the Grupo Español para el Estudio del SIDA (GESIDA) (www.gesida.seimc.org) were followed. The specific drugs included in the combinations were chosen by the physician who was in charge of the patient.
The primary study end-point was the rate of SVR, defined as an undetectable plasma HCV-RNA 6 months after the end of treatment. Therapy was permanently discontinued after 12 weeks in patients in whom plasma HCV-RNA did not decline 2 logs or became negative at this time point and had started therapy after March 2003, the time when this rule became mandatory in our cohort. Therapy was also prematurely stopped in patients recruited before or after this date if plasma HCV-RNA did not become undetectable after 24 weeks. The efficacy analyses of HCV therapy were done according to the principle of intention to treat, considering missing values as failures.
The associations between SVR and the following variables were assessed: sex, age, hospital where the patient was treated, body mass index, risk factor for HCV transmission, HCV genotype, baseline plasma HCV-RNA load, baseline serum level of alanine aminotransferase, presence of advanced liver fibrosis according to the Knodell scoring system modified by Scheuer in patients who had a pre-treatment liver biopsy,13 type of pegylated interferon given, dose of ribavirin, use of haematopoietic growth factors (erythropoietin or granulocyte colony-stimulating factor), length of HCV infection, self-reported compliance with HCV therapy, CDC clinical category, baseline plasma HIV viral load and CD4 cell counts, and antiretroviral drugs and combinations used along with the treatment of chronic hepatitis C. The length of HCV infection was estimated in intravenous drug users as the time elapsed from the first year sharing needles to the time when patients started HCV therapy.
Continuous variables are expressed as medians [interquartile range (Q1–Q3)] and the categorical variables as numbers (percentage). In the univariate analysis, continuous variables were compared by the Student's t-test and the categorical variables using Yate's corrected 
2 test or Fisher's test. Variables associated with SVR in the univariate analysis with a P value <0.2 were entered in stepwise logistic regression models. The goodness-of-fit of the models was assessed by the Hosmer–Lemeshow test. The results of the best-fitted model were chosen.
The study was designed and performed according to the Helsinki declaration and was approved by the Ethics Committee of the Hospital Universitario de Valme.
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Results |
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Characteristics of the study population
Three hundred and ten patients fulfilled the inclusion criteria. The main baseline features of these patients are shown in Table 1. Thirty-one out of 114 (27%) subjects carrying HCV genotype 2 or 3 received therapy with pegylated interferon and ribavirin for 24 weeks, whereas the remainder were treated for 48 weeks. Thirty-six patients out of 216 (17%) who had undergone a liver biopsy showed cirrhosis. Two hundred and sixty-seven (86%) individuals received a dose of ribavirin higher than 10.6 mg/kg.
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ART regimens
Two hundred and fifty-eight (83%) patients were receiving ART when pegylated interferon plus ribavirin was started. Median (Q1–Q3) CD4 cell counts in patients with ART and no ART were 517 (380–730) and 530 (425–717), respectively (P = 0.457). Two hundred and sixteen (84%) patients with ART and none without ART showed undetectable HIV-RNA load on starting therapy against HCV. The antiretroviral drugs and combinations used in these patients at baseline are shown in Table 2. Two further patients started ART during the course of HCV therapy, one with zidovudine, lamivudine and abacavir and the other with stavudine, lamivudine and lopinavir boosted with ritonavir. In one patient, the full antiretroviral regimen had to be switched from stavudine, lamivudine and abacavir to tenofovir, nevirapine and nelfinavir, as a result of virological failure. A single drug change was carried out in 26 (10%) further patients (Table 3). All these changes were due to suspected drug toxicity, except for one case, in which abacavir was discontinued at the request of the patient. Tenofovir had to be stopped less frequently than zidovudine and didanosine (1% versus 13%, P = 0.01 and 1% versus 12%, P = 0.07, respectively). There was no difference between the rate of discontinuation of tenofovir and that of the remaining nucleos(t)ide reverse transcriptase inhibitors [N(t)RTIs] (Table 3). Abacavir tended to be stopped less frequently than zidovudine (4% versus 13%, P = 0.084) and, to a lesser extent, than didanosine (4% versus 12%, P = 0.167). However, the frequency of discontinuation of stavudine was similar to that of zidovudine (7% versus 13%, P = 0.310) and didanosine (7% versus 12%, P = 0.473) (Table 3).
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Response to HCV therapy
One hundred and forty-three (46%) patients had undetectable plasma HCV-RNA load at the end of treatment. One hundred and fourteen of them showed SVR 6 months after stopping treatment, thus resulting in an overall rate of SVR of 37%. Two patients with response at the end of treatment were lost to the follow-up for the subsequent 6 months. Twenty-seven patients, i.e. 19% out of those who achieved response at the end of treatment, had a relapse. Therapy was permanently discontinued due to adverse effects of pegylated interferon and/or ribavirin in 40 (13%) patients after a median (Q1–Q3) exposure of 17 (6–24) weeks. Twenty-four (8%) subjects ceased treatment on their own decision. The median (Q1–Q3) length of therapy against HCV in these patients was 23 (5–26) weeks. The dose of anti-HCV drugs had to be temporally or permanently reduced in 62 (20%) patients. The dose of pegylated interferon was reduced in 48 (15%) patients and that of ribavirin in 19 (6%).
The rates of end of treatment response and SVR by genotype are shown in Figure 1. Twenty-three (74%) patients with genotype 2 or 3 treated for 24 weeks showed SVR versus 45 (54%) out of those who received therapy for 48 weeks (P = 0.08).
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Predictors of SVR
HCV genotype 2 or 3, baseline plasma HCV-RNA load lower than 600 000 IU/mL, CD4 cell counts higher than or equal to 300 cells/mm3 and an exposure to the therapy 80% of the planned dose were independent predictors of SVR (Table 4). Ninety-one (35%) patients receiving ART when starting pegylated interferon plus ribavirin therapy achieved SVR versus 23 (44%) subjects without ART (P = 0.287). There was no association between being treated with any specific third drug at baseline (nevirapine, efavirenz or PIs) and the rate of SVR. Use of zidovudine and stavudine at baseline tended to be associated with a poorer and a better rate of SVR, respectively, in the univariate analysis, but these associations did not remain independent in the multivariate study (Table 4). Patients receiving abacavir also responded less commonly than those who did not take this drug, but differences did not reach the level of statistical significance (Table 4). Among 207 patients receiving a three-drug regimen including one PI or one NNRTI, those treated with a N(t)RTI backbone including tenofovir plus lamivudine or stavudine plus lamivudine responded more frequently than those were given zidovudine plus lamivudine, abacavir plus lamivudine or other N(t)RTI backbones (Figure 2), although, again, no statistically significant differences were reached. However, when the entire population was stratified according to the ART strategy received at baseline, 47 (44%) of those who were on tenofovir or stavudine plus lamivudine plus one PI or one NNRTI achieved SVR versus 44 (29%) of the patients receiving other ART strategies (adjusted OR 2.08, 95% CI 1.16–3.70, P = 0.014). The rate of SVR among the patients treated with tenofovir or stavudine plus lamivudine plus one PI or one NNRTI was similar to that achieved by the patients without ART (Table 4). A similar trend to a higher rate of SVR was observed both in patients with genotype 1 or 4 and in those with genotype 2 or 3 taking no HAART as well as in those receiving tenofovir or stavudine plus lamivudine plus one PI or one NNRTI. Thus, the rate of SVR attained among patients with genotype 1 or 4 was 30% in those who were treated with tenofovir or stavudine plus lamivudine plus one PI or one NNRTI, 24% in the subpopulation without HAART and 18% in those on other ART strategies (P = 0.16). The respective rates of SVR in patients with genotype 2 or 3 were 68%, 70% and 49% (P = 0.10).
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There was no association between therapy with specific antiretroviral drugs or ART combinations at baseline and the frequency of voluntary dropouts, the percentage of patients with a compliance with pegylated interferon plus ribavirin equal or >80%, the frequency of reductions of pegylated interferon dose or the rate of discontinuation of therapy against HCV due to adverse events. Ribavirin dose had to be reduced in 11 (14%) patients treated with zidovudine and in 8 (3.5%) subjects who were not treated with zidovudine (P = 0.002). The rate of reductions of ribavirin dose also tended to be associated with the ART strategy. In fact, 1.9% of individuals with no ART, 3.8% of those receiving tenofovir or stavudine plus lamivudine plus one PI or one NNRTI and 9.2% of the patients on other ART regimens needed a reduction in the ribavirin dose (P = 0.063). No patient on abacavir plus lamivudine and one of those who was receiving tenofovir plus abacavir (6%) needed a ribavirin dose reduction.
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Discussion |
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These results show that the ART strategy used in HIV/HCV-coinfected patients on starting therapy with pegylated interferon plus ribavirin is a predictor of SVR. Indeed, patients with no ART and those who take combinations of a PI or a NNRTI with a nucleos(t)ide backbone of tenofovir plus lamivudine or stavudine plus lamivudine respond better than those receiving other ART combinations, a finding that has not been reported previously.
The rates of SVR in randomized clinical trials conducted in HIV/HCV-coinfected patients with pegylated interferon plus ribavirin ranged from 14% to 38% for HCV genotype 1 or 4 and from 44% to 73% for genotype 2 or 3.4–7 Thus, the figures found in this cohort study are within this range, showing that the results obtained in real-life are not different from results found under experimental conditions, although the broadness of the results in trials was very important.
The fact that concomitant ART is a predictor of SVR is partly explained by the interactions of the nucleos(t)ide backbone drugs with the therapy against HCV. Ribavirin increases the phosphorylation of didanosine. Thus, when didanosine is given along with ribavirin, the risk of mitochondrial toxicity, including hyperlactataemia, lactic acidosis and pancreatitis, increases markedly.12,14,15 Owing to this, the use of didanosine along with ribavirin is not recommended. For the patients included in this study, didanosine was required to be discontinued because of adverse events more commonly than the remaining N(t)RTIs, except for zidovudine. On the other hand, zidovudine may enhance the anaemia caused by ribavirin,15 therefore reducing the tolerability of this drug. Accordingly, ribavirin dose had to be more frequently reduced in patients taking zidovudine in this study, and it is known that patients who receive <80% of the planned dose of ribavirin achieve a lower rate of SVR.16
Tenofovir is a weaker inhibitor of mitochondrial DNA polymerase and other mitochondrial functions than other N(t)RTIs.17 In clinical trials, there has been no evidence of mitochondrial toxicity due to tenofovir.18 In addition, the frequency of anaemia is lower in patients taking tenofovir-based combinations compared with that observed in patients treated with zidovudine-including regimens.19 Because of this, tenofovir had to be permanently discontinued less frequently than zidovudine or didanosine and it was not associated with ribavirin dose reductions in this study. Similarly, haematological toxicity does not ensue from stavudine treatment. On the other hand, stavudine is associated with an excess risk of hyperlactataemia and lactic acidosis, but, when it is not co-administered with didanosine, the risk is substantially lower.15,21 In fact, a link between stavudine administration and hyperlactataemia has not been found in patients with concomitant therapy with pegylated interferon and ribavirin in some clinical trials.7 Owing to these reasons, combinations based on tenofovir or stavudine, both associated with lamivudine as the nucleoside backbone, were associated with higher rates of SVR in this study.
A higher rate of failure to achieve early virological response has been reported in patients included in the Ribavic study who were taking abacavir along with pegylated interferon and ribavirin.20 However, no association between abacavir use and SVR was found in that study.7 Herein, use of abacavir showed a non-significant association with poorer SVR. Nevertheless, abacavir was given in some of the patients along with zidovudine, which can be a confounder. When we tried to control for this confounder by analysing only patients receiving abacavir plus lamivudine or abacavir plus tenofovir, the former group, but not the latter, showed a trend to a poorer SVR. However, these groups were too small to draw conclusions. Definitely, the above stated findings on the association of abacavir with SVR, along with the rate of SVR observed in this study in patients taking abacavir plus lamivudine warrant further studies focusing on the role of abacavir on the response to the therapy with pegylated interferon plus ribavirin in HCV/HIV-coinfected patients.
The association between the use of NNRTI or PI in ART combinations and the rate of SVR is a matter of concern. On the one side, the neuropsychiatry effects of efavirenz might be additive with those of pegylated interferon, leading to a poorer tolerability of HCV therapy. On the other side, a negative impact of PI use on SVR was found in the Ribavic study,7 warranting further clarification of this topic.21 In our study, the use of PI, nevirapine and efavirenz was not associated with a lower SVR, which suggests that all these third drugs can be used in patients under therapy with pegylated interferon plus ribavirin without a negative impact on the response.
Most predictors of SVR other than ART found in this study were expected. Indeed, HCV genotype has been the strongest predictor of SVR in all clinical trials and cohort studies carried out in HIV/HCV-coinfected patients.4–10 Similarly, lower plasma HCV-RNA burden has been a predictor of response in many studies.4,8,10 Compliance with therapy has also been found to be associated with the rate of SVR, both in HCV-monoinfected individuals and in HIV/HCVs-coinfected populations.7,16,22 However, baseline CD4 cell count has not been found to be a predictor of response in other studies. Patients receiving standard interferon with lower CD4 cell counts responded worse than those who had higher counts,23 but this finding has not been confirmed when pegylated interferon has been used.4–10 However, we have to take into account that clinical trials and cohort studies have included mostly patients with high CD4 cell counts, which could have hampered finding differences according to this parameter.
This study has two main limitations. On the one hand, its retrospective design, which might have led to unnoticed biases. However, the rates of response, relapses and dropouts, and the predictors of response other than ART coincide with those found in clinical trials carried out in coinfected patients to a large extent.4–7 Moreover, the results of the impact of ART on SVR are very consistent with the potential negative effects of each drug, either due to interactions or to their own adverse effects, as has been discussed above. These data lead us to think that this study does not have important biases. On the other hand, in spite of the fact that the present study included a sample size larger than any clinical trial or cohort study published so far, some drug categories were too small to allow comparisons. Owing to this, we found significant differences only when N(t)RTI backbone categories with similar figures of SVR, such as stavudine plus lamivudine and tenofovir plus lamivudine, were grouped. Likewise, the association among ART strategy and SVR did not reach statistical significance when HCV genotype categories were analysed separately, probably due to lack of statistical power. The fact that our study is based on daily clinical practice, therefore reflecting the actual results of the usual care of patients, partly counterbalance the above stated limitations.
The rate of SVR in patients without ART was 44%. This is still far from that found in HCV-monoinfected patients,1,2 but it is one-fifth higher than the median SVR observed in this study. This finding supports that HIV/HCV-coinfected patients should receive therapy with pegylated interferon and ribavirin early, in an ideal manner when they still do not need ART. At this time, CD4 cell count is higher, which is another predictor of favourable response. However, cohort studies show that most HIV/HCV-coinfected patients starting therapy against hepatitis C do need concomitant ART.8–10 In these subjects, an adequate choice of ART may enhance the chance of SVR. In fact, patients receiving a combination of tenofovir or stavudine plus lamivudine plus one PI or one NNRTI on starting HCV therapy had rates of response similar to the population without ART in this study. Since tenofovir has shown similar efficacy against HIV and less toxicity than stavudine, this drug combined with lamivudine—and probably with emtricitabine, as the antiviral activity and the toxicity profile of both drugs are similar—seems to be the preferred nucleos(t)ide backbone in patients who are going to be treated against hepatitis C. On the other hand, an earlier start of ART may be considered in patients in whom treatment with pegylated interferon and ribavirin is planned and the CD4 cell count is near to the point when ART must be started. In these patients, concomitant ART may prevent lymphocytopenia associated with interferon and keeps the CD4 cell counts above 300/mm3. It is likely that the combination of an adequate ART strategy and a high CD4 cell count during therapy prompt higher rates of SVR, closer to that observed in HCV-monoinfected patients than those we currently achieve.
In summary, concomitant ART in HCV/HIV-coinfected patients on pegylated interferon plus ribavirin not only has significant interactions and adverse effects, but also can reduce the chance of SVR. A N(t)RTI backbone of tenofovir plus lamivudine is associated with a rate of SVR similar to that found in patients without ART. Therapy based on stavudine plus lamivudine can be considered an alternative in patients in whom tenofovir cannot be used.
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Transparency declarations |
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J. A. P. reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbot, Gilead and Boehringer Ingelheim Pharmaceuticals. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbot and Boehringer Ingelheim Pharmaceuticals and has received lecture fees from GlaxoSmithKline, Roche, Abbot, Bristol-Myers Squibb, Boehringer Ingelheim and Schering-Plough Pharmaceuticals. J. A. M. has received a research grant from GlaxoSmithKline. D. M. reports having participated as an investigator in a clinical trial supported by GlaxoSmithKline. She has received consulting fees from Roche, Abbot and Bristol-Myers Squibb. A. R. reports having received consulting fees from Bristol-Myers Squibb, Abbot, Gilead, Roche Pharma and Boehringer Ingelheim Pharmaceuticals. M. G.-S. reports having participated as an investigator in clinical trials supported by Roche and GlaxoSmith-Kline. She has received lecture fees from Boehringer Ingelheim. The remaining authors have no conflicts of interest.
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Funding |
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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: PI 051546) and the ISCIII-RETIC RD06/006.
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For the Grupo para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). 
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References |
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