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EPIDEMIOLOGY AND SOCIAL

Increased incidence of antiretroviral drug discontinuation among patients with viremic hepatitis C virus coinfection and high hyaluronic acid, a marker of liver fibrosis

Grint, Daniela; Peters, Larsb,c; Rockstroh, Juergen K.d; de Wit, Stephanee; Mitsura, Victor M.f; Knysz, Brygidag; Pedersen, Courth; Kirk, Oleb,c; Lundgren, Jens D.b,c; Mocroft, Amandaa for EuroSIDA in EuroCoord

Author Information
doi: 10.1097/QAD.0000000000000069

Abstract

Introduction

Coinfection with HIV and hepatitis C virus (HCV) is common due to shared transmission routes. In Europe, coinfection rates range from 20% in central and northern regions to 50% in southern and eastern regions [1]. Antiretroviral therapy (ART) for HIV has led to a dramatic decrease in AIDS-related mortality and morbidity, and in some countries, liver end-stage-related disease is the most common cause of death in coinfected patients [2].

Most antiretroviral drugs, specifically protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized by the hepatic cytochrome P450 enzyme system [3]; therefore, advanced hepatic disease caused by HCV infection could impair this metabolism leading to an increased risk of drug toxicity. HCV coinfection has been linked with an increased risk of drug-related hepatotoxicity in several observational studies [4,5]; however, as most previous studies have been small, used only HCV antibodies to define HCV infection, or lacked information on fibrosis, the role of HCV replication and liver fibrosis in causing ART-related toxicity remains unclear. Furthermore, as most liver enzyme elevations are asymptomatic and resolve spontaneously, the clinical consequences of these findings in terms of antiretroviral discontinuations are not well described.

In EuroSIDA, we have previously shown that HIV/HCV coinfected patients were more likely to discontinue antiretroviral drugs due to toxicity or patient/physician choice (TOXPC) than HIV monoinfected patients [6,7]. In the present study, we have included a much larger population of HIV/HCV coinfected patients with well characterized HCV status with the aim of investigating the influence of HCV viremia on the risk of antiretroviral discontinuation and to identify specific antiretroviral drug classes and individual drugs at the highest risk of discontinuation. Furthermore, the role of liver fibrosis in the risk of antiretroviral discontinuation was investigated in all HCV or HBV coinfected patients who have previously been tested for plasma hyaluronic acid, a biomarker of liver fibrosis [8].

Methodology

Study participants and data collection

The EuroSIDA study is a large prospective observational cohort of 18 913 HIV-positive individuals in 108 centers across Europe, Israel, and Argentina. The study has been described in detail previously [9]. At recruitment, in addition to demographic and clinical information, a complete ART history is obtained together with the most recent CD4+ cell count and HIV-RNA measurements. At each follow-up visit, details on all CD4+ cell count and HIV-RNA values measured since last follow-up are collected, as are the dates of starting and stopping each antiretroviral drug used. Patient follow-up of the current study is to the end of December 2012.

Information on the collection of HCVAb, HCV-RNA, and HCV genotype data has been reported elsewhere [10]. In brief, HCVAb status has been collected since 1997; centers that have determined HCV genotype or measured HCV-RNA are requested to provide that information to the coordinating center along with the other EuroSIDA data at 6-monthly intervals. The EuroSIDA plasma repository was set up in 1997 and aims to collect plasma samples from individuals at 6-monthly intervals. In 2006, all individuals with unknown HCVAb status and a stored plasma sample were identified and HCVAb status was determined. Individuals who tested positive were then tested for HCV-RNA and genotype.

Hyaluronic acid has been shown to be an accurate noninvasive marker of liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients [11,12]. In healthy controls, 0–75 ng/ml has been defined as the normal range, with a value above 100 ng/ml indicative of significant hepatic fibrosis [8,12]. Details of the collection of hyaluronic acid data in EuroSIDA have been reported elsewhere [13]. In brief, hyaluronic acid was measured among the subset of patients positive for HCVAb and/or hepatitis B surface antigen (HBsAg) with stored plasma samples available. All hyaluronic acid measurements were taken per protocol and not as a result of clinical disease management.

Statistical methods

All EuroSIDA patients receiving combination antiretroviral therapy (cART), defined as at least three antiretroviral drugs of any class, with known HCVAb status during prospective follow-up were included. HCVAb-negative patients are included to compare the rate of drug discontinuation among HIV monoinfected patients with those coinfected with HCV. Throughout the study, baseline was defined as the date of initiating a new cART regimen (either the first cART regimen or a new regimen due to drug switching), recruitment to the study, or 1 January 1999 (when EuroSIDA began collecting reasons for treatment discontinuation), whichever occurred later.

Switches from single agent drugs to combination pills containing the same drugs were not considered to be treatment discontinuations. Due to the way that data are collected in EuroSIDA, it is not always possible to differentiate between combination pills and single agents. Consequently, when more than one drug is stopped at the same time, the reason for discontinuing is attributed to all stopped drugs.

Multivariable Poisson regression models were used to assess the risk of cART discontinuation due to TOXPC, using Generalized Estimating Equations and robust standard errors, allowing for multiple discontinuations among patients. Factors adjusted for in the population with known HCVAb status were as follows: age, sex, ethnicity, HIV transmission group, region of Europe, HCV genotype, and time-updating HIV-RNA, CD4+ cell count, HCV-RNA, and HBsAg status. Follow-up was counted until any component of cART was discontinued, censoring patients 1 month before initiation of interferon-based therapy due to potential drug switching to avoid drug interactions with HCV treatment. If after a discontinuation a patient remained on three or more antiretroviral drugs or subsequently initiated cART again at a later date, they re-entered the analysis with a new baseline with follow-up counted until the next discontinuation.

Hyaluronic acid was additionally adjusted for in a subset analysis of patients with hyaluronic acid measured. The population of patients included in this subset were all positive for HCVAb or HBsAg. Due to the stability of hyaluronic acid levels over a short period of time [13], follow-up was counted within a 2-year window either side of a hyaluronic acid measurement.

Sensitivity analysis

Sensitivity analyses further adjusted for time-updating alanine transaminase (ALT) and aspartate transaminase (AST) levels, in patients with these data available, in order to examine whether HCV-RNA and hyaluronic acid levels were predictors of antiretroviral treatment discontinuation independent of raised liver enzymes. Sensitivity analyses were also performed using toxicity endpoints. An analysis was also performed using multiple imputations to replace missing HCV-RNA data.

All analyses were performed using SAS (version 9.2, SAS Institute, Cary, North Carolina, USA).

Results

Hepatitis C virus RNA and drug discontinuation due to toxicity or patient/physician choice

In total, 8873 drug discontinuations due to TOXPC in 49215 person years of follow-up (PYFU) from 9535 patients [2744 HCVAb-positive; HCV-RNA available for 1904; 1538 (80.8%) HCV viremic over the course of follow-up] with known HCVAb status were included, at an incidence of 18.0 (95% confidence interval, CI 17.7–18.4) TOXPC drug discontinuations per 100 PYFU. The breakdown of drug discontinuations was patient and physician choice (69%), and toxicity (31%); among toxicities, the most commonly reported were from the gastrointestinal tract (35%), other toxicities (21%), nervous system (20%), kidneys (13%), and liver (7%).

Baseline characteristics split by HCV status are shown in Table 1. The majority of patients were white (88.3%) men (73.3%) with a median age of 41 (interquartile range, IQR 35–48). A total of 75.1% of patients positive for HCVAb with detectible HCV-RNA were injecting drug users compared with 2.9% of those HCVAb-negative. Among those with detectible HCV-RNA, the genotype distribution was G1 (48.4%), G2 (3.0%), G3 (24.7%), and G4 (13.4%) with 10.5% having no genotype data. The median HCV viral load was 5.8 (IQR 5.3–6.3) log10 IU/ml.

Table 1
Table 1:
Baseline characteristics by hepatitis C virus status.

HCVAb positivity was associated with increased risk of TOXPC drug discontinuations overall [adjusted incidence rate ratio (aIRR): 1.28 (95% CI 1.15–1.43; P <0.0001) vs. HCVAb negative] and across all drug classes (data not shown). Patients with viremic HCV infection were at increased risk of TOXPC drug discontinuations overall [aIRR: 1.44 (95% CI 1.22–1.69; P = 0.0078) vs. aviremic HCV] (Fig. 1), with similar patterns observed across all drug classes. The largest HCV viremia signal was seen among NNRTIs wherein viremic HCV-infected patients had 59% increased risk [aIRR: 1.59 (95% CI 1.18–2.14; P = 0.0021)]. For NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs), HCVAb-negative patients had borderline significance for reduced risk of TOXPC drug discontinuations compared with aviremic HCV infection [aIRR: 0.78 (95% CI 0.59–1.03; P = 0.078) and aIRR: 0.83 (95% CI 0.69–1.01; P = 0.059), respectively].

Fig. 1
Fig. 1:
Incidence rate ratios for toxicity or patient/physician choice drug discontinuation by hepatitis C virus status.Comparisons of the effect of hepatitis C virus (HCV) viremia on toxicity and patient/clinician choice (TOXPC) drug discontinuation. Models adjusted for age, sex, ethnicity, HIV transmission group, region of Europe, HCV genotype, time-updating HIV-RNA, CD4+ cell count, HCV-RNA, and hepatitis B surface antigen status. *Crude incidence rate per 100 person years follow-up (PYFU).

Figure 2 further analyzes the effect of viremic HCV infection compared to aviremic infection by considering individual drugs. Viremic HCV infection was significantly associated with TOXPC drug discontinuations for efavirenz [aIRR: 1.75 (95% CI 1.23–2.49; P = 0.0020)], lamivudine [aIRR: 1.35 (95% CI 1.05–1.74; P = 0.022)], tenofovir [aIRR: 1.50 (95% CI 1.12–2.00; P = 0.0065)], stavudine [aIRR: 1.51 (95% CI 1.01–2.23; P = 0.042)], and didanosine [aIRR: 2.02 (95% CI 1.30–3.15; P = 0.0019)], compared with aviremic infection.

Fig. 2
Fig. 2:
Incidence rate ratios of toxicity or patient/physician choice drug discontinuation for viremic hepatitis C virus vs. aviremic hepatitis C virus infection by drug/class.Comparison of the effect of viremic hepatitis C virus (HCV) vs. aviremic HCV infection on toxicity and patient/clinician choice (TOXPC) drug discontinuation among drug classes and single agents. Models adjusted for age, sex, ethnicity, HIV transmission group, region of Europe, HCV genotype, time-updating HIV-RNA, CD4+ cell count, HCV-RNA, and hepatitis B surface antigen status. Drugs with at least 100 discontinuations in this population included. *Crude incidence rate per 100 person years follow-up (PYFU).

Alanine transaminase and aspartate transaminase adjustment in hepatitis C virus-RNA population

ALT or AST was measured over the follow-up period in 8690 of 9535 (91.1%) of this population with a median eight measurements per patient (IQR 3–13); 1378 (14.5%) developed transaminase levels three times the upper limit of the normal range. Transaminase levels three times the upper limit of the normal range were strongly associated with treatment discontinuation across all drug classes (P <0.001 for all). After adjustment for ALT and AST, the size of the effect of viremic HCV infection was slightly reduced for all drug classes [aIRR: 1.36 (95% CI 1.08–1.71; P = 0.0079, aIRR: 1.49 (95% CI 1.11–2.01; P = 0.0089), and aIRR: 1.37 (95% CI 1.13–1.67; P = 0.0015), for protease inhibitors, NNRTIs, and NRTIs, respectively, vs. aviremic infection], although viremic HCV infection remained a highly significant predictor of treatment discontinuation. Further, adjustment for ALT and AST did not alter the finding that HCVAb-negative patients were at borderline reduced risk of drug discontinuation compared with those with aviremic HCV infection among the NNRTIs and NRTIs.

Hyaluronic acid and drug discontinuation due to toxicity or patient/physician

In a subset analysis, plasma hyaluronic acid levels were available in 935 HCVAb-positive and/or HBsAg-positive patients. The median number of hyaluronic acid measurements per patient was 2 (IQR 2–2; range: 1–4). A total of 455 TOXPC drug discontinuations were observed in the hyaluronic acid subset in 1707 PYFU, at an incidence of 26.7 (95% CI 24.6–28.8) TOXPC drug discontinuations per 100 PYFU. Baseline characteristics of this population subset are shown in Table 2. The hyaluronic acid categories were generally well balanced, though there were more patients from the West Central region (40.1 vs. 30.5%) and fewer patients HCVAb-negative (19.7 vs. 32.4%) with hyaluronic acid more than 100 ng/ml, although all HCVAb-negative patients were HBsAg-positive.

Table 2
Table 2:
Baseline characteristics of the hyaluronic acid subset.

Hyaluronic acid more than 100 ng/ml was associated with 37% increased risk of TOXPC drug discontinuation [aIRR: 1.37 (95% CI 1.08–1.73; P = 0.010) vs. hyaluronic acid ≤100 ng/ml] (Fig. 3). Interestingly, after adjustment for hyaluronic acid in this subset, the effect of viremic HCV infection became nonsignificant, falling from the aIRR of 1.44 in Fig. 1 to an aIRR of 1.00 (95% CI 0.66–1.50; P = 0.99) vs. aviremic infection. Hyaluronic acid more than 100 ng/ml was associated with increased risk of antiretroviral discontinuations for the protease inhibitors [aIRR: 1.40 (95% CI 1.04–1.89; P = 0.029) vs. hyaluronic acid ≤100 ng/ml] and with borderline significance for the NRTIs [aIRR: 1.33 (95% CI 0.99–1.78; P = 0.057) vs. hyaluronic acid ≤100 ng/ml], but not the NNRTIs [aIRR: 1.29 (95% CI 0.75–2.21; P = 0.35) vs. hyaluronic acid ≤100 ng/ml] (Fig. 3), although the effect sizes were similar across drug classes with fewer events and limited power among the NNRTIs. Among individual drugs, hyaluronic acid more than 100 ng/ml was associated with increased risk of antiretroviral drug discontinuation for the NRTIs zidovudine [aIRR: 1.87 (95% CI 1.04–3.38; P = 0.037) vs. hyaluronic acid ≤100 ng/ml] and didanosine [aIRR: 2.55 (95% CI 1.43–4.55; P <0.0001)].

Fig. 3
Fig. 3:
Incidence rate ratios of toxicity or patient/physician choice drug discontinuation for hyaluronic acid more than 100 ng/ml vs. hyaluronic acid 100 ng/ml or less by drug/class.Comparison of the effect of hyaluronic acid more than 100 ng/ml vs. hyaluronic acid 100 ng/ml or less on toxicity and patient/clinician choice (TOXPC) drug discontinuation among drug classes and single agents. Models adjusted for age, sex, ethnicity, HIV transmission group, region of Europe, hepatitis C virus (HCV) genotype, time-updating HIV-RNA, CD4+ cell count, HCV-RNA, hepatitis B surface antigen status, and serum hyaluronic acid. Drugs with at least 25 discontinuations in this population included. *Crude incidence rate per 100 person years follow-up (PYFU).

Alanine transaminase and aspartate transaminase adjustment in hyaluronic acid population

ALT or AST was measured in 716 of 935 (76.6%) of this population with a median three measurements per patient (IQR 2–5); 134 (14.3%) developed transaminase levels three times the upper limit of the normal range. Transaminase levels three times the upper limit of the normal range were not associated with treatment discontinuation for any drug classes in this subset (P >0.5 for all). Consequently, adjustment for ALT and AST did not alter the results shown in Fig. 3.

Discussion

This study described the incidence of antiretroviral treatment discontinuation due to TOXPC according to HCV infection status and the level of liver fibrosis. Data from large clinical cohorts are scarce on the effect of liver fibrosis on the rate of antiretroviral drug discontinuation as they have required liver biopsy. However, in this study using the biomarker plasma hyaluronic acid as a surrogate for liver fibrosis, we found that patients with hyaluronic acid more than 100 ng/ml were at increased risk of TOXPC drug discontinuations compared with those with hyaluronic acid 100 ng/ml or less. This was the case overall and among the protease inhibitors with borderline significance for the NRTIs, whereas the effect of high hyaluronic acid was in the same direction, but did not reach significance among the NNRTIs, likely due to reduced power. Adjustment for transaminases did not alter these findings, which suggest that high hyaluronic acid, or significant liver fibrosis, is an independent predictor of antiretroviral treatment discontinuation from raised liver enzymes. This is particularly pertinent for the protease inhibitor drug class, which is considered liver-friendly and has not been strongly associated with raised transaminases [14–18], as our findings could suggest that liver fibrosis can lead to protease inhibitor toxicity.

Many studies have documented rapid progression of liver fibrosis in HIV/HCV coinfected patients [19–21]; other studies have shown an association between liver fibrosis and ART-associated hepatotoxicity [22,23]. As protease inhibitors are predominantly metabolized by the P450 enzyme system [3], our findings could suggest that liver damage inhibiting this metabolism is causing overdosing of these drugs leading to treatment discontinuation. Alternatively, patients with advanced liver fibrosis could be less tolerant to side-effects attributed to protease inhibitors. Surprisingly, the same effect did not reach significance among NNRTIs, which are metabolized in the same way [3], though this was likely due to reduced statistical power. Whereas hyaluronic acid more than 100 ng/ml was associated with 37% increased risk of drug discontinuation of efavirenz, though not statistically significant, high levels of hyaluronic acid were not associated with drug discontinuations of nevirapine. Other studies to examine the relationship between fibrosis and ART-associated toxicity have acknowledged a higher risk of hepatotoxicity and raised transaminases during NNRTI use [24–26], specifically for nevirapine [27]. In this study, it is possible that hyaluronic acid was not found to be associated with discontinuation of nevirapine as the drug's link to liver fibrosis and tendency to raise transaminases is most important within the first 6 weeks of use [28], with the median time to discontinuation of nevirapine being 7.7 months. Further, we cannot rule out confounding by indication, whereby the deleterious influence of nevirapine and the NNRTI drug class may have been underestimated because of less frequent use of these drugs in patients with HIV/HCV coinfection.

The borderline hyaluronic acid effect seen for the NRTI class is driven mostly by the significant effects seen for zidovudine and didanosine, which have been associated with liver toxicity [29–32]. Although zidovudine and didanosine are no longer in routine use in the western world, it remains important to study these drugs as they are still used in the resource-limited setting. These two drugs along with stavudine are contraindicated when initiating treatment for HCV [33–35], and treatment switches away from these drugs prior to initiating HCV treatment are likely. However, we censor 1 month prior to initiation of HCV treatment and in sensitivity analyses censoring 6 months prior to initiation of HCV treatment, the results were identical. Use of nucleoside analogues, in particular didanosine and stavudine, have been associated with increased levels of liver fibrosis among HIV patients [29,31] and it is likely that this increased liver fibrosis is leading to hepatotoxicity. Zidovudine, although primarily removed from the body via renal excretion, has a metabolizing contribution from the P450 enzyme system [3], and as with the protease inhibitors, it may be this mechanism hindered by liver fibrosis that leads to toxicity and treatment discontinuation.

HCVAb positivity was associated with increased risk of TOXPC drug discontinuation in line with previous work on the topic [4,6,7]. Expanding this to study the effect of HCV viremia, we found that patients with viremic HCV infection were at consistently higher risk of TOXPC drug discontinuation compared with those with aviremic HCV infection. HCV viral load and duration of HCV infection have previously been identified as predictors of liver fibrosis [29,36]; indeed, as the effect of HCV viremia became nonsignificant when adjusting for hyaluronic acid in this study, our results suggest that liver fibrosis, as measured by elevated hyaluronic acid, caused by HCV viral replication is the driving force behind antiretroviral drug discontinuation and not viral replication per se. The significant effects of viremic HCV infection seen for the NRTIs lamivudine and tenofovir can be partially explained by their use in combination pills. In EuroSIDA, it is not always possible to differentiate between combination pills and single agent regimens. Of 669 discontinuations attributed to lamivudine in the HCV viremia population, just 25 (3.7%) were discontinuations when lamivudine was the only drug stopped. Further, the effects of lamivudine and emtricitabine could be inflated by switches from one drug to the other. The common combination of efavirenz and tenofovir could explain some of the effects seen for tenofovir, as efavirenz was strongly associated with drug discontinuation. Alternatively, viremic HCV infection has been associated with increased risk of chronic kidney disease [37,38], which due to the primary renal excretion of tenofovir [3] and its link with chronic renal impairment [39] would often lead to discontinuation.

An explanation for greater risk of antiretroviral discontinuation among viremic HCV patients could include heightened transaminase levels among patients with chronic HCV, as they have less room for treatment-induced transaminase increases before treatment will be discontinued. ALT/AST levels three times the upper limit of the normal range were highly significant predictors of treatment discontinuation, as we might expect due to their indication of treatment withdrawal due to hepatotoxicity [40]. However, after adjustment for ALT/AST, the effect of viremic HCV infection among all drug classes remained highly significant, indicating that HCV viremia is a significant predictor of drug discontinuation independent of raised transaminases.

We also found some evidence that patients with aviremic HCV infection remained at higher risk of drug discontinuation than HCVAb-negative patients among the NNRTI and NRTI drug classes. A possible explanation for the residual excess in TOXPC drug discontinuations after successful clearance of HCV viremia, in comparison to HIV monoinfected patients, could be HBV infection. In sensitivity analysis removing HBV-positive patients, the HCVAb-negative effect became nonsignificant among NNRTIs (P >0.1), but remained for the NRTIs, which suggests that although confounding HBV infection at least partially explains this finding, it is likely that unmeasured lifestyle factors associated with HCV coinfection explain some of the differences between HCVAb-negative and HCVAb-positive patients.

This study has several limitations. Although hyaluronic acid has been identified as a promising biomarker for significant liver fibrosis, an important limitation to its use in daily clinical practise is a substantial postprandial increase in the first 2 h after food intake [41]; however, the influence of food intake would underestimate the effect of hyaluronic acid in this study. Further, due to the limited amount of hyaluronic acid data available and the method allowing a 2-year window either side of a hyaluronic acid measurement, hyaluronic acid measurements attributed to the time of drug discontinuation could have occurred after the event.

In the analysis of individual drugs, particularly in the hyaluronic acid subset, the number of events and follow-up often meant we lacked sufficient power to detect small differences in the rate of treatment discontinuation. A combined endpoint of drug discontinuation due to toxicity or patient/clinician choice was used in this study. Whereas the definition of toxicity is clear, patient and clinician choice potentially reflects many different reasons. However, in sensitivity analyses restricting only to the toxicity endpoints, the results did not differ from those presented here. Any minor differences from the main analysis presented here enhanced the effects of HCV viremia and hyaluronic acid (data not shown).

A multiple imputations analysis replacing the missing HCV-RNA data in Table 1 was performed to repeat the analysis in Fig. 1. The results were very similar with viremic HCV infection consistently associated with increased risk of drug discontinuation for all drug classes (data not shown). In this analysis, the HCVAb-negative patients were also at reduced risk of drug discontinuation compared with those with aviremic HCV infection; however, this could be explained by the misclassification of some viremic patients to the aviremic category by the imputation methods (Supp. figure 1, http://links.lww.com/QAD/A423).

In conclusion, this study found that patients with chronic HCV infection were at greater risk of antiretroviral drug discontinuation compared with patients with aviremic HCV infection, but that the effect seems to be explained by more advanced liver fibrosis among patients with HCV viremia. The effect of fibrosis on risk of treatment discontinuation was seen mainly for the protease inhibitors and older NRTIs and was independent of liver transaminase levels.

Acknowledgements

D.G. led the study with supporting contributions from L.P., J.D.L., and A.M. D.G. performed the statistical analyses. D.G., J.D.L., L.P., O.K., and A.M. designed the study and D.G. drafted the article. All coauthors contributed to redrafting and refinement of the study. A.M. supervised the study.

The EuroSIDA Study Group: The multicentre study group on EuroSIDA (national coordinators in parenthesis).

Argentina: (M Losso), M Kundro, Hospital JM Ramos Mejia, Buenos Aires. Austria: (N Vetter), PulmologischesZentrum der Stadt Wien, Vienna; R Zangerle, Medical University Innsbruck, Innsbruck. Belarus: (I Karpov), A Vassilenko, Belarus State Medical University, Minsk, VM Mitsura, Gomel State Medical University, Gomel; O Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N Clumeck), S De Wit, M Delforge, Saint-Pierre Hospital, Brussels; E Florence, Institute of Tropical Medicine, Antwerp; L Vandekerckhove, University Ziekenhuis Gent, Gent. Bosnia-Herzegovina: (V Hadziosmanovic), KlinickiCentarUniverziteta Sarajevo, Sarajevo. Bulgaria: (K Kostov), Infectious Diseases Hospital, Sofia. Croatia: (J Begovac), University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L Machala), D Jilich, Faculty Hospital Bulovka, Prague; D Sedlacek, Charles University Hospital, Plzen. Denmark: (J Nielsen), G Kronborg,T Benfield, M Larsen, Hvidovre Hospital, Copenhagen; J Gerstoft, T Katzenstein, A-B E Hansen, P Skinhøj, Rigshospitalet, Copenhagen; C Pedersen, Odense University Hospital, Odense; L Ostergaard, Skejby Hospital, Aarhus, U B Dragsted, Roskilde Hospital, Roskilde; L N Nielsen, Hillerod Hospital, Hillerod. Estonia: (K Zilmer), West-Tallinn Central Hospital, Tallinn; JelenaSmidt, NakkusosakondSiseklinik, Kohtla-Järve. Finland: (M Ristola), Helsinki University Central Hospital, Helsinki. France: (C Katlama), Hôpital de la Pitié-Salpétière, Paris; J-P Viard, Hôtel-Dieu, Paris; P-M Girard, Hospital Saint-Antoine, Paris; P Vanhems, University Claude Bernard, Lyon; C Pradier, Hôpital de l’Archet, Nice; F Dabis, D Neau, Unité INSERM, Bordeaux, C Duvivier, Hôpital Necker-EnfantsMalades, Paris. Germany: (J Rockstroh), UniversitätsKlinik Bonn; R Schmidt, MedizinischeHochschule Hannover; J van Lunzen, O Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; HJ Stellbrink, IPM Study Center, Hamburg; M Bickel, JW Goethe University Hospital, Frankfurt; J Bogner, MedizinischePoliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J Kosmidis), P Gargalianos, G Xylomenos, J Perdios, Athens General Hospital; H Sambatakou, IppokrationGenereal Hospital, Athens. Hungary: (D Banhegyi), SzentLásló Hospital, Budapest. Iceland: (M Gottfredsson), Landspitali University Hospital, Reykjavik. Ireland: (F Mulcahy), St. James's Hospital, Dublin. Israel: (I Yust), D Turner, M Burke, Ichilov Hospital, Tel Aviv; S Pollack, G Hassoun, Rambam Medical Center, Haifa; S Maayan, Hadassah University Hospital, Jerusalem. Italy: (A D’ArminioMonforte), Istituto Di ClinicaMalattieInfettive e Tropicale, Milan; R Esposito, I Mazeu, C Mussini, Università Modena, Modena; C Arici, OspedaleRiuniti, Bergamo; R Pristera, OspedaleGeneraleRegionale, Bolzano; F Mazzotta, A Gabbuti, Ospedale S Maria Annunziata, Firenze; V Vullo, M Lichtner, University di Roma la Sapienza, Rome; A Chirianni, E Montesarchio, M Gargiulo, PresidioOspedaliero AD Cotugno, Monaldi Hospital, Napoli; G Antonucci, A Testa, G D‘Offizi, C Vlassi, M Zaccarelli, A Antorini, IstitutoNazionaleMalattieInfettiveLazzaroSpallanzani, Rome; A Lazzarin, A Castagna, N Gianotti, Ospedale San Raffaele, Milan; M Galli, A Ridolfo, Osp. L. Sacco, Milan.Latvia: (B Rozentale), I Zeltina, Infectology Centre of Latvia, Riga. Lithuania: (S Chaplinskas), Lithuanian AIDS Centre, Vilnius. Luxembourg: (T Staub), R Hemmer, Centre Hospitalier, Luxembourg. Netherlands: P Reiss), AcademischMedisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (V Ormaasen), A Maeland, J Bruun, Ullevål Hospital, Oslo. Poland: (B Knysz) J Gasiorowski, Medical University, Wroclaw; A Horban, E Bakowska, Centrum DiagnostykiiTerapii AIDS, Warsaw; A Grzeszczuk, R Flisiak, Medical University, Bialystok; A Boron-Kaczmarska, M Pynka, M Parczewski, Medical Univesity, Szczecin; M Beniowski, E Mularska, OsrodekDiagnostykiiTerapii AIDS, Chorzow; H Trocha, Medical University, Gdansk; E Jablonowska, E Malolepsza, K Wojcik, WojewodzkiSzpitalSpecjalistyczny, Lodz. Portugal: (F Antunes), M Doroana, L Caldeira, Hospital Santa Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Lisbon; F Maltez, Hospital Curry Cabral, Lisbon. Romania: (D Duiculescu), Spitalul de BoliInfectioasesiTropicale: Dr Victor Babes, Bucarest. Russia: (A Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; A Rakhmanova, St Petersburg AIDS Centre, St Peterburg; S Buzunova, Novgorod Centre for AIDS, Novgorod, I Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E Kuzovatova, Nizhny Novgorod Scientific and Research Institute, Nizhny Novogrod. Serbia: (D Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M Mokráš), D Staneková, Dérer Hospital, Bratislava.Slovenia: (J Tomazic), University Clinical Centre Ljubljana, Ljubljana. Spain: (J González-Lahoz), V Soriano, P Labarga, Hospital Carlos III, Madrid; S Moreno, J. M. Rodriguez, Hospital Ramon y Cajal, Madrid; B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, Hospital Germans TriasiPujol, Badalona; JM Gatell, JM Miró, Hospital Clinic i Provincial, Barcelona; P Domingo, M Gutierrez, G Mateo, MA Sambeat, Hospital Sant Pau, Barcelona; J Medrano, Hospital Universitario de Alava, Vitoria-Gasteiz. Sweden: (A Blaxhult), Venhaelsan-Sodersjukhuset, Stockholm; L Flamholc, Malmö University Hospital, Malmö, A Thalme, A Sonnerborg, Karolinska University Hospital, Stockholm. Switzerland: (B Ledergerber), R Weber, University Hospital, Zürich; P Francioli, M Cavassini, Centre HospitalierUniversitaireVaudois, Lausanne; B Hirschel, E Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H Furrer, Inselspital Bern, Bern; M Battegay, L Elzi, University Hospital Basel; P Vernazza, Kantonsspital, St. Gallen. Ukraine: (E Kravchenko), N Chentsova, Kiev Centre for AIDS, Kiev; V Frolov, G Kutsyna, Luhansk State Medical University; Luhansk; S Servitskiy, Odessa Region AIDS Center, Odessa; A Kuznetsova, Kharkov State Medical University, Kharkov; G Kyselyova, Crimean Republican AIDS centre, Simferopol. United Kingdom: (B Gazzard), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; AM Johnson, D Mercey, Royal Free and University College London Medical School, London (University College Campus); A Phillips, MA Johnson, A Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); C Orkin, Royal London Hospital, London; J Weber, G Scullard, Imperial College School of Medicine at St. Mary's, London; M Fisher, Royal Sussex County Hospital, Brighton; C Leen, Western General Hospital, Edinburgh.

Members of Steering Committee are as follows: J Gatell, B Gazzard, A Horban, I Karpov, B Ledergerber, M Losso, A D’ArminioMonforte, C Pedersen, A Rakhmanova, M Ristola, J Rockstroh (Chair), S De Wit (Vice-Chair)

Additional voting members are as follows: J Lundgren, A Phillips, and P Reiss.

Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94–1637), BIOMED 2 (CT97–2713), the 5th Framework (QLK2–2000-00773) and the 6th Framework (LSHP-CT-2006-018632), and the 7th Framework (FP7/2007-2013, EuroCoord n° 260694) programs. Current support also includes unrestricted grants by Gilead, Pfizer, BMS, Merck and Co. The participation of centers from Switzerland was supported by The Swiss National Science Foundation (Grant 108787).

Conflicts of interest

O.K. has received honorarium, consultancy, and/or lecture fees from Abbott, Gilead, GSK, Janssen, Merck, Tibotec, and Viiv. A.M. has received honorarium, consultancy, or guest speaker fees from Pfizer, Merck, Gilead, BI, and BMS. J.R. has received consultancy or lecture fees from Bionor, BMS, BI, GSK, ViiV, Abbott, Gilead, Pfizer, Merck, Tibotec, and Janssen. All other authors have no conflicts of interest to report for the present study.

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Keywords:

coinfection; combination antiretroviral therapy; hepatitis C virus; HIV; hyaluronic acid; significant fibrosis; toxicity; treatment discontinuation

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