Antiviral Therapy 13:

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1 Antiviral Therapy 13: Original article Differences in virological response to pegylated interferon and ribavirin between hepatitis C virus (HCV)-monoinfected and HCV HIV-coinfected patients Cristina Tural 1, Josep Antón Galeras 2, Ramon Planas 3, Susanna Coll 2, Guillem Sirera 1, Dolors Giménez 2, Anna Salas 1, Celestino Rey-Joly 1, Isabel Cirera 2, Carmen Márquez 2, Jordi Tor 1, Sebastià Videla 1, Montserrat García-Retortillo 2, Bonaventura Clotet 1 and Ricard Solà 2 * 1 HIV Clinical Unit, Internal Medicine Department, Fundació de la Lluita contra la SIDA, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain 2 Liver Section, Gastroenterology Service, IMIM-Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Hepatology Unit, Gastroenterology Department, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain *Corresponding author: m@imas.imim.es Background: Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV) HIV-coinfected patients. Methods: A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients (n=104) were compared. All patients received PEG-IFN-α2a 180 µg/week plus ribavirin 800 1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000 1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12. Results: The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR. Conclusions: Differences in efficacy of PEG-IFN-α2a plus ribavirin treatment between HCV HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose. Introduction Hepatitis C viral clearance with pegylated interferon (PEG-IFN) plus ribavirin (RBV) is achieved in 60 84% of hepatitis C virus (HCV)-monoinfected patients [1,2] and in only 29 55% of HCV HIV-coinfected patients [3 9]. It is unknown whether the diminished efficacy of PEG-IFN plus RBV in HCV HIV-coinfected patients is caused by the higher prevalence of host and viral factors associated with IFN resistance in the HCV HIV-coinfected population [10 18] or to modifiable factors such as treatment duration and dosing of PEG-IFN and RBV [1 9]. It has been suggested that the use of fixed 800 mg/day doses of RBV in studies of HCV HIV- coinfected patients [3 9] instead of the optimized doses of 800 1,200 mg/day in studies of HCV-monoinfected patients (1,000 mg/day in HCV genotype 1 if <75 kg or 1,200 mg/day if 75 kg and 800 mg/day in HCV genotype 3) could be one of the factors responsible for the reduced efficacy [2]. Several studies on the kinetics of HCV under PEG IFN therapy have demonstrated the association of early changes in HCV RNA levels with the success of this therapeutic regimen in treating HCV chronic infection [19] International Medical Press

2 C Tural et al. The objective of our study was to investigate possible differences in viral response, especially during the first 12 weeks, between HCV HIV-coinfected patients and HCV-monoinfected patients receiving PEG-IFN-α2a plus an optimized dose of RBV. Methods Study design This was a prospective cohort study with a concurrent matched external cohort. The first cohort comprised 104 consecutive HCV HIV-coinfected patients. The second comprised 104 HCV-monoinfected patients matched by genotype, sex (1:1 ratio) and age (10% aged <35 years, 80% aged years and 10% aged >50 years) with patients in the HCV HIV-coinfected cohort. Patients with HCV genotype 1 in both cohorts received PEG-IFN-α2a (Pegasys ; Roche, Basel, Switzerland) 180 µg/week plus oral RBV (Copegus ; Roche) twice daily according to body weight (patients weighing <75 kg received 1,000 mg/day and patients weighing 75 kg received 1,200 mg/day), whereas patients with HCV genotype 2 or 3 received 800 mg of RBV regardless of HIV status. The duration of therapy for both cohorts was 48 weeks except for patients in the HCV-monoinfected cohort with HCV genotypes 2 and 3, who received treatment for 24 weeks. After the end of therapy patients were followed for a further 24 weeks. Patients The cohort of HCV HIV-coinfected patients and the matching cohort of HCV-monoinfected patients were recruited between January 2003 and March 2005 from patients attending the University Hospital Germans Trias i Pujol and the Hospital del Mar, two tertiary teaching hospitals in Barcelona, Spain. Patients had to be eligible for PEG-IFN-α2a and RBV therapy according to the most recent consensus statements [20]. Moreover, HCV HIV-coinfected patients had to have a CD4 + T-cell count >200 cells/mm 3 regardless of HIV RNA viral load. Patient evaluation All patients were evaluated as outpatients for safety, tolerance and efficacy for 72 weeks, except patients in the HCV-monoinfected cohort with HCV genotypes 2 and 3 who were evaluated for 48 weeks. We performed a qualitative HCV PCR assay in serum (Cobas Amplicor HCV Test; Roche Molecular Systems, Mannheim, Germany; limit of detection 50 IU/ml) at weeks 4, 12, 24 and 48 in all patients and at week 72 in HCV HIVcoinfected patients with HCV genotypes 2 and 3 and all patients with HCV genotype 1 and 4. Serum HCV RNA levels were determined by quantitative PCR assay with a limit of detection of 600 IU/ml (Cobas Amplicor HCV Monitor Test; Roche Molecular Systems) at baseline and at weeks 4, 8 and 12 during treatment. HCV genotype was determined using the LiPA HCV assay (Bayer, Innogenetics, Gent, Belgium). Rapid virological response (RVR) was defined as undetectable HCV RNA levels (<50 IU/ml) at week 4. Early virological response (EVR) was defined as undetectable levels (<50 IU/ml) or 2 log 10 IU/ml drop in HCV RNA at week 12. End-of-treatment response (EOTR) was defined as undetectable levels at the end of treatment. Non-responders were defined as those who did not achieve EVR or undetectable HCV RNA at week 24. Relapse was defined as detectable HCV RNA in plasma 24 weeks after the end of treatment, although levels were undetected at the end of treatment. Sustained virological response (SVR) was defined as serum HCV RNA level <50 IU/ml 24 weeks after the end of therapy. Treatment was discontinued in patients who did not achieve EVR or had detectable HCV RNA levels at week 24. Baseline liver biopsy samples were graded according the Metavir classification [21]. The study was approved by the institutional review boards of the two participating centres. Statistical analyses The sample size (104 patients in each group) was calculated by comparing EVR rates on the basis of previous studies. Thus, we assumed an EVR rate of 71% in the HCV HIV-coinfected group according to the APRICOT study [3] and of 85% in the HCVmonoinfected group according to the study of Fried et al. [1] with an α value of 0.05 and a power of 80%. We estimated a 10% drop-out rate during follow-up. Two analysis sets were defined. The per-protocol analysis set included only those patients who completed the prescribed period of treatment. In the full analysis set, patients who abandoned therapy because of adverse events or intolerance after receiving 1 dose of study medication were considered treatment failures. Changes in HCV RNA from baseline to weeks 4, 8 and 12 were assessed for the per-protocol analysis set. In addition, RVR, EVR, EOTR, SVR, non-response (NR) and relapse were analysed for the two analysis sets. Group comparisons were performed using the Student s t-test and Mann Whitney U test for quantitative variables and χ 2 test to compare proportions. Stepwise multiple logistic regressions were used to determine the factors associated with SVR. Variables included in the analyses were age, gender, body weight, HIV coinfection, pretreatment HCV viral load (log 10 IU/ml), HCV genotype (1 or non-1), pretreatment alanine aminotransferase levels, pretreatment Metavir fibrosis score (F1 F2 or F3 F4), pretreatment values of haemoglobin, leukocytes and platelet count, evidence of RVR and International Medical Press

3 Optimized ribavirin doses in HCV HIV coinfection Figure 1. Patient disposition 259 Patients screened 4 Lost to follow-up 3 Refused 111 HCV HIVcoinfected 148 HCV-monoinfected 104 Included 104 Included 44 Not included after matched selection 102 (98%) Completed 4 weeks of treatment 104 (100%) Completed 4 weeks of treatment 97 (93%) Completed 12 weeks of treatment 104 (100%) Completed 12 weeks of treatment 90 (87%) Completed 24 weeks of treatment 102 (98%) Completed 24 weeks of treatment 87 (84%) Completed prescribed treatment period Reasons for withdrawal Patient refusal (n=5) Safety reasons (n=12) 102 (98%) Completed prescribed treatment period Reasons for withdrawal Safety reasons (n=2) HCV, hepatitis C virus. percentage of PEG-IFN-α2a and RBV received during treatment (100%, 80 99% or <80%). We also included the CD4 + T-cell count, pretreatment HIV viral load (detectable or undetectable), highly active antiretroviral therapy (yes or no), protease inhibitor, non-nucleoside reverse transcriptase inhibitor and tenofovir or abacavir therapy in the analysis performed in the subgroup of HCV HIV-coinfected patients. A variable was added to the stepwise model if the adjusted χ 2 statistic was significant at the P<0.1 level and deleted if the Wald χ 2 statistic was not significant at the P<0.05 level. Results were presented as absolute values and percentages or means ±se. All data analyses were conducted using Statview 5.0 (SAS Institute Inc., Cary, NC, USA) and JMP 5.0 statistical software for Mac OS 9 and X (Apple Computer Inc., Cupertino, CA, USA). Results Patient characteristics Figure 1 shows the patient disposition of the study and Table 1 shows the baseline characteristics of the patients. As expected, the proportion of patients with a history of intravenous drug use and with advanced stages of liver fibrosis was significantly higher in the HCV HIVcoinfected cohort. By contrast, patients in the HCV HIV-coinfected cohort had significantly lower body weight, and there was a higher proportion of former intravenous drug users among them. At baseline, HCV RNA levels were slightly higher in the HCV HIV-coinfected cohort, but this difference was not statistically significant. However, among patients with genotype 1, HCV RNA load was higher in the HCV HIV-coinfected cohort than in the HCV-monoinfected cohort (mean ±se of 6.2 ±0.1 and 5.9 ±0.1 log 10 IU/ml, respectively, P=0.01). The majority of patients (74%) in the HCV HIV-coinfected cohort were on antiretroviral therapy (24% were on protease inhibitors, 46% were on nonnucleoside reverse transcriptase inhibitors, 17% were taking abacavir and 46% were taking tenofovir). HIV replication was well controlled (68% of the patients had an HIV RNA below the limit of detection) and the immune status of the patients was good (mean ±se CD4 + T-cell count 523 ±25 cells/mm 3 and only 15.4% of the Antiviral Therapy

4 C Tural et al. patients had a CD4 + T-cell count <300 cells/mm 3 ). Overall, 13 patients (11 in the HCV HIV-coinfected cohort and 2 in the HCV-monoinfected cohort) did not undergo liver biopsy because of patient decision. All HCV-monoinfected patients and 97 of the HCV HIV-coinfected patients (93.2%) completed the first 12 weeks of treatment (P=0.007). The reasons for treatment withdrawal in the HCV HIV-coinfected cohort were severe anaemia (three patients, only one of whom was taking zidovudine), hyperthyroidism (one patient), severe depression (one patient), severe unexplained asthaenia (one patient) and patient decision (one patient). Two of these seven premature withdrawals occurred before week 4 of treatment. After week 12 of the treatment, a further 10 patients in the HCV HIV-coinfected cohort and 2 in the HCV-monoinfected cohort did not complete the prescribed treatment period (84% of HCV HIV-coinfected patients and 98% of HCV-monoinfected patients completed the prescribed period of treatment; P=0.003). Reasons for treatment withdrawal among the 10 HCV HIV-coinfected patients were severe neutropaenia and thrombocytopaenia (two patients), rash (two patients), hyperthyroidism (two patients), severe depression (two patients) and patient decision (two patients). Changes in HCV RNA during the first 12 weeks of therapy Figure 2 shows the early HCV viral load reduction during the first 12 weeks of therapy. The cumulative decrease in HCV RNA levels was significantly lower in the HCV HIV-coinfected cohort. Among patients with HCV genotype 1, the decrease in HCV RNA level was also lower in HCV HIV-coinfected patients than HCV-monoinfected patients, although the difference was not statistically significant until week 12 (P=0.03). By contrast, genotype 2 and 3 patients showed an early and marked reduction in the viral load which was significantly lower among patients in the HCV HIVcoinfected cohort (P=0.007 at week 4); however, this difference was no longer evident after week 4 (P=0.2). The decrease in the viral load was similar in both groups of patients infected by genotype 4. Virological response to therapy In the intention-to-treat analyses, among patients harbouring HCV genotype 1, EVR, EOTR and SVR were significantly lower in the HCV HIV-coinfected cohort than in the HCV-monoinfected cohort, whereas the proportion of NR was higher in the HCV HIVcoinfected cohort (Table 2); there were no differences in RVR. Among patients with HCV genotype 2 and 3 the only significant difference between the two cohorts was in the number acheiving RVR. In patients with HCV genotype 4, the proportion of patients achieving RVR, EVR, EOTR, SVR or NR was similar in the two cohorts. Overall, the proportion of relapsers was similar in the two cohorts. We performed the same analyses pooling HCV genotypes 1 and 4, and the differences between both cohorts and within genotype groups were maintained. The differences in virological response between both cohorts were also observed when data were analysed for the per-protocol population (SVR in intention-totreat and per-protocol analysis was 43% in the HCV HIV-coinfected versus 67% in HCV-monoinfected Table 1. Baseline characteristics of the patients Characteristic HCV HIV-coinfected patients (n=104) HCV-monoinfected patients (n=104) P-value Mean age, years (±se) 40 (0.5) 40 (0.9) NS Male gender, n (%) 70 (67.3) 71 (68.3) NS Mean body weight, kg (±se) 67 (2) 71 (1) 0.02 Intravenous drug users, n (%) 90 (86.5) 23 (22.1) Mean ALT, IU/I (±se) 92 (7) 101 (8) NS Mean HCV RNA, log 10 IU/ml (±se) 6.1 (0.07) 5.97 (0.05) 0.1 HCV RNA<600,000 log 10 IU/ml, n (%) 28 (26.9) 33 (31.7) NS Genotype 1, n , n 2 4 3, n , n Metavir fibrosis score 3 or 4, n (%) 35 (37.6) 21 (20.6) Mean haemoglobin, g/dl (±se) 14.8 (0.1) 15.1 (0.1) NS Mean leukocyte count, 10 3 cells/ml (±se) 6,253 (254) 6,925 (228) NS Platelet count, 10 3 cells/ml (±se) 144 (94) 171 (11) NS ALT, alanine aminotransferase; HCV, hepatitis C virus; NS, not significant International Medical Press

5 Optimized ribavirin doses in HCV HIV coinfection cohort and 49% in the coinfected versus 69% in the monoinfected cohort, respectively). We also evaluated the cumulative proportion of patients with HCV RNA below the limit of detection (HCV RNA<50 IU/ml) at weeks 4, 12 and 24. There were statistically significant differences in the cumulative proportion of patients with undetectable HCV RNA at weeks 4, 12 and 24 when all the patients were analysed. However, when this analysis was performed by genotype, the differences between HCV HIV-coinfected and HCV-monoinfected patients did not become apparent until week 24 for genotype 1, whereas these differences were only apparent at week 4 in genotypes 2 and 3. HCV RNA<50 IU/ml at week 4 had the highest positive predictive value for SVR in HCV HIV-coinfected and HCV-monoinfected patients (97% and 95%, respectively), whereas EVR had the highest negative predictive value in both populations (100%). Predictive factors of sustained virological response Stepwise, backward, multiple logistic regression analyses showed that genotype, pretreatment HCV RNA level, fibrosis stage and presence of HIV coinfection predicted SVR. However, when achieving RVR was included in the model, the only independent predictors of SVR were achieving RVR, fibrosis stage and female gender (Table 3). SVR rate in patients who achieved RVR was 95.2% and was similar in patients with genotype 1 or genotype 2 or 3 (100% and 93.5%, respectively). By contrast, SVR rates were considerably lower among patients without RVR (42.1%). In this group, SVR rates were lower for patients with genotype 1 in the HCV HIV-coinfected cohort than for those in the HCVmonoinfected cohort (39.1% and 58.8%, respectively); this difference was not significant. Among HCV HIV-coinfected patients, achieving RVR was the only variable independently associated with Figure 2. Cumulative decrease in HCV RNA A 0 Baseline Week 4 Week 8 Week 12 B 0 Baseline Week 4 Week 8 Week 12 HCV RNA, log 10 IU/ml HCV RNA, log 10 IU/ml ANOVA P= ± ± ± ± ± ± ANOVA P= ± ±0 2.8 ± ± ± ±0.1 C 0 Baseline Week 4 Week 8 Week 12 D 0 Baseline Week 4 Week 8 Week 12 HCV RNA, log 10 IU/ml ANOVA P= ± ±0.2 4 ± ± ± ±0.1 HCV RNA, log 10 IU/ml ANOVA P=NS 1.9 ± ± ± ± ± ±0.3 HCV HIV-coinfected HCV-monoinfected Cumulative decrease in hepatitis C virus (HCV) RNA from baseline to weeks 4, 8 and 12 for patients who completed 12 weeks of treatment. Data points are mean ±se. (A) All patients (n=201). (B) Patients harbouring genotype 1 (n=106). (C) Patients harbouring genotypes 2 or 3 (n=63). (D) Patients harbouring genotype 4 (n=32). P-values are shown for ANOVA for the entire period. NS, not significant. Antiviral Therapy

6 C Tural et al. Table 2. Virological response to PEG-IFN-α2a plus weight-based dose of ribavirin in HCV HIV-coinfected and HCV-monoinfected patients by intention-to-treat analyses HCV HIV-coinfected patients (n=104) HCV-monoinfected patients (n=104) P-value Virological Global G1 G2/3 G4 Global G1 G2/3 G4 response (n=104) (n=55) (n=33) (n=16) (n=104) (n=55) (n=33) (n=16) Global G1 G2/3 G4 RVR, n (%) 25 (24) 6 (10.9) 17 (51.5) 2 (12.5) 40 (38.5) 6 (10.9) 29 (87.9) 5 (31.2) 0.04 NS NS EVR, n (%) 77 (74) 35 (63.6) 30 (90.9) 12 (75) 95 (91.3) 48 (87.3) 33 (100) 14 (87.5) NS NS EOTR, n (%) 65 (62.5) 26 (47.3) 29 (87.9) 10 (62.5) 90 (86.5) 44 (80) 33 (100) 13 (81.2) NS NS NR, n (%) 39 (37.5) 29 (52.7) 4 (12.1) 6 (37.5) 14 (13.5) 11 (20) 0 (0) 3 (18.7) NS NS Relapse, n (%) 20 (19.2) 11 (20) 5 (15.1) 4 (25) 20 (19.2) 13 (23.6) 4 (12.1) 3 (18.7) NS NS NS NS SVR, n (%) 45 (43.3) 15 (27.3) 24 (72.7) 6 (37.5) 70 (67.3) 31 (56.4) 29 (87.9) 10 (62.5) NS NS EOTR, end-of-treatment response; EVR, early virological response; G1, genotype 1; G2/3, genotype 2 or 3; G4, genotype 4; HCV, hepatitis C virus; NR, non-response; NS, not significant; PEG-IFN, pegylated interferon; RVR, rapid virological response; SVR, sustained virological response. Table 3. Univariate and multivariate analysis of factors associated with sustained virological response Variable Strata Crude OR (95% CI) Adjusted OR (95% CI) P-value Age Per year 0.31 ( ) Gender Male or female 0.48 ( ) 0.41 ( ) 0.03 Body weight Per 1 kg 0.46 ( ) HIV coinfection HIV or no HIV 0.45 ( ) 0.66 ( ) 0.26 Fibrosis score 3 4 or ( ) 0.28 ( ) HCV genotype 1 or non ( ) 0.73 ( ) 0.60 Serum HCV RNA Per 1 log ( ) 0.30 ( ) 0.26 ALT serum level Per 1 UI/ml 1.38 ( ) Haemoglobin Per 1 g/dl 0.44 ( ) Leukocyte count Per cells/µl 0.36 ( ) Platelets Per cells/µl 5.80 ( ) Rapid virological response Yes or no ( ) ( ) < ALT, alanine aminotransferase; CI, confidence interval; HCV, hepatitis C virus; OR, odds ratio. achieving SVR. Concomitant treatment with abacavir, tenofovir, protease inhibitors or non-nucleoside reverse transcriptase inhibitors was not independently associated with achieving SVR. Thus, the SVR among patients taking protease inhibitors, non- nucleoside reverse transcriptase inhibitors, abacavir and tenofovir was 35%, 36%, 39% and 54%, respectively. Discussion Our study demonstrates the differences in virological response to PEG-IFN-α2a plus an optimized dose of RBV between two sex-, age- and HCV genotype-matched cohorts of HCV-monoinfected and HCV HIV-coinfected patients. Differences between cohorts were HCV-genotype dependent, reflecting the different kinetic behaviour of genotype 1 and genotype 2 or 3, during the first 12 weeks of PEG-IFN-α2a therapy, regardless of HIV status. Thus, among patients with HCV genotype 2 or 3, we found a significantly sharper decrease in HCV RNA in HCV-monoinfected patients compared with HCV HIVcoinfected patients only at week 4, whereas significant differences among patients with HCV genotype 1 were observed only after 12 weeks of therapy. Accordingly, we have found significant differences in the proportion of patients achieving EVR, EOTR, SVR and NR between HCV HIV-coinfected and HCV-monoinfected patients only in the case of patients with HCV genotype 1. By contrast, the differences between both cohorts in RVR rate were observed only in patients with HCV genotypes 2 or 3. Additionally, we have shown that RVR is the strongest predictive factor of SVR in patients receiving PEG-IFNα2a and an optimized dose of RBV, irrespective of HIV status. Our study is the first cohort study with a concurrent control group that demonstrates the different kinetic behaviour of HCV under PEG-IFN-α2a plus an optimized dose of RBV between HCV HIV-coinfected and HCV-monoinfected patients. In addition to the use of low fixed doses (800 mg/day) instead of the optimized dose (1,000 1,200 mg/day according to body weight) of RBV used in most trials of HCV HIV-coinfected patients [3 9] and the greater number of premature discontinuations resulting from the clinical profile of HCV HIV-coinfected patients International Medical Press

7 Optimized ribavirin doses in HCV HIV coinfection [22], a number of hypotheses all poorly understood have been put forward to explain the lower efficacy of treatment with PEG-IFN-α2a and RBV in HCV HIV-coinfected patients. These include the immunological background [10,11,14], the greater complexity of HCV quasispecies in HCV HIV-coinfected patients [15 18], faster liver fibrosis progression [23 25] and the possibility of altered pharmacokinetics, particularly of RBV, in HCV HIV-coinfected patients [26 29]. The potential interactions between RBV and other nucleoside analogues administered concomitantly with RBV have been recently evaluated. Most of these studies showed a negative effect of abacavir in the achievement of SVR, suggesting an inhibitory competition between both drugs [27 29]. However, our study failed to show an independent association between abacavir and viral clearance in the HCV HIV-coinfected cohort. Early studies comparing the kinetics of HCV in HCV HIV-coinfected and HCV-monoinfected patients receiving PEG-IFN-α2a and RBV showed a longer halflife of HCV in HCV HIV-coinfected patients [30,31]. However, these differences have not been found in the most recent studies. Sherman et al. [32] did not find any differences in the first and second phase of viral kinetics, suggesting that IFN response pathways are not affected in HCV HIV-coinfected pati ents, but they observed a delayed viral clearance in HCV HIVcoinfected patients caused by higher viral titre at baseline. Findings of a recent study by Shire et al. [15] are consistent with these results. Our study demonstrates that the most important modifiable factors, such as PEG-IFN-α2a and RBV dosing or the lower adherence to this therapeutic regimen in the HCV HIV-coinfected patients, cannot explain the differences found in the virological response between both cohorts because all patients received the same treatment regimen and differences were also observed for the per-protocol analysis. However, our study is subject to several limitations that preclude us from determining which viral or host factors associated with HIV infection are mainly responsible for the lower efficacy in HCV HIVcoinfected patients. First, although the two cohorts did not differ according to baseline HCV RNA, significant differences were found for baseline HCV RNA between HCV HIV-coinfected and HCV-monoinfected patients harbouring HCV genotype 1; the lower proportion of patients achieving EVR, EOTR or SVR in the HCV HIV-coinfected cohort could be explained by this fact, in line with the findings of other authors [32]. Second, as expected, HCV HIV-coinfected patients had a more advanced stage of liver fibrosis than HCV-monoinfected patients [23 25], which is a well known independent factor for reduced response to IFN-α therapy [33,34]. Finally, there was a higher proportion of former intravenous drug users in the HCV HIV-coinfected cohort, which could explain the higher number of premature discontinuations between weeks 12 and 24 in this group. The role of high dosages of RBV in determining the likelihood of achieving SVR in HCV genotype 1 monoinfected patients has been widely demonstrated [2,35]. By contrast, the results of randomized trials assessing the optimal dose of RBV in HCV HIV-coinfected patients have not been published, although such data would be important as most consensus statements recommend an RBV dose of 1,000 1,200 mg/day instead of the fixed dose of 800 mg/day to treat chronic HCV genotype 1 infection in these patients [36,37]. The findings of such studies are crucial because, although the efficacy results should favour high doses of RBV, these benefits could be offset by a higher incidence of adverse reactions giving rise to dose reductions or premature withdrawal of treatment. If this proves to be the case, it would make strategies to improve therapeutic adherence and the administration of haematopoietic growth factor all the more important. Recently, the efficacy results of the PRESCO study, a multicentre observational study in HCV HIV- coinfected patients who received treatment with PEG-IFN-α2a and a weight-based RBV dose of 1,000 1,200 mg/day, have been published [38]. Unlike our investigation, Ramos et al. [38] found no differences in the proportion of patients who achieved HCV RNA<50 IU/ml at week 4 or of patients achieving an EVR between HCV HIV-coinfected patients of that study and HCVmonoinfected patients from the Pegasys International Study group cohort used by the authors for comparison. Besides differences in the study design, possible explanations for the discrepancy could be the unexpectedly high response rate at week 4 in HCV HIV-coinfected patients harbouring HCV genotype 1 observed in the PRESCO study (33% in the PRESCO study versus 11% in our study) as well as the low RVR found in HCV-monoinfected patients in our study (32% in the PRESCO study versus 11% in our study). Other studies have shown similar results at week 4 with PEG-IFN plus a weight-based dose of RBV in HCV-monoinfected patients [39,40]. Our study further highlights the importance of RVR which, when included in statistical models with other variables often associated with achieving SVR (such as genotype, baseline RNA levels or HIV serum status), was strongly and independently associated with the probability of achieving SVR and the significance of the association of these other variables with SVR was weakened. This has important repercussions for the clinical management of patients with chronic HCV infection because those who will respond to PEG-IFN-α2a and an optimized RBV dose can already be identified after 4 weeks of treatment even when other baseline factors predictive of failure are present. Antiviral Therapy

8 C Tural et al. In summary, the results of our study show that differences in efficacy of treatment with PEG-IFN-α2a plus RBV between HCV HIV-coinfected and HCV-monoinfected patients are evident despite using optimized doses of RBV of 800 mg/day in HCV genotype 3 and weight-based dose of RBV in HCV genotype 1. The role of liver fibrosis and HCV RNA levels before therapy deserves further study. Acknowledgements The authors thank Dr Gregory Morley for editorial support in the preparation of this manuscript. We would like also to thank Centros de Investigación Biomédica en Red en Enfermedades Hépaticas y Digestivas (CIBERehd) for logistic support and Diego Lázaro for data management. Disclosure statement This study has been partially funded by the Spanish AIDS network Red Temática Cooperativa de Investigación en SIDA (RD06/0006), by the Fondo de Investigaciones Sanitarias (FIS; PI051550) and by a grant from the Instituto de Salud Carlos III (IC; C03/02). References 1. 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