Differences in HCV Viral Decline between Low and Standard-Dose Pegylated-Interferon-Alpha-2a with Ribavirin in HIV/HCV Genotype 3 Patients

Differences in HCV Viral Decline between Low and Standard-Dose Pegylated-Interferon-Alpha-2a with Ribavirin in HIV/HCV Genotype 3 Patients Antonio Rivero-Jua ´rez 1,2 , Luis F. Lopez-Cortes 3 , Angela Camacho 1,2 , Almudena Torres-Cornejo 3 , Juan A. Pineda 4 , Manuel Marquez-Solero 5 , Antonio Caruz 6 , Rosa Ruiz-Valderas 3 , Julian Torre- Cisneros 1,2 , Alicia Gutierrez-Valencia 3 , Antonio Rivero 1,2 * 1Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Cordoba, Spain, 2Maimonides Institute for Biomedical Research, Cordoba, Spain, 3Enfermedades Infecciosas, Microbiologı ´a y Medicina Preventiva, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocı ´o/Consejo Superior de Investigaciones Cientı ´ficas/Universidad de Sevilla, Seville, Spain, 4Unit of Infectious Diseases, Hospital Universitario de Valme, Seville, Spain, 5Unit of Infectious Diseases, Hospital Universitario Virgen de la Victoria, Malaga, Spain, 6Immunogenetics Unit, Faculty of Sciences, Universidad de Jae ´n, Jaen, Spain Abstract Background: The aim of the study was to analyze the different impact of standard and low-dose Peg-IFN-a2a/RBV therapies on HCV viral decline in HIV/HCV genotype 3 co-infected patients during the first weeks of treatment. Methods: Plasma HCV viral decline was analyzed between baseline and weeks 1, 2 and 4 in two groups of treatment-naı ¨ve HCV genotype 3 patients with HIV co-infection. The Standard Dose Group (SDG) included patients who received Peg-IFN at 180 mg/per week with a weight-adjusted dose of ribavirin; Low-Dose Group (LDG) patients received Peg-IFN at 135 mg/per week with 800 mg/day ribavirin. The effect of IL28B genotype on HCV viral decline was evaluated in both groups. HCV viral decline was analyzed using a multivariate linear regression model. Results: One hundred and six patients were included: 48 patients in the SDG and 58 in the LDG. HCV viral decline for patients in the LDG was less than for those in the SDG (week 1:1.7260.74 log 10 IU/mL versus 1.7860.67 log 10 IU/mL, p = 0.827; week 2:2.360.89 log 10 IU/mL versus 3.0161.02 log 10 IU/mL, p = 0.013; week 4:3.5261.2 log 10 IU/mL versus 4.0961.1 log 10 IU/mL, p = 0.005). The linear regression model identified the Peg-IFN/RBV dose as an independent factor for HCV viral decline at week 4. Conclusions: Our results showed that HCV viral decline was less for patients in the low-dose group compared to those receiving the standard dose. Until a randomized clinical trial is conducted, clinicians should be cautious about using lower doses of Peg-IFN/RBV in HIV/HCV genotype 3 co-infected patients. Citation: Rivero-Jua ´rez A, Lopez-Cortes LF, Camacho A, Torres-Cornejo A, Pineda JA, et al. (2012) Differences in HCV Viral Decline between Low and Standard- Dose Pegylated-Interferon-Alpha-2a with Ribavirin in HIV/HCV Genotype 3 Patients. PLoS ONE 7(11): e48959. doi:10.1371/journal.pone.0048959 Editor: Wenzhe Ho, Temple University School of Medicine, United States of America Received August 16, 2012; Accepted October 2, 2012; Published November 8, 2012 Copyright: ß2012 Rivero-Jua ´rez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was partly supported by grants from the Fundacio ´n Progreso y Salud, Consejerı ´a de Salud de la Junta de Andalucı ´a (grants for health research projects: refs. 0036/2010, PI-0247-2010 and PI-0208 and 0124/2008) and the Spanish Health Ministry (ISCIII-RETIC RD06/006, and projects PI10/0164 and PI10/01232). AR is the recipient of a research extension grant from the Fundacio ´n Progreso y Salud, Consejerı ´a de Salud de la Junta de Andalucı ´a (Reference AI- 0011-2010); JAP is the recipient of extension grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: AR has received consulting fees from Bristol-Myers Squibb, Abbott, Gilead, Roche and Boehringer Ingelheim. JAP has received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott, Gilead, Merck Sharp & Dohme, Janssen-Cilag and Boehringer Ingelheim. LFLC has received funds for speaking at symposia organized on behalf of Abbott Laboratories, Bristol-Myers Squibb, GlaxoSmithkline, Gilead Sciences, MSD, Janssen-Cilag S. A., and Viiv Healthcare. They have received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott and Boehringer Ingelheim, and lecture fees from GlaxoSmithKline, Roche, Abbott, Bristol-Myers Squibb, Boehringer Ingelheim and Schering-Plough. The remaining authors have no conflicts of interest to declare. This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials. * E-mail: [email protected] Introduction The best determinant of response to hepatitis C virus (HCV) treatment using pegylated-interferon (Peg-IFN) in combination with ribavirin (Peg-IFN/RBV) is the HCV genotype itself. Rates of sustained virological response (SVR) in genotypes 1 or 4 HCV patients co-infected with HIV vary between 17 and 46% in different studies, while for genotype 3 HCV/HIV co-infected patients these values range between 43 and 71% [1,2]. The higher treatment response rate for genotype 3 HCV patients is due the higher rate of HCV viral clearance in the first weeks of therapy [3]. On the other hand, it has also been observed that HCV genotype 3 patients progress more rapidly to advanced stages of liver fibrosis and hepatic steatosis and are at a significantly higher risk of developing hepatocellular carcinoma [4–6]. For these reasons, patients infected with HCV genotype 3 constitute a population which requires the early implementation of treatment. PLOS ONE | www.plosone.org 1 November 2012 | Volume 7 | Issue 11 | e48959 The current recommended treatment for genotype 3 HCV/ HIV co-infected patients is 48 weeks with Peg-IFN-a2a or Peg- IFN-a2b (180 mg/kg and 1.5 mg/kg per week, respectively) combined with ribavirin (weight-adjusted) [7,8]. However, neither duration of treatment nor drug dose have been clearly optimized. For genotype 3 HCV monoinfected patients, the recommended length of treatment is 24 weeks, and even 12–16 weeks for patients achieving rapid virological response (RVR), and lower doses of Peg-IFN/RBV have been shown to achieve similar SVR rates to the standard dose [9–11]. However, because of the different responses to treatment, more rapid progression to liver fibrosis, interaction with antiretroviral treatment drugs and immunological characteristics, the results cannot be extrapolated to HIV/HCV co-infected patients [12,13]. Early viral kinetics gives clinicians valuable information about the outcome of HCV treatment. Several studies have shown that HCV viral decay in the first weeks after start of treatment can help identify which patients will respond to treatment and which will not [14–19]. HCV viral decline during the first weeks of treatment is also useful for analyzing the effects of different drug doses, including the impact on HCV clearance. The aim of this study was to analyze the different impacts of standard and lower-than- standard dose Peg-IFN-a2a/RBV therapy on HCV viral decline in HIV/HCV genotype 3 coinfected patients during the first weeks after start of treatment. Methods Patients, Study Design and Treatment Regimen Two groups of HIV/HCV genotype 3 co-infected patients who were naı ¨ve to HCV treatment were included in the study. The Standard Dose Group (SDG) included patients enrolled in a prospective study designed to evaluate the efficacy of a treatment strategy for chronic hepatitis C genotype 3, who were administered Peg-IFN-a2a at 180 mg/per week combined with a weightadjusted dose of ribavirin (1000 mg/day for ,75 kg, 1200 mg/ day for $75 kg); length of treatment (24 or 48 weeks) was determined according to whether or not RVR was achieved. The Low Dose Group (LDG) included patients enrolled in an open-label, single-arm clinical trial (Reference: NCT00553930) evaluating the efficacy of Peg-IFN-a2a at a dose of 135 mg/per week combined with a daily ribavirin dose of 800 mg. Ethical Aspects The SDG study was designed and carried out according to the Helsinki declaration and was approved by the Ethics Committee of the Hospital Reina Sofia of Cordoba. (Reference: NCT00553930). All patients were informed and signed an informed consent form before participating in the study. The protocol of the LDG trial and supporting CONSORT checklist are available as supporting information; see [20]. The study protocol was approved by the Agencia Espan˜ola del Medicamento and a central ethics committee (Comite´ Autono´mico de Ensayos Clı ´nicos, Consejerı ´a de Salud, Junta de Andalucı ´a). The study was conducted according to the Declaration of Helsinki and current guidelines on Good Clinical Practices. This trial is registered at NIH register (ClinicalTrials.gov: NCT00553930) and EMEA (NuEudraCT: 2007-000814-35). Data Collection Host, clinical and virological characteristics were collected. Fibrosis stage was determined by biopsy or liver transient elastography (FibroScanH, Echosen. Paris). Significant fibrosis was defined as a METAVIR fibrosis score of F2–F4 in liver biopsy or a liver stiffness value of $8.9 kPa [21]. Virological Evaluation Plasma HCV RNA load measurements were conducted at baseline and weeks 1, 2 and 4, using a quantitative PCR assay (Cobas TaqMan, Roche Diagnostic Systems Inc., Pleasanton, CA, USA) and using a detection limit of 15 IU/mL. Viral load was expressed as log 10 IU/mL. IL28B Genotyping DNA was extracted using the automated MagNA Pure DNA extraction method (Roche Diagnostics Corporation. Indianapolis, IN 46250, USA). Single nucleotide polymorphism (SNP) rs129679860, located 3 kilobases upstream of the IL28B, and in strong linkage disequilibrium with a non-synonymous coding variant in the IL28B gene (213A.G, K70R; rs81031142), was genotyped. Genotyping was carried out using a custom TAQMAN assay (Applied Biosystems, Foster City, California, USA) on DNA isolated from whole blood samples, on a Stratagene MX3005 thermocycler with MXpro software (Stratagene, La Jolla, California, USA), following the manufacturer’s instructions. The researchers responsible for genotyping were blinded to other patient data. The IL28B genotype was defined as CC or non-CC (TT/CT). Statistical Analysis Continuous variables were expressed as mean 6standard deviation or median (Q1–Q3) and were analyzed by the Student’s ttest, Mann-Whitney U-test or Kruskal-Wallis test. Categorical variables were expressed as numbers of cases (percentage). Frequencies were compared using the x 2 test or Fisher’s exact test. Significance was defined as a pvalue of less than 0.05. Plasma HCV RNA decline, according to SDG and LDG dose, was analyzed from baseline to weeks 1, 2 and 4. The effect of IL28B genotype on HCV viral decline was also analyzed in both treatment groups. Patients presenting an undetectable HCV viral load at any time point during the study were excluded when calculating reduction of HCV RNA levels at a later time. A multivariate linear regression model was used to analyze HCV viral decline between baseline and the various time points. In addition, two linear regression models of HCV viral decline from baseline to the different time points were analyzed according to treatment group. The analysis was performed using the SPSS statistical software package, version 18.0 (IBM Corporation, Somers, NY, USA). Results One hundred and six HIV/HCV genotype 3 co-infected patients were included in the study. Forty-eight (45.3%) patients were included in the SDG and 58 (54.7%) in the LDG. The baseline population characteristics of the two groups are shown in Table 1. HCV Viral Decline According to Treatment Group HCV viral decline of patients given the lower dose treatment was less than for those in the SDG, at weeks 2 and 4 after start of treatment, although not at week 1 (week 1:1.7260.74 log 10 IU/ mL versus 1.7860.67 log 10 IU/mL, p = 0.827; week 2:2.360.89 log 10 IU/mL versus 3.0161.02 log 10 IU/mL, p = 0.013; week 4:3.5261.2 log 10 IU/mL versus 4.0961.1 log 10 IU/mL, p = 0.005) (Figure 1). The multivariate linear regression models of factors associated with HCV viral decline at weeks 1, 2 and 4 showed that Low versus Standard-Dose of HCV Treatment PLOS ONE | www.plosone.org 2 November 2012 | Volume 7 | Issue 11 | e48959 the steeper and sustained HCV viral decline from week 2 to week 4 was associated with a lower baseline HCV RNA viral load and with patients in the SDG (Table 2). IL28B-CC and HCV viral decline were not associated. Table 1. Baseline Population Characteristics. Characteristic SDG LDG P N4858 Male. N (%) 39 (81.2) 51 (87.9) 0.379 Age (years). Mean (SD) 40.4 (8.86) 43.6 (5.37) 0.612 Use of HAART, n (%) 45 (93.7) 52 (89.6) 0.588 AIDS diagnosis in the past, n (%) 13 (27.1) 10 (17.2) 0.213 Baseline CD4 count (cells/mm 3 ). mean (SD) 479.9 (234.7) 496.5 (266.4) 0.743 PIDU, n (%) 43 (89.5) 48 (82.7) 0.454 HCV baseline viral load (log 10 IU/ mL). Mean (SD) 5.72 (0.75) 5.51 (1) 0.247 Liver fibrosis stage F2–F4. n (%) 32 (66.6) 33 (56.9) 0.277 Liver Cirrhosis. n (%) 12 (25) 21 (36.2) 0.253 ALT (IU/L). Mean (SD) 80.3 (47.7) 91 (57) 0.409 AST (IU/L). Mean (SD) 65.5 (35.2) 79.9 (33) 0.541 Total fasting cholesterol (mg/dL). Mean (SD) 156.1 (40.4) 147 (37) 0.325 LDL cholesterol (mg/dL). Mean (SD) 86.8 (33.6) 76 (29) 0.147 Platelet count (10 3 /mL). Mean (SD) 183 (65) 176 (68) 0.654 IL28B-CC genotype. N (%) 13 (43.4) { 24 (53.3) { 0.409 Standard drug dose group (SDG); low drug dose group (LDG); human immunodeficiency virus (HIV); highly active antiretroviral treatment (HAART); acquired immunodeficiency syndrome criteria in the past (AIDS); previous intravenous drug user (PIDU); hepatitis C virus (HCV); interleukin 28B (IL28B). { Available for 30 patients. { Available for 45 patients. doi:10.1371/journal.pone.0048959.t001 Figure 1. Mean HCV viral decline between baseline and weeks 1, 2 and 4 for the standard drug dose group (SDG) and the low drug dose group (LDG). doi:10.1371/journal.pone.0048959.g001 Table 2. Multivariate linear regression model of HCV viral decline between baseline and weeks 1, 2 and 4 after start of treatment. HCV decline at week 1 Factor Condition B P Treatment Group SDG 20.175 0.327 Baseline HCV viral load (log 10 IU/mL) 0.059 0.637 Significant liver fibrosis stage Yes 20.247 0.676 IL28B genotype Non-CC 0.296 0.113 HCV decline at week 2 Factor Condition B P Treatment Group SDG 0.274 0.037 Baseline HCV viral load 0.329 0.026 Significant liver fibrosis stage Yes 20.113 0.340 IL28B genotype Non-CC 20.103 0.551 HCV decline at week 4 Factor Condition B P Treatment Group SDG 0.335 0.025 Baseline HCV viral load 0.339 0.002 Significant liver fibrosis stage Yes 20.180 0.092 IL28B genotype Non-CC 20.041 0.791 adjusted coefficient (B), hepatitis C virus (HCV), interleukin 28B (IL28B), standard drug dose group (SDG). R 2 = 0.327. doi:10.1371/journal.pone.0048959.t002 Low versus Standard-Dose of HCV Treatment PLOS ONE | www.plosone.org 3 November 2012 | Volume 7 | Issue 11 | e48959 HCV Viral Decline According to Treatment Group and IL28B Genotype Among SDG patients, there were no differences of HCV viral decline by IL28B genotype at week 1 (1.8260.91 log 10 IU/mL versus 1.7460.87 log 10 IU/mL, p = 0.852), week 2 (361.1 log 10 IU/mL versus 3.0861.09 log 10 IU/mL, p = 0.807) or week 4 (4.1460.84 log 10 IU/mL versus 4.1761.06 log 10 IU/mL, p = 0.938) (Figure 2A). Similarly, no differences of HCV viral decline by IL28B genotype were found among LDG patients at week 1 (2.0760.47 log 10 IU/mL versus 1.4261.08 log 10 IU/mL, p = 0.071), week 2 (2.4660.86 log 10 IU/mL versus 2.0361.35 log 10 IU/mL, p = 0.257) or week 4 (3.4460.94 log 10 IU/mL versus 3.2661.01 log 10 IU/mL, p = 0.573) (Figure 2B). Among IL28B-CC genotype patients, HCV viral decline was greater in the SDG than in the LDG at weeks 2 and 4, but not at week 1 (week 1: p = 0.362; week 2: p = 0.051; week 4: p = 0.033). Likewise, HCV viral decline was greater among SDG patients carrying the IL28B non-CC genotype than among their LDG non-CC counterparts, at weeks 2 and 4 (week 1: p = 0.343; week 2: p = 0.034; week 4: p = 0.037). Rapid Virological Response Rate HCV viral load for 6 (5.6%) patients could not be evaluated at week 4. Of the remaining 100 patients, 66 (66%) achieved RVR: thirty-five (72.9%) in the SDG, and 31 (59.6%) in the LDG (p = 0.174). RVR rates by treatment group and IL28B genotype are shown in Table 3. Discussion In our study, HCV viral decay of patients who received lowdose Peg-IFN/RBV treatment was less during the first weeks of treatment than for those receiving the standard Peg-IFN/RBV dose. This finding suggests that a lower Peg-IFN/RBV dose has less antiviral activity than the standard dose. High viral decline during the first weeks of treatment leads to a high RVR rate [3]. Several factors have been identified as determining HCV viral decay [3,21]. Our study found that HCV viral decay correlated with Peg-IFN dose in HIV/HCV genotype 3 co-infected patients, with steeper viral decline from week 2 to week 4 in the SDG compared to the LDG. Our study also found that the dose of Peg-IFN administered during treatment was the most important factor affecting HCV viral decline in these patients. RVR rates in our study were also higher in the SDG compared to the LDG (72.9% versus 59.6%), although the differences between the two groups were not statistically significant. This point should be interpreted with caution, since a better powered cohort might be required for statistically significant associations, due to the high RVR rate among HCV genotype 3 patients. Reducing the dose in drug-based HCV therapy for monoinfected HCV genotype 3 patients has been studied in various clinical trials. Firstly, reducing the dose of Peg-IFNa2a from 180 mg/per week to 135 mg/per week was shown to give similar RVR and SVR rates [9,10]. Secondly, SVR rates did not differ significantly according to whether a lower daily dose or a weightadjusted dose of ribavirin was used [22–24]. A reduced dose of both drugs is, therefore, applicable to this patient population. However, in HCV genotype 3 patients co-infected with HIV, a low-dose Peg-IFN/RBV combination would have a considerable impact, in terms of a high SVR, greater cost savings and fewer adverse events than the standard dose. A previous open-label, Figure 2. Mean HCV viral decline by IL28B genotype for the standard dose group (SDG) (Figure 2A) and the low-dose group (LDG) (Figure 2B). doi:10.1371/journal.pone.0048959.g002 Table 3. Rapid virological response (RVR) rate by treatment group and IL28B genotype. Treatment group IL28B genotype RVR. N (%) P SDG CC 9 (40.9) 0.748 Non-CC 12 (44.4) LDG CC 13 (38.2) 0.642 Non-CC 12 (35.3) IL28B genotype Treatment group RVR. N (%) P CC SDG 9 (40.9) 0.642 LDG 13 (38.2) Non-CC SDG 12 (44.4) 0.221 LDG 12 (35.3) Interleukin 28B (IL28B), rapid virological response (RVR), standard drug dose group (SDG), low drug dose group (LDG). doi:10.1371/journal.pone.0048959.t003 Low versus Standard-Dose of HCV Treatment PLOS ONE | www.plosone.org 4 November 2012 | Volume 7 | Issue 11 | e48959 single-arm pilot clinical trial involving 58 HCV/HIV co-infected patients receiving low doses of Peg-IFN/RBV found that SVR rates were 58.3% based on intention-to-treat [20]. The main limitation of this study was the fact that it was not randomized but a single-arm study whose results were compared with those observed in earlier clinical trials The results of the pilot study suggested that a lower Peg-IFN/RBV dose might be as effective as the standard dose, so supporting the design of a randomized controlled trial. There are no data however about the efficacy or safety of standard Peg-IFN/RBV dose compared to a lower-than standard dose. To the best of our knowledge, this is the first study to compare the efficacy of HCV viral clearance using low-dose and standarddose drug therapy in HIV/HCV co-infected patients in the first weeks after treatment starts. Our findings suggest that the antiviral activity of the lower Peg-IFN/RBV dose is weaker than with the standard dose, which does not support equating the two for HIV/ HCV co-infected patients. Our results also suggest that HCV viral decline during the first weeks of treatment would be dosedependent, although the mechanism responsible for the difference is unknown. In our study, we found no relation between IL28B genotype and viral decline in either of the regimens evaluated. The positive effect on treatment response associated with the IL28B-CC genotype has only been observed in patients bearing genotype 1/4 [25,26]. In fact, a previous study developed by our group reported that variations in IL28B do not have a positive impact on HCV viral decline in the first weeks after start of therapy using a standard drug dose [3]. Nor did IL28B-CC have a positive effect on RVR or SVR at standard or low drug doses in patients bearing genotype 3 [20,25]. Our study has several limitations. Firstly, our study is not a randomized clinical trial, and the presence of significant bias cannot therefore be ruled out. Secondly, due to the higher RVR rate in HCV genotype 2/3 patients, our study did not have the statistical power to detect differences in RVR rate by drug treatment dose. Thirdly, our study looked at the impact of IL28B by determining only SNP rs12979860, although the impact observed for this is not expected to be different from the other known IL28B SNP (rs8099917). In conclusion, our results show that patients who received 135 mg/per week with a 800 mg/day ribavirin dose had less HCV viral decline in the first weeks after treatment started than those who received 180 mg/per week with a weight-adjusted ribavirin dose. The implications of weaker HCV viral decline in terms of treatment outcome are unknown, although it would be expected for a weaker HCV decline to lead to a lower RVR and consequently to a lower SVR. In order to resolve this point, our findings provide justification for the design of a randomized clinical trial to compare the specific efficacy endpoints of the two Peg-IFN/RBV doses in HIV/HCV co-infected patients.Until such a randomized clinical trial with these specific endpoints is conducted, therefore, clinicians should be cautious about using lower-than-standard Peg-IFN/RBV doses in HIV/HCV genotype 3 co-infected patients. Author Contributions Conceived and designed the experiments: ARJ LFLC AR. Performed the experiments: ARJ LFLC JAP A. Camacho MMS AR. Analyzed the data: ARJ AR. Contributed reagents/materials/analysis tools: AR ARJ LFLC A. Camacho ATC JAP MMS A. Caruz RRV JTC AGV. Wrote the paper: ARJ AR. Critical discussion of the manuscript: AR ARJ LFLC A. Camacho ATC JAP MMS A. Caruz RRV JTC AGV. References 1. Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, et al. 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Am J Gastroenterol. 99: 971–81. Low versus Standard-Dose of HCV Treatment PLOS ONE | www.plosone.org 5 November 2012 | Volume 7 | Issue 11 | e48959 23. Jacobson IM, Brown RS, Freilich B, Afdhal N, WIN-R Study Group, et al. (2007) Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology; 46: 971–81. 24. Ferenci P, Brunner H, Laferl H, Scherzer TM, Austrian Hepatitis Study Group, et al. (2008) A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotype 2 and 3. Hepatology. 47: 1816–23. 25. Pineda JA, Caruz A, Rivero A, Neukam K, Salas I, et al. (2010) Prediction of response to pegylated interferon plus ribavirin by IL28B gene variation in patients coinfected with HIV and hepatitis C virus. Clin Infect Dis. 51: 788–95. 26. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, et al. (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 461: 399–401. Low versus Standard-Dose of HCV Treatment PLOS ONE | www.plosone.org 6 November 2012 | Volume 7 | Issue 11 | e48959