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      Trend of estimated glomerular filtration rate during ombistasvir/paritaprevir/ritonavir plus dasabuvir ± ribavirin in HIV/HCV co-infected patients

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      1 , 2 , * , 3 , 1 , 4 , 5 , 5 , 6 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 27
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          Abstract

          The renal function is a key-issue in HIV/HCV co-infected patients, nevertheless, it has not established so far whether HCV treatment with new direct acting agents could impact on estimated glomerular filtration rate (eGFR) variations. In the present work, we examined the real-life data on renal function that have been prospectively collected in the SIMIT compassionate-use program of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in 144 HIV/HCV genotype 1 co-infected patients. The population was 74% male, 30.5% in CDC stage C, with median age of 52 years (48.0–56.5) and median liver stiffness of 7.8 kPa (6.7–9.2). Median baseline eGFR was 102.0 (90.8–108.1), changing to 99.8 (83.5–104.8) at the end of treatment (EoT), and 100.0 (87.3–105.6) 12 weeks after the EoT (FU12), p<0.0001. No patient had grade 3–4 increase of creatinine. At EoT 60/144 (41.7%) patients had ≥ 5% reduction in their eGFR, confirmed at FU12 in 39/60 (65.0%) cases. Longer duration of HCV infection (cut-off 12.9 years), lower HCV-RNA viral load (cut-off 1,970,160 IU/ml) and lower platelet count (cut-off 167,000 x10 6/L) were significantly associated with eGFR decline at logistic analysis ( adjOR 2.9, 95%CI 1.0–8.8, p = 0.05; adjOR 3.5, 95%CI 1.2–10.4, p = 0.02; adjOR 2.8, 95%CI 1.1–6.8, p = 0.03, respectively). After repeating the analysis throughout a mixed model, a higher eGFR decline was highlighted in patients concomitantly treated with tenofovir (p = 0.0001), ribavirin (p = 0.0001), or integrase inhibitors (p <0.0001), with longer duration of HIV (p = 0.0002) and HCV infection (p = 0.035), lower baseline HCV RNA (p <0.0001), previous HCV treatment (p<0.0001), and older age (p<0.0001). In conclusion, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in HIV/HCV patients, and the median decline of 2 ml/min in eGFR, albeit statistically significant, is of doubtful clinical significance. The role of aging, concomitant therapies and duration of HIV/HCV infection needs to be further investigated.

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          Most cited references42

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          Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline.

          The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed clinical practice guidelines in 2012 to provide guidance on the evaluation, management, and treatment of chronic kidney disease (CKD) in adults and children who are not receiving renal replacement therapy. The KDIGO CKD Guideline Development Work Group defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence that had been summarized by an evidence review team. Searches of the English-language literature were conducted through November 2012. Final modification of the guidelines was informed by the KDIGO Board of Directors and a public review process involving registered stakeholders. The full guideline included 110 recommendations. This synopsis focuses on 10 key recommendations pertinent to definition, classification, monitoring, and management of CKD in adults.
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            Sofosbuvir and ribavirin in HCV genotypes 2 and 3.

            In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection. We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval [CI], 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus. Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. (Funded by Gilead Sciences; VALENCE ClinicalTrials.gov number, NCT01682720.).
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              All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase III Study

              Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; http://ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (Hepatology 2015;61:1127–1135)
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Writing – original draft
                Role: Conceptualization
                Role: Formal analysis
                Role: InvestigationRole: Writing – original draft
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – original draft
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – original draft
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 February 2018
                2018
                : 13
                : 2
                : e0192627
                Affiliations
                [1 ] University of Genova (DISSAL), Infectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy
                [2 ] Infectious Diseases Clinic, Policlinico Hospital San Martino, Genova, Italy
                [3 ] Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy
                [4 ] Clinical Department, National Institute for Infectious Diseases, INMI L. Spallanzani, Rome, Italy
                [5 ] Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
                [6 ] 1st Division of Infectious Diseases, ASST Fatebenefratelli-Sacco, Milan, Italy
                [7 ] Institute of Infectious Disease, University of Bari, Bari, Italy
                [8 ] Division of Infectious and Tropical Diseases, IRCCS Policlinico San Matteo, Pavia, Italy
                [9 ] Infectious Diseases Clinic, University Hospital, Modena, Italy
                [10 ] Department of Internal and Specialty Medicine University Infectious Diseases Unit, AOU Senese, Siena, Italy
                [11 ] Department of Infectious and Tropical Diseases, University Hospital, Padova, Italy
                [12 ] Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
                [13 ] Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
                [14 ] Clinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, Milan, Italy
                [15 ] Infectious Diseases Unit, Sapienza University of Rome, Latina, Italy, and Department of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
                [16 ] Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy
                [17 ] Division of Infectious Diseases, AO Papa Giovanni XXIII, Bergamo, Italy
                [18 ] Division of Infectious Diseases, AO Niguarda Ca' Granda Hospital, Milan, Italy
                [19 ] Division of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, Brescia, Italy
                [20 ] Division of Infectious Diseases, Department of Internal Medicine, San Gerardo Hospital, University of Milan-Bicocca, Milan, Italy
                [21 ] First Division of Infectious Diseases, S. Giovanni di Dio e Ruggi d'Aragona Hospital, Salerno, Italy
                [22 ] Division of Infectious Diseases, Department of Clinical and Experimental Medicine, ARNAS Garibaldi Hospital, University of Catania, Catania, Italy
                [23 ] Infectious Diseases Unit, Department of Biomedical Sciences and Public Health, Marche Polytechnic University c/o Ospedali Riuniti, Ancona, Italy
                [24 ] Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
                [25 ] Department of Public Health and Infectious Diseases, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
                [26 ] III U.O.C. P.O. Cotugno, AORN Ospedali dei Colli, Naples, Italy
                [27 ] Clinical Infectious Diseases, Department. of Systems Medicine, Tor Vergata University, Rome, Italy
                [28 ] Clinical Infectious Diseases, Sant'Andrea Hospital—Sapienza University of Rome, Rome, Italy
                [29 ] Unit of Infectious Diseases, University Hospital of Ferrara, Ferrara, Italy
                National Taiwan University Hospital, TAIWAN
                Author notes

                Competing Interests: AbbVie provided study drugs at no charge which were distributed through a competitive enrollment program. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-1436-5089
                Article
                PONE-D-17-31618
                10.1371/journal.pone.0192627
                5819795
                29462201
                644b315d-d0bf-483d-99c2-7fc5b324762e
                © 2018 Taramasso 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.

                History
                : 4 September 2017
                : 26 January 2018
                Page count
                Figures: 1, Tables: 3, Pages: 15
                Funding
                Funded by: AbbVie (ITA)
                AbbVie provided study drugs at no charge which were distributed through a competitive enrollment program. No additional financial support was provided for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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