EVALDO STANISLAU AFFONSO DE ARAUJO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/47 - Laboratório de Hepatologia por Vírus, Hospital das Clínicas, Faculdade de Medicina
LIM/47 - Laboratório de Hepatologia por Vírus, Hospital das Clínicas, Faculdade de Medicina
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- HCV kinetic and modeling analyses indicate similar time to cure among sofosbuvir combination regimens with daclatasvir, simeprevir or ledipasvir(2016) DAHARI, Harel; CANINI, Laetitia; GRAW, Frederik; UPRICHARD, Susan L.; ARAUJO, Evaldo S. A.; PENARANDA, Guillaume; COQUET, Emilie; CHICHE, Laurent; RISO, Aurelie; RENOU, Christophe; BOURLIERE, Marc; COTLER, Scott J.; HALFON, PhilippeBackground & Aims: Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost. Methods: 58 chronic HCV patients were treated with 12-week sofosbuvir + simeprevir (n = 19), sofosbuvir + daclatasvir (n = 19), or sofosbuvir + ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12 weeks post EOT. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid. Results: All but one patient who relapsed achieved SVR. Mean age was 60 +/- 11 years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV <15 IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13 weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir + ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43-45% and 17-30% in subjects who had HCV <15 IU/ml at weeks 2 and 4, respectively. Conclusions: The use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16-20% per 100-treated persons.
- Very early prediction of response to HCV treatment with PEG-IFN-alfa-2a and ribavirin in HIV/HCV-coinfected patients(2011) ARAUJO, E. S. A.; DAHARI, H.; NEUMANN, A. U.; CAVALHEIRO, N. de Paula; MELO, C. E.; MELO, E. S. de; LAYDEN, T. J.; COTLER, S. J.; BARONE, A. A.The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV-coinfected patients. Twenty-six patients (15 HCV genotype-1 and 11 genotype-3) were treated with a 48-week regimen of peginterferon-alfa-2a (PEG-IFN) (180 mu g/week) and weight-based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 +/- 0.3 days after initiation of therapy, followed by a 0.3- to 12.9-fold viral rebound until the administration of the second dose of PEG-IFN, which were not associated with SVR or HCV genotype. A viral decline < 1.19 log for genotype-1 and < 0.97 log for genotype-3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second-phase viral decline slope (i.e., measured from day 2 to 29) < 0.3 log/week had a NPV = 100% for SVR. We conclude that first-phase viral decline at day 2 and second-phase viral decline slope (< 0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of nonresponse in patients with HCV and HIV.
- Inter- and Intra-Host Viral Diversity in a Large Seasonal DENV2 Outbreak(2013) ROMANO, Camila Malta; LAUCK, Michael; SALVADOR, Felipe S.; LIMA, Celia Rodrigues; VILLAS-BOAS, Lucy S.; ARAUJO, Evaldo Stanislau A.; LEVI, Jose Eduardo; PANNUTI, Claudio Sergio; O'CONNOR, David; KALLAS, Esper GeorgesBackground: High genetic diversity at both inter-and intra-host level are hallmarks of RNA viruses due to the error-prone nature of their genome replication. Several groups have evaluated the extent of viral variability using different RNA virus deep sequencing methods. Although much of this effort has been dedicated to pathogens that cause chronic infections in humans, few studies investigated arthropod-borne, acute viral infections. Methods and Principal Findings: We deep sequenced the complete genome of ten DENV2 isolates from representative classical and severe cases sampled in a large outbreak in Brazil using two different approaches. Analysis of the consensus genomes confirmed the larger extent of the 2010 epidemic in comparison to a previous epidemic caused by the same viruses in another city two years before (genetic distance = 0.002 and 0.0008 respectively). Analysis of viral populations within the host revealed a high level of conservation. After excluding homopolymer regions of 454/Roche generated sequences, we found 10 to 44 variable sites per genome population at a frequency of >1%, resulting in very low intra-host genetic diversity. While up to 60% of all variable sites at intra-host level were non-synonymous changes, only 10% of inter-host variability resulted from non-synonymous mutations, indicative of purifying selection at the population level. Conclusions and Significance: Despite the error-prone nature of RNA-dependent RNA-polymerase, dengue viruses maintain low levels of intra-host variability.
- Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir +/- Ribavirin for HCV in Brazilian Adults with Advanced Fibrosis(2018) PESSOA, Mario G.; V, Jose Ramalho-Madruga; ALVES, Katia; NUNES, Estevao P.; CHEINQUER, Hugo; BRANDAO-MELLO, Carlos E.; MENDES-CORREA, Maria C.; FERRAZ, Maria L.; FERREIRA, Paulo R. A.; ALVARES-DA-SILVA, Mario R.; COELHO, Henrique S.; AFFONSO-DE-ARAUJO, Evaldo S.; FURTADO, Juvencio; PARANA, Raymundo; SILVA, Giovanni; LARI, Sara A.; LIU, Li; TRIPATHI, Rakesh; PILOT-MATIAS, Tami; COHEN, Daniel E.; SHULMAN, Nancy S.; MARTINELLI, AnaIntroduction and aim. Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection. Material and methods. All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12). Results. The study enrolled 222 patients, 214 achieved an SVR 12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR 12 was achieved in 111/112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event. Discussion. The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).
conferenceObject Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 infection in treatment-naive patients: efficacy in difficult-to-treat patient sub-populations in the QUEST 1 and 2 phase III trials(2013) JACOBSON, Ira M.; DORE, Gregory J.; FOSTER, Graham R.; FRIED, Michael W.; MANNS, Michael P.; MARCELLIN, Patrick; POORDAD, Fred; ARAUJO, Evaldo S.; PEETERS, Monika; LENZ, Oliver; OUWERKERK-MAHADEVAN, Sivi; ROSA, Guy De La; KALMEIJER, Ronald; SINHA, Rekha; BEUMONT-MAUVIEL, Maria- Pharmacodynamics of PEG-IFN-alpha-2a and HCV Response as a Function of IL28B Polymorphism in HIV/HCV-Coinfected Patients(2011) ARAUJO, Evaldo Stanislau Affonso de; DAHARI, Harel; COTLER, Scott J.; LAYDEN, Thomas J.; NEUMANN, Avidan U.; MELO, Carlos Eduardo; BARONE, Antonio AlciWe examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models. African Americans and whites had a similar distribution of IL28B genotypes (P = 0.5). The IL28B CC genotype was overrepresented (P = 0.015) in patients infected with HCV genotype-3 compared with genotype-1. In both genotype-1 and genotype-3, the first-phase viral decline and the average pegylated interferon-alpha-2a effectiveness during the first week of therapy were larger (trend P <= 0.12) in genotype-CC compared with genotypes-TC/TT. In genotype-1 patients, the second slower phase of viral decline (days 2-29) and infected cells loss rate, delta, were larger (P = 0.02 and 0.11, respectively) in genotype-CC than in genotypes-TC/TT. These associations were not observed in genotype-3 patients.
conferenceObject SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR TREATMENT OF CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAIVE PATIENTS: RESULTS FROM QUEST-2, A PHASE III TRIAL(2013) MANNS, M.; MARCELLIN, P.; POORDAD, F. P. Fred; ARAUJO, E. Stanislau Affonso de; BUTI, M.; HORSMANS, Y.; JANCZEWSKA, E. J. Ewa; VILLAMIL, F.; PEETERS, M.; LENZ, O.; OUWERKERK-MAHADEVAN, S.; KALMEIJER, R.; BEUMONT-MAUVIEL, M.Background and Aims: Simeprevir is a potent, once-daily, oral, investigational HCV NS3/4A protease inhibitor. QUEST-2 (NCT01290679) is a Phase III, randomised, double-blind, placebo-controlled trial assessing the efficacy, safety and tolerability of simeprevir versus placebo as part of a regimen including peginterferon a-2α (pegIFNα-2a) or pegIFNα-2b/ribavirin (PR) in treatment-naïve patients chronically infected with genotype-1 HCV.Safety and SVR12 results from a primary (Week 60) analysis are presented. Methods: Patients (n=391), randomised 2:1 and stratified by HCV genotype-1 subtype and host IL28B genotype, received simeprevir (150mg QD)+PR or placebo+PR for 12 weeks, followed by PR alone. Total treatment duration was 24 or 48 weeks (simeprevir group) based on response-guided therapy (RGT) criteria (HCVRNA < 25IU/mL Week 4 and undetectable Week 12) or 48 weeks (placebo group). Table 1 Percentage of patients achieving SVR12 Placebo/PR Simeprevir/PR All patients 50% 81% Treated with pegIFNα-2a/pegIFNα-2b 62%/42% 88%/78% Patients who met RGT criteria not applicable 86% IL28B genotype CC/CT/TT 81%/41%/19% 96%/80%/58% HCV subtype 1a or other/1b 46%/53% 80%/82% METAVIR score F0–F2/F3–F4 51%/47% 85%/66% Results: Simeprevir/PR was superior to placebo/PR; SVR12: 81 vs 50%, respectively (p < 0.001). The majority (91%) of simeprevir-treated patients met RGT criteria and completed treatment at Week 24. Overall, 79% of simeprevir and 13% of placebo-treated patients achieved RVR. Treatment with simeprevir/PR led to lower rates of on-treatment failure and relapse compared to placebo/PR (7 vs 32% and 13 vs 24%, respectively). The incidence of AEs was similar between groups, regardless of the pegIFN used. The most common AEs were fatigue, influenza-like illness, pruritus and headache. A slightly higher proportion of simeprevir patients experienced rash and photosensitivity, compared to placebo (27 vs 20% and 4 vs 1%, respectively). There was no difference in the proportion of patients experiencing anaemia. Conclusions: Simeprevir 150mg QD was well tolerated, leading to a high SVR12 rate of 81% when administered with either pegIFNα-2a or pegIFNα-2b. The majority of patients (91%) receiving simeprevir was able to shorten therapy to 24 weeks.- A Summary of the 18th International Symposium on Hepatitis C Virus and Related Viruses(2012) POLYAK, Stephen J.; MORISHIMA, Chihiro; SCOTT, John D.; COX, Andrea; ARAUJO, Evaldo Stanislau Affonso de; HIGGS, Martin R.; LOO, Yueh-Ming; GOLDEN-MASON, Lucy; LINDENBACH, Brett D.; BAUMERT, Thomas F.; RANDALL, Glenn; GALE JR., Michael
conferenceObject SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR TREATMENT OF CHRONIC HCV GENOTYPE 1 INFECTION IN TREATMENT-NAIVE EUROPEAN PATIENTS IN THE QUEST-1 AND QUEST-2 PHASE III TRIALS(2014) FOSTER, G. R.; JACOBSON, M.; DORE, G. J.; FRIED, M.; MANNS, M.; MARCELLIN, P.; POORDAD, F.; ARAUJO, E. S. Affonso de; PEETERS, M.; LENZ, O.; OUWERKERK-MAHADEVAN, S.; ROSA, G. De La; KALMEIJER, R.; SINHA, R.; BEUMONT-MAUVIEL, M.- Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial(2014) MANNS, Michael; MARCELLIN, Patrick; POORDAD, Fred; ARAUJO, Evaldo Stanislau Affonso de; BUTI, Maria; HORSMANS, Yves; JANCZEWSKA, Ewa; VILLAMIL, Federico; SCOTT, Jane; PEETERS, Monika; LENZ, Oliver; OUWERKERK-MAHADEVAN, Sivi; ROSA, Guy De La; KALMEIJER, Ronald; SINHA, Rekha; BEUMONT-MAUVIEL, MariaBackground Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection. Methods In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2: 1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 mu g once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 mu g, 80 mu g, 100 mu g, 120 mu g, or 150 mu g once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented. Findings 209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32.2%, 95% CI 23.3-41.2; p<0.0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment). Interpretation Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin.