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We enrolled 21 patients with laboratory-confirmed yellow fever (YF), hospitalized at Eduardo de Menezes Hospital, Brazil, to be treated with sofosbuvir, a drug approved for hepatitis C. Given the absence of specific YF antiviral treatments, the off-label nonrandomized sofosbuvir treatment aimed to address high disease severity and the risk of fatal outcomes. Patients received a daily dose of 400 mg sofosbuvir from 4 to 10 days post–symptom onset. YF viral load (VL) comparisons were made between treated and nontreated patients who either survived or died. The genomic VL for the treated group steadily decreased after day 7 post–symptom onset, suggesting that sofosbuvir might reduce YF VL. This study underscores the urgent need for YF antiviral therapies, advocating for randomized clinical trials to further explore sofosbuvir's role in YF treatment. [ABSTRACT FROM AUTHOR]

The local manufacture of advanced pharmaceutical products has been a long-standing objective of health and industry policy in many developing countries, including in Latin America. This strategy has been applied to fight epidemics such as HIV/AIDS, malaria, and the COVID-19 pandemic. However, we still know little about the politics and governance that enable such arrangements, especially when there is no consent from the originator company. This study focuses on the case of Brazil, a country that is well-known for its health-industry policy, which includes the local production of direct-acting antivirals (DAAs), a new treatment for hepatitis C. We seek to explain the factors that have contributed to Brazil’s successful production of generic versions of DAAs, and, later, to the decision by the Ministry of Health (MoH) to procure drugs from multinational pharmaceutical companies rather than from local laboratories. A lack of support for domestic production by important stakeholders, the patent holder’s attempt to block domestic production and the MoH’s adoption of more modern treatment guidelines under a different procurement logic all created an unfavourable environment for local production and procurement of DAAs. Our study draws implications for middle-income countries that wish to produce drugs domestically without voluntary license agreements. [ABSTRACT FROM AUTHOR]

The efficacy of direct-acting antivirals (DAAs) in the treatment of chronic hepatitis C (CHC) in liver transplant recipients is poorly understood, and several factors, including immunosuppression, drug interactions, elevated viraemia, and intolerance to ribavirin (RBV), can reduce cure rates. We conducted a real-life study on liver transplant recipients with CHC treated with a combination of sofosbuvir (SOF) and daclatasvir (DCV) or simeprevir (SIM), with or without RBV, followed-up for 12 to 24 weeks. The treatment effectiveness was assessed by determining the sustained virological response (SVR) rates at 12 or 24 weeks after the treatment cessation. Eighty-four patients were evaluated, with a mean age of 63.4 ± 7.4 years, HCV genotype 1 being the most prevalent (63.1%). Nineteen patients (22.7%) had mild fibrosis (METAVIR < F2) and 41 (48.8%) significant fibrosis (METAVIR = F2). The average time between liver transplantation and the start of treatment was 4 years (2.1-6.6 years). The SOF + DCV regimen was used in 58 patients (69%). RBV in combination with DAAs was used in seven patients (8.3%). SVR was achieved in 82 patients (97.6%), and few relevant adverse events could be attributed to DAA therapy, including a patient who stopped treatment due to a headache. There was a significant reduction in ALT, AST, GGT and FA levels, or the APRI index after 4 weeks of treatment, which remained until 12/24 weeks post-treatment. DAA treatment of CHC in liver-transplanted patients achieved a high SVR rate and resulted in the normalization of serum levels of liver enzymes. [ABSTRACT FROM AUTHOR]

Real‐world data evaluating the effectiveness of direct‐acting antivirals (DAAs) in hepatitis C virus (HCV) treatment have been reported from different regions. Our aim was to evaluate the effectiveness and clinical outcomes of daclatasvir (DCV) and sofosbuvir (SOF) ± ribavirin (RBV) in a prospective multicentre cohort study including patients from Argentina and Brazil who received DCV/SOF ± RBV for 12 or 24 weeks from 2015 to 2018. Multivariable logistic regression models were carried out to identify factors associated with failure to achieve sustained virologic response (SVR) as a primary end point, and to death, decompensation, hepatocellular carcinoma (HCC) or liver transplantation (LT) as a composite secondary end point. From a total of 1517 patients treated with DCV/SOF, 906 completed 12 weeks post‐treatment evaluation and were included in the analysis. Overall SVR12 rate was 96.1% (95% CI: 94.6%‐97.2%), and 95% (95% CI: 92.8%‐96.6%) in patients with cirrhosis. LT recipients and presence of cirrhosis were independently associated with failure to achieve SVR. During post‐SVR12 follow‐up, cumulative incidence of the secondary end point was 2.4% (95% CI: 1.5%‐3.6%); two patients died from nonliver‐related causes and two from HCC, five underwent LT, 12 developed HCC and 17 patients developed hepatic decompensation. Independent variables associated with these composite secondary end points were prior to HCV treatment and presence of cirrhosis. In conclusion, although the high pangenotypic effectiveness of DCV/SOF ± RBV was confirmed in our real‐life cohort, patients with compensated and decompensated cirrhosis showed higher risk of non‐SVR and complication appearance during treatment or after achieving SVR. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Sofosbuvir(SOF)‐based regimens have been administrated with excellent efficacy in chronic hepatitis C. Few uncontrolled (“real‐life”) studies consider the assessment of renal function when evaluating their post‐treatment outcomes. This study aims to evaluate renal biomarkers in a “real‐life” experience with chronic hepatitis C patients treated with SOF therapy in a long‐term follow‐up. Methods: Serum and urinary biomarkers were analysed before, at the end of therapy (EoT), after 12 weeks (sustained virological response—SVR) and one year (1y) post‐treatment. Patients were categorized according to baseline glomerular filtration rate (GFR—cut‐off 45 mL/min/1.73 m2). Results: Ninety‐four patients with a mean age of 59.9 ± 8.5 years were included; 98.9% of patients reached SVR. Significant improvement in renal biomarkers was observed in patients with GFR ≥45 mL/min/1.73 m2, as indicated by a progressive increase in mean GFR values until 1y. No evidence of tubular dysfunction was identified. Patients with baseline GFR <45 mL/min/1.73 m2 did not experience alterations in renal biomarkers; however, a mean change of +10.7 in GFR values was observed. We noticed significant upper stage transition in the CKD classification, and 58.7% of patients achieved G1 stage at 1y (P < .0001). What is new and conclusion: In a “real‐life experience” of a Brazilian centre, SOF therapy appears to guarantee renal safety for patients with chronic hepatitis C followed until one year after treatment. [ABSTRACT FROM AUTHOR]

Background Direct-acting antivirals (DAA) are currently used for the treatment of chronic hepatitis C (HCV). However, few studies describe the adverse effects (AE) associated with DAA therapy in "real-word" cohorts. Aim To evaluate AE in Brazilian chronic HCV patients after DAA-therapy. Setting A reference center for hepatitis treatment in Rio de Janeiro, Brazil. Methods An observational "real-world" study was conducted with 102 chronic HCV patients undergoing DAA therapy for 12 or 24 weeks. The self-reported AE were correlated with cirrhosis status, genotype, age, current therapeutic schemes and comorbidities. Serious AE were also investigated. Main outcome measure Frequency of AE during DAA therapy. Results Overall, mean ± SD age was 60.9 ± 9.4 years, 67% were females, HCV-genotype 1 was the most prevalent (81%) and 74% were cirrhotic. Moreover, all patients reached sustained virological response. About 90% of patients reported at least one AE associated with current treatment, with a mean of 2.7 symptoms per patient. The most frequently reported AE were fatigue (43%), headache (42%), neuropsychiatric symptoms (30%) and nausea (26%). Furthermore, hemoglobin < 12 mg/dL was the most frequent (38%) laboratory abnormality observed. Neuropsychiatric symptoms were the only AE significantly different in treatment-experienced group when compared to naïve patients (41.7 vs. 12.5, P = 0.002). The higher frequency of AE did not correlate with the presence of previous treatment, cirrhosis, genotype, age, current therapeutic schemes with DAA or comorbidities. Conclusion DAA-based therapeutic regimens demonstrated safety in a Brazilian "real-world" cohort of chronic hepatitis C patients. [ABSTRACT FROM AUTHOR]

Introduction and aim. There is almost no data regarding the efficacy of direct acting antivirals (DAAs) therapy in Brazil. The aim of this historical cohort study is to describe the sustained virologic response (SVR) rate among real-world compensated chronic hepatitis C patients in three hepatology centers from Southern Brazil. Materials and methods. Patients were included if they had at least 12 weeks follow-up after the end of therapy. Patients that were lost to follow-up or had treatment prematurely interrupted for any reason were considered treatment failure in this intention to treat analysis. Results. 219 patients were analyzed. Mean age was 57.4 ± 10.9 years and 142/219 (64.8%) were male. Genotype 1 was present in 166 patients (75.8%; 1a 29.2%, 1b 46.6%); Genotypes 2, 3 and 4 in 8 (3.7%), 43 (19.6%) and 2 (0.9%), respectively. 96 (43.8%) were cirrhotic. 134 (59.5%) were treatment experienced. DAA therapies were: sofosbuvir (SOF) + ribavirin (RBV) in 10 patients; SOF + simeprevir (SMV) ± RBV in 73; SOF + pegylated interferon (PEG-IFN) + RBV in 6; SOF + daclatasvir (DCV) ± RBV in 51, SOF + ledipasvir (LDV) ± RBV in 61, and paritaprevir/ ritonavir + ombitasvir + dasabuvir (PTVr/OBV/DSV) ± RBV in 18 patients. SVR-12 was achieved in 208/219 (95%). Ten patients had virologic failure: 6 cirrhotic, 7 treatment experienced, and 6 either genotype 3 or 1a. No adverse event was attributed to the DAA therapy. Conclusions. Real world experience with DAA therapy in Southern Brazil showed a high rate of SVR and excellent tolerability. Failure to achieve SVR was mainly observed among patients with at least one negative predictor of response: cirrhosis and/or genotypes 1a or 3. [ABSTRACT FROM AUTHOR]

Purpose - New hepatitis C medicines such as sofosbuvir underline the need to balance considerations of innovation, clinical evidence, budget impact and equity in health priority-setting. The purpose of this paper is to examine the role of public participation in addressing these considerations. Design/methodology/approach - The paper employs a comparative case study approach. It explores the experience of four countries - Brazil, England, South Korea and the USA - in making coverage decisions about the antiviral sofosbuvir and involving the public and patients in these decision-making processes. Findings - Issues emerging from public participation ac tivities include the role of the universal right to health in Brazil, the balance between innovation and budget impact in England, the effect of unethical medical practices on public perception in South Korea and the legitimacy of priority-setting processes in the USA. Providing policymakers are receptive to these issues, public participation activities may be re-conceptualized as processes that illuminate policy problems relevant to a particular context, thereby promoting an agenda-setting role for the public. Originality/value - The paper offers an empirical analysis of public involvement in the case of sofosbuvir, where the relevant considerations that bear on priority-setting decisions have been particularly stark. The perspectives that emerge suggest that public participation contributes to raising attention to issues that need to be addressed by policymakers. Public participation activities can thus contribute to setting policy agendas, even if that is not their explicit purpose. However, the actualization of this contribution is contingent on the receptiveness of policymakers. [ABSTRACT FROM AUTHOR]

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.

The outbreaks of Zika virus (ZIKV) infection in Brazil, 2015–2016, were associated with severe congenital malformations. Our translational study aimed to test the efficacy of the antiviral agent sofosbuvir (SOF) against vertical transmission of ZIKV and the associated congenital syndrome (CZS), using a rhesus monkey model. Eight pregnant macaques were successfully infected during the organogenesis phase with a Brazilian ZIKV strain; five of them received SOF from two to fifteen days post-infection. Both groups of dams showed ZIKV-associated clinical signals, detectable ZIKV RNA in several specimens, specific anti-ZIKV IgM and IgG antibodies, and maternal neutralizing antibodies. However, malformations occurred only among non-treated dam offspring. Compared to non-treated animals, all SOF-treated dams had a shorter ZIKV viremia and four of five neonates had undetectable ZIKV RNA in blood and tissue samples. These results support further clinical evaluations aiming for the prevention of CZS. • The antiviral agent sofosbuvir has proven to reduce the Zika virus (ZIKV) viral load in cell culture and mouse models. • The efficacy and the safe use of sofosbuvir have not been tested in pregnancy of humans. • Pregnant rhesus monkeys, experimentally infected with ZIKV, were treated with sofosbuvir. • ZIKV-associated foetal malformations and demise were confirmed in the rhesus model. • All but one sofosbuvir-treated dams' offspring had undetectable ZIKV RNA in blood and tissue samples. [ABSTRACT FROM AUTHOR]

We aimed to conduct a cost-utility analysis of available interferon-free treatments for genotype 1 chronic hepatitis C patients at the early disease stage from a Brazilian public health system perspective. Results The treatment GLE+PIB dominated all other treatments: it was associated with a lower treatment cost and similar QALY compared to the other strategies, followed by SOF+VEL. Conclusions The present cost-utility analysis shows that GLE+PIB was the most cost-effective treatment, followed by SOF+VEL, whereas sofosbuvir + daclatasvir was considerate the least cost-effective. [Extracted from the article]

Purpose: To identify factors associated with the development of adverse drug reactions (ADR) in ribavirin therapeutic regimens., Methods: A multicenter, prospective study was conducted in three public health hospitals in Rio de Janeiro between November 2015 and March 2018. Inclusion criteria were defined by patient follow-up at pharmaceutical consultation at the time of drug dispensing as those who used sofosbuvir in combination with simeprevir, daclatasvir, and/or ribavirin. All patients were invited to participate in the study during the first interview. Adverse drug reactions were reported according to the treatment regimen and frequency of occurrence. Statistical analysis was used to compare adverse reactions between treatments and their associated factors., Results: A total of 405 patients were included in the study (mean age 59.6 ± 9.6 years); 61.0% were female, 88.1% were infected with genotype 1, and 65.4% were cirrhotic. The most prescribed treatment was the combination of sofosbuvir, daclatasvir, and ribavirin (55.3%). The majority of patients reported at least one ADR during treatment (83.2%), of which fatigue, anemia, and headache were the most common. Being female (OR = 1.86, [1.08-3.20]) and use of ribavirin (OR: 2.39; 95% CI [1.38-4.13]) were predictors for the development of ADR, which was also associated with development of anemia (OR: 10.28; 95% CI: [5.78-18.30]). Treatment efficacy was 98.1%., Conclusions: Direct-acting antiviral has been shown to be safe and effective. Therefore, use of ribavirin is questionable due to associated adverse reactions and similar efficacy to other treatments., (© 2019 John Wiley & Sons, Ltd.)

Introduction: An ongoing outbreak of yellow fever (YF) has been reported in Brazil with 1261 confirmed cases and 409 deaths since July 2017. To date, there is no specific treatment available for YF. Recently published papers describing in vitro and animal models suggest a potential effect of antiviral drugs (approved for the treatment of hepatitis virus) against flaviviruses, including YF. The primary aim of this study is to analyse the effect of sofosbuvir on viral kinetics and clinical outcomes among patients presenting with YF. This is a multicentre open-label randomised controlled trial with 1:1 individual allocation, stratified by severity and by recruiting centre., Methods and Analysis: Adults with suspected or confirmed YF infection and symptoms lasting up to 15 days are screened. Eligible and consenting patients are randomised to receive oral sofosbuvir 400 mg daily for 10 days or to receive standard clinical care. Viral kinetics are measured daily and the reduction in YF plasma viral load from the sample at inclusion to 72 hours after randomisation will be compared between active and control groups. Clinical outcomes include severity meeting criteria for intensive care support, liver transplantation, in-hospital mortality and mortality within 60 days., Ethics and Dissemination: Ethics approval was obtained at the participating sites and at the national research ethics committee (CAAE 82673018.6.1001.0068). The trial has been submitted for ethical approval at additional potential recruiting centres. Results of the study will be published in journals and presented at scientific meetings., Trial Registration: Brazilian Clinical Trials Registry (RBR-93dp9n)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Yellow fever is an acute febrile illness for which there is no specific antiviral treatment. Since 2016, Brazil has experienced two outbreaks, and collective health measures have been adopted to contain these grievances. However, published data about the drug sofosbuvir against flaviviruses are promising, suggesting the relevance of conducting future clinical trials.

Introduction: Chronic hepatitis C virus infection is one of the major causes of cirrhosis, hepatocellular carcinoma and liver transplantation. Treatment using direct-acting antivirals has revolutionized the treatment of hepatitis C virus, increasing long-term prognosis after cure. The goal of the present study was to evaluate the effectiveness of direct-acting antivirals in a Public Health System in southern Brazil., Methods: A retrospective study evaluated all patients with chronic hepatitis C virus infection who underwent treatment at one center of the Public Health Department of the State of Rio Grande do Sul - Brazil, according to the Brazilian Clinical Protocol and Therapeutic Guidelines. The effectiveness was assessed in terms sustained virological response 12 weeks after the end of treatment., Results: A total of 1002 patients who were treated for chronic hepatitis C virus infection were evaluated. The mean age was 58.6 years, 557 patients (55.6%) were male and 550 (54.9%) were cirrhotic. Overall sustained virological response was observed in 936 (93.4%) patients. There was a difference in sustained virological response rate varied according to sex, 91.6% in men and 95.7% in women (p = 0.009), length of treatment in genotype 1, 92.7% with 12 weeks and 99.1 with 24 weeks (p = 0.040), and genotype, 94.7% in genotype 1, 91.7% in genotype 2, and 91.4% in genotype 3 (p = 0.047)., Conclusion: The treatment of chronic hepatitis C virus infection for genotypes 1, 2 or 3 with the therapeutic regimens established by the Brazilian guidelines showed high rates of SVR, even in cirrhotic patients., (Copyright © 2018 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.)

A strong correlation between Zika virus (ZIKV) infection and severe neurological disease in newborns and occasionally adults has emerged in the Brazilian outbreak. Efficient human cell-based assays are required to test candidate inhibitors of ZIKV replication. The aim of this work was to investigate ZIKV propagation and quantification in different cell lines. The human (U87, A549, Huh7), mosquito (C6/36) and monkey (VERO E6) cell lines tested were all permissive to ZIKV infection. When assessed by plaque forming units (PFU) in three different target cell lines, the maximal production of ZIKV was achieved in Huh7 at day 3 post-infection (6.38±0.44 log 10 PFU/ml). The C6/36 cell line showed a low and slow production of virus when compared with other cell lines. A549 readout cells generated a larger number of plaques compared to Huh7 but not to VERO E6 cells. ZIKV PFU and RNA titers showed the highest correlation when Huh7 and A549 were used as the producer and readout cells, respectively. Also, U87 cells produced ZIKV RNA titers which were highly correlated with PFU independently from the readout cell line. Using the best virus-cell system, sofosbuvir and ribavirin EC 50 were 1.2μM and 1.1μM when measured through plaque assay, and 4.2μM and 5.2μM when measured by quantitative real time PCR (qRT-PCR), respectively. In summary, ZIKV can efficiently infect different human cell lines and rapidly reach peak viral titers. Overall, A549 cells appear to be as efficient as the VERO E6 gold standard for plaque assay allowing the use of human, rather than simian, cells for evaluating candidate anti-ZIKV compounds by the reference assay. The possibility to replace the labor-intensive plaque assay with the more rapid and easy-to-perform qRT-PCR is appealing and warrants further investigation., (Copyright © 2017 Elsevier B.V. All rights reserved.)