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1.
Clin Microbiol Infect ; 28(4): 611.e1-611.e7, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1828108

ABSTRACT

OBJECTIVES: Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV before and after DAA therapy. METHODS: Before and 12 weeks after sustained virological response (SVR12) to DAA therapy, 22 cell populations were analysed by mass cytometry in blood collected from ten healthy control individuals and 20 HCV-infected patients with (ten patients) or without (ten patients) human immunodeficiency virus (HIV) infection. RESULTS: HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies (median, interquartile range (IQR); control, HCV, HCV/HIV) of intermediate monocytes (1.2, IQR 0.47-1.46; 1.76, IQR 0.83-2.66; 0.78, IQR 0.28-1.77), non-classical monocytes (1.11, IQR 0.49-1.26; 0.9, IQR 0.18-0.99; 0.54, IQR 0.28-1.77), conventional dendritic cells type 2 (0.55, IQR 0.35-0.59; 0.31, IQR 0.16-0.38; 0.19, IQR 0.11-0.36) and CD56dim natural killer cells (8.08, IQR 5.34-9.79; 4.72, IQR 2.59-6.05) 3.61, IQR 2.98-5.07) were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells (0.07, IQR 0.06-0.10; 0.10, IQR 0.09-0.19; 0.19, IQR 0.12-0.25), activated CD4 T cells (0.28, IQR 0.21-0.36; 0.56, IQR 0.33-0.77; 0.40, IQR 0.22-0.53) and activated CD8 T cells (0.23, IQR 0.14-0.42; 0.74, IQR 0.30-1.65; 0.80, IQR 0.58-1.16) were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV- and HCV/HIV-infected patients, respectively. Most alterations persisted at SVR12. CONCLUSIONS: Chronic HCV and HCV/HIV infections induce profound and durable perturbations of innate and adaptive immune homeostasis.


Subject(s)
HIV Infections , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/therapeutic use , CD8-Positive T-Lymphocytes , HIV Infections/complications , HIV Infections/drug therapy , Hepacivirus , Hepatitis C/complications , Hepatitis C/drug therapy , Hepatitis C, Chronic/drug therapy , Humans
2.
Cochrane Database Syst Rev ; 8: CD011564, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1813438

ABSTRACT

BACKGROUND: Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov  and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020. SELECTION CRITERIA: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D3 (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D2; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C. AUTHORS' CONCLUSIONS: Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed.


Subject(s)
Hepatitis C, Chronic , Adult , Dietary Supplements , Female , Humans , Male , Middle Aged , Quality of Life , Vitamin D
3.
Lancet Glob Health ; 10 Suppl 1: S6, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1773859

ABSTRACT

BACKGROUND: The prevalence of hepatitis C in people who use injectable drugs along the USA-Mexico border is very high (>90%). In 2019, the Mexican government committed to providing hepatitis C treatment with priority for people who use injectable drugs, people living with HIV, and people living in prison or jail, yet the immediate plan for prioritized treatment allocation and rollout remained unclear prior to the COVID-19 pandemic. Understanding which prevention and intervention strategies and at what level of scale-up can achieve the WHO goal of 80% incidence reduction by 2030 along the border is needed. METHODS: We adapted our previously published dynamic, deterministic model of hepatitis C transmission among people who use injectable drugs to determine the direct-acting antiviral treatment allocations in combination with harm-reduction interventions (opiate agonist therapy and needle and syringe programmes) needed to achieve the WHO elimination goal between 2021 and 2030. Our model is calibrated and parameterised to epidemiological data from Ciudad Juarez (where approximately 10 000 people who use injectable drugs reside and the seroprevalence of hepatitis C among people who use injectable drugs is 92%) and minimal harm reduction. FINDINGS: To reduce hepatitis C incidence by 80% between 2021 and 2030, 910 direct-acting antiviral treatments per 10 000 people who use injectable drugs in Ciudad Juarez per year are needed. Overall, fewer treatments are required if combined with harm reduction. If opiate agonist therapy and needle and syringe programmes are scaled-up to 50%, approximately 30-40% fewer people who use injectable drugs would need to be treated each year (650 direct-acting antiviral treatments per 10 000 people who use injectable drugs per year). Between 2021 and 2030, using direct-acting antivirals alone, an estimated total of 8190 people who use injectable drugs in Ciudad Juarez would need to be treated, compared with 6255 (nearly 25%) fewer people who use injectable drugs overall if treatment is scaled-up alongside 50% of opiate agonist therapy and needle and syringe programmes combination intervention coverage. INTERPRETATION: Hepatitis C treatment with direct-acting antivirals should be prioritised for people who use injectable drugs along the USA-Mexico border and progress towards hepatitis C elimination should be monitored. Regional hepatitis C micro-elimination among people who use injectable drugs could be possible if national treatment allocations are prioritised and distributed to people who use injectable drugs as planned and in the presence of essential harm-reduction programmes. FUNDING: National Institutes of Health; Fogarty International Center grant D43TW009343; and National Institute of Allergy and Infectious Diseases and National Institute on Drug Abuse grant R01AI147490.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Hepatitis C , Substance Abuse, Intravenous , Antiviral Agents/therapeutic use , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis C/prevention & control , Hepatitis C, Chronic/epidemiology , Humans , Mexico/epidemiology , Pandemics , Seroepidemiologic Studies , Substance Abuse, Intravenous/epidemiology , World Health Organization
4.
Viruses ; 14(3)2022 03 14.
Article in English | MEDLINE | ID: covidwho-1765953

ABSTRACT

Virus pandemics have happened, are happening and will happen again. In recent decades, the rate of zoonotic viral spillover into humans has accelerated, mirroring the expansion of our global footprint and travel network, including the expansion of viral vectors and the destruction of natural spaces, bringing humans closer to wild animals. Once viral cross-species transmission to humans occurs, transmission cannot be stopped by cement walls but by developing barriers based on knowledge that can prevent or reduce the effects of any pandemic. Controlling a local transmission affecting few individuals is more efficient that confronting a community outbreak in which infections cannot be traced. Genetic detection, identification, and characterization of infectious agents using next-generation sequencing (NGS) has been proven to be a powerful tool allowing for the development of fast PCR-based molecular assays, the rapid development of vaccines based on mRNA and DNA, the identification of outbreaks, transmission dynamics and spill-over events, the detection of new variants and treatment of vaccine resistance mutations, the development of direct-acting antiviral drugs, the discovery of relevant minority variants to improve knowledge of the viral life cycle, strengths and weaknesses, the potential for becoming dominant to take appropriate preventive measures, and the discovery of new routes of viral transmission.


Subject(s)
Hepatitis C, Chronic , Viruses , Animals , Antiviral Agents , High-Throughput Nucleotide Sequencing , Pandemics
5.
Viruses ; 14(3)2022 02 25.
Article in English | MEDLINE | ID: covidwho-1765943

ABSTRACT

: Background:There are limited data available on the influence of direct-acting antivirals used to treat chronic hepatitis C (CHC) on growth in children. In this study, we aimed to analyze the growth parameters in children treated with ledipasvir/sofosbuvir (LDV/SOF). METHODS: We included38 patients (16 girls and 22 boys) aged 10-17 years treated with LDV/SOF for CHC (33 infected with genotype 1 and 5 with genotype 4; 36 were treated for 12 weeks, and 2 for 24 weeks according to the current guidelines). Patient weight and height were measured at baseline, after 4 weeks of treatment, at the end of the treatment (EOT), and 12 weeks and one year after the EOT. Body mass index (BMI), BMI z and height-for-age (HA) z scores were calculated according to the WHO Child Growth Standards and Growth reference data using the WHO anthropometric calculator AnthroPlus v. 1.0.4. In addition, correlations between BMI z scores and liver fibrosis (liver stiffness measurement, LSM), the aspartate transaminase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4) and liver steatosis (controlled attenuation parameter, CAP) were analyzed. RESULTS: At baseline, 5/38 (13%) patients were obese (BMI z score >2 SD), 4/38 (11%) were overweight, and 29 (76%) were normal. A significant increase was observed in mean weight, height and BMI both 12 weeks and one year after the treatment compared to the baseline, whereas no differences were observed for BMI z scores and HA z scores. Baseline BMI z scores correlated with alanine aminotransferase levels (r = 0.33, 95% CI 0.01-0.58, p =0.04), LSM (r = 0.40, 95% CI 0.09-0.65, p =0.01), the APRI (r = 0.33, 95% CI 0.02-0.59, p =0.03), and the CAP (r = 0.40, 95% CI 0.08-0.64, p =0.01). No similar correlations were reported at 12 weeks posttreatment. CONCLUSIONS: Treatment with LDV/SOF in children with CHC (genotypes 1 and 4) did not negatively influence the patients' growth. However, higher baseline BMI z scores correlated with more advanced liver fibrosis and steatosis in children with CHC.


Subject(s)
Hepatitis C, Chronic , Sofosbuvir , Adolescent , Antiviral Agents/therapeutic use , Benzimidazoles , Child , Drug Therapy, Combination , Female , Fluorenes , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/genetics , Humans , Liver Cirrhosis/drug therapy , Male , Sofosbuvir/therapeutic use , Treatment Outcome
6.
Public Health ; 205: 182-186, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1751168

ABSTRACT

OBJECTIVES: In 2015, the Republic of Georgia initiated a National Hepatitis C Elimination Program, with a goal of 90% reduction in prevalence of chronic hepatitis C virus (HCV) infections by 2020. In this article, we explore the impact of the COVID-19 pandemic on the 2020 hepatitis C cascade of care in Georgia. STUDY DESIGN: Retrospective analytic study. METHODS: We used a national screening registry that includes hospitals, blood banks, antenatal clinics, harm reduction sites, and other programs and services to collect data on hepatitis C screening. A separate national treatment database was used to collect data on viremia and diagnostic testing, treatment initiation, and outcome including testing for and achieving sustained virologic response (SVR). We used these databases to create hepatitis C care cascades for 2020 and 2019. Bivariate associations for demographic characteristics and screening locations per year and care cascade comparisons were assessed using a chi-squared test. RESULTS: In 2020 compared to 2019, the total number of persons screened for HCV antibodies decreased by 25% (from 975,416 to 726,735), 59% fewer people with viremic infection were treated for HCV infection (3188 vs. 7868), 46% fewer achieved SVR (1345 vs. 2495), a significantly smaller percentage of persons with viremic infection initiated treatment for HCV (59% vs. 62%), while the percentage of persons who achieved SVR (99.2% vs. 99.3%) remained stable. CONCLUSIONS: The COVID-19 pandemic had a negative impact on the hepatitis C elimination program in Georgia. To ensure Georgia reaches its elimination goals, mitigating unintended consequences of delayed diagnosis and treatment of hepatitis C due to the COVID-19 pandemic are paramount.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/therapeutic use , COVID-19/epidemiology , Female , Georgia/epidemiology , Georgia (Republic)/epidemiology , Hepacivirus , Hepatitis C/diagnosis , Hepatitis C/epidemiology , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/epidemiology , Humans , Pandemics , Pregnancy , Retrospective Studies
7.
Viruses ; 14(3)2022 03 16.
Article in English | MEDLINE | ID: covidwho-1742735

ABSTRACT

Enhancing treatment uptake for hepatitis C to achieve the elimination goals set by the World Health Organization could be achieved by reducing the treatment duration. The aim of this study was to compare the sustained virological response at week 12 (SVR12) after four weeks of glecaprevir/pibrentasvir (GLE/PIB) + ribavirin compared to eight weeks of GLE/PIB and to estimate predictors for SVR12 with four weeks of treatment through a multicenter open label randomized controlled trial. Patients were randomized 2:1 (4 weeks:8 weeks) and stratified by genotype 3 and were treatment naïve of all genotypes and without significant liver fibrosis. A total of 27 patients were analyzed for predictors for SVR12, including 15 from the first pilot phase of the study. In the 'modified intention to treat' group, 100% (7/7) achieved cure after eight weeks and for patients treated for four weeks the SVR12 was 58.3% (7/12). However, patients with a baseline viral load <2 mill IU/mL had 93% SVR12. The study closed prematurely due to the low number of included patients due to the COVID-19 pandemic. Our results suggest that viral load should be taken into account when considering trials of short course treatment.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Aminoisobutyric Acids , Antiviral Agents/therapeutic use , Benzimidazoles , Cyclopropanes , Hepatitis C, Chronic/drug therapy , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Pandemics , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines , Ribavirin/therapeutic use , Sulfonamides
8.
Viruses ; 14(3)2022 02 28.
Article in English | MEDLINE | ID: covidwho-1715780

ABSTRACT

Following the availability of highly effective direct-acting antivirals (DAAs) to treat hepatitis C infection, the uptake of treatment by people living with hepatitis C rose dramatically in high- and middle-income countries but has since declined. To achieve the World Health Organization's (WHO) 2030 target to eliminate hepatitis C as a public health threat among people who inject drugs, an increase in testing and treatment is required, together with improved coverage of harm reduction interventions. The population that remains to be treated in high- and middle-income countries with high hepatitis C prevalence are among the most socially disadvantaged, including people who inject drugs and are involved in the criminal justice system, a group with disproportionate hepatitis C prevalence, compared with people in the wider community. Imprisonment provides an unrivalled opportunity for screening and treating large numbers of people for hepatitis C, who may not access mainstream health services in the community. Despite some implementation challenges, evidence of the efficacy, acceptability, and cost-effectiveness of in-prison hepatitis treatment programs is increasing worldwide, and evaluations of these programs have demonstrated the capacity for treating people in high numbers. In this Perspective we argue that the scale-up of hepatitis C prevention, testing, and treatment programs in prisons, along with the investigation of new and adapted approaches, is critical to achieving WHO elimination goals in many regions; the Australian experience is highlighted as a case example. We conclude by discussing opportunities to improve access to prevention, testing, and treatment for people in prison and other justice-involved populations, including harnessing the changed practices brought about by the COVID-19 pandemic.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/therapeutic use , Australia/epidemiology , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis C/prevention & control , Humans , Pandemics , Prisons
9.
BMC Public Health ; 22(1): 371, 2022 02 21.
Article in English | MEDLINE | ID: covidwho-1708042

ABSTRACT

BACKGROUND: While the availability of generic direct-acting antivirals (DAAs) opens the door for large-scale treatment, the care for people living with hepatitis C virus (HCV) in Malaysia is shifting toward a tripartite partnership between the public health system, correctional settings and civil society organizations (CSOs). This study aimed to explore the barriers to scaling up HCV treatment in Malaysia from the perspective of key stakeholders. METHODS: Eighteen focus-group discussions (FGDs) were conducted with 180 individuals, who actively engaged in coordinating, executing or supporting the implementation of the national strategic plan for HCV. An analytical framework was adapted to guide the data collection and thematic analysis. It covered four key aspects of HCV treatment: geographical accessibility, availability, affordability and acceptability. RESULTS: Movement restrictions in times of coronavirus disease 2019 (COVID-19) outbreaks and being marginalized translated into barriers to treatment access in people living with HCV. Barriers to treatment initiation in health and correctional settings included limited staffing and capacity; disruption in material supply; silos mentality and unintegrated systems; logistical challenges for laboratory tests; and insufficient knowledge of care providers. Although no-cost health services were in place, concerns over transportation costs and productivity loss also continued to suppress the treatment uptake. Limited disease awareness, along with the disease-related stigma, further lowered the treatment acceptability. CONCLUSIONS: This study disclosed a series of supply- and demand-side barriers to expanding the treatment coverage among people living with HCV in Malaysia. The findings call for strengthening inter-organizational collaborations to overcome the barriers.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Hepatitis C , Antiviral Agents/therapeutic use , Health Services , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis C, Chronic/drug therapy , Humans , Malaysia , SARS-CoV-2
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 272: 121012, 2022 May 05.
Article in English | MEDLINE | ID: covidwho-1671114

ABSTRACT

Simeprevir and sofosbuvir are direct-acting antiviral drugs approved for the treatment of chronic HCV infection. Reports demonstrate the similarities between HCV and SARS-CoV-2 in terms of structure and replication mechanism. Therefore, it is suggested that a combination of simeprevir and sofosbuvir may be considered for COVID-19 patients. To date, no spectrophotometric methods have been published for quantitative analysis of simeprevir and sofosbuvir in combination. In this work, two simple spectrophotometric methods allowed quantitative analysis of the studied drugs in the mixed form. The zero-order direct method allowed quantitative analysis of simeprevir at 333 nm, with sofosbuvir showing zero absorbance values. The dual wavelength method allowed quantitative analysis of sofosbuvir by measuring the difference in absorbance values at 259.40 and 276 nm, where the difference in absorbance values of simeprevir was zero. With the applied methods, the investigated drugs in the mixtures and tablets prepared in the laboratory were successfully analyzed quantitatively with acceptable results.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antiviral Agents/therapeutic use , Drug Therapy, Combination , Genotype , Hepacivirus , Hepatitis C, Chronic/drug therapy , Humans , SARS-CoV-2 , Simeprevir , Sofosbuvir
11.
Nihon Yakurigaku Zasshi ; 157(1): 31-37, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1609118

ABSTRACT

Remdesivir is a direct-acting antiviral agent that inhibits viral RNA synthesis developed by Gilead Sciences, Inc. in the United States. It has been shown to have antiviral activity against single-stranded RNA viruses, including coronaviruses, in cell culture systems and animal models, and has been developed as a therapeutic agent for Ebola virus infection since 2015. however, to date, it has not been approved in any country. A novel coronavirus infection (COVID-19) was identified in Wuhan, Hubei Province, China in Dec, 2019, and is a respiratory disease characterized by fever, cough, and dyspnea. In severe cases, it may cause serious pneumonia, multi-organ failure and death. Gilead Sciences, Inc. U.S. embarked on the development of COVID-19 as a therapeutic drug, using remdesivir, which has shown in vitro and in vivo antiviral activities against MERS-CoV and SARS-CoV, which are single-stranded RNA coronaviruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The in vitro antiviral activity of remdesivir against SARS-CoV-2, which causes COVID-19, was confirmed and clinical studies were initiated in February 2020. Based on the results of clinical studies conducted by the National Institute of Allergy and Infectious Diseases (NIAID) and Gilead Sciences, Inc. and experience of administration from a compassionate use, an exceptional approval system based on the "Pharmaceuticals and Medical Devices Act" was also approved in Japan as of May 7, 2020 for the indication of "infections caused by SARS-CoV-2." In this article, the background of the development and clinical results of remdesivir are described.


Subject(s)
COVID-19 , Hemorrhagic Fever, Ebola , Hepatitis C, Chronic , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Hemorrhagic Fever, Ebola/drug therapy , Hepatitis C, Chronic/drug therapy , Humans , SARS-CoV-2
12.
Int J Drug Policy ; 101: 103570, 2022 03.
Article in English | MEDLINE | ID: covidwho-1587942

ABSTRACT

BACKGROUND: Healthcare delivery was disrupted during the COVID-19 pandemic, requiring minimized in-person contact between patients and clinicians. During the pandemic, people with opioid use disorder (OUD) were not only at elevated risk for COVID-19, but had markedly reduced access to treatment for OUD, Hepatitis C virus (HCV) and HIV due to recommended decreased in-person visits. METHODS: From March 15-June 15, 2020 at the syringe services program (SSP) in New Haven, Connecticut, USA, a differentiated care model evolved with reduced clinical demands on people who inject drugs (PWID) to ensure screening and treatment for HCV, HIV and OUD, with a focus on HCV treatment. This model involved a single, bundled screening, evaluation, testing (SET) and monitoring strategy for all three conditions, minimal in-person visits, followed by tele-health communication between patients, outreach workers and clinicians. In-person visits occurred only during induction onto methadone and phlebotomy at baseline and phlebotomy 12 weeks post-treatment for HCV to measure sustained virological response (SVR). Patients received supportive texts/calls from outreach workers and clinicians. RESULTS: Overall, 66 actively injecting PWID, all with OUD, underwent bundled laboratory screening; 35 had chronic HCV infection. Participants were 40 years (mean), mostly white (N = 18) men (N = 28) and 12 were unstably housed. Two were lost to-follow-up and 2 were incarcerated, leaving 31 who started pan-genotypic direct-acting antivirals (DAAs). The mean time from referral to initial phlebotomy and initiation of DAAs was 6.9 and 9.9 days, respectively. Fourteen additional patients were newly started on buprenorphine and 6 started on methadone; three and four, respectively, were on treatment at baseline. Overall, 29 (93.5%) PWID who initiated DAAs achieved SVR; among unstably housed persons the SVR was 83.3%. CONCLUSIONS: In response to COVID-19, an innovative differentiated care model for PWID at an SSP evolved that included successful co-treatment for HCV, HIV and OUD using a client-centered approach that reduces treatment demands on patients yet supports ongoing access to evidence-based treatments.


Subject(s)
COVID-19 , Drug Users , Hepatitis C, Chronic , Hepatitis C , Opioid-Related Disorders , Substance Abuse, Intravenous , Telemedicine , Antiviral Agents , Hepacivirus , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis C, Chronic/drug therapy , Humans , Male , Opioid-Related Disorders/drug therapy , Opioid-Related Disorders/therapy , Pandemics , Pharmaceutical Preparations , SARS-CoV-2 , Substance Abuse, Intravenous/epidemiology , Syringes
13.
J Chem Inf Model ; 61(12): 5906-5922, 2021 12 27.
Article in English | MEDLINE | ID: covidwho-1569200

ABSTRACT

Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such as Remdesivir. A computational approach was used to identify the most favorable binding site to the SARS-CoV-2 Spike S2 segment and to perform virtual screening. Compounds selected from modeling were evaluated in a live SARS-CoV-2 infection assay. An Arbidol (ARB) derivative with substitutions at both the C-4 and C-6 positions was found to exhibit a modest improvement in activity and solubility properties in comparison to ARB. However, all of the derivatives were found to only be partial inhibitors, rather than full inhibitors in a virus-induced cytopathic effect-based assay. The binding mode is also corroborated by parallel modeling of a series of oleanolic acid trisaccharide saponin fusion inhibitors shown to bind to the S2 segment. Recently determined experimental structures of the Spike protein allowed atomic resolution modeling of fusion inhibitor binding as a function of pH, and the implications for the molecular mechanism of direct-acting fusion inhibitors targeting the S2 segment are discussed.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Antiviral Agents/pharmacology , Humans , Indoles , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Structure-Activity Relationship , Virus Internalization
14.
World J Gastroenterol ; 27(42): 7362-7375, 2021 Nov 14.
Article in English | MEDLINE | ID: covidwho-1526867

ABSTRACT

BACKGROUND: Chronic liver disease, particularly cirrhosis, is associated with worse outcomes in patients infected with coronavirus disease 2019 (COVID-19). AIM: To assess outcomes of COVID-19 infection among patients with pre-existing hepatitis C with or without liver cirrhosis. METHODS: This multicenter, retrospective cohort study included all cases of confirmed co-infection of severe acute respiratory syndrome coronavirus 2 and chronic hepatitis C with or without liver cirrhosis who were admitted to six hospitals (Al-Sahel Hospital, Al-Matareya Hospital, Al-Ahrar Hospital, Ahmed Maher Teaching Hospital, Al-Gomhoreya Hospital, and the National Hepatology and Tropical Medicine Research Institute) affiliated with the General Organization for Teaching Hospitals and Institutes in Egypt. Patients were recruited from May 1, 2020, to July 31, 2020. Demographic, laboratory, imaging features, and outcomes were collected. Multivariate regression analysis was performed to detect factors affecting mortality. RESULTS: This retrospective cohort study included 125 patients with chronic hepatitis C and COVID-19 co-infection, of which 64 (51.20%) had liver cirrhosis and 40 (32.00%) died. Fever, cough, dyspnea, and fatigue were the most frequent symptoms in patients with liver cirrhosis. Cough, sore throat, fatigue, myalgia, and diarrhea were significantly more common in patients with liver cirrhosis than in non-cirrhotic patients. There was no difference between patients with and without cirrhosis regarding comorbidities. Fifteen patients (23.40%) with liver cirrhosis presented with hepatic encephalopathy. Patients with liver cirrhosis were more likely than non-cirrhotic patients to have combined ground-glass opacities and consolidations in CT chest scans: 28 (43.75%) vs 4 (6.55%), respectively (P value < 0.001). These patients also were more likely to have severe COVID-19 infection, compared to patients without liver cirrhosis: 29 (45.31%) vs 11 (18.04%), respectively (P value < 0.003). Mortality was higher in patients with liver cirrhosis, compared to those with no cirrhosis: 33 (51.56%) vs 9 (14.75%), respectively (P value < 0.001). All patients in Child-Pugh class A recovered and were discharged. Cirrhotic mortality occurred among decompensated patients only. A multivariate regression analysis revealed the following independent factors affecting mortality: Male gender (OR 7.17, 95%CI: 2.19-23.51; P value = 0.001), diabetes mellitus (OR 4.03, 95%CI: 1.49-10.91; P value = 0.006), and liver cirrhosis (OR 1.103, 95%CI: 1.037-1.282; P value < 0.0001). We found no differences in liver function, COVID-19 disease severity, or outcomes between patients who previously received direct-acting antiviral therapy (and achieved sustained virological response) and patients who did not receive this therapy. CONCLUSION: Patients with liver cirrhosis are susceptible to higher severity and mortality if infected with COVID-19. Male gender, diabetes mellitus, and liver cirrhosis are independent factors associated with increased mortality risk.


Subject(s)
COVID-19 , Coinfection , Hepatitis C, Chronic , Antiviral Agents/therapeutic use , Coinfection/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Liver Cirrhosis/epidemiology , Male , Retrospective Studies , SARS-CoV-2
15.
Clin Immunol ; 233: 108888, 2021 12.
Article in English | MEDLINE | ID: covidwho-1517099

ABSTRACT

Human interferon alpha (hIFN-α) administration constitutes the current FDA approved therapy for chronic Hepatitis B and C virus infections. Additionally, hIFN-α treatment efficacy was recently demonstrated in patients with COVID-19. Thus, hIFN-α constitutes a therapeutic alternative for those countries where vaccination is inaccessible and for people who did not respond effectively to vaccination. However, hIFN-α2b exhibits a short plasma half-life resulting in the occurrence of severe side effects. To optimize the cytokine's pharmacokinetic profile, we developed a hyperglycosylated IFN, referred to as GMOP-IFN. Given the significant number of reports showing neutralizing antibodies (NAb) formation after hIFN-α administration, here we applied the DeFT (De-immunization of Functional Therapeutics) approach to develop functional, de-immunized versions of GMOP-IFN. Two GMOP-IFN variants exhibited significantly reduced ex vivo immunogenicity and null antiproliferative activity, while preserving antiviral function. The results obtained in this work indicate that the new de-immunized GMOP-IFN variants constitute promising candidates for antiviral therapy.


Subject(s)
Hepatitis B, Chronic/immunology , Hepatitis C, Chronic/immunology , Interferon-alpha/immunology , Recombinant Proteins/immunology , Adult , Amino Acid Sequence , Animals , Antibodies, Neutralizing/immunology , Antiviral Agents/immunology , Antiviral Agents/pharmacology , CHO Cells , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Cattle , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cells, Cultured , Cricetinae , Cricetulus , Drug Stability , HEK293 Cells , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/virology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Humans , Interferon-alpha/genetics , Interferon-alpha/pharmacology , Recombinant Proteins/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/physiology
16.
Toxicol Sci ; 185(2): 119-127, 2022 01 24.
Article in English | MEDLINE | ID: covidwho-1501143

ABSTRACT

COVID-19 (Coronavirus Disease 2019), the disease caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) is an ongoing global public health emergency. As understanding of the health effects of COVID-19 has improved, companies and agencies worldwide have worked together to identify therapeutic approaches, fast-track clinical trials and pathways for emergency use, and approve therapies for patients. This work has resulted in therapies that not only improve survival, reduce time of hospitalization, and time to recovery, but also include preventative measures, such as vaccines. This manuscript discusses development programs for 3 products that are approved or authorized for emergency use at the time of writing: VEKLURY (remdesivir, direct-acting antiviral from Gilead Sciences, Inc.), REGEN-COV (casirivimab and imdevimab antibody cocktail from Regeneron Pharmaceuticals Inc.), and Comirnaty (Pfizer-BioNTech COVID-19 Vaccine [Pfizer, Inc.-BioNTech]), and perspectives from the U.S. Food and Drug Administration.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antiviral Agents , COVID-19 Vaccines , Drug Combinations , Humans , SARS-CoV-2
17.
Expert Rev Anti Infect Ther ; 20(4): 567-575, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1488110

ABSTRACT

BACKGROUND: Several randomized trials have evaluated the effects of sofosbuvir-based direct-acting antivirals on the clinical outcomes in patients with COVID-19. METHODS: A systematic literature search with no language restrictions was performed on electronic databases and preprint repositories to identify eligible randomized trials published up to 8 July 2021. A random-effects model was used to estimate the pooled odds ratio (OR) for outcomes of interest with the use of sofosbuvir combined with direct-acting antiviral agents relative to the nonuse of sofosbuvir-based direct-acting antiviral agents at 95% confidence intervals (CI). RESULTS: The meta-analysis of 11 trials (n = 2,161) revealed statistically significant reduction in the odds of mortality (pooled odds ratio = 0.59; 95% confidence interval 0.36 to 0.99) but no statistically significant difference in the odds of development of composite endpoint of severe illness (pooled odds ratio = 0.79; 95% confidence interval 0.43 to 1.44) with the administration of sofosbuvir-based direct-acting antiviral agents among patients with COVID-19, relative to non-administration of sofosbuvir-based direct-acting antiviral agents.Subgroup analysis with seven trials involving sofosbuvir-daclatasvir revealed no significant mortality benefit (pooled odds ratio = 0.77; 95% confidence interval 0.48 to 1.22). CONCLUSION: Sofosbuvir-based direct-acting antiviral agents have no protective effects against the development of severe illness in patients with COVID-19 with the current dosing regimen. Whether sofosbuvir-based direct-acting antiviral agents could offer mortality benefits would require further investigations.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Antiviral Agents , COVID-19/drug therapy , Drug Therapy, Combination , Hepatitis C, Chronic/drug therapy , Humans , Randomized Controlled Trials as Topic , SARS-CoV-2 , Sofosbuvir
18.
In Vivo ; 35(6): 3377-3383, 2021.
Article in English | MEDLINE | ID: covidwho-1485630

ABSTRACT

BACKGROUND/AIM: Liver injury has been frequently reported in association with SARS-CoV-2 infection, but data are still lacking regarding the impact of pre-existing liver damage and neoplasia on SARS-CoV-2 infection outcome and vice-versa. This study aimed to assess the effects of SARS-CoV-2 infection on hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infected patients, both in therapeutic-naïve and patients treated with direct acting antivirals. PATIENTS AND METHODS: We conducted a retrospective cohort study on 21 patients with a personal history of HCV infection, that have been diagnosed with different forms of HCC and who were subsequently infected with SARS-CoV-2. Patients were monitored by liver function tests, tumoral markers, blood cell count, and coagulation profile periodically. RESULTS: Solitary HCC nodules were predominant among the subjects who achieved sustained virologic response, while multinodular and infiltrative patterns were mostly prevalent among the treatment-naïve group. Most patients had mild and moderate COVID-19 infections. CONCLUSION: Within the current global pandemic crisis, cancer patients are highly vulnerable and in need of constant monitoring. Among patients with HCC, the ones with cured HCV infection may be at a lower risk of fatality than those with active HCV infection, when diagnosed with SARS-CoV-2 infection.


Subject(s)
COVID-19 , Carcinoma, Hepatocellular , Hepatitis C, Chronic , Hepatitis C , Liver Neoplasms , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/complications , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/epidemiology , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/epidemiology , Humans , Liver Cirrhosis/drug therapy , Liver Neoplasms/complications , Liver Neoplasms/drug therapy , Liver Neoplasms/epidemiology , Retrospective Studies , SARS-CoV-2
19.
J Chemother ; 34(2): 73-86, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1459998

ABSTRACT

Viral infections are particularly common among children. They often have a mild course, are self-limiting and do not need any specific treatment. However, in some cases, the disease can be severe and lead to permanent disabilities. A variety of antiviral drugs are available for the treatments of certain infectious agents: for instance, acyclovir is used to treat herpes simplex virus encephalitis. Recommendations for flu treatment may change according to the current epidemiological surveillance data, on the basis of which antiviral sensibility can be forecast: recommended drugs for the 2020-21 flu season are oseltamivir, zanamivir, peramivir and baloxavir. Some drugs are used to treat congenital infections, such as valganciclovir and ganciclovir in congenital cytomegalovirus infection. Antiretroviral prophylaxis in newborns from HIV-1 infected mothers must be initiated as soon as possible, with one or more drugs according to therapeutic regimens based on the baby's risk category. According to the most recent guidelines, antiretroviral therapy must be started at diagnosis. Several antiretroviral drugs are available today and approved for use in children, so several combinations can be made. However, out of the 29 antiretroviral drugs approved for adults, only 38% (11/29) are approved for children under the age of two and about 60% (18/29) for children under the age of twelve. Treatment with direct antiviral agents against hepatitis C virus is approved for children over the age of three; it consists in different therapeutic regimens chosen on the basis of the viral genotype (ledipasvir/sofosbuvir for genotypes 1, 4, 5 and 6, sofosbuvir/ribavirin for genotypes 2 and 3, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for all genotypes) and it has dramatically changed the course of the illness. Many molecules have been studied in order to treat SARS-CoV-2 infection, but only remdesivir seems to play a role in shortening recovery time, although inclusion criteria are very specific and data on the use in children is limited.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Adult , Antiviral Agents/therapeutic use , Child , Drug Therapy, Combination , Genotype , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Humans , Infant, Newborn , Ribavirin/therapeutic use , SARS-CoV-2
20.
Am J Gastroenterol ; 116(8): 1738-1740, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1444536

ABSTRACT

INTRODUCTION: Direct-acting antivirals (DAAs) are curative treatments for hepatitis C. However, initiation of these treatments requires adequate healthcare access. Coronavirus 2019 (COVID-19) resulted in restrictions to healthcare services in March 2020. We examined the impact of COVID-19 on the number of individuals dispensed DAAs. METHODS: This is a cross-sectional study examining the number of individuals dispensed DAAs in Ontario, Canada, from 2018 to 2020. Time-series models determined the impact of healthcare restrictions on DAA dispensations. RESULTS: Healthcare restrictions resulted in a 49.3% decrease in DAA dispensations (P = 0.026). DISCUSSION: COVID-19-related healthcare restrictions significantly affected access to DAAs. Studies exploring the long-term effects on reduced treatment are needed.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 , Drug Prescriptions/statistics & numerical data , Hepatitis C, Chronic/drug therapy , Cross-Sectional Studies , Humans , Ontario
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