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1.
Infect Dis Poverty ; 13(1): 39, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38802954

ABSTRACT

BACKGROUND: Migrants, mainly undocumented and low-income refugees, are at high risk of hepatitis C virus (HCV) infection, but are a difficult-to-reach and to-treat population. The aim of the study was to evaluate the effectiveness of a test and treat model with direct-acting antiviral for HCV infection in these migrants coming from low-income and living in southern Italy. METHODS: A prospective, multicenter, collaborative study based on a four-phase-program (educational counseling, screening, linkage-to-care and treatment) was designed in southern Italy; the study started in June 2018, was stopped in February 2020 because of the outbreak of SARS-CoV2 infection in Italy and was resumed in February 2021 until November 2021. After educational counseling on infectious diseases that are transmitted through blood or sexually pseudonymized HCV screening was offered to all undocumented migrants and low-income refugees observed at one of the 1st level clinical centers. The HCV-RNA-positive subjects were referred to one of the 3rd level units of Infectious Diseases (ID) and treated with a 12-week course of sofosbuvir-velpatasvir and observed for 12 weeks after the end of direct antiviral agents (DAA) treatment. STATISTICAL ANALYSIS: For the descriptive analysis, the categorical variables were reported as absolute numbers and relative frequencies. Continuous variables were summarized as mean and standard deviation (SD) if normally distributed, or as a median and interquartile range (IQR) if not normally distributed. We used Pearson chi-square or Fisher's exact test for categorical variables and Student's t test or Mann-Whitney test for continuous variables. A P value < 0.05 was considered to be statistically significant. Analyses were performed with SPSS 21.0. RESULTS: Of the 3501migrants observed in the study period, 3417 (97.6%) agreed to be screened; 185 (4.7%) were anti-HCV-positive and, of these, 53 (28.6%) were HCV-RNA-positive. Of these 53 subjects, 48 (90.5%) were referred to an ID unit and started DAA treatment. The HCV-RNA-positive-subjects were older [median 36 years (IQR: 32-21) vs 27.19 (IQR: 30.5-19.25); P = 0.001], and less frequently males [35 (66.03 %) vs 119 (90.1%), P < 0 .0001] than seronegative participants. They more frequently came from Eastern Europe (70.8%) stayed longer in Italy [months of stay in Italy, mean ± SD: 51.02 ± 52.84 vs 25.7 ± 42.65, P = 0.001], and had more years of schooling [years of schooling, mean ± SD: 9.61±2.81 vs 7.10 ± 4, P = 0.0001]. HCV-RNA-positive-subjects less frequently reported piercing, tattoos and tribal scars as risk factors (23.6%). Of these 48 HCV RNA positive subjects who started DAA, 47 (97.9%) showed a sustained virological response and one dropped-out in follow-up after DAA treatment. No subject had any adverse event. CONCLUSIONS: This model of HCV screening and linkage to care seems effective to eliminate HCV infectionin a difficult-to-reach and to-treat population, such as undocumented migrants and low-income refugees. The participation of cultural mediators in the study made possible a better interaction between migrants and physicians, as is evident from the large number of subjects enrolled. Eliminating HCV among migrants will have a long-term positive impact from a public health and healthcare perspective by reducing the number of individuals who potentially develop HCV-related complications such as liver cirrhosis and hepatocellular carcinoma and reducing the circulation of HCV in the regions that host them which often, as in the case of Italy, are low endemic for HCV infection.


Subject(s)
Antiviral Agents , Hepatitis C , Transients and Migrants , Humans , Italy/epidemiology , Antiviral Agents/therapeutic use , Prospective Studies , Male , Female , Adult , Middle Aged , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis C/virology , Transients and Migrants/statistics & numerical data , Hepacivirus/drug effects , Hepacivirus/genetics , Sofosbuvir/therapeutic use , Young Adult , Mass Screening , Refugees , Poverty
2.
Sci Rep ; 14(1): 10244, 2024 05 03.
Article in English | MEDLINE | ID: mdl-38702350

ABSTRACT

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.


Subject(s)
Antiviral Agents , Hepacivirus , Sofosbuvir , Adult , Female , Humans , Male , Middle Aged , Africa, Central , Africa, Western , Aminoisobutyric Acids , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Benzimidazoles/therapeutic use , Benzimidazoles/adverse effects , Benzopyrans , Carbamates/therapeutic use , Cyclopropanes/therapeutic use , Cyclopropanes/adverse effects , Drug Therapy, Combination , Feasibility Studies , Fluorenes/therapeutic use , Fluorenes/adverse effects , Genotype , Hepacivirus/genetics , Hepacivirus/drug effects , Hepatitis C/drug therapy , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/adverse effects , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Proline/therapeutic use , Quinoxalines , Ribavirin/therapeutic use , Ribavirin/adverse effects , Sofosbuvir/therapeutic use , Sofosbuvir/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Sustained Virologic Response , Treatment Outcome
3.
Sci Rep ; 14(1): 11840, 2024 05 23.
Article in English | MEDLINE | ID: mdl-38782988

ABSTRACT

The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.


Subject(s)
Antiviral Agents , Cryoglobulinemia , Vasculitis , Humans , Cryoglobulinemia/drug therapy , Cryoglobulinemia/etiology , Antiviral Agents/therapeutic use , Male , Vasculitis/drug therapy , Vasculitis/virology , Middle Aged , Female , Aged , Hepacivirus/drug effects , Ribavirin/therapeutic use , Sofosbuvir/therapeutic use , Imidazoles/therapeutic use , Valine/analogs & derivatives , Valine/therapeutic use , Pyrrolidines/therapeutic use , B-Cell Activating Factor , Interferon-alpha/therapeutic use , Drug Therapy, Combination , Hepatitis C/drug therapy , Hepatitis C/complications , Hepatitis C/virology , Treatment Outcome , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/virology , Carbamates
4.
PLoS One ; 19(5): e0303265, 2024.
Article in English | MEDLINE | ID: mdl-38739590

ABSTRACT

More than 58 million individuals worldwide are inflicted with chronic HCV. The disease carries a high risk of end stage liver disease, i.e., cirrhosis and hepatocellular carcinoma. Although direct-acting antiviral agents (DAAs) have revolutionized therapy, the emergence of drug-resistant strains has become a growing concern. Conventional cellular models, Huh7 and its derivatives were very permissive to only HCVcc (JFH-1), but not HCV clinical isolates. The lack of suitable host cells had hindered comprehensive research on patient-derived HCV. Here, we established a novel hepatocyte model for HCV culture to host clinically pan-genotype HCV strains. The immortalized hepatocyte-like cell line (imHC) derived from human mesenchymal stem cell carries HCV receptors and essential host factors. The imHC outperformed Huh7 as a host for HCV (JFH-1) and sustained the entire HCV life cycle of pan-genotypic clinical isolates. We analyzed the alteration of host markers (i.e., hepatic markers, cellular innate immune response, and cell apoptosis) in response to HCV infection. The imHC model uncovered the underlying mechanisms governing the action of IFN-α and the activation of sofosbuvir. The insights from HCV-cell culture model hold promise for understanding disease pathogenesis and novel anti-HCV development.


Subject(s)
Hepacivirus , Hepatocytes , Humans , Hepatocytes/virology , Hepatocytes/pathology , Hepacivirus/genetics , Hepacivirus/physiology , Antiviral Agents/pharmacology , Sofosbuvir/pharmacology , Cell Line , Virus Replication , Interferon-alpha/pharmacology , Hepatitis C/virology , Apoptosis , Mesenchymal Stem Cells/virology , Mesenchymal Stem Cells/metabolism
5.
Int J Biol Macromol ; 267(Pt 2): 131629, 2024 May.
Article in English | MEDLINE | ID: mdl-38631585

ABSTRACT

Current management of HCV infection is based on Direct-Acting Antiviral Drugs (DAAs). However, resistance-associated mutations, especially in the NS3 and NS5B regions are gradually decreasing the efficacy of DAAs. Among the most effective HCV NS3/4A protease drugs, Sofosbuvir also develops resistance due to mutations in the NS3 and NS5B regions. Four mutations at positions A156Y, L36P, Q41H, and Q80K are classified as high-level resistance mutations. The resistance mechanism of HCV NS3/4A protease toward Sofosbuvir caused by these mutations is still unclear, as there is less information available regarding the structural and functional effects of the mutations against Sofosbuvir. In this work, we combined molecular dynamics simulation, molecular mechanics/Generalized-Born surface area calculation, principal component analysis, and free energy landscape analysis to explore the resistance mechanism of HCV NS3/4A protease due to these mutations, as well as compare interaction changes in wild-type. Subsequently, we identified that the mutant form of HCV NS3/4A protease affects the activity of Sofosbuvir. In this study, the resistance mechanism of Sofosbuvir at the atomic level is proposed. The proposed drug-resistance mechanism will provide valuable guidance for the design of HCV drugs.


Subject(s)
Antiviral Agents , Drug Resistance, Viral , Hepacivirus , Molecular Dynamics Simulation , Mutation , Sofosbuvir , Viral Nonstructural Proteins , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , DEAD-box RNA Helicases , Drug Resistance, Viral/genetics , Hepacivirus/drug effects , Hepacivirus/genetics , Hepacivirus/enzymology , Nucleoside-Triphosphatase , Serine Endopeptidases , Serine Proteases , Sofosbuvir/pharmacology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteases
6.
Int J Drug Policy ; 127: 104396, 2024 May.
Article in English | MEDLINE | ID: mdl-38593518

ABSTRACT

BACKGROUND: There exist many barriers to hepatitis C virus (HCV) treatment for those with substance use disorder (SUD) or who lack access to routine medical care. A hospital-based telehealth program was developed to provide treatment opportunities for hospitalized patients living with HCV. METHODS: This single site prospective cohort study conducted from July 2022 to March 2023 aimed to measure linkage to care with an HCV clinician and initiation of HCV treatment in hospitalized patients. Patients were assessed in-person by a social worker then seen via telehealth by a clinician who prescribed either glecaprevir/pibrentasvir or sofosbuvir/velpatasvir. Treatment was initiated with pharmacist assistance. The team conducted in-person and/or telephonic outreach during and after hospitalization. Cure was confirmed by sustained virologic response at 12 weeks (SVR12) post-treatment. RESULTS: A total of 25 patients were enrolled and completed telehealth visits. All patients had a history of SUD and 18 (72 %) were unstably housed. Nineteen patients (76 %) initiated treatment, and 14 (56 %) successfully completed treatment. Twelve patients (48 %) completed post-treatment labs, including two who prematurely discontinued treatment. Eleven patients (44 %) achieved confirmed cure with SVR12. CONCLUSION: A hospital-based, multidisciplinary telehealth program can be an innovative care model to successfully treat HCV in a difficult-to-treat patient populations.


Subject(s)
Antiviral Agents , Sofosbuvir , Sustained Virologic Response , Telemedicine , Humans , Male , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Female , Middle Aged , Prospective Studies , Sofosbuvir/administration & dosage , Adult , Quinoxalines/administration & dosage , Quinoxalines/therapeutic use , Drug Combinations , Sulfonamides/administration & dosage , Carbamates/administration & dosage , Pyrrolidines/administration & dosage , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Benzimidazoles/therapeutic use , Benzimidazoles/administration & dosage , Cohort Studies , Hospitalization/statistics & numerical data , Hepatitis C, Chronic/drug therapy , Aged , Lactams, Macrocyclic
7.
Dig Dis Sci ; 69(5): 1551-1561, 2024 May.
Article in English | MEDLINE | ID: mdl-38580885

ABSTRACT

Patients with chronic hepatitis C virus (HCV) infection and decompensated cirrhosis are an important population for antiviral therapy yet under-represented in clinical trials. HCV direct-acting antiviral (DAA) therapies, unlike interferon-containing regimens, can be safely utilized in decompensated patients. Per guidelines from the American Association for the Study of Liver Diseases (AASLD), therapy of choice in HCV and decompensated cirrhosis is sofosbuvir, an HCV polymerase inhibitor, combined with a replication complex inhibitor (NS5A inhibitor) with or without ribavirin. Combination therapy with a HCV protease inhibitor and an NS5A inhibitor is effective in this population but is specifically not recommended in AASLD guidelines due to safety concerns. Important risk factors for further decompensation during DAA therapy are serum albumin < 3.5 g/dL, MELD (Model for End-Stage Liver Disease) score > 14, or HCV genotype 3 infection. Although sustained virologic response (SVR) is achieved less often in patients with decompensated vs compensated cirrhosis, in clinical studies response rates are > 80%. Both Child-Turcotte-Pugh Class at baseline and viral genotype can affect these response rates. Achieving SVR lowers risk of mortality, but to a lesser extent than in individuals with compensated cirrhosis. Likewise, treating patients for HCV infection along with successful treatment for hepatocellular carcinoma improves risks of both liver-related and overall mortality. In fewer than one third of cases, treating transplant-eligible, HCV-infected patients pre-transplant enables their delisting from transplant wait lists.


Subject(s)
Antiviral Agents , Hepatitis C, Chronic , Liver Cirrhosis , Humans , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Liver Cirrhosis/virology , Liver Cirrhosis/drug therapy , Drug Therapy, Combination , Hepacivirus/genetics , Hepacivirus/drug effects , Sustained Virologic Response , Sofosbuvir/therapeutic use
8.
Clin J Gastroenterol ; 17(3): 505-510, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38587568

ABSTRACT

Hepatitis C virus (HCV) reactivation has been reported to be caused due to several anticancer drugs and immunosuppressive agents; however, HCV reactivation after steroid monotherapy has rarely been reported. Here, we report the case of a 65-year-old Japanese man with HCV infection who developed HCV reactivation after the administration of prednisolone (PSL) for 6 days for sudden deafness. In the patient history, the positivity for anti-HCV antibody was observed, but serum level of HCV RNA was not measured. Two months after PSL administration, the patient experienced an alanine aminotransferase (ALT) flare and the serum level of HCV RNA was observed to be 6.2 log IU/mL; then, the patient was admitted to our hospital for hepatitis treatment. Based on the clinical course and laboratory findings, the patient was diagnosed with HCV reactivation. Although the ALT levels decreased spontaneously during follow-up, they did not drop to normal range; subsequently, sofosbuvir and ledipasvir treatments were started. A sustained virological response 24 weeks after the end of treatment was achieved. This case study suggests that HCV reactivation with hepatitis flare can occur even after a steroid monotherapy, and doctors should pay attention to HCV reactivation when administering PSL for patients with HCV infection.


Subject(s)
Antiviral Agents , Hearing Loss, Sudden , Hepacivirus , Prednisolone , Virus Activation , Humans , Male , Aged , Prednisolone/therapeutic use , Hearing Loss, Sudden/drug therapy , Hearing Loss, Sudden/etiology , Hearing Loss, Sudden/virology , Virus Activation/drug effects , Antiviral Agents/therapeutic use , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/complications , Sofosbuvir/therapeutic use , Fluorenes/therapeutic use , Fluorenes/adverse effects , Benzimidazoles/therapeutic use , Benzimidazoles/adverse effects , Alanine Transaminase/blood , RNA, Viral/blood , Glucocorticoids/therapeutic use , Glucocorticoids/adverse effects
9.
Luminescence ; 39(4): e4742, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38637644

ABSTRACT

A simple, rapid, and low-cost technique was developed to allow reliable analysis of the anti-hepatitis C drug sofosbuvir in bulk, tablet form, and spiked human plasma. This method depends on the ability of sofosbuvir to quench the fluorescence of the newly synthesized 2-amino-3-cyano-4,6-dimethylpyridine (reagent 3). Elemental analysis and spectral data were used to validate the structure of the synthesized reagent. The newly synthesized reagent exhibited a satisfactory level of fluorescence emission at 365 nm after excitation at 247 nm. All experimental variables that might affect the quenching process were analyzed and optimized. Linearity, range, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ) were all validated in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The concentration range was shown to be linear between 0.1 and 1.5 µg/mL. The technique was effectively utilized for sofosbuvir analysis in both its tablet dosage form and spiked human plasma, with mean percentage recoveries of 100.13 ± 0.35 and 94.26 ± 1.69, respectively.


Subject(s)
Fluorescent Dyes , Sofosbuvir , Humans , Spectrometry, Fluorescence/methods , Tablets
11.
BMC Infect Dis ; 24(1): 301, 2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38468199

ABSTRACT

BACKGROUND: Globally, 80 million people are suffering from chronic Hepatitis C virus (HCV) infection. Sofosbuvir ribavirin-based anti-HCV therapy is associated with anemia and other adverse effects. Polymorphisms of Inosine triphosphatase (ITPA) gene may cause functional impairment in the Inosine triphosphate pyrophosphatase enzyme, resulting in enhanced sustained viral response (SVR) and protection from ribavirin-associated anemia in patients on therapy. The study objective was to investigate the effect of Inosine triphosphatase gene polymorphism on SVR achievement, hemoglobin decline and ribavirin dose reduction in patients on therapy. METHODS: This prospective cohort study was of 170 hepatitis C infected patients received 6-month sofosbuvir ribavirin therapy. Patient viral load, reduction in ribavirin amount, liver function test, and complete blood count were noted monthly. Inosine triphosphatase variants rs1127354 and rs7270101 were assessed through the restriction fragment length polymorphism and confirmed using Sanger sequencing. The impact of polymorphism on cumulative reduction of ribavirin, and anti-HCV therapy outcome were studied. RESULTS: A total of 74.3% of patients had ITPA rs1127354 CC genotype, 25.7% were CA and AA 0%. The frequency of ITPA genotype rs7270101-AA was 95%, AC 5%, and CC was 0%. ITPA rs1127354-CA had a notably positive impact on SVR achievement with a zero-relapse rate. ITPA rs1127354-CA genotype was significantly (P ˂0.05) protective against ≥ 2 g/dl Hb reduction from baseline to 1st, 2nd and 6th months of therapy. During treatment, Hb reduction ≥ 10 g/dl was frequently observed in rs1127354-CC genotype and rs7270101-AA genotype patients. Ribavirin dose reduction was significantly (P ˂0.05) high in rs1127354-CC genotype as compared to genotype CA whereas no significant difference was observed in ribavirin dose reduction in rs7270101 AA and non-AA genotype. Patient baseline characteristics such as age, body mass index, rs1127354-CC genotype, and baseline Hb were significantly associated with significant Hb reduction. CONCLUSION: Pretreatment evaluation of ITPA polymorphism can be a diagnostic tool to find out patients at risk of anemia and improve treatment adherence. ITPA genotype rs1127354-CA contributes to improved compliance with ribavirin dose and protects against hemoglobin decline in HCV patients while taking ribavirin-based therapy. However, ITPA rs1127354, rs7270101 polymorphism have no significant impact on SVR achievement.


Subject(s)
Anemia , Hepatitis C, Chronic , Hepatitis C , Humans , Ribavirin/adverse effects , Sofosbuvir/adverse effects , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/genetics , Antiviral Agents/adverse effects , Inosine Triphosphatase , Hepacivirus/genetics , Prospective Studies , Polymorphism, Single Nucleotide , Pyrophosphatases/genetics , Pyrophosphatases/therapeutic use , Anemia/chemically induced , Anemia/genetics , Hepatitis C/drug therapy , Genotype , Hemoglobins/genetics , Treatment Outcome
12.
Sci Rep ; 14(1): 5682, 2024 03 07.
Article in English | MEDLINE | ID: mdl-38453980

ABSTRACT

Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including cirrhosis. It may be used alone or with other drugs. Ribavirin is an antiviral medication used to treat HCV infection. It is not effective when used alone and must be used in combination with other medications, such as sofosbuvir. This study pertains to a comprehensive assessment of the deleterious effects of sofosbuvir (an antiviral drug against chronic HCV) or sofosbuvir combined with ribavirin (an antiviral drug against RNA and DNA viruses) on several biological activities of the body, including hematological, hormonal, biochemical, histological, and immunohistochemical examinations during a long-standing period on male healthy rats. In addition, fertility assessments were performed, including sperm collections and semen parameter investigations. This study was conducted on 21 male rats divided into three equal groups. Group I (control group) received distilled water; group II (sofosbuvir group) received sofosbuvir (4 mg/kg); and group III (sofosbuvir + ribavirin) received sofosbuvir (4 mg/kg) plus ribavirin (30 ml/kg). All groups received the specific drug for six months. Blood and tissue samples were collected for hematological, hormonal, biochemical, histological, and immunohistochemical examinations. In addition, sperm collection and assessments of semen parameters were performed. Results revealed that sofosbuvir causes a highly significant decrease in the mean of most hematological, immunological, hormonal, and biochemical parameters, except for a few numbers of parameters such as neutrophils, monocytes, basophils, cortisol, GOT, and lipase, which exhibit a significant increase. The same occurred in the sofosbuvir + ribavirin group, but at much higher levels, as most hematological, immunological, hormonal, and biochemical parameters exhibit a highly significant decrease except for monocytes, triglyceride, and lipase, which exhibit a significant increase. When compared to the sofosbuvir group alone, the sofosbuvir + ribavirin group demonstrated a highly significant decline in the mean of most hematological, immunological, hormonal, and biochemical parameters except lymphocytes and triglycerides, which exhibit a substantial increase. For the reproductive parameters, both groups exhibit a significant decrease in the total sperm motility percentage. Finally, it can be concluded that sofosbuvir causes acute pancreatitis and combined immunodeficiency. Ribavirin is associated with hormonal deficiency, which indicates the occurrence of hypopituitarism. Moreover, sofosbuvir and ribavirin synergistically affect myelosuppression and cause iron-deficiency anemia. However, sofosbuvir, or its combination with ribavirin, is associated with a reduced risk of hepatocellular carcinoma. Besides, adding ribavirin to be combined with sofosbuvir improved the immunodeficiency caused by sofosbuvir; this confirms that using ribavirin with sofosbuvir reduces the side effects of both alone.


Subject(s)
Hepatitis C, Chronic , Pancreatitis , Humans , Adult , Child , Male , Animals , Rats , Antiviral Agents/adverse effects , Sofosbuvir/adverse effects , Ribavirin/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepacivirus/genetics , Acute Disease , Treatment Outcome , Drug Therapy, Combination , Pancreatitis/chemically induced , Semen , Sperm Motility , Liver Cirrhosis/complications , Lipase/genetics , Genotype
13.
Int J Infect Dis ; 143: 107017, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38521450

ABSTRACT

Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.


Subject(s)
Antiviral Agents , Immunocompromised Host , Sofosbuvir , Yellow Fever Vaccine , Yellow Fever , Humans , Female , Adult , Yellow Fever/immunology , Yellow Fever Vaccine/adverse effects , Yellow Fever Vaccine/immunology , Sofosbuvir/therapeutic use , Sofosbuvir/adverse effects , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Rituximab/adverse effects , Rituximab/therapeutic use
14.
Intern Med J ; 54(4): 678-681, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38450913

ABSTRACT

We transplanted six solid organs from three hepatitis C virus (HCV) polymerase chain reaction (PCR)-positive donors during 2018-2023. Recipients were treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir for 4-12 weeks, with all six achieving sustained virological response without significant adverse events. As occurs in other jurisdictions, solid organ transplants from HCR PCR-positive donors can be safely utilised in Australia.


Subject(s)
Hepatitis C, Chronic , Hepatitis C , Humans , Hepacivirus/genetics , Antiviral Agents/therapeutic use , Western Australia/epidemiology , Sofosbuvir/therapeutic use , Tissue Donors , Polymerase Chain Reaction , Hepatitis C, Chronic/drug therapy , Hepatitis C/diagnosis , Hepatitis C/drug therapy
15.
Korean J Gastroenterol ; 83(3): 111-118, 2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38522854

ABSTRACT

Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.


Subject(s)
Aminoisobutyric Acids , Benzimidazoles , Cyclopropanes , Fluorenes , Hepatitis C, Chronic , Lactams, Macrocyclic , Leucine/analogs & derivatives , Liver Neoplasms , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines , Sulfonamides , Humans , Male , Sofosbuvir/therapeutic use , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepacivirus/genetics , Retrospective Studies , Treatment Outcome , Liver Neoplasms/drug therapy , Genotype , Drug Therapy, Combination
16.
Lancet Gastroenterol Hepatol ; 9(4): 366-382, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38367631

ABSTRACT

Direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection have delivered high response rates (>95%) and simplified the management of HCV treatment, permitting non-specialists to manage patients without advanced liver disease. We collected and reviewed global data on the registration and reimbursement (government subsidised) of HCV therapies, including restrictions on reimbursement. Primary data collection occurred between Nov 15, 2021, and July 24, 2023, through the assistance of a global network of 166 HCV experts. We retrieved data for 160 (77%) of 209 countries and juristrictions. By mid-2023, 145 (91%) countries had registered at least one of the following DAA therapies: sofosbuvir-velpatasvir, sofosbuvir-velpatasvir-voxilaprevir, glecaprevir-pibrentasvir, sofosbuvir-daclatasvir, or sofosbuvir. 109 (68%) countries reimbursed at least one DAA therapy. Among 102 low-income and middle-income countries (LMICs), 89 (87%) had registered at least one HCV DAA therapy and 53 (52%) reimbursed at least one DAA therapy. Among all countries with DAA therapy reimbursement (n=109), 66 (61%) required specialist prescribing, eight (7%) had retreatment restrictions, seven (6%) had an illicit drug use restriction, five (5%) had an alcohol use restriction, and three (3%) had liver disease restrictions. Global access to DAA reimbursement remains uneven, with LMICs having comparatively low reimbursement compared with high-income countries. To meet WHO goals for HCV elimination, efforts should be made to assist countries, particularly LMICs, to increase access to DAA reimbursement and remove reimbursement restrictions-especially prescriber-type restrictions-to ensure universal access.


Subject(s)
Benzimidazoles , Benzopyrans , Carbamates , Hepatitis C, Chronic , Hepatitis C , Heterocyclic Compounds, 4 or More Rings , Humans , Sofosbuvir/adverse effects , Antiviral Agents/adverse effects , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/epidemiology , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepacivirus/genetics
17.
Int J Mol Sci ; 25(4)2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38396699

ABSTRACT

Dengue virus (DENV) causes dengue fever and dengue hemorrhagic fever, and DENV infection kills 20,000 people annually worldwide. Therefore, the development of anti-DENV drugs is urgently needed. Sofosbuvir (SOF) is an effective drug for HCV-related diseases, and its triphosphorylated metabolite inhibits viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of HCV. (2'R)-2'-Deoxy-2'-fluoro-2'-methyluridine (FMeU) is the dephosphorylated metabolite produced from SOF. The effects of SOF and FMeU on DENV1 replication were analyzed using two DENV1 replicon-based methods that we previously established. First, a replicon-harboring cell assay showed that DENV1 replicon replication in human hepatic Huh7 cells was decreased by SOF but not by FMeU. Second, a transient replicon assay showed that DENV1 replicon replication in Huh7 cells was decreased by SOF; however, in hamster kidney BHK-21 cells, it was not suppressed by SOF. Additionally, the replicon replication in Huh7 and BHK-21 cells was not affected by FMeU. Moreover, we assessed the effects of SOF on infectious DENV1 production. SOF suppressed infectious DENV1 production in Huh7 cells but not in monkey kidney Vero cells. To examine the substrate recognition of the HCV and DENV1 RdRps, the complex conformation of SOF-containing DENV1 RdRp or HCV RdRp was predicted using AlphaFold 2. These results indicate that SOF may be used as a treatment for DENV1 infection.


Subject(s)
Hepatitis C , Sofosbuvir , Animals , Cricetinae , Chlorocebus aethiops , Humans , Sofosbuvir/pharmacology , Antiviral Agents/pharmacology , Vero Cells , RNA-Dependent RNA Polymerase , Virus Replication , Hepacivirus/genetics
18.
BMC Gastroenterol ; 24(1): 73, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38355447

ABSTRACT

BACKGROUND: Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the first DAA developed by a Chinese local enterprise, which is suitable for combined use with other drugs to treat genotype 1b chronic hepatitis C. However, previous reports have never compared the real-world data of ECS and DNV. PATIENTS AND METHODS: 178 chronic hepatitis C patients were retrospectively recruited, and 94cases were accepted with Sofosbuvir/Velpatasvir ± Ribavirin (ECS group), and others (n = 84 treated with DNV combination therapy (DNV group). The HCV genotype, virological response, adverse effects and some laboratory biochemical indexes were contrasted between above two groups in the real world study. RESULTS: DNV group had significantly lower level of alpha-fetoprotein (AFP), lower rates of decompensated cirrhosis ( P < 0.05). ECS group possessed more 6a (31.91% vs.13.10%) while DNV group was provided with more 1b (48.81% vs. 22.34%) patients. Significantly poor liver function was detected in ECS group at 4-week treatment (ALT and AST) and 12-week follow-up (AST) (all P < 0.05). The SVR12 undetectable rates of both groups were 100%, and no serious event was observed during the treatment and follow-up in both groups. CONCLUSION: In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C.


Subject(s)
Benzimidazoles , Benzopyrans , Carbamates , Cyclopropanes , Drug Combinations , Hepatitis C, Chronic , Hepatitis C , Isoindoles , Lactams, Macrocyclic , Proline , Sulfonamides , Humans , Antiviral Agents/adverse effects , China , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C, Chronic/genetics , Heterocyclic Compounds, 4 or More Rings/adverse effects , Liver Cirrhosis/drug therapy , Proline/analogs & derivatives , Retrospective Studies , Ribavirin/adverse effects , Sofosbuvir/adverse effects , Treatment Outcome
19.
Clin Transplant ; 38(2): e15260, 2024 02.
Article in English | MEDLINE | ID: mdl-38369851

ABSTRACT

BACKGROUND: National data demonstrate that hepatitis C virus (HCV)-infected organ donors are increasingly being used in the US, including for lung transplantation. We aimed to assess whether there were any differences in the acute or chronic rejection rates at 1 year following lung transplantation from HCV-viremic versus uninfected donors. METHODS: We retrospectively reviewed all lung transplant recipients at our institution from April 1, 2017 to October 1, 2020 and then assessed various outcomes between those who received a transplant from HCV-viremic donors versus HCV-negative donors. Primary outcome was to determine if there was a higher incidence of acute and/or chronic allograft rejection when using HCV NAT+ lung donation. We carried out univariate and multivariate analyses. RESULTS: We transplanted 135 patients during the study period, including 18 from HCV-viremic donors. Standard induction therapy with basiliximab and maintenance triple drug immunosuppression was utilized per UC San Diego protocol. All 17 patients receiving HCV-viremic organs developed acute HCV infection and were treated in the postoperative period with 12 weeks of direct acting antivirals (DAA). HCV genotypes included 1, 2, and 3. DAA used included glecaprevir/pibrentasvir (12), sofosbuvir/velpatasvir (1), and ledipasvir/sofosbuvir (2) with drug choice determined by patient's medical insurance coverage. Sustained virological response at 12 weeks after end of DAA therapy (SVR12), indicative of a cure, was achieved in all (100%) recipients. No recipient had a serious adverse event related to HCV infection. The lung transplant recipient (LTR) HCV-viremic donors had lower rates of clinically significant rejection (5.9% vs. 11% LTR HCV-nonviremic donors), and no chronic lung allograft dysfunction at 1 year (vs. 5.9% LTR HCV-nonviremic donors). One-year survival was 100% in the LTR HCV-viremic donors compared to 95.8% in the LTR HCV-nonviremic donors. CONCLUSIONS: We demonstrate the feasibility and success of using HCV NAT + donors with excellent results and without a higher incidence of rejection. Longer term follow-up and a larger sample size are needed to allow this to be a more widely accepted practice for lung transplant programs and payors.


Subject(s)
Hepatitis C, Chronic , Hepatitis C , Lung Transplantation , Humans , Sofosbuvir/therapeutic use , Hepacivirus , Antiviral Agents/therapeutic use , Retrospective Studies , Hepatitis C/drug therapy , Tissue Donors
20.
J Pediatr Gastroenterol Nutr ; 78(4): 957-972, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38369891

ABSTRACT

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and HCV-related liver disease has advanced considerably thanks to development and improvements in therapy. Direct-acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype-specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age-specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource-limited settings.


Subject(s)
Benzimidazoles , Benzopyrans , Carbamates , Hepatitis C, Chronic , Hepatitis C , Heterocyclic Compounds, 4 or More Rings , Adult , Child , Adolescent , Humans , Sofosbuvir/therapeutic use , Hepatitis C, Chronic/drug therapy , Antiviral Agents/therapeutic use , Resource-Limited Settings , Drug Therapy, Combination , Hepacivirus/genetics , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Genotype , Treatment Outcome
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