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Polish Archives of Internal Medicine Feb 2024Pangenotypic therapies for infections with hepatitis C virus (HCV), although universal and highly effective, entail a risk of treatment failure.
INTRODUCTION
Pangenotypic therapies for infections with hepatitis C virus (HCV), although universal and highly effective, entail a risk of treatment failure.
OBJECTIVES
Our study aimed to identify the population of HCV‑infected patients most difficult to cure with the sofosbuvir / velpatasvir (SOF/VEL) regimen.
PATIENTS AND METHODS
The effectiveness of the SOF/VEL regimen with a possible addition of ribavirin (RBV) was evaluated in populations known to be less responsive to treatment, and then in a population characterized by the combination of all factors impairing effectiveness, comprising patients treated with this regimen in the EpiTer‑2 multicenter retrospective study.
RESULTS
A total of 2267 patients were treated with SOF/VEL±RBV. Of those, 2078 (96.4%) achieved sustained virologic response. The cure rate was 93.5% among 646 patients infected with genotype (GT) 3, 92.3% among 635 patients with cirrhosis, 95.5% in a population of 1233 men, and 94.1% among 421 patients with body mass index (BMI) above 30. An analysis in a group of 43 men with cirrhosis and obesity infected with GT3 showed the effectiveness of pangenotypic therapy at only 79.1%, falling to 66.7% in individuals with previous treatment failure.
CONCLUSIONS
In a large population of SOF/VEL‑treated HCV‑infected patients, we showed relatively low effectiveness of the regimen in treatment‑experienced men with cirrhosis and obesity, infected with GT3. Triple therapy should be considered when initiating the treatment of HCV infections in this group, which, however, needs to be confirmed in further studies. Previous studies were conducted in less demanding populations, because they did not take into account sex and BMI, which significantly affect the treatment effectiveness.
Topics: Male; Humans; Sofosbuvir; Hepacivirus; Antiviral Agents; Retrospective Studies; Hepatitis C; Ribavirin; Treatment Outcome; Liver Cirrhosis; Obesity; Benzimidazoles; Benzopyrans; Carbamates; Heterocyclic Compounds, 4 or More Rings
PubMed: 38164647
DOI: 10.20452/pamw.16644 -
Turkiye Parazitolojii Dergisi Dec 2023Crimean-Congo hemorrhagic fever (CCHF) is the most common tick-borne viral hemorrhagic fever in our country and the world. While investigating the etiology of fever,...
OBJECTIVE
Crimean-Congo hemorrhagic fever (CCHF) is the most common tick-borne viral hemorrhagic fever in our country and the world. While investigating the etiology of fever, tick contact should be questioned, especially in rural areas, and CCHF should be remembered. This study aimed to review the characteristics of the cases detected in Bayburt, one of the cities where CCHF is endemic.
METHODS
A total of 100 patients aged 16 years and older who were diagnosed with CCHF in our clinic between April 2020 and October 2022 were included in the study. Demographic, epidemiological, and clinical characteristics, treatments, and prognoses of the patients were reviewed retrospectively through the hospital automation system and CCHF information system of The Ministry of Health.
RESULTS
Sixty one (61%) of the patients included in the study were male, and their primary age (± standard deviation) was 50.4±15.7. 77% of the patients engaged in farming and or animal husbandry, and 71% were living in rural areas. The highest number of cases was in June and July. 63% of the patients had a history of a tick bite. At the first presentation, there were complaints of fatigue (95%), generalized body pain (84%), headache (67%), and fever (65%), in order of frequency. Ribavirin was started in 52 (52%) patients. One patient admitted in the late period died, and 99 patients were discharged with good recovery.
CONCLUSION
CCHF is an important public health problem that has been causing seasonal epidemics in our country for nearly two decades. Although sporadic cases have been reported from almost every region, the disease is endemic in some areas. Since signs and symptoms are not specific, the disease can be easily missed when tick contact is not questioned. Therefore CCHF should be considered in patients presenting with fever and thrombocytopenia in rural areas, especially in the spring and summer months.
Topics: Animals; Humans; Male; Female; Hemorrhagic Fever, Crimean; Hemorrhagic Fever Virus, Crimean-Congo; Retrospective Studies; Cities; Tick Bites; Ticks
PubMed: 38149444
DOI: 10.4274/tpd.galenos.2023.39200 -
Exploratory Research in Clinical and... Dec 2023Hepatitis C Virus (HCV) remains a challenging health problem worldwide, with increasing incidence despite being curable with Direct Acting Antiviral (DAA) agents.
BACKGROUND
Hepatitis C Virus (HCV) remains a challenging health problem worldwide, with increasing incidence despite being curable with Direct Acting Antiviral (DAA) agents.
OBJECTIVE
This study aimed to describe the utilization, reimbursement, and price trends of HCV treatments and evaluate the influence of treatment guidelines and policies.
METHODS
A retrospective, descriptive drug utilization study conducted using the outpatient pharmacy data extracted from the Centers for Medicaid and Medicare Services State Drug Utilization Data between 2001 and 2021. All HCV treatments approved in the US were included, conventional therapy (CT), and DAA agents. The annual secular trends were calculated for each medication's total number of prescriptions, reimbursements, and prices. The average reimbursement per prescription was calculated and utilized as a proxy of prices. The HCV treatment guideline and policies and legislation were evaluated overtime to measure the impact on the trends.
RESULTS
Despite CT having a higher total utilization, DAA agents commanded significantly greater reimbursements, with 4.1 billion USD for CT and 19.45 billion USD for DAA agents. CT utilization increased rapidly and dominated the market until 2011, peaking at 379,696 prescriptions in 2003 but declining afterward. DAA agents' utilization increased rapidly in their first year: i.e., sofosbuvir reached 50,377 prescriptions with 1.3 billion USD in 2014, while ledipasvir/sofosbuvir reached 79,387 prescriptions with 2 billion USD in 2015. The average price per prescription was high for the DAA agents, like 24,992 USD for sofosbuvir and 22,787 USD for ledipasvir/sofosbuvir, compared to CT medications ribavirin, around 500 USD, and pegINF, around 3000 USD. The new DAA agents replaced CT, and initiating market competition among DAA agents.
CONCLUSION
The introduction of multiple DAA agents slightly changed their prescription prices but remained high during the study period. The recent increase in HCV incidence cases indicates accessibility issues for costly and effective DAA agents, with treatment guidelines and policies playing a critical role in shaping these trends.
PubMed: 38145237
DOI: 10.1016/j.rcsop.2023.100383 -
International Journal of Molecular... Dec 2023Here, we report the in-host hepatitis E virus (HEV) quasispecies evolution in a chronically infected patient who was treated with three different regimens of ribavirin...
Here, we report the in-host hepatitis E virus (HEV) quasispecies evolution in a chronically infected patient who was treated with three different regimens of ribavirin (RBV) for nearly 6 years. Sequential plasma samples were collected at different time points and subjected to RNA extraction and deep sequencing using the MiSeq Illumina platforms. Specifically, we RT-PCR amplified a single amplicon from the core region located in the open-reading frame 2 (ORF2). At the nucleotide level (genotype), our analysis showed an increase in the number of rare haplotypes and a drastic reduction in the frequency of the master (most represented) sequence during the period when the virus was found to be insensitive to RBV treatment. Contrarily, at the amino acid level (phenotype), our study revealed conservation of the amino acids, which is represented by a high prevalence of the master sequence. Our findings suggest that using mutagenic antivirals concomitant with high viral loads can lead to the selection and proliferation of a rich set of synonymous haplotypes that express the same phenotype. This can also lead to the selection and proliferation of conservative substitutions that express fitness-enhanced phenotypes. These results have important clinical implications, as they suggest that using mutagenic agents as a monotherapy treatment regimen in the absence of sufficiently effective viral inhibitors can result in diversification and proliferation of a highly diverse quasispecies resistant to further treatment. Therefore, such approaches should be avoided whenever possible.
Topics: Humans; Antiviral Agents; Hepatitis E virus; Mutagens; Quasispecies; Ribavirin
PubMed: 38139013
DOI: 10.3390/ijms242417185 -
Cancer Reports (Hoboken, N.J.) Feb 2024The main differences in cases of sudden elevation of hepatic enzyme levels during immunochemotherapy are the reactivation of the hepatitis B virus or drug-induced liver...
BACKGROUND
The main differences in cases of sudden elevation of hepatic enzyme levels during immunochemotherapy are the reactivation of the hepatitis B virus or drug-induced liver injury. Here, we report a case of acute liver injury caused by the hepatitis E virus (HEV) during chemotherapy for malignant lymphoma, wherein the patient was successfully treated for the hepatitis and resumed chemotherapy to completion.
CASE
A 57-year-old woman visited her local doctor because she felt lightweight and tired. The patient underwent lower gastrointestinal endoscopy and was diagnosed with a malignant lymphoma of the small intestine (diffuse large B-cell lymphoma). The patient had a history of oral consumption of undercooked pork liver to improve anemia and was diagnosed with acute hepatitis E.
CONCLUSION
This report highlights the successful treatment of HEV infection in a patient undergoing immunosuppressive therapy for malignant lymphomas. A novel aspect of this study is the safe and effective use of ribavirin, an antiviral medication, along with continued chemotherapy, which resulted in sustained virological response (SVR) and the completion of the planned chemotherapy regimen. This report also provides new insights into the management of HEV infections in immunosuppressed patients undergoing chemotherapy and emphasizes the importance of considering HEV as a potential cause of acute liver injury in such cases. The successful use of ribavirin along with continued chemotherapy offers a promising treatment strategy for clinicians to consider in similar scenarios.
Topics: Female; Humans; Middle Aged; Ribavirin; Hepatitis E; Antiviral Agents; Lymphoma, Large B-Cell, Diffuse
PubMed: 38124270
DOI: 10.1002/cnr2.1957 -
Cellular and Molecular Gastroenterology... 2024A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver...
BACKGROUND & AIMS
A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA entry and HBe-SC in the natural history of CHB.
METHODS
To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n = 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed.
RESULTS
Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination.
CONCLUSIONS
R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.
Topics: Animals; Humans; Mice; Akkermansia; Cholesterol; Clostridiales; Hepatitis B e Antigens; Hepatitis B, Chronic; Gastrointestinal Microbiome
PubMed: 38092311
DOI: 10.1016/j.jcmgh.2023.12.003 -
American Journal of Transplantation :... Mar 2024Immunocompromised patients are at risk of chronic hepatitis E (HEV) infection. Recurrent T cell and borderline rejections in a pediatric patient with high HEV copy...
Immunocompromised patients are at risk of chronic hepatitis E (HEV) infection. Recurrent T cell and borderline rejections in a pediatric patient with high HEV copy numbers led us to study HEV infection within renal transplants. To investigate the frequency of renal HEV infection in transplanted patients, 15 samples from patients with contemporaneous diagnoses of HEV infection were identified at our center. Ten samples had sufficient residual paraffin tissue for immunofluorescence (IF) and RNA-fluorescence-in-situ-hybridization (RNA-FISH). The biopsy of the pediatric index patient was additionally sufficient for tissue polymerase chain reaction and electron microscopy. HEV RNA was detected in paraffin tissue of the index patient by tissue polymerase chain reaction. Subsequently, HEV infection was localized in tubular epithelial cells by IF, RNA-FISH, and electron microscopy. One additional biopsy from an adult was positive for HEV by RNA-FISH and IF. Focal IF positivity for HEV peptide was observed in 7 additional allografts. Ribavirin therapy was not successful in the pediatric index patient; after relapse, ribavirin is still administered. In the second patient, successful elimination of HEV was achieved after short-course ribavirin therapy. HEV infection is an important differential diagnosis for T cell rejection within transplanted kidneys. Immunostaining of HEV peptide does not necessarily prove acute infection. RNA-FISH seems to be a reliable method to localize HEV.
Topics: Adult; Humans; Child; Hepatitis E; Hepatitis E virus; Ribavirin; Antiviral Agents; Paraffin; RNA, Viral; Kidney; Peptides
PubMed: 38072120
DOI: 10.1016/j.ajt.2023.11.016 -
The Protein Journal Feb 2024Recent clinical data have identified infant patients with lethal ITPA deficiencies. ITPA is known to modulate ITP concentrations in cells and has a critical function in...
Recent clinical data have identified infant patients with lethal ITPA deficiencies. ITPA is known to modulate ITP concentrations in cells and has a critical function in neural development which is not understood. Polymorphism of the ITPA gene affects outcomes for both ribavirin and thiopurine based therapies and nearly one third of the human population is thought to harbor ITPA polymorphism. In a previous site-directed mutagenesis alanine screen of the ITPA substrate selectivity pocket, we identified the ITPA mutant, E22A, as a gain-of function mutant with enhanced ITP hydrolysis activity. Here we report a rational enzyme engineering experiment to investigate the biochemical properties of position 22 ITPA mutants and find that the E22D ITPA has two- and four-fold improved substrate selectivity for ITP over the canonical purine triphosphates ATP and GTP, respectively, while maintaining biological activity. The novel E22D ITPA should be considered as a platform for further development of ITPA therapies.
Topics: Humans; Pyrophosphatases; Inosine Triphosphatase; Polymorphism, Genetic; Genotype
PubMed: 38066288
DOI: 10.1007/s10930-023-10162-0 -
Antimicrobial Agents and Chemotherapy Jan 2024Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme...
Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate (PtdIns (3, 5)P2) and has been implicated in virus trafficking the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study, we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus and . PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, while improving the cell integrity of human nasal air-liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium and mouse , with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus . Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses.
Topics: Humans; Animals; Mice; Influenza, Human; Oseltamivir; Hemorrhagic Fever, Ebola; Antiviral Agents; Nasal Mucosa
PubMed: 38063402
DOI: 10.1128/aac.01050-23 -
PLoS Pathogens Dec 2023Plant viruses seriously disrupt crop growth and development, and classic protein-targeted antiviral drugs could not provide complete protection against them. It is...
Plant viruses seriously disrupt crop growth and development, and classic protein-targeted antiviral drugs could not provide complete protection against them. It is urgent to develop antiviral compounds with novel targets. Photodynamic therapy shows potential in controlling agricultural pests, but nonselective damage from reactive oxygen species (ROS) unexpectedly affects healthy tissues. A G-quadruplex (G4)-forming sequence in the tobacco mosaic virus (TMV) genome was identified to interfere the RNA replication in vitro, and affect the proliferation of TMV in tobacco. N-methyl mesoporphyrin IX stabilizing the G4 structure exhibited inhibition against viral proliferation, which was comparable to the inhibition effect of ribavirin. This indicated that G4 could work as an antiviral target. The large conjugate planes shared by G4 ligands and photosensitizers (PSs) remind us that the PSs could work as antiviral agents by targeting G4 in the genome of TMV. Chlorin e6 (Ce6) was identified to stabilize the G4 structure in the dark and selectively cleave the G4 sequence by producing ROS upon LED-light irradiation, leading to 92.2% inhibition against TMV in vivo, which is higher than that of commercial ningnanmycin. The inhibition of Ce6 was lost against the mutant variants lacking the G4-forming sequence. These findings indicated that the G-quadruplex in the TMV genome worked as an important structural element regulating viral proliferation, and could act as the antiviral target of photodynamic therapy.
Topics: Tobacco Mosaic Virus; Reactive Oxygen Species; Antiviral Agents; Photochemotherapy; Cell Proliferation; Structure-Activity Relationship
PubMed: 38060599
DOI: 10.1371/journal.ppat.1011796