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Cell Dec 2022Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog,...
Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Ca channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca1.1 and Ca1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Ca channels.
Topics: Sofosbuvir; Amiodarone; Antiviral Agents; Myocytes, Cardiac; Binding Sites; Calcium Channels, L-Type; Calcium
PubMed: 36417914
DOI: 10.1016/j.cell.2022.10.024 -
The Lancet. Gastroenterology &... Mar 2018Despite revised guidelines that no longer exclude people who inject drugs (PWID) from treatment for hepatitis C virus (HCV) infection, many clinicians are reluctant to...
BACKGROUND
Despite revised guidelines that no longer exclude people who inject drugs (PWID) from treatment for hepatitis C virus (HCV) infection, many clinicians are reluctant to treat recent PWID. This study aimed to evaluate the efficacy of sofosbuvir and velpatasvir therapy in people with chronic HCV infection and recent injection drug use.
METHODS
In this open-label, single-arm phase 4 trial (SIMPLIFY), we recruited participants with recent injection drug use (past 6 months) and chronic HCV genotype 1-6 infection from seven countries (19 sites). Participants received oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. Therapy was given in 1-week electronic blister packs to record the time and date of each dose. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after completion of treatment (SVR12; defined as HCV RNA <12 IU/mL), analysed in all patients who received at least one dose. This study is registered with ClinicalTrials.gov, number NCT02336139, and follow-up is ongoing to evaluate the secondary endpoint of HCV reinfection.
FINDINGS
Between March 29, and Oct 31, 2016, we enrolled 103 participants; 29 (28%) of whom were female, nine (9%) had cirrhosis, 36 (35%) had HCV genotype 1, five (5%) had genotype 2, 60 (58%) had genotype 3, and two (2%) had genotype 4. 61 (59%) participants were receiving opioid substitution therapy during the study, 76 (74%) injected in the past month, and 27 (26%) injected at least daily in the past month. 100 (97%) of 103 participants completed treatment; two people were lost to follow-up and one person died from an overdose. There were no virological failures. 97 (94%, 95% CI 88-98) of 103 people achieved SVR12. Three participants with an end-of-treatment response did not have a SVR; two were lost to follow-up and one had reinfection. Drug use before and during treatment did not affect SVR12. Treatment-related adverse events were seen in 48 (47%) patients (one grade 3, no grade 4). Seven (7%) patients had at least one serious adverse event; only one such event (rhabdomyolysis, resolved) was possibly related to the therapy. One case of HCV reinfection was observed.
INTERPRETATION
HCV treatment should be offered to PWID, irrespective of ongoing drug use. Recent injection drug use should not be used as a reason to withhold reimbursement of HCV therapy.
FUNDING
Gilead Sciences.
Topics: Administration, Oral; Adult; Antiviral Agents; Carbamates; Drug Administration Schedule; Drug Packaging; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Medication Adherence; Middle Aged; Recurrence; Risk Factors; Sofosbuvir; Substance Abuse, Intravenous; Sustained Virologic Response
PubMed: 29310928
DOI: 10.1016/S2468-1253(17)30404-1 -
The Lancet. Gastroenterology &... Apr 2022Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus...
BACKGROUND
Despite widespread availability of direct-acting antivirals including generic formulations, limited progress has been made in the global adoption of hepatitis C virus (HCV) treatment. Barriers to treatment scale-up include availability and access to diagnostic and monitoring tests, health-care infrastructure, and requirement for frequent visits during treatment.
METHODS
ACTG A5360 was a phase 4, open-label, single-arm trial across 38 sites in Brazil, South Africa, Thailand, Uganda, and the USA. Key inclusion criteria were age of 18 years or older, evidence of active HCV infection (HCV RNA >1000 IU/mL) and HCV treatment-naive; patients with compensated cirrhosis and HIV/HCV co-infection were included but their enrolment was capped. All participants received a fixed dose combination of oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. The minimal monitoring (MINMON) approach consisted of four components: (1) there was no pre-treatment genotyping; (2) the entire treatment course (84 tablets) was dispensed at entry; (3) there were no scheduled visits or laboratory monitoring; and (4) there were two points of remote contact, at week 4 for adherence and week 22, to schedule outcome assessment at week 24 (-2 weeks to +4 weeks). Participants who missed the week 24 window could return for a visit to assess treatment response any time before week 72. Unplanned visits for any reason were permissible before the week 24 visit. The primary efficacy outcome was sustained virological response (SVR), defined as HCV RNA less than the lower limit of quantification measured at least 22 weeks post-treatment initiation; the primary safety outcome was serious adverse events. The primary efficacy analysis included all participants who initiated treatment, using a missing=failure approach. The primary safety analysis included all participants who initiated treatment and had at least one post-treatment assessment. This trial is registered at ClinicalTrials.gov, NCT03512210.
FINDINGS
Between Oct 22, 2018, and July 19, 2019, 400 participants were enrolled across all 38 sites; 399 initiated treatment. At the SVR assessment visit, 355 (89%) of 397 participants reported taking 100% of the trial medication during the 12-week treatment period; two patients did not have any follow-up visits after the entry visit and were excluded from the safety analyses. Overall, 379 of the 399 who initiated treatment had an SVR (95·0%, 95% CI 92·4-96·7). 14 (4%) of 397 participants reported serious adverse events between treatment initiation and week 28; none were treatment related or led to treatment discontinuation or death. 15 (4%) of 399 participants had unplanned visits; none were related to treatment.
INTERPRETATION
In this diverse global population of people with HCV, the MINMON approach with sofosbuvir-velpatasvir treatment was safe and achieved SVR comparable to standard monitoring observed in real-world data. Coupled with innovative case finding strategies, this strategy could be crucial to the global HCV elimination agenda.
FUNDING
US National Institutes of Health and Gilead Sciences.
Topics: Adolescent; Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; RNA; Sofosbuvir; Treatment Outcome; United States
PubMed: 35026142
DOI: 10.1016/S2468-1253(21)00397-6 -
British Journal of Clinical Pharmacology Sep 2016
Topics: Antiviral Agents; Carbamates; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Pyrrolidines; Sofosbuvir; Valine
PubMed: 27198488
DOI: 10.1111/bcp.13011 -
The Korean Journal of Internal Medicine Jul 2023
Topics: Humans; Sofosbuvir; Lactams, Macrocyclic; Hepatitis C; Antiviral Agents; Hepatitis C, Chronic; Hepacivirus; Genotype; Treatment Outcome; Drug Therapy, Combination
PubMed: 37424499
DOI: 10.3904/kjim.2023.248 -
The Korean Journal of Internal Medicine Jul 2023Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be...
BACKGROUND/AIMS
Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in HCV-infected Korean adults.
METHODS
This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir-velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment.
RESULTS
Of 53 participants receiving sofosbuvir-velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir-velpatasvir-voxilaprevir achieved SVR 12. Overall, sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported.
CONCLUSION
Treatment with sofosbuvir-velpatasvir or sofosbuvir-velpatasvir-voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.
Topics: Adult; Humans; Sofosbuvir; Antiviral Agents; Hepatitis C, Chronic; Hepatitis C; Hepacivirus; Drug Therapy, Combination; Republic of Korea; Genotype; Treatment Outcome
PubMed: 37424500
DOI: 10.3904/kjim.2022.252 -
Expert Opinion on Pharmacotherapy 2016Hepatitis C virus (HCV) is a chronic infection that disproportionately impacts people living with HIV. In the past, HCV therapy was less effective in individuals with... (Review)
Review
INTRODUCTION
Hepatitis C virus (HCV) is a chronic infection that disproportionately impacts people living with HIV. In the past, HCV therapy was less effective in individuals with HIV co-infection. However, the advent of direct-acting antivirals has revolutionized HCV treatment with high rates of success in patients both with and without HIV.
AREAS COVERED
In this paper, we review the evidence supporting the use of ledipasvir and sofosbuvir (LDV/SOF) for the treatment of HCV in patients with HIV co-infection. Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of LDV/SOF in individuals with HCV and HIV co-infection.
EXPERT OPINION
This treatment is highly effective in achieving HCV cure or sustained virologic response, however further studies need to done to address efficacy of treatment in people with uncontrolled HIV, concerns regarding drug-interactions with antiretroviral therapy, and potential for shorter duration treatment.
Topics: Antiviral Agents; Benzimidazoles; Coinfection; Drug Interactions; Drug Resistance, Viral; Drug Therapy, Combination; Fluorenes; HIV Infections; Hepatitis C, Chronic; Humans; Sofosbuvir
PubMed: 26898158
DOI: 10.1517/14656566.2016.1157580 -
Medicine Oct 2022The sofosbuvir-velpatasvir single-tablet regimen (Epclusa) is a newly FDA-approved inhibitor of hepatitis C virus (HCV). This meta-analysis aimed to investigate the... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The sofosbuvir-velpatasvir single-tablet regimen (Epclusa) is a newly FDA-approved inhibitor of hepatitis C virus (HCV). This meta-analysis aimed to investigate the safety and efficacy of velpatasvir-sofosbuvir in the treatment of chronic HCV infection.
METHODS
A comprehensive literature search of PubMed, Cochrane CENTRAL, EMBASE and Web of Science was conducted. Data from eligible studies were pooled in a fixed-effect meta-analysis model, using Open-Meta and RevMan software's.
RESULTS
Pooled data showed that velpatasvir-sofosbuvir achieved sustained virological response (SVR12) rates of 94.2% (95% CI 90.7-97.7%, P < .001) in 1277 patients. The addition of ribavirin did not significantly increase the SVR12 (RR = 1.03, 95%CI [0.95, 1.11]) in HCV genotype-1 patients and the SVR12 (RR = 1.09, 95%CI [0.86, 1.38]) in HCV genotype-2 patients. However, adding ribavirin significantly increased SVR12 (RR = 1.13, 95% CI [1.04, 1.23]) in genotype-3 patients.
CONCLUSION
In conclusion, the 12-week regimen of sofosbuvir-velpatasvir was highly effective in HCV patients. Except for genotype-3, adding ribavirin was not associated with significant improvements in SVR12 rates.
Topics: Humans; Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Ribavirin; Sofosbuvir; Treatment Outcome
PubMed: 36281168
DOI: 10.1097/MD.0000000000031183 -
Journal of the Formosan Medical... Nov 2022Hepatitis C virus (HCV) genotype 6 mainly distributes in Southeast Asia and South China. Because of the low prevalence in developed countries, optimal treatment for HCV...
BACKGROUND
Hepatitis C virus (HCV) genotype 6 mainly distributes in Southeast Asia and South China. Because of the low prevalence in developed countries, optimal treatment for HCV genotype 6 in real-world setting remains to be determined. We aimed to evaluate the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV genotype 6 infection in Taiwan.
METHODS
A total of 286 patients with chronic hepatitis C (CHC) genotype 6, 161 receiving 12-week SOF/VEL and 125 receiving 8-week GLE/PIB, were enrolled. All patients were followed up for 12 weeks after treatment completion. Demographic information, HCV viral load (VL), profiles of lipid and sugar, and adverse events were recorded and reviewed.
RESULTS
Sustained virological response (SVR) rates of SOF/VEL and GLE/PIB evaluated by intention-to-treat analysis were 99.38% and 100%, respectively. SVR achieved 100%, regardless of cirrhosis or viral load (cutoff: 6 MIU/mL), of both regimens by per-protocol analysis. Skin itching was the most common adverse event, with an overall incidence of 6.64% which was more prevalent in GLE/PIB (12.0%) than SOF/VEL (2.48%). A significant decrease in the estimated glomerular filtration rate was observed in patients receiving SOF/VEL but not in those receiving GLE/PIB at the time of SVR. No patient discontinued treatment due to adverse event.
CONCLUSION
The high SVR and excellent safety of SOF/VEL and GLE/PIB in real-world setting reveals that the two DAA regimens are favorable options for treatment of HCV genotype 6 in Taiwan and Asia.
Topics: Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Benzopyrans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Lipids; Proline; Pyrrolidines; Quinoxalines; Sofosbuvir; Sugars; Sulfonamides; Treatment Outcome
PubMed: 35581112
DOI: 10.1016/j.jfma.2022.04.020 -
Scientific Reports Jun 2022Worsened lipid profiles were observed in chronic hepatitis C (CHC) patients during direct-acting antivirals (DAAs) treatment, among which combination drugs confounded...
Worsened lipid profiles were observed in chronic hepatitis C (CHC) patients during direct-acting antivirals (DAAs) treatment, among which combination drugs confounded the effect of individual ingredient on lipid. Tenofovir alafenamide (TAF) also worsened lipid profiles in HIV patients. Structural similarity between sofosbuvir (SOF) and TAF prompted us to investigate rapid increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in CHC patients treated with SOF-based DAAs. A retrospective study was performed to analyze 487 CHC patients receiving DAAs with SVR12. Relative risks on elevating TC and LDL-C were analyzed by logistic regression to determine SOF-based over non-SOF-based regimens. TC or LDL-C levels at baseline, week-4 and SVR12 were compared by Wilcoxon matched-pairs signed rank test. Week 4 or SVR12 to baseline ratios of serum TC or LDL-C between regimens were compared by Mann-Whitney's test. 487 patients were treated with Harvoni (SOF-based, 206 patients), Epclusa (SOF-based, 124 patients), Maviret (non-SOF-based, 122 patients), or Zepatier (non-SOF-based, 35 patients). At week 4 during drug treatment, Harvoni, Epclusa, and Maviret induced statistically significant elevation of TC and LDL-C, but Zepatier did not. SOF-based regimens had 2.72-fold higher relative risk (RR) causing 10% elevation of TC (95% CI 1.84-4.02, p < 0.001) and 2.04-fold higher RR causing 10% elevation of LDL-C (95% CI 1.39-3.01, p < 0.001) than non-SOF-based DAAs. SOF-based DAAs were associated with significantly larger amplitude of increases in TC and LDL-C than non-SOF-based DAAs during the initial 4 weeks of treatment, but the increases were not sustained to SVR12.
Topics: Antiviral Agents; Cholesterol; Cholesterol, LDL; Drug Therapy, Combination; Genotype; HIV Infections; Hepacivirus; Hepatitis C, Chronic; Humans; Retrospective Studies; Ribavirin; Sofosbuvir; Treatment Outcome
PubMed: 35705594
DOI: 10.1038/s41598-022-13657-5