A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection.

Retrospective data showed that when we administered ledipasvir/sofosbuvir (LDV/SOF) to patients with hepatitis B and C coinfection, there was a modest reduction in hepatitis B surface antigen (HBsAg). Therefore, we hypothesize that similar HBsAg reduction can be seen in hepatitis B virus (HBV) monoinfected subjects. Primary and secondary efficacy endpoints are the decline in HBsAg and HBV DNA at Week 12 from baseline, respectively. We conducted an open-label Phase 2 pilot study to evaluate the safety, tolerability, and antiviral activity of LDV and/or SOF for HBV. Eligible subjects were either suppressed on antivirals (Group B) or inactive chronic HBV (Group A, C, D). Group A and B received LDV/SOF. Group C and D received SOF 400 mg and LDV 90 mg, respectively. All subjects completed the study, and all related adverse events (AEs) were mild. No discontinuations due to AEs or hepatitis flare occurred. At Week 12, HBsAg decline (log10 IU/ml) was similar between Group A (0.399) and B (0.400), less in Group C (0.207), and none in Group D, and there was HBV DNA decline in the inactive chronic HBV groups. LDV and SOF are safe and well tolerated when given to chronic hepatitis B subjects and have modest antiviral activity, particularly when given in combination.

Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.

BACKGROUND AND AIMS: Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT. METHODS: Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine. RESULTS: All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT. CONCLUSIONS: Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03118674.

In-depth investigation of the Silymarin effect on the pharmacokinetic parameters of sofosbuvir, GS-331007 and ledipasvir in rat plasma using LC-MS.

The use of complementary medicine (CMD) for liver support in Hepatitis C virus (HCV) patients sometimes coincides with the administration of oral antiviral drugs to eradicate the virus. This calls for a deep investigation of CMD effects on the pharmacokinetic parameters of these drugs to ensure their safety and efficacy. Silymarin (SLY), as a CMD, was selected to be given orally to healthy male rats with sofosbuvir (SFB) and ledipasvir (LED), a common regimen in HCV treatment. A new and sensitive LC-MS method was validated for the bioassay of SLY, LED, SFB and its inactive metabolite, GS-331007, in spiked plasma with lower limits of quantitation of 10, 1, 4 and 10 ng/ml, respectively. Moreover, the method was further applied to conduct a full pharmacokinetic profile of SFB, GS-331007 and ledipasvir with and without SLY. It was found that co-administration of SLY may expose the patient to unplanned high serum concentrations of SFB and LED. This could be accompanied by a decrease in SFB efficacy, potentially leading to therapeutic failure and the emergence of viral resistance.

Ledipasvir/sofosbuvir for HCV genotype 1, 2, 4-6 infection: Real-world evidence from a nationwide registry in Taiwan.

BACKGROUND/PURPOSE: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. METHODS: Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). RESULTS: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P < 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common. CONCLUSION: LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.

The effectiveness and safety of direct-acting antivirals for hepatitis C virus treatment: A single-center experience in Saudi Arabia.

Background: The introduction of direct-acting antivirals (DAA) to treat the hepatitis C virus (HCV) overcame many drawbacks of interferon-based therapy. DAA achieved sustained viral response (SVR) rates above 90% and overcame many drawbacks of pegylated interferon regimens.The HCV genotype (GT) distribution varies by geographical area, with GT-4 being most prevalent in the Middle East region, including Saudi Arabia. Yet, the real-world evidence about using DAAs in the Saudi population is limited.Thus, the aim of this study to investigate the effectiveness and safety of DAAs in Saudi patients with HCV infection. Methods: A retrospective cohort study included patients treated with DAAs from 2015 to 2017 at a tertiary care hospital in Riyadh, Saudi Arabia. All patients with HCV treated with either ledipasvir plus sofosbuvir (LDS/SOF) ± ribavarin (RBV) or ombitasvir-paritaprevir-ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± RBV were included. Using a per-protocol analysis, the effectiveness outcome was the end-of-treatment response (EOTr) and Sustained virologic reponce12 weeks after competing the regimen (SVR12). The secondary safety outcome was the adverse event related to the therapy reported by the patients. Results: A total of 97 patients were included; with the majority infected with GT-4 (64 %), followed by GT-1 (18 %), in addition to 8 % having a mixed GT (1 + 4). The EOTr and SVR12 rates were 98 % and 96 %, respectively. SVR12 was 94.4 % within the LDS/SOF ± RBV group and 97.7 % within the OBV/PTV/r ± DSV ± RBV group. Only 4 % had a response failure due to relapse or breakthrough, and all were infected with mixed GT1 + 4. Medications were well tolerated with minimal side effects, including vomiting, nausea, and weakness. Conclusion: DAAs regimens are associated with high rates of SVR12 and are well tolerated with a good safety profile in Saudi HCV-infected patients.

Proton pump inhibitor usage reduces sustained viral response rates for veterans with HIV/HCV coinfection on ledipasvir/sofosbuvir: a real-world study from a multicentre VA cohort.

Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2 -receptor antagonist [H2 B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2 B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74-0.99, p = .03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26-0.85, p = .01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.

Efficacy and safety of ledipasvir/sofosbuvir for hepatitis C among drug users: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Limited data is available on the efficacy of direct acting anti-viral drugs on hepatitis C in drug users. The aim of this meta-analysis was to comprehensively analyze the efficacy and safety of LDV/SOF in drug users infected with the hepatitis C virus (HCV). METHODS: The PubMed, Cochrane library, Embase and Web of Science databases were searched for articles published till April 2021 on HCV-positive drug users who were treated with ledipasvir/sofosbuvir (LDV/SOF). The primary endpoint was pooled sustained virological response at 12 weeks (SVR12) with 95% confidence interval (95% CI). Funnel plots and Egger's test were used to assess the publication bias. RESULTS: A total of 12 studies and 711 subjects treated with LDV/SOF-based regimen for HCV were included, and the pooled SVR12 rate was 89.8% (95% CI 85.9-92.7). The pooled SVR12 rate of genotype 1 drug users was 92.4% (95% CI 88.6-95.0). Subgroup analysis showed that pooled SVR12 rates of patients treated with LDV/SOF and LDV/SOF ± RBV were 89.2% (95% CI 83.4-93.1), 90.4% (95% CI 83.6-94.5) respectively. In addition, the SVR12 rates were 88% (95% CI 70.7-95.7) for 8 weeks, 89.9% (95% CI 81.0-94.9) for 12 weeks and 82.2% (95% CI 24.9-98.5) for 24 weeks of treatment. CONCLUSION: LDV/SOF is a safe and relatively effective treatment for hepatitis C in drug users.

Treatment of hepatitis C virus infection with direct-acting antiviral agent-based regimens in Iranian patients with hereditary bleeding disorders.

BACKGROUND: Chronic hepatitis C (CHC) is one of the most important comorbidities in patients with hereditary bleeding disorders (HBD). The present study aimed at evaluating the effectiveness of direct-acting antiviral agent (DAA)-based interferon-free HCV antiviral regimens in patients with HBD. PATIENTS AND METHODS: The present study was performed on the patients with HBD and CHC between 2015 and 2019. Sofosbuvir-based interferon-free regimens with or without ribavirin were prescribed to treat HCV infection. The main endpoint of the study was to determine the sustained virologic response (SVR), assessed 12 weeks after the completion of treatment. RESULTS: A total of 147 patients with a mean age of 41.1 years were enrolled in the study; 4.1% of them were co-infected with HIV, 25.2% had cirrhosis, and 76.9% of them were diagnosed with hemophilia A. HCV genotype-1 includes the largest number (68.1%) of patients. 46.3% of patients were treatment-naïve and others had a treatment history with interferon-based regimens. Out of 147 patients, 15 patients were lost to follow-up during treatment or for SVR evaluation or discontinued treatment. 132 subjects completed treatment and were evaluated for SVR, 12 weeks after the completion of treatment. All of the patients achieved SVR 12 (SVR rate: 100%, 95% CI 97.2-100%). CONCLUSION: Hepatitis C DAA-based regimens are the effective treatments for CHC in patients with HBD, regardless of the treatment modifiers such as previous treatment experience, cirrhosis, HIV co-infection, and HCV genotype.

Pharmacokinetic interaction between atorvastatin and fixed-dose combination of sofosbuvir/ledipasvir in healthy male Egyptian volunteers.

PURPOSE: Comorbid conditions of heart and liver disorders added to HCV-induced hepatic steatosis make co-administration of statins, and direct-acting antivirals is common in clinical practice. This study aimed to evaluate the pharmacokinetic interaction of atorvastatin and fixed-dose combination of sofosbuvir/ledipasvir "FDCSL" with rationalization to the underlying mechanism. METHODS: A randomized, three-phase crossover study that involves 12 healthy volunteers was performed. Participants received a single-dose of atorvastatin 80 mg alone, atorvastatin 80-mg plus tablets containing 400/90 mg FDCSL, or tablets containing 400/90 mg FDCSL alone. Plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for atorvastatin, sofosbuvir, ledipasvir, and sofosbuvir metabolite "GS-331007," and their pharmacokinetics parameters were determined. RESULTS: Compared to atorvastatin alone, the administration of FDCSL caused a significant increase in both areas under the concentration-time curve from time zero to infinity (AUC0-∞) and maximum plasma concentration (Cmax) of atorvastatin by 65.5% and 156.0%, respectively. Also, atorvastatin caused a significant increase in the AUC0-∞ and Cmax of sofosbuvir by 32.0% and 11.0%, respectively. Similarly, AUC0-∞ and Cmax of sofosbuvir metabolite significantly increased by 84.0% and 74.0%, respectively. However, ledipasvir AUC0-∞ showed no significant change after atorvastatin intake. The elimination rate in all drugs revealed no significant changes. CONCLUSION: After concurrent administration of FDCSL with atorvastatin, the AUC0-∞ of both atorvastatin and sofosbuvir were increased. Caution should be taken with close monitoring for possible side effects after co-administration of atorvastatin and FDCSL in clinical practice.

Health-related quality of life in patients with chronic hepatitis C treated with sofosbuvir-based treatment at 1-year post-sustained virological response.

PURPOSE: Long-term effects on patient health-related quality of life (HRQoL) after direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) are unknown. We assessed the impact of DAA-mediated HCV clearance on HRQoL from DAA initiation to 1 year after confirmed sustained virological response at 24 weeks post-treatment (SVR24). METHODS: HRQoL was evaluated using the eight-item Short Form Health Survey (SF-8). Chronic HCV-infected patients were treated for 12 weeks with sofosbuvir-based DAAs. SF-8 was administered at baseline, treatment cessation, SVR24, and 1-year post-SVR24. RESULTS: A total of 109 chronic HCV-infected patients were enrolled. The average SF-8 scores were higher than the Japanese national standard values for bodily pain (BP) and mental health at baseline and for general health at 1-year post-SVR24. None of the SF-8 scores differed significantly between baseline and 1-year post-SVR24. Regarding age, sex, liver status, and treatment regimen, the SF-8 scores at 1-year post-SVR24 were affected by only age; individuals aged < 65 years had significantly higher physical component score (PCS), physical functioning, role physical, and BP scores than older individuals. In the multivariable analysis, only age of ≥ 65 years was significantly associated with influencing PCS at 1-year post-SVR24. However, no significant factors were identified for mental component score. CONCLUSION: Upon long-term assessment, although more factors trended higher than national standard values at 1-year post-SVR24 than at baseline, there were no significant changes within factors. As PCS tended to be associated with age, patients aged ≥ 65 years should be carefully monitored for PCS.

Effectiveness and safety of ledipasvir/sofosbuvir for genotype 2 chronic hepatitis C infection: Real-world experience from Taiwan.

BACKGROUND/PURPOSE: Genotype 2 (GT2) hepatitis C virus infection is the second common genotype in Taiwan. Real-world experience of ledipasvir/sofosbuvir (LDV/SOF) for GT2 infection is limited. The aim of this study is to evaluate the effectiveness and safety of LDV/SOF in patients with GT2 chronic hepatitis C (CHC) infection. METHODS: CHC patients with GT2 infection receiving 12 weeks LDV/SOF from three hospitals were enrolled. HCV RNA was checked at baseline, end-of-treatment and 12 weeks after completing treatment. Demographic data, adverse events, renal function and metabolic profiles were recorded. RESULTS: Among 392 enrolled patients, 33 patients (8.4%) were cirrhotic. Sustained virological response (SVR) rate was 96.7% (379/392) by intention-to-treat analysis and 97.2% (379/390) by per-protocol analysis. The SVR rate was lower in cirrhotic patients than in non-cirrhotic patients (90.6% vs 97.8%, p = 0.053). Two cirrhotic patients who took LDV/SOF plus ribavirin both achieved SVR. Neither drug-related severe adverse events nor discontinuation due to drug-related adverse event were reported. The estimated glomerular filtration rate (eGFR) remained stable in patients with chronic kidney disease 3a/3b. CONCLUSION: Twelve weeks of LDV/SOF treatment provided an excellent and safe regimen for GT2 CHC infection, particularly in non-cirrhotic patients.

Assessment of outcome for sample of Iraqi patients with chronic hepatitis C virus infection treated by Ledipasvir/sofosbuvir drug.

OBJECTIVE: To evaluate the response to treatment by the new directly acting antivirals drugs Sofosbuvir and Ledipasvir (Harvoni), on Iraqi patients diagnosed with hepatitis C infection genotype1 and genotype 4. METHODS: This prospective study was conducted in the Gastroenterology unit of Al- Yarmouk Teaching Hospital, Baghdad, Iraq, from February 2019 to February 2020. Included were one hundred patients diagnosed with hepatitis C by antibody test and viral load. All non-cirrhotic participants received a drug containing 400 mg sofosbuvir /90 mg ledipasvir once daily for 12 weeks, whereas the cirrhotics had to take it for 24 weeks. Lab. Investigations and viral load were assessed at baseline, and twelve weeks after end of treatment. RESULTS: The predominant genotype was 1 with 58 (58 %) patients whereas genotype 4 had 42 (42%) patients. Liver cirrhosis was present in 9(9%) patients and severe renal impairment in 27(27%) patients. Undetectable viral load at the end of treatment (week 12) was observed in 96 (96%) patients whereas 4 (4%) patients were reported as non-responders. CONCLUSIONS: Excellent therapeutic results were achieved with generic combination of sofosbuvir/ledipasvir. The regimen is highly effective and tolerable with the highest viral response observed in HCV patients with genotype 1and 4, inclusive of patients with chronic renal failure or cirrhosis.

Safety and Efficacy of 8 Weeks Ledipasvir/Sofosbuvir for Chronic Hepatitis C Genotype 4 in Children Aged 4-10 Years.

OBJECTIVE: To evaluate the safety and efficacy of shortened 8-week regimen of ledipasvir/sofosbuvir (LED/SOF) combination therapy in treatment-naïve children without cirrhosis aged 4-10 years of age with chronic hepatitis C virus (HCV) infection. STUDY DESIGN: This observational single arm prospective study included 30 treatment-naïve children (20 males) with proved chronic HCV fulfilling inclusion criteria. Their body weights ranged from 17 to 26 kg. Four patients were excluded from the study. All the included children received a single oral dose of LED/SOF 45/200 mg for 8 weeks. Body weight, HCV-RNA, complete blood count, and liver function tests were monitored at 0, 2, 4, and 8 weeks and sustained virologic response was evaluated after 12 weeks after treatment (SVR12). The emergence of any side effects was also monitored. RESULTS: The most common risk factor (53.3%) was an parent or sibling with HCV infection. Twenty-nine patients (96.7%) were negative for HCV-RNA by week 2 of treatment and 1 patient became negative by week 4. The end of treatment response and SVR12 were 100%. Transaminases levels declined and returned to normal levels by week 2. Major side effects were fatigue in 90% (27/30) and headache in 76.7% (23/30). Side effects were minimal, tolerable, and did not interfere with daily activity or necessitate treatment discontinuation. CONCLUSIONS: A shortened 8-week regimen of LED/SOF (45/200 mg) is safe and effective with 100% SVR12 in treatment-naïve children with cirrhosis aged 4-10 years with chronic HCV infection genotype 4.

Effects of sofosbuvir/ledipasvir therapy on chronic hepatitis C virus genotype 4, infected children of 3-6 years of age.

BACKGROUND & AIMS: Treatment of children aged 3-6 genotype 4 is still limited by the interferon side effects. We aimed in this study to evaluate the effectiveness and safety of sofosbuvir/ledipasvir in children (3-6 years) genotype 4 chronic HCV-infected patients. METHODS: In total, 22 consecutive chronic HCV-infected patients (mean age 4.8 ± 0.9years, 19 males) were included in this prospective study. All patients received sofosbuvir 200 mg/ledipasvir 45 mg in a single oral daily dose. Patients were randomly subdivided into two groups according the duration of treatment into 8 and 12 weeks. All the clinical and laboratory data were collected. All the side effects were recorded from the patients or their parents. Follow-up were made at Week 4, 8 and 12 and 12 weeks after the end of treatment (SVR12). RESULTS: The overall SVR12 rate was 100%. At Week 4, 9/11 patients in the 12-week group (81.8%; 95% CI: 52.3%-94.7%) achieved virologic negativity, vs 10/11 (90.9%; 95% CI: 62.3%-98.4%) in the 8-week group. At Week 8, 10/11 (90.8%; 95% CI: 62.3%-98.4%) in the 12-week group vs 11/11 (100%; 95% CI: 74.1%-100%) in the 8-week group were virologically negative. The reported side effects were cough, abdominal pain, nausea, vomiting and diarrhoea especially early in the treatment. The main complaint was difficulty in swallowing the tablets in the youngest patient at the beginning of the course of treatment. All patients were compliant to treatment. CONCLUSION: Sofosbuvir/ledipasvir combination is safe and tolerable in the chronic infected HCV genotype 4 infected children (3-6 years). The 8-week treatment duration is similarly effective as the 12-week duration.

Twelve weeks of ledipasvir/sofosbuvir all-oral regimen for patients with chronic hepatitis C genotype 2 infection: Integrated analysis of three clinical trials.

AIM: The combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for the treatment of various hepatitis C virus (HCV) genotypes across many countries. This article presents an integrated analysis of three prospective phase II/III trials in the Asia-Pacific region to evaluate the efficacy and safety of 12 weeks of LDV/SOF in HCV genotype 2 patients without cirrhosis or with compensated cirrhosis. METHODS: A total of 200 patients were included in the integrated analysis. The primary end-point was the rate of sustained virologic response for 12 weeks after the end of therapy (SVR12), analyzed by fibrosis stage, treatment history, HCV genotype subtype, and presence of baseline resistance-associated substitutions (RAS). Safety was evaluated by adverse events and laboratory abnormalities. RESULTS: Twelve weeks of treatment with LDV/SOF was associated with high SVR12 rates (overall 98%) in patients with genotype 2 HCV, irrespective of fibrosis stage, treatment history, genotype 2 subtype, and presence of baseline non-structural protein 5A resistance-associated substitution (NS5A RAS), and LDV/SOF was well tolerated. CONCLUSIONS: Twelve weeks of treatment with LDV/SOF provides a highly effective and safe treatment for patients with genotype 2 HCV, including those with advanced fibrosis. As a ribavirin-free and protease inhibitor-free regimen with minimal on-treatment monitoring requirements, LDV/SOF can potentially play a crucial role in achieving the WHO's goal of HCV elimination.

Ledipasvir and sofosbuvir for 12 weeks for hepatitis C virus genotype 2 infection: A propensity score matched analysis.

AIM: Hepatitis C virus genotype 2 is common in East Asia, sub-Saharan Africa, and Latin America. However, many countries in these areas lag behind other areas of the world in government approval for new direct-acting antivirals. The aim of this study was to evaluate the treatment outcome of ledipasvir/sofosbuvir (LDV/SOF) for patients with chronic hepatitis C virus genotype 2 infection. METHODS: This is a two-part multicenter, real-world cohort study. Study 1 consisted of 58 consecutive patients who were treated with LDV/SOF for 12 weeks. Study 2 used propensity score matching for LDV/SOF (n = 58) and glecaprevir/pibrentasvir (n = 207) treatment groups (1:1) with a set of clinically important variables. Sustained viral response 12 weeks after the end of treatment (SVR12) and adverse events were evaluated in both studies. RESULTS: In study 1, the overall SVR12 rates of the intention-to-treat and modified intention-to-treat populations were 94.8% (55/58) and 96.5% (55/57), respectively. High SVR12 rates were observed in almost all subgroups, including older age, compensated cirrhosis, and treatment experience. In study 2, propensity score matching of the entire study population yielded 52 matched pairs with similar baseline characteristics. There were no statistically significant differences between the LDV/SOF (96.1%) and glecaprevir/pibrentasvir (98.0%) groups in the overall SVR12 rates of the modified intention-to-treat populations, and their rates of treatment discontinuation and adverse events were similar. CONCLUSIONS: Treatment with LDV/SOF for hepatitis C virus genotype 2 resulted in a high rate of SVR12 and excellent tolerability. The outcomes of LDV/SOF were very similar to those of glecaprevir/pibrentasvir.

Real-world effectiveness and safety of ledipasvir/sofosbuvir for genotype 6 chronic hepatitis C patients in Taiwan.

BACKGROUND AND AIM: Infection with hepatitis C virus (HCV) genotype (GT) 6 is uncommon in Taiwan, and reports of ledipasvir/sofosbuvir (LDV/SOF) treatment for GT6 are few. This study evaluates the effectiveness and safety of LDV/SOF in treating chronic hepatitis C (CHC) patients with GT6 infection. METHODS: CHC patients that were infected with GT6 and treated for 12 weeks with LDV/SOF at two hospitals were enrolled. All patients were followed for an additional 12 weeks after the completion of LDV/SOF treatment. Demographics, HCV viral load, lipid and sugar profiles, and adverse events were recorded and reviewed. RESULTS: A total of 127 patients were enrolled. Cirrhosis was found in 68.2% of them. Sustained virological response (SVR), determined by per-protocol analysis, was 97.6%. The SVR rates for cirrhosis versus non-cirrhosis (96.5% vs 100%, P = 0.229) and low versus high viral load (cutoff value: 106  IU/mL; 100% vs 95.6%, P = 0.108) were similar. Following HCV clearance, significantly lower glycosylated hemoglobin was present both in patients with or without diabetes mellitus. Twenty-three (18.1%) patients exhibited adverse events, and each adverse event presented with an incidence of 0.8% to 3.1%. Neuropsychiatric symptoms were the most common. During treatment, 18 patients (14.2%) had alanine aminotransferase elevations consistent with more than grade 1 abnormalities, and none had signs of decompensation. Renal function remained unchanged. CONCLUSION: The high SVR and excellent safety of LDV/SOF treatment for GT6 CHC patients suggest that LDV/SOF is a favorable option for treating GT6 CHC patients in Taiwan and Asia.

Micellar-based spectrofluorimetric method for the selective determination of ledipasvir in the presence of sofosbuvir: application to dosage forms and human plasma.

A fast, low-cost, sensitive, and selective spectrofluorimetric method for the determination of ledipasvir was developed and validated. The method is based on an enhancement in the native fluorescence intensity of ledipasvir by 500% of its original value by the formation of hydrogen bonds between the cited drug and Tween-20 in the micellar system (pH = 5.0). All fluorescence measurements were carried out at 425 nm and 340 nm for emission and excitation wavelengths, respectively. A linear relationship between the concentration of ledipasvir and the observed fluorescence intensity was achieved in the range of 0.1-2.0 µg ml-1 with 0.028, 0.084 µg ml-1 , for detection and quantitation limits, respectively. The acquired selectivity and sensitivity using the proposed method facilitate the analysis of ledipasvir in spiked human plasma with sufficient percentage recovery (95.36-99.30%). The proposed method was developed and validated according to International Council for Harmonisation (ICH) guidelines. Moreover, the cited drug was successfully determined in its pharmaceutical dosage form using the proposed method. In addition, the validity of the proposed results was statistically confirmed using Student's t-test, variance ratio F-test, and interval hypothesis test.

Resistance-associated substitution and ledipasvir/sofosbuvir therapy in Mongolian chronic hepatitis C patients.

BACKGROUND: Mongolia has the highest prevalence of hepatitis C virus (HCV) infection worldwide. Ledipasvir/sofosbuvir (LDV/SOF) was introduced to Mongolia since 2016 for HCV eradication. It has been reported that HCV resistance-associated substitutions (RASs) would affect the effectiveness of LDV/SOF in western chronic hepatitis C (CHC) patients. We thus investigated the effectiveness of LDV/SOF and the impact of RAS on the treatment outcome in Mongolian CHC patients. METHODS: Patients with genotype (GT) 1b HCV infection were prospectively enrolled in Mongolia and treated with LDV/SOF for 12 weeks. The proportion of pre-treatment NS5A Y93H RAS in viral quasispecies was measured with next-generation sequencing. The endpoint of LDV/SOF effectiveness was sustained virological response at post-treatment week 12 (SVR12). RESULTS: A total of 94 CHC patients were evaluated. The baseline Y93H proportion was <1% in 74 patients, 1-15% in 7, 15-50% in 2, and ≥50% in 11. All patients completed 12-week LDV/SOF treatment and the SVR rate was 90.4%. The rate of failure to achieve SVR12 for patients with Y93H < 1%, 1-15%, and ≥15% were 0%, 14.3%, and 61.5%, respectively (p for trend = 0.001). In univariable analysis, older age, baseline alanine transaminase level <40 U/mL, and a higher proportion of Y93H were associated with treatment failure. In multivariable analysis, only a higher proportion of Y93H was associated with treatment failure (p = 0.022). CONCLUSION: LDV/SOF therapy achieves a high SVR rate in Mongolian CHC GT1b patients without baseline Y93H RAS. A higher proportion of Y93H may severely undermine the effectiveness of LDV/SOF.

Validated Reversed-Phase Liquid Chromatographic Method with Gradient Elution for Simultaneous Determination of the Antiviral Agents: Sofosbuvir, Ledipasvir, Daclatasvir, and Simeprevir in Their Dosage Forms.

A simple, rapid, sensitive, and precise reversed-phase liquid chromatographic method was developed and validated for the simultaneous determination of four direct-acting antivirals, sofosbuvir (SF), ledipasvir (LD), declatasvir (DC), and simeprevir (SM), in their respective pharmaceutical formulations. Effective chromatographic separation was achieved on an Agilent Eclipse plus C8 column (250 mm × 4.6 mm, 5 µm) at 40 °C with gradient elution using a mobile phase composed of acetonitrile:phosphate buffer (pH 6.5). The quantification of SF and DC was based on peak area measurements at 260 nm, while the quantification of LD and SM was achieved at 330 nm. The linearity was acceptable from 1.0 to 20.0 µg/mL for the studied drugs, with correlation coefficients >0.999. The analytical performance of the newly proposed HPLC procedure was thoroughly validated according to ICH guidelines in terms of linearity, precision (RSD%, 0.39-1.57), accuracy (98.05-101.90%), specificity, limit of detection (LOD) (0.022-0.039 µg/mL), limit of quantification (LOQ) (0.067-0.118 µg/mL), and robustness. The validated HPLC method was successfully used to analyze the abovementioned drugs in their pure and dosage forms without interference from common excipients present in commercial formulations.