Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with...Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.展开更多
Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV th...Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV therapy.Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy.Furthermore,the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety.In particular,sofosbuvir,a nucleotide-based NS5 B inhibitor,prevents HCV RNA synthesis by acting as a "chain terminator".Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response.The current review summarizes the efficacy and safety of sofosbuvir therapy.展开更多
AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutiv...AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutive Chinese KT patients with HCV infection. They were given sofosbuvir combined with daclatasvir, with or without ribavirin. They were monitored regularly during and after the treatment. RESULTS Six patients were recruited in our prospective study cohort. All patients were male and naive to directacting antiviral treatment. The treatment duration was 12 wk. Most patients(4/6) were infected with HCV genotype 1b. HCV RNA was undetectable at week 4 after treatment and at the end of treatment in all patients. Sustained virological response rate at 12 wk was 100%(6/6). Two patients had to accept a half dose of sofosbuvir due to serum creatinine elevation during treatment. Kidney function in the remaining patients was stable. No serious adverse events(AEs) were observed. No patient discontinued antiviral therapy due to side effects. CONCLUSION Sofosbuvir and daclatasvir for treatment of KT recipients with HCV infection are highly efficient and safe. Patients tolerated the medications well, and no serious AEs were observed. Larger prospective cohort studies are needed to validate these results.展开更多
AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus(HCV)/human immunodeficiency virus(HIV) co-infection in an urban HIV clinic.METHODS A retro...AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus(HCV)/human immunodeficiency virus(HIV) co-infection in an urban HIV clinic.METHODS A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016.All patients included were receiving antiretroviral therapy(ART) with HIV RNA values of 100 copies/m L or fewer regardless of baseline HCV RNA level.The primary end point was a sustained virologic response of HCV at 12 wk(SVR12) after the end of therapy.RESULTS Of the 40 patients enrolled,55% were black,22.5% had been previously treated for HCV,and 25% hadcirrhosis.The patients were on a wide range of ART.Overall,39 patients(97.5%) had a SVR 12 after the end of therapy,including rates of 97.1% in patients with HCV genotype 1 a and 100% in those with HCV genotype 1 b.One patient with HCV genotype 3 a was included and achieved SVR12.Rates of SVR12 were similar regardless of previous treatment or the presence of compensated cirrhosis.Only 1 patient experienced relapse at week 12 following treatment and deep sequencing didn't reveal any resistance associated mutation in the NS5A or NS5B region.Interestingly,7(17.5%) patients who were adherent to ART experienced HIV viral breakthrough which resolved after continuing the same ART regimen.Two(5%) patients experienced HIV-1 virologic rebound due to noncompliance with HIV therapy,which resolved after resuming the same ART regimen.No severe adverse events were observed and no patient discontinued treatment because of adverse events.The most common adverse events included headache(12.5%),fatigue(10%),and diarrhea(2.5%).CONCLUSION This retrospective study demonstrated the high rates of SVR12 of ledipasvir/sofosbuvir on HCV eradication in patients co-infected with HCV and HIV,regardless of HCV baseline levels,HCV treatment history or cirrhosis condition.The oral combination of ledipasvir/sofosbuvir represents a safe and well tolerated HCV treatment option that does not require modification for many of the common HIV ART.Occasional HIV virologic rebound occurred but later resolved without the need to change ART.展开更多
AIM To evaluate sustained viral response(SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus(HCV) patients with RNA < 6 million IU/m L.METHODS We performed a retrospective c...AIM To evaluate sustained viral response(SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus(HCV) patients with RNA < 6 million IU/m L.METHODS We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir(LDV/SOF) therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/m L. Primary outcome was an achievement of SVR at 12 wk after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.RESULTS Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment(imaging, AST, platelet count) and 47% had documented liver fibrosis testing(biopsy, vibration-controlled transient elastography, serum biomarkers). Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR = 1.02, 95%CI: 0.48-2.17, P = 0.962]. The AUROC for hepatitis C RNA viral load was 0.734(P < 0.001, 95%CI: 0.66-0.82). HCV RNA 2.2 million IU/m L was identified as the cutoff value with sensitivity 73% and specificity 64%. HCV RNA < 2.2 million IU/m L was associated with significantly higher SVR 98% with OR = 0.22(95%CI: 0.1-0.49, P < 0.001) compared to SVR 92% in HCV RNA ≥ 2.2 million IU/m L. No death or morbidities were reported.CONCLUSION Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic, untreated HCV genotype 1 patients with HCV RNA < 6 million IU/m L.展开更多
Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited res...Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited response with a number of side effects. Recently, results for phase III trials of ledipasvir and sofosbuvir combination therapy have been announced. In treatmentnave patients, 12 wk of therapy with ledipasvir and sofosbuvir showed a sustained virological response(SVR) rate of 99%. In treatment experienced patients, 12-24 wk of therapy with ledipasvir and sofosbuvir in the absence or presence of ribavirin showed an SVR rate of 94%-99%. In cirrhotic patients the rate of SVR was 86% and 99% for 12 and 24 wk of therapy, respectively. The ledipasvir and sofosbuvir therapy showed very good results in different subgroups of patients regardless of patient's race, alanine aminotransferase levels, sex and host genetic factors. The combination therapy was well tolerated with no emergence of resistant mutants. The most common adverse effects were nausea, headache and fatigue. With the availability of interferon free therapy with minimal adverse effects, it will be easy to decrease the future morbidity and mortality caused by HCV infection.展开更多
Chronic hepatitis C virus(HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipas...Chronic hepatitis C virus(HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipasvir/sofosbuvir with or without concomitant weight-based ribavirin was approved with a very significant increase in the sustained virological response. However, new side effects have been associated. We report the first case of an HCV infected patient treated for 12 wk with the combination of sofosbuvir/ledipasvir plus ribavirin who developed a miliary tuberculosis(TB) infection while on therapy. The patient was a 65-year-old woman, who referred malaise, asthenia, hyporexia, 7 kg weight loss, productive cough, evening fever and night sweats, right after finishing the treatment. The chest computed tomography-scan revealed a superior mediastinal widening secondary to numerous lymphadenopathies with extensive necrosis and bilateral diffuse lung miliary pattern with little subsequent bilateral pleural effusion, highly suggestive of lymph node tuberculosis with lung miliary spread. A bronchoscopy was performed and bronchial suction showed more than 50 acid-alcohol resistant bacillus per line. A Mycobacterium tuberculosis DNA was detected in blood by polymerase chain reaction, which confirmed the diagnosis of miliary tuberculosis. Some cases of TB infection have been identified with α-interferon-based therapy and with the triple therapy of pegylated interferon, ribavirin and boceprevir or telaprevir. However, significant infection has not been reported with sofosbuvir/ledipasvir plus ribavirin.We believe that the case is relevant to increase awareness of opportunistic infections and particularly TB infection. Although the international guidelines offer no recommendation regarding TB screening, we wonder whether it would be advisable to screen for opportunistic infections prior to the introduction of HCV therapy.展开更多
BACKGROUND Direct-acting antiviral(DAA)therapy regimens are highly effective at eliminating hepatitis C virus(HCV)infection but rates of sustained virologic response(SVR)are lower in patients with decompensated cirrho...BACKGROUND Direct-acting antiviral(DAA)therapy regimens are highly effective at eliminating hepatitis C virus(HCV)infection but rates of sustained virologic response(SVR)are lower in patients with decompensated cirrhosis or hepatocellular carcinoma.Since many of these patients will be referred for liver transplant,they will require retreatment after transplantation.Sofosbuvir/velpatasvir/voxilaprevir(SOF/VEL/VOX)is recommended by guidelines as the preferred regimen to treat HCV in DAA-experienced patients following liver transplant however there is limited data.CASE SUMMARY We present the cases of six liver transplant recipients who had previous treatment failure with sofosbuvir-based DAA therapy prior to transplantation and who then received SOF/VEL/VOX after transplant.CONCLUSION This case series demonstrate the real-world efficacy and safety of SOF/VEL/VOX in the post liver transplant setting.Treatment was successful with all patients achieving SVR,it was well tolerated,and there were minimal drug-drug interactions with their immunosuppressants.展开更多
Sofosbuvir is one of the new direct-acting antiviral drugs against hepatitis C virus(HCV) infection. This drug has recently been launched into the market, and generic versions of the medication are expected to be prod...Sofosbuvir is one of the new direct-acting antiviral drugs against hepatitis C virus(HCV) infection. This drug has recently been launched into the market, and generic versions of the medication are expected to be produced by local drug producers in some countries. Therefore, new methods are required to control sofosbuvir in pharmaceuticals. In the present study, a new method based on reversed phase(RP)-ultra-high performance liquid chromatography(UHPLC) coupled to diode array detection(DAD) and mass spectrometry(MS) was developed to facilitate the qualitative and quantitative analysis of sofosbuvir in film coated tablets. A wavelength of 260 nm was selected to perform a cost-effective quantification and the method showed adequate linearity,with an R^2 value of 0.9998, and acceptable values of accuracy(75%–102%) and precision(residual standard deviation < 5%). The detection and quantification limits were 0.07 μg/mL and 0.36 μg/mL, respectively.Furthermore, the use of high-resolution MS enabled us to ensure the specificity, check impurities and better sensitivity. Therefore, this methodology promises to be suitable not only for the routine analysis of sofosbuvir in pharmaceutical dosage forms, but also for potential degradants.展开更多
BACKGROUND The effectiveness of sofosbuvir/ribavirin(SOF/RBV) combination therapy,which is one of the 1 st-choice therapeutic options for patients with hepatitis C virus(HCV) genotype 2(HCV-G2) in Japan according to t...BACKGROUND The effectiveness of sofosbuvir/ribavirin(SOF/RBV) combination therapy,which is one of the 1 st-choice therapeutic options for patients with hepatitis C virus(HCV) genotype 2(HCV-G2) in Japan according to the most recent version of the Japan Society of Hepatology guideline, for patients who experienced failure of the ombitasvir/paritaprevir/ritonavir plus ribavirin(OBV/PTV/r+RBV) combination therapy, which was another option for patients with HCV-G2, is unknown.CASE SUMMARY We evaluated the effects of SOF/RBV combination therapy in two patients with genotype 2 a who could not achieve a sustained virological response(SVR) by OBV/PTV/r+RBV combination therapy. One patient was complicated with VogtKoyanagi-Harada(VKH) disease. Resistance-associated variations before SOF/RBV combination therapy were not detected in two patients. Both patients had an SVR at 12 wk after the treatment(SVR12). Regarding adverse events(AEs), itching, chill, a dull feeling in the throat and cough as well as increase of alanine transaminase level were shown in one patient, while a headache and deterioration of light aversion probably due to the recurrence of VKH disease were shown in the other patients. In addition, the latter patient developed arthralgia and morning stiffness approximately 7 wk after the therapy and turned out to be diagnosed with rheumatoid arthralgia.CONCLUSION SOF/RBV therapy might be effective for patients experiencing failure of OBV/PTV/r+RBV therapy, but caution should be taken regarding the AEs.展开更多
AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir(SOF) and ledipasvir(LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1.METHODS This multicenter, retrospective study consi...AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir(SOF) and ledipasvir(LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1.METHODS This multicenter, retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan. Demographic, clinical, virological, and adverse effects(AE)-related data obtained during and after SOF/LDV therapy were collected from medical records. These patients were divided into two groups, younger(aged < 75 years) and elderly(aged ≥ 75 years). Virological data and AEs were analyzed by age group.RESULTS The sustained virological response(SVR) rates at 12 wk after treatment were 99.2%, 99.4%, and 98.7% in the overall population and in patients aged < 75 and ≥ 75 years, respectively. Common AEs during therapy were headache, pruritus, constipation, and insomnia. These occurred in fewer than 10% of patients, and their incidence was not significantly different between the younger and elderly groups. Two patients discontinued treatment, one due to a skin eruption and the other due to cerebral bleeding. CONCLUSION Compared with younger patients, elderly patients had a similar virological response and tolerance to SOF/LDV therapy.展开更多
Purpose: The aim is evaluation of the efficacy of triple therapy of sofosbuvir, pegylated INFalpha 2a and ribavirin in treatment of chronic hepatitis C (CHC) patients genotype 4 who have high fibrosis. Materials and M...Purpose: The aim is evaluation of the efficacy of triple therapy of sofosbuvir, pegylated INFalpha 2a and ribavirin in treatment of chronic hepatitis C (CHC) patients genotype 4 who have high fibrosis. Materials and Methods: Fifty HCV patients with high fibrosis (F3 & F4) were included in the study. Results: SVR rate was 54%;non-responders rate was 12% and relapsers rate was 34%. When comparing SVR between F3 group patients and F4 group, it was 88% and 66% respectively, which means that SVR was higher in the F3 group. Conclusion: Triple therapy including pegylated INFalpha 2a is not an ideal therapy in treatment of CHC patients genotype 4 with cirrhosis because of low sustained virological response rates and high incidence of side effects.展开更多
AIM To study impact of baseline mental health disease on hepatitis C virus(HCV) treatment; and Beck's Depression Inventory(BDI) changes with sofosbuvir- andinterferon-based therapy.METHODS This is a retrospective ...AIM To study impact of baseline mental health disease on hepatitis C virus(HCV) treatment; and Beck's Depression Inventory(BDI) changes with sofosbuvir- andinterferon-based therapy.METHODS This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and na?ve to HCV therapy. Two of the studies included HCV mono-infected participants only(SPARE, SYNERGY-A), and 3 included human immunodeficiency virus(HIV)/HCV co-infected participants only(ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon(IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease(MHD) were identified(defined as either a DSM Ⅳ diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response(SVR) and adherence(pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher's Exact, and t-test with significance defined as a P value less than 0.05.RESULTS Baseline characteristics did not differ significantly between all participants with and without MHD groups treated with sofosbuvir-based therapy. Among patients treated with sofosbuvir-based therapy, the percentage of patients with MHD who achieved SVR was the same as those without(SPARE: 60.9% of those MHD compared to 67.6% in those without, P = 0.78; SYNERGY-A: 100% of both groups; ERADICATE: 100% compared to 97.1%). There was no statistically significant difference in pill counts, adherence to study visits between groups, nor mean serum concentrations of GS-331007 for each group at week 2 of treatment(P = 0.72). Among patients with HIV co-infection, pre-treatment BDI scores were similar among patients treated with sofosbuvir, and those treated with interferon(sofosbuvir-based 5.24, IFN-based 6.96; P = 0.14); however, a dichotomous effect on was observed during treatment. Among participants treated with directly acting antiviral(DAA)-based therapy, mean BDI scores decreased from 5.24(pre-treatment) to 3.28 during treatment(1.96 decrease, P = 0.0034) and 2.82 post-treatment. The decrease in mean score from pre- to post-treatment was statistically significant(-2.42, P = 0.0012). Among participants treated with IFN-based therapy, mean BDIscore increased from 6.96 at pre-treatment to 9.19 during treatment(an increase of 2.46 points, P = 0.1), and then decreased back to baseline post-treatment(mean BDI score 6.3, P = 0.54). Overall change in mean BDI scores from pre-treatment to during treatment among participants treated with DAA-based and IFN-therapy was statistically significant(-1.96 and +2.23, respectively; P = 0.0032). This change remained statistically significant when analysis was restricted to participants who achieved SVR(-2.0 and +4.36, respectively; P = 0.0004).CONCLUSION Sofosbuvir-based therapy is safe and well tolerated in patients with MHD. A decline in BDI associated with sofosbuvir-based HCV treatment suggests additional MHD benefits, although the duration of these effects is unknown.展开更多
A new stability indicating reverse phase chromatographic method was developed for the analysis of Heptisis C Drug Sofosbuvir. The developed UPLC method was superior in technology to conventional RP-HPLC with respect t...A new stability indicating reverse phase chromatographic method was developed for the analysis of Heptisis C Drug Sofosbuvir. The developed UPLC method was superior in technology to conventional RP-HPLC with respect to resolution, speed, solvent consumption and analysis cost. Sofosbuvir was subjected to the thermal, hydrolytic, oxidative, and photolytic degradation, according to ICH guidelines. The drug depicted degradation in acidic, basic and oxidative conditions and it was stable to other stress conditions (thermal and photolytic). Identified degradation products were isolated using mass supported auto purification system and characterized by NMR techniques (<sup>1</sup>H NMR, D<sub>2</sub>O Exchange, <sup>13</sup>C NMR, <sup>31</sup>P NMR, <sup>19</sup>F NMR, HSQC and HMBC) and HRMS experiments. Isolated acid degradation impurity was showing molecular weight of 416.08, molecular formula C<sub>16</sub>H<sub>18</sub>FN<sub>2</sub>O<sub>8</sub>P and its name as (R)-((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl hydrogen phosphate. Isolated base degradation impurity-A was showing molecular weight of 453.13, molecular formula C<sub>16</sub>H<sub>25</sub>FN<sub>3</sub>O<sub>9</sub>P and its name as (S)-isopropyl 2-((R)-(((2R, 3R, 4R, 5R)-5-(2, 4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorylamino)propanoate. Isolated base degradation impurity-B was showing molecular weight of 411.08, molecular formula C<sub>13</sub>H<sub>19</sub>FN<sub>3</sub>O<sub>9</sub><sub> </sub>P and its name as (S)-2-((R)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methox-y)(hydroxy)phos-phorylamino)propanoic acid. In oxidative degradation study, degradation was observed very less and with obtained quantity (less than 2 mg) recorded <sup>1</sup>H NMR and HRMS analysis. From the spectral data degradation product was showing molecular weight of 527.15, molecular formula C<sub>22</sub>H<sub>27</sub>FN<sub>3</sub>O<sub>9</sub>P and its name as (S)-isopropyl 2-((S)-(((2R, 4S, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-3-oxotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate. The developed chromatographic method was validated as per ICH guidelines and proved suitable for the stability testing and quality control of the drug Sofosbuvir展开更多
BACKGROUND Hepatitis C virus(HCV)is a leading cause of liver cirrhosis and hepatocellular carcinoma globally.Sofosbuvir/velpatasvir(SOF/VEL)is an effective pangenotypic direct-acting antiviral combination for treatmen...BACKGROUND Hepatitis C virus(HCV)is a leading cause of liver cirrhosis and hepatocellular carcinoma globally.Sofosbuvir/velpatasvir(SOF/VEL)is an effective pangenotypic direct-acting antiviral combination for treatment of chronic HCV infection.While the addition of ribavirin(RBV)to SOF/VEL improved sustained virological response(SVR12)in genotype 3(GT3)decompensated cirrhosis patients,the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear.AIM To evaluate the efficacy and safety of SOF/VEL,with or without RBV in GT3 compensated cirrhosis patients.METHODS We searched four electronic databases(PubMed/Medline,Embase,Cochrane Library and Web of Science)from inception up to June 2021 using both free text and MeSH terms.There was no restriction on language,geography,publication dates and publication status(full text or abstracts).All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL,with or without RBV,were included,regardless of age,gender or prior treatment experience.The primary outcome was sustained virological response 12-wk posttreatment(SVR12).The secondary outcome was treatment-related adverse events,as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL.The pooled relative risk(RR),95%CI and heterogeneity(I^(2))were estimated using Review Manager version 5.3.RESULTS From 1752 citations,a total of seven studies(2 randomized controlled trials,5 cohort studies)with 1088 subjects were identified.The SVR12 was similar in GT3 compensated cirrhosis patients,regardless of the use of RBV,for both the intention-to-treat RR 1.03,95%CI:0.99-1.07;I^(2)=0%)and the per-protocol analysis(RR:1.03,95%CI:0.99-1.07;I^(2)=48%).The overall pooled rate of treatment-related adverse events was 7.2%.Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL(RR:4.20,95%CI:1.29-13.68;I^(2)=0%).Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions.However,addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients.CONCLUSION Ribavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL.Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.展开更多
BACKGROUND Although clinical use of sofosbuvir plus ribavirin has been approved for patients infected with genotype 2 hepatitis C virus,patients≥75-years-old have not been included in previous clinical trials.AIM To ...BACKGROUND Although clinical use of sofosbuvir plus ribavirin has been approved for patients infected with genotype 2 hepatitis C virus,patients≥75-years-old have not been included in previous clinical trials.AIM To evaluate the real-world safety and efficacy of sofosbuvir plus ribavirin for elderly patients(≥75-years-old)compared to nonelderly patients,we conducted a post-marketing prospective cohort study.METHODS We treated 265 patients with genotype 2 hepatitis C virus using standard approved doses of sofosbuvir(400 mg/d)plus ribavirin adjusted by body weight,administered orally for 12 wk.RESULTS Sustained virological response rates for the overall cohort,patients<65-years-old,≥65-years-old but<75-years-old,and≥75-years-old were 97%(258/265),98%(93/95),97%(84/87),and 98%(81/83),respectively(P=0.842).Logistic regression analyses identified history of hepatocellular carcinoma treatment and alpha-fetoprotein as factors significantly associated with sustained virological response.Alpha-fetoprotein was the only independent factor identified.Sustained virological response rate was significantly lower for patients with hepatocellular carcinoma treatment(91%)than for patients without history of hepatocellular carcinoma treatment(98%,P=0.004).One patient(0.4%)discontinued treatment due to drug-induced pneumonia.Dose reduction or interruption of ribavirin was required for 12.1%(32/265)of patients because of anemia,including 7.7%(14/182)of patients<75-years-old and 21.7%(18/83)of patients≥75-years-old(P=0.002).CONCLUSION Although ribavirin dose reduction or interruption was required with advanced age,sofosbuvir plus ribavirin appears tolerable and highly effective even in patients≥75-years-old.展开更多
The direct acting antivirals(DAAs)are now the standard of care for hepatitis C virus(HCV)treatment with high and effective sustained virologic responserate(SVR)and great safety profile,including solid organ transplant...The direct acting antivirals(DAAs)are now the standard of care for hepatitis C virus(HCV)treatment with high and effective sustained virologic responserate(SVR)and great safety profile,including solid organ transplant patients.There are increasing reports showing DAAs are effective with high SVR rates and safety profile in kidney transplant recipients.There are reports on drug-drug interaction(DDI)between tacrolimus with DAAs.However,data remain lacking on potential DDIs between tacrolimus and DAA regimens and the management process.This case series reports three kidney transplant patients on tacrolimus who were successfully treated for HCV with multidisciplinary approach,although there was DDI between tacrolimus with sofosbuvir/velpatasvir and glecaprevir/pibrentasvir,which required tacrolimus dose adjustment to maintain therapeutic level during and after DAA treatment.Such DDIs should be aware of and closely monitored by pharmacist and physicians with tacrolimus dose adjustment as needed during and right after DAA treatment in post-kidney transplant patients.展开更多
Glecaprevir/pibrentasvir in combination with sofosbuvir may serve as a safe and effective option for treatment of recurrent hepatitis C virus post-liver transplant in patients who previously failed direct-acting antiv...Glecaprevir/pibrentasvir in combination with sofosbuvir may serve as a safe and effective option for treatment of recurrent hepatitis C virus post-liver transplant in patients who previously failed direct-acting antivirals.展开更多
基金Supported by Grants from the National Key Basic Research Program of China, No. 2009CB522507, No. 2012CB519005Beijing Nova Program of China, No. Z12110702512071
文摘Combination therapy with peginterferon (pegIFN)-α and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-α and RBV than pegIFN-α and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-α and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-α-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies.
文摘Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV therapy.Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy.Furthermore,the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety.In particular,sofosbuvir,a nucleotide-based NS5 B inhibitor,prevents HCV RNA synthesis by acting as a "chain terminator".Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response.The current review summarizes the efficacy and safety of sofosbuvir therapy.
基金Supported by the Project of Science and Technology Development Plan of Jinan City,No.201506004Youth Fund of the Second Hospital of Shandong University,No.Y2014010014
文摘AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutive Chinese KT patients with HCV infection. They were given sofosbuvir combined with daclatasvir, with or without ribavirin. They were monitored regularly during and after the treatment. RESULTS Six patients were recruited in our prospective study cohort. All patients were male and naive to directacting antiviral treatment. The treatment duration was 12 wk. Most patients(4/6) were infected with HCV genotype 1b. HCV RNA was undetectable at week 4 after treatment and at the end of treatment in all patients. Sustained virological response rate at 12 wk was 100%(6/6). Two patients had to accept a half dose of sofosbuvir due to serum creatinine elevation during treatment. Kidney function in the remaining patients was stable. No serious adverse events(AEs) were observed. No patient discontinued antiviral therapy due to side effects. CONCLUSION Sofosbuvir and daclatasvir for treatment of KT recipients with HCV infection are highly efficient and safe. Patients tolerated the medications well, and no serious AEs were observed. Larger prospective cohort studies are needed to validate these results.
文摘AIM To evaluate the safety and efficacy of ledipasvir/sofosbuvir on hepatitis C eradication in patients with hepatitis C virus(HCV)/human immunodeficiency virus(HIV) co-infection in an urban HIV clinic.METHODS A retrospective cohort study of 40 subjects co-infected with HIV-1 and HCV treated with the fixed-dose combination of ledipasvir and sofosbuvir for 12 wk from 2014 to 2016.All patients included were receiving antiretroviral therapy(ART) with HIV RNA values of 100 copies/m L or fewer regardless of baseline HCV RNA level.The primary end point was a sustained virologic response of HCV at 12 wk(SVR12) after the end of therapy.RESULTS Of the 40 patients enrolled,55% were black,22.5% had been previously treated for HCV,and 25% hadcirrhosis.The patients were on a wide range of ART.Overall,39 patients(97.5%) had a SVR 12 after the end of therapy,including rates of 97.1% in patients with HCV genotype 1 a and 100% in those with HCV genotype 1 b.One patient with HCV genotype 3 a was included and achieved SVR12.Rates of SVR12 were similar regardless of previous treatment or the presence of compensated cirrhosis.Only 1 patient experienced relapse at week 12 following treatment and deep sequencing didn't reveal any resistance associated mutation in the NS5A or NS5B region.Interestingly,7(17.5%) patients who were adherent to ART experienced HIV viral breakthrough which resolved after continuing the same ART regimen.Two(5%) patients experienced HIV-1 virologic rebound due to noncompliance with HIV therapy,which resolved after resuming the same ART regimen.No severe adverse events were observed and no patient discontinued treatment because of adverse events.The most common adverse events included headache(12.5%),fatigue(10%),and diarrhea(2.5%).CONCLUSION This retrospective study demonstrated the high rates of SVR12 of ledipasvir/sofosbuvir on HCV eradication in patients co-infected with HCV and HIV,regardless of HCV baseline levels,HCV treatment history or cirrhosis condition.The oral combination of ledipasvir/sofosbuvir represents a safe and well tolerated HCV treatment option that does not require modification for many of the common HIV ART.Occasional HIV virologic rebound occurred but later resolved without the need to change ART.
文摘AIM To evaluate sustained viral response(SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus(HCV) patients with RNA < 6 million IU/m L.METHODS We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir(LDV/SOF) therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/m L. Primary outcome was an achievement of SVR at 12 wk after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.RESULTS Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment(imaging, AST, platelet count) and 47% had documented liver fibrosis testing(biopsy, vibration-controlled transient elastography, serum biomarkers). Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR = 1.02, 95%CI: 0.48-2.17, P = 0.962]. The AUROC for hepatitis C RNA viral load was 0.734(P < 0.001, 95%CI: 0.66-0.82). HCV RNA 2.2 million IU/m L was identified as the cutoff value with sensitivity 73% and specificity 64%. HCV RNA < 2.2 million IU/m L was associated with significantly higher SVR 98% with OR = 0.22(95%CI: 0.1-0.49, P < 0.001) compared to SVR 92% in HCV RNA ≥ 2.2 million IU/m L. No death or morbidities were reported.CONCLUSION Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic, untreated HCV genotype 1 patients with HCV RNA < 6 million IU/m L.
文摘Hepatitis C virus(HCV) has infected more than 200 million people around the globe. From 2001-2011, interferon plus ribavirin remained the standard of care for patients with HCV infection. The therapy had a limited response with a number of side effects. Recently, results for phase III trials of ledipasvir and sofosbuvir combination therapy have been announced. In treatmentnave patients, 12 wk of therapy with ledipasvir and sofosbuvir showed a sustained virological response(SVR) rate of 99%. In treatment experienced patients, 12-24 wk of therapy with ledipasvir and sofosbuvir in the absence or presence of ribavirin showed an SVR rate of 94%-99%. In cirrhotic patients the rate of SVR was 86% and 99% for 12 and 24 wk of therapy, respectively. The ledipasvir and sofosbuvir therapy showed very good results in different subgroups of patients regardless of patient's race, alanine aminotransferase levels, sex and host genetic factors. The combination therapy was well tolerated with no emergence of resistant mutants. The most common adverse effects were nausea, headache and fatigue. With the availability of interferon free therapy with minimal adverse effects, it will be easy to decrease the future morbidity and mortality caused by HCV infection.
文摘Chronic hepatitis C virus(HCV) infection is one of the main causes of chronic liver disease worldwide. In the last 5 years, treatment for HCV infection has experienced a marked development. In 2014, the use of ledipasvir/sofosbuvir with or without concomitant weight-based ribavirin was approved with a very significant increase in the sustained virological response. However, new side effects have been associated. We report the first case of an HCV infected patient treated for 12 wk with the combination of sofosbuvir/ledipasvir plus ribavirin who developed a miliary tuberculosis(TB) infection while on therapy. The patient was a 65-year-old woman, who referred malaise, asthenia, hyporexia, 7 kg weight loss, productive cough, evening fever and night sweats, right after finishing the treatment. The chest computed tomography-scan revealed a superior mediastinal widening secondary to numerous lymphadenopathies with extensive necrosis and bilateral diffuse lung miliary pattern with little subsequent bilateral pleural effusion, highly suggestive of lymph node tuberculosis with lung miliary spread. A bronchoscopy was performed and bronchial suction showed more than 50 acid-alcohol resistant bacillus per line. A Mycobacterium tuberculosis DNA was detected in blood by polymerase chain reaction, which confirmed the diagnosis of miliary tuberculosis. Some cases of TB infection have been identified with α-interferon-based therapy and with the triple therapy of pegylated interferon, ribavirin and boceprevir or telaprevir. However, significant infection has not been reported with sofosbuvir/ledipasvir plus ribavirin.We believe that the case is relevant to increase awareness of opportunistic infections and particularly TB infection. Although the international guidelines offer no recommendation regarding TB screening, we wonder whether it would be advisable to screen for opportunistic infections prior to the introduction of HCV therapy.
文摘BACKGROUND Direct-acting antiviral(DAA)therapy regimens are highly effective at eliminating hepatitis C virus(HCV)infection but rates of sustained virologic response(SVR)are lower in patients with decompensated cirrhosis or hepatocellular carcinoma.Since many of these patients will be referred for liver transplant,they will require retreatment after transplantation.Sofosbuvir/velpatasvir/voxilaprevir(SOF/VEL/VOX)is recommended by guidelines as the preferred regimen to treat HCV in DAA-experienced patients following liver transplant however there is limited data.CASE SUMMARY We present the cases of six liver transplant recipients who had previous treatment failure with sofosbuvir-based DAA therapy prior to transplantation and who then received SOF/VEL/VOX after transplant.CONCLUSION This case series demonstrate the real-world efficacy and safety of SOF/VEL/VOX in the post liver transplant setting.Treatment was successful with all patients achieving SVR,it was well tolerated,and there were minimal drug-drug interactions with their immunosuppressants.
基金the postdoctoral grant associated to the Excellence Project P11-CTS-7625, which was also financed by the previous entity
文摘Sofosbuvir is one of the new direct-acting antiviral drugs against hepatitis C virus(HCV) infection. This drug has recently been launched into the market, and generic versions of the medication are expected to be produced by local drug producers in some countries. Therefore, new methods are required to control sofosbuvir in pharmaceuticals. In the present study, a new method based on reversed phase(RP)-ultra-high performance liquid chromatography(UHPLC) coupled to diode array detection(DAD) and mass spectrometry(MS) was developed to facilitate the qualitative and quantitative analysis of sofosbuvir in film coated tablets. A wavelength of 260 nm was selected to perform a cost-effective quantification and the method showed adequate linearity,with an R^2 value of 0.9998, and acceptable values of accuracy(75%–102%) and precision(residual standard deviation < 5%). The detection and quantification limits were 0.07 μg/mL and 0.36 μg/mL, respectively.Furthermore, the use of high-resolution MS enabled us to ensure the specificity, check impurities and better sensitivity. Therefore, this methodology promises to be suitable not only for the routine analysis of sofosbuvir in pharmaceutical dosage forms, but also for potential degradants.
文摘BACKGROUND The effectiveness of sofosbuvir/ribavirin(SOF/RBV) combination therapy,which is one of the 1 st-choice therapeutic options for patients with hepatitis C virus(HCV) genotype 2(HCV-G2) in Japan according to the most recent version of the Japan Society of Hepatology guideline, for patients who experienced failure of the ombitasvir/paritaprevir/ritonavir plus ribavirin(OBV/PTV/r+RBV) combination therapy, which was another option for patients with HCV-G2, is unknown.CASE SUMMARY We evaluated the effects of SOF/RBV combination therapy in two patients with genotype 2 a who could not achieve a sustained virological response(SVR) by OBV/PTV/r+RBV combination therapy. One patient was complicated with VogtKoyanagi-Harada(VKH) disease. Resistance-associated variations before SOF/RBV combination therapy were not detected in two patients. Both patients had an SVR at 12 wk after the treatment(SVR12). Regarding adverse events(AEs), itching, chill, a dull feeling in the throat and cough as well as increase of alanine transaminase level were shown in one patient, while a headache and deterioration of light aversion probably due to the recurrence of VKH disease were shown in the other patients. In addition, the latter patient developed arthralgia and morning stiffness approximately 7 wk after the therapy and turned out to be diagnosed with rheumatoid arthralgia.CONCLUSION SOF/RBV therapy might be effective for patients experiencing failure of OBV/PTV/r+RBV therapy, but caution should be taken regarding the AEs.
文摘AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir(SOF) and ledipasvir(LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1.METHODS This multicenter, retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan. Demographic, clinical, virological, and adverse effects(AE)-related data obtained during and after SOF/LDV therapy were collected from medical records. These patients were divided into two groups, younger(aged < 75 years) and elderly(aged ≥ 75 years). Virological data and AEs were analyzed by age group.RESULTS The sustained virological response(SVR) rates at 12 wk after treatment were 99.2%, 99.4%, and 98.7% in the overall population and in patients aged < 75 and ≥ 75 years, respectively. Common AEs during therapy were headache, pruritus, constipation, and insomnia. These occurred in fewer than 10% of patients, and their incidence was not significantly different between the younger and elderly groups. Two patients discontinued treatment, one due to a skin eruption and the other due to cerebral bleeding. CONCLUSION Compared with younger patients, elderly patients had a similar virological response and tolerance to SOF/LDV therapy.
文摘Purpose: The aim is evaluation of the efficacy of triple therapy of sofosbuvir, pegylated INFalpha 2a and ribavirin in treatment of chronic hepatitis C (CHC) patients genotype 4 who have high fibrosis. Materials and Methods: Fifty HCV patients with high fibrosis (F3 & F4) were included in the study. Results: SVR rate was 54%;non-responders rate was 12% and relapsers rate was 34%. When comparing SVR between F3 group patients and F4 group, it was 88% and 66% respectively, which means that SVR was higher in the F3 group. Conclusion: Triple therapy including pegylated INFalpha 2a is not an ideal therapy in treatment of CHC patients genotype 4 with cirrhosis because of low sustained virological response rates and high incidence of side effects.
文摘AIM To study impact of baseline mental health disease on hepatitis C virus(HCV) treatment; and Beck's Depression Inventory(BDI) changes with sofosbuvir- andinterferon-based therapy.METHODS This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and na?ve to HCV therapy. Two of the studies included HCV mono-infected participants only(SPARE, SYNERGY-A), and 3 included human immunodeficiency virus(HIV)/HCV co-infected participants only(ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon(IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease(MHD) were identified(defined as either a DSM Ⅳ diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response(SVR) and adherence(pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher's Exact, and t-test with significance defined as a P value less than 0.05.RESULTS Baseline characteristics did not differ significantly between all participants with and without MHD groups treated with sofosbuvir-based therapy. Among patients treated with sofosbuvir-based therapy, the percentage of patients with MHD who achieved SVR was the same as those without(SPARE: 60.9% of those MHD compared to 67.6% in those without, P = 0.78; SYNERGY-A: 100% of both groups; ERADICATE: 100% compared to 97.1%). There was no statistically significant difference in pill counts, adherence to study visits between groups, nor mean serum concentrations of GS-331007 for each group at week 2 of treatment(P = 0.72). Among patients with HIV co-infection, pre-treatment BDI scores were similar among patients treated with sofosbuvir, and those treated with interferon(sofosbuvir-based 5.24, IFN-based 6.96; P = 0.14); however, a dichotomous effect on was observed during treatment. Among participants treated with directly acting antiviral(DAA)-based therapy, mean BDI scores decreased from 5.24(pre-treatment) to 3.28 during treatment(1.96 decrease, P = 0.0034) and 2.82 post-treatment. The decrease in mean score from pre- to post-treatment was statistically significant(-2.42, P = 0.0012). Among participants treated with IFN-based therapy, mean BDIscore increased from 6.96 at pre-treatment to 9.19 during treatment(an increase of 2.46 points, P = 0.1), and then decreased back to baseline post-treatment(mean BDI score 6.3, P = 0.54). Overall change in mean BDI scores from pre-treatment to during treatment among participants treated with DAA-based and IFN-therapy was statistically significant(-1.96 and +2.23, respectively; P = 0.0032). This change remained statistically significant when analysis was restricted to participants who achieved SVR(-2.0 and +4.36, respectively; P = 0.0004).CONCLUSION Sofosbuvir-based therapy is safe and well tolerated in patients with MHD. A decline in BDI associated with sofosbuvir-based HCV treatment suggests additional MHD benefits, although the duration of these effects is unknown.
文摘A new stability indicating reverse phase chromatographic method was developed for the analysis of Heptisis C Drug Sofosbuvir. The developed UPLC method was superior in technology to conventional RP-HPLC with respect to resolution, speed, solvent consumption and analysis cost. Sofosbuvir was subjected to the thermal, hydrolytic, oxidative, and photolytic degradation, according to ICH guidelines. The drug depicted degradation in acidic, basic and oxidative conditions and it was stable to other stress conditions (thermal and photolytic). Identified degradation products were isolated using mass supported auto purification system and characterized by NMR techniques (<sup>1</sup>H NMR, D<sub>2</sub>O Exchange, <sup>13</sup>C NMR, <sup>31</sup>P NMR, <sup>19</sup>F NMR, HSQC and HMBC) and HRMS experiments. Isolated acid degradation impurity was showing molecular weight of 416.08, molecular formula C<sub>16</sub>H<sub>18</sub>FN<sub>2</sub>O<sub>8</sub>P and its name as (R)-((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl hydrogen phosphate. Isolated base degradation impurity-A was showing molecular weight of 453.13, molecular formula C<sub>16</sub>H<sub>25</sub>FN<sub>3</sub>O<sub>9</sub>P and its name as (S)-isopropyl 2-((R)-(((2R, 3R, 4R, 5R)-5-(2, 4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorylamino)propanoate. Isolated base degradation impurity-B was showing molecular weight of 411.08, molecular formula C<sub>13</sub>H<sub>19</sub>FN<sub>3</sub>O<sub>9</sub><sub> </sub>P and its name as (S)-2-((R)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methox-y)(hydroxy)phos-phorylamino)propanoic acid. In oxidative degradation study, degradation was observed very less and with obtained quantity (less than 2 mg) recorded <sup>1</sup>H NMR and HRMS analysis. From the spectral data degradation product was showing molecular weight of 527.15, molecular formula C<sub>22</sub>H<sub>27</sub>FN<sub>3</sub>O<sub>9</sub>P and its name as (S)-isopropyl 2-((S)-(((2R, 4S, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-3-oxotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate. The developed chromatographic method was validated as per ICH guidelines and proved suitable for the stability testing and quality control of the drug Sofosbuvir
基金Supported by the Nurturing Clinician Scientist Scheme(NCCS)award by SingHealth Duke-NUS Academic Medical Centre and National Medical Research Council Singapore.
文摘BACKGROUND Hepatitis C virus(HCV)is a leading cause of liver cirrhosis and hepatocellular carcinoma globally.Sofosbuvir/velpatasvir(SOF/VEL)is an effective pangenotypic direct-acting antiviral combination for treatment of chronic HCV infection.While the addition of ribavirin(RBV)to SOF/VEL improved sustained virological response(SVR12)in genotype 3(GT3)decompensated cirrhosis patients,the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear.AIM To evaluate the efficacy and safety of SOF/VEL,with or without RBV in GT3 compensated cirrhosis patients.METHODS We searched four electronic databases(PubMed/Medline,Embase,Cochrane Library and Web of Science)from inception up to June 2021 using both free text and MeSH terms.There was no restriction on language,geography,publication dates and publication status(full text or abstracts).All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL,with or without RBV,were included,regardless of age,gender or prior treatment experience.The primary outcome was sustained virological response 12-wk posttreatment(SVR12).The secondary outcome was treatment-related adverse events,as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL.The pooled relative risk(RR),95%CI and heterogeneity(I^(2))were estimated using Review Manager version 5.3.RESULTS From 1752 citations,a total of seven studies(2 randomized controlled trials,5 cohort studies)with 1088 subjects were identified.The SVR12 was similar in GT3 compensated cirrhosis patients,regardless of the use of RBV,for both the intention-to-treat RR 1.03,95%CI:0.99-1.07;I^(2)=0%)and the per-protocol analysis(RR:1.03,95%CI:0.99-1.07;I^(2)=48%).The overall pooled rate of treatment-related adverse events was 7.2%.Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL(RR:4.20,95%CI:1.29-13.68;I^(2)=0%).Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions.However,addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients.CONCLUSION Ribavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL.Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.
文摘BACKGROUND Although clinical use of sofosbuvir plus ribavirin has been approved for patients infected with genotype 2 hepatitis C virus,patients≥75-years-old have not been included in previous clinical trials.AIM To evaluate the real-world safety and efficacy of sofosbuvir plus ribavirin for elderly patients(≥75-years-old)compared to nonelderly patients,we conducted a post-marketing prospective cohort study.METHODS We treated 265 patients with genotype 2 hepatitis C virus using standard approved doses of sofosbuvir(400 mg/d)plus ribavirin adjusted by body weight,administered orally for 12 wk.RESULTS Sustained virological response rates for the overall cohort,patients<65-years-old,≥65-years-old but<75-years-old,and≥75-years-old were 97%(258/265),98%(93/95),97%(84/87),and 98%(81/83),respectively(P=0.842).Logistic regression analyses identified history of hepatocellular carcinoma treatment and alpha-fetoprotein as factors significantly associated with sustained virological response.Alpha-fetoprotein was the only independent factor identified.Sustained virological response rate was significantly lower for patients with hepatocellular carcinoma treatment(91%)than for patients without history of hepatocellular carcinoma treatment(98%,P=0.004).One patient(0.4%)discontinued treatment due to drug-induced pneumonia.Dose reduction or interruption of ribavirin was required for 12.1%(32/265)of patients because of anemia,including 7.7%(14/182)of patients<75-years-old and 21.7%(18/83)of patients≥75-years-old(P=0.002).CONCLUSION Although ribavirin dose reduction or interruption was required with advanced age,sofosbuvir plus ribavirin appears tolerable and highly effective even in patients≥75-years-old.
文摘The direct acting antivirals(DAAs)are now the standard of care for hepatitis C virus(HCV)treatment with high and effective sustained virologic responserate(SVR)and great safety profile,including solid organ transplant patients.There are increasing reports showing DAAs are effective with high SVR rates and safety profile in kidney transplant recipients.There are reports on drug-drug interaction(DDI)between tacrolimus with DAAs.However,data remain lacking on potential DDIs between tacrolimus and DAA regimens and the management process.This case series reports three kidney transplant patients on tacrolimus who were successfully treated for HCV with multidisciplinary approach,although there was DDI between tacrolimus with sofosbuvir/velpatasvir and glecaprevir/pibrentasvir,which required tacrolimus dose adjustment to maintain therapeutic level during and after DAA treatment.Such DDIs should be aware of and closely monitored by pharmacist and physicians with tacrolimus dose adjustment as needed during and right after DAA treatment in post-kidney transplant patients.
文摘Glecaprevir/pibrentasvir in combination with sofosbuvir may serve as a safe and effective option for treatment of recurrent hepatitis C virus post-liver transplant in patients who previously failed direct-acting antivirals.
