gs-5816 and Hepatitis-C

The combination of Sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) is an effective, safe rescue therapy for patients with previous treatment failure. Direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection in diabetics with a history of hypoglycemia could improve insulin resistance due to HCV clearance. However, some studies have shown that SOF/VEL/VOX causes grade 3 hyperglycemia and other adverse events, which contradicts the findings of other DAA studies.. To analyze the incidence of grade 3 hyperglycemia of SOF/VEL/VOX for chronic HCV infection.. We searched electronic databases from the inception of each database until October 2021. A random-effects model was employed to pool data. The study was conducted according to the PRISMA guidelines, and quality assessment was performed by using the Cochrane risk-of-bias tool for randomized controlled trials (RCTs). The study protocol was registered on the INPLASY database (Registration No. 2021120109).. Five RCTs were included in this review. Overall, 49 of 2315 patients had grade 3 hyperglycemia with a risk ratio of 0.015 (95% confidence interval, 0.010-0.020;. Although the incidence of hyperglycemia was rare in diabetic patients with HCV, it is recommended that glucose levels be closely monitored during the first 3 months of therapy and that diabetes medication be modified if necessary.

Topics: Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Hyperglycemia; Randomized Controlled Trials as Topic; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Neoplasms; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

The sofosbuvir-velpatasvir single-tablet regimen (Epclusa) is a newly FDA-approved inhibitor of hepatitis C virus (HCV). This meta-analysis aimed to investigate the safety and efficacy of velpatasvir-sofosbuvir in the treatment of chronic HCV infection.. A comprehensive literature search of PubMed, Cochrane CENTRAL, EMBASE and Web of Science was conducted. Data from eligible studies were pooled in a fixed-effect meta-analysis model, using Open-Meta and RevMan software's.. Pooled data showed that velpatasvir-sofosbuvir achieved sustained virological response (SVR12) rates of 94.2% (95% CI 90.7-97.7%, P < .001) in 1277 patients. The addition of ribavirin did not significantly increase the SVR12 (RR = 1.03, 95%CI [0.95, 1.11]) in HCV genotype-1 patients and the SVR12 (RR = 1.09, 95%CI [0.86, 1.38]) in HCV genotype-2 patients. However, adding ribavirin significantly increased SVR12 (RR = 1.13, 95% CI [1.04, 1.23]) in genotype-3 patients.. In conclusion, the 12-week regimen of sofosbuvir-velpatasvir was highly effective in HCV patients. Except for genotype-3, adding ribavirin was not associated with significant improvements in SVR12 rates.

Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Humans; Ribavirin; Sofosbuvir; Treatment Outcome

Hepatitis C virus (HCV) affects approx. 3% of the world's population and accounts for ca 300 000 deaths per year. 80% of individuals with HCV develop chronic symptoms which, when untreated, may cause cirrhosis (27%) or hepatocellular carcinoma (25%). The hepatitis C virus is a (+)ssRNA enveloped virus of the family Flaviviridae. Seven major HCV genotypes and their subtypes (a, b) have been identified. In the 1990s, interferons alpha-2 were used in the treatment of HCV and in the next decade HCV therapy was based on pegylated interferon alpha-2 in combination with ribavirin. Since 2011, interferons alpha, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, NS5B RNA polymerase inhibitors have been approved for clinical use. Monotherapy is avoided in medication due to rapidly developing viral resistance. A total of 113 papers were included comprising original publications and reviews. The paper reviews the molecular targets and chemical structures of drugs used in HCV treatment. Indications and contraindications for anti-HCV drugs are also discussed together with application regimens.

Topics: Animals; Antiviral Agents; DNA-Directed RNA Polymerases; Enzyme Inhibitors; Hepatitis C; Humans; Molecular Structure; Molecular Targeted Therapy; Protease Inhibitors

Treatment for hepatitis C has escalated rapidly since the advent of direct-acting antivirals. Although there are highly efficacious, pangenotypic regimens available as standard of care, 5-10% of patients do not achieve virological cure. The recently approved fixed-dose combination of sofosbuvir, velpatasvir and voxilaprevir provides an option for retreatment in patients who have failed prior regimens and have characteristics which make them difficult to treat. This review provides a summary of the evidence for use of Vosevi

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Sofosbuvir; Sulfonamides

Despite the high efficacy of direct acting antivirals (DAAs) not all patients successfully clear hepatitis C virus infection, in fact, approximately 1-3% fail to reach a sustained virological response 12 weeks after end of treatment. DAA failures are characterized by advanced liver disease, specific genotypes/subtypes and resistance associated substitutions to the DAA class they have been treated with. Current European Association for the Study of the Liver guidelines recommend three therapeutic options for such patients. The first is a 12 week course of sofosbuvir (SOF), velpatasvir (VEL) and voxilaprevir (VOX), which has shown to be effective in 90-99% of patients and was granted A1 level recommendation. The second option, reserved for patients who have predictors of failure consists in 12 weeks regimen with glecaprevir (GLE) and pibrentasvir (PIB), effective in 90-97%. Finally, although not supported by published data, for especially difficult to treat patients there should theoretically be a benefit in prolonged combinations of SOF+GLE/PIB or SOF/VEL/VOX±ribavirin. This review presents the latest evidence from both clinical trials and real-life on such therapeutic strategies.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Macrocyclic Compounds; Proline; Quinoxalines; Randomized Controlled Trials as Topic; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Failure

To review the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C virus (HCV) infection.. A literature search through PubMed was conducted (August 2010 to August 2017) using the terms GS-9857, voxilaprevir, and NS3/4A protease inhibitor.. Studies of sofosbuvir/velpatasvir/voxilaprevir were identified.. Sofosbuvir/velpatasvir/voxilaprevir is indicated for adult patients with chronic HCV without cirrhosis or with compensated cirrhosis who have (1) genotype 1 through 6 and have previously been treated with an NS5A inhibitor or (2) genotype 1a or 3 and have previously been treated with sofosbuvir without an NS5A inhibitor. POLARIS-1 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 12 weeks was highly effective in patients with HCV genotype 1 through 6 who had prior exposure to an NS5A inhibitor. POLARIS-2 failed to demonstrate that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was noninferior to sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 6 who had no prior exposure to direct-acting antivirals (DAAs). POLARIS-3 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 and compensated cirrhosis who had no prior exposure to DAAs. POLARIS-4 demonstrated that sofosbuvir/velpatasvir/voxilaprevir was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 3 who had prior exposure to DAAs but not an NS5A inhibitor. The most common adverse reactions were headache, fatigue, diarrhea, and nausea.. Sofosbuvir/velpatasvir/voxilaprevir is safe and effective to treat HCV in patients who have previously been treated with DAAs.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Sofosbuvir; Sulfonamides

Direct acting antivirals (DAA's) have revolutionized the treatment of hepatitis C (HCV). However, questions persist concerning their efficacy in minority populations.. In this review, the authors review outcomes for treatment of HCV by race and ethnicity among the clinical trials that have led to the current recommended treatments for HCV. The authors highlight the efficacy and safety differences by race and ethnicity. They also highlight deficiencies within the literature including small populations of racial/ethnic minorities within HCV clinical trials. DAA's can achieve cure rates for HCV over 95% with the use of once daily medications that have minimal side effects and few significant drug-drug interactions. Regimens with high pan-genotypic efficacy have further simplified treatment paradigms. The purpose of this review is to describe the data on DAA's in treating HCV in racial/ethnic populations.. While the overall data in racial/ethnic minority populations is sparse, DAA's appear to have high efficacy in curing HCV in diverse racial/ethnic populations. Although achieving high sustained virologic response (SVR) rates, there are also data that suggests that some disparities in SVR persist, especially when considering shorter regimens for HCV treatment in racial/ethnic populations.

Topics: Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles

Hepatitis C virus (HCV) is a significant public health burden worldwide, owing in large part to ineffective and poorly tolerated treatments. The antivirals have evolved over time to become more effective and better tolerated with cure rates increasing from an average of 50% to a complete virologic response. This article summarizes the latest Food and Drug Administration (FDA)-approved addition to combination treatment for patients with HCV, voxilaprevir plus sofosbuvir/velpatasvir.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Sofosbuvir; Sulfonamides; Treatment Outcome

The fixed-dose combination of three direct-acting antivirals (DAA), namely sofosbuvir, velpatasvir and voxilaprevir is the first pangenotypic, single tablet regimen developed for the treatment of HCV infection. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy and safety of the co-formulation are reviewed. Information on drug absorption, distribution, metabolism and excretion of each of the three antivirals is evaluated. Finally, antiviral activity, safety and potential for drug interactions in phase II/III clinical trials in distinct patient populations are discussed. Expert opinion: The triple co-formulation of sofosbuvir-velpatasvir-voxilaprevir represents a major step towards HCV eradication. It depicts high efficacy even in patients infected with viruses harboring resistance-associated substitutions (RAS), including those selected after DAA failures. Likewise, very high success rates and good tolerance are seen in special patient populations, including decompensated cirrhotics, HIV coinfection, organ transplantation or renal insufficiency. A pill once daily for 8 weeks gives SVR rates above 95%. In prior DAA failures, extending treatment to 12 weeks maximizes SVR rates.

Topics: Aminoisobutyric Acids; Animals; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Interactions; Drug Resistance, Viral; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Sofosbuvir; Sulfonamides; Tablets; Treatment Outcome

To review the pharmacology, efficacy, and safety of sofosbuvir/velpatasvir in the treatment of patients with hepatitis C virus (HCV) infection.. A literature search through PubMed was conducted (June 2008 to August 2016) using the terms GS-5816, velpatasvir, and sofosbuvir. References from retrieved articles and the prescribing information were reviewed for any additional material.. The literature search was limited to human studies published in English. Phase I, II, and III studies of sofosbuvir/velpatasvir for HCV were identified.. Sofosbuvir/velpatasvir is safe and effective to treat HCV genotypes 1, 2, 3, 4, 5, and 6 in patients with or without compensated cirrhosis. The addition of ribavirin is recommended in patients with decompensated cirrhosis.

Topics: Adult; Antiviral Agents; Carbamates; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Sofosbuvir; Treatment Outcome

Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for "difficult-to-treat" HCV-infected patients. "First generation" HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. "Second generation" NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.

Topics: Animals; Carbamates; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Mutation; Pyrrolidines; Valine; Viral Nonstructural Proteins

Mathematical models explain how antivirals control viral infections. Hepatitis C virus (HCV) treatment results in at least 2 phases of decline in viremia. The first phase reflects clearance of rapidly produced virions. The second phase is hypothesized to derive from loss of infected cells but has been challenging to prove.. Using single-cell methods, we quantified the number of hepatitis C virus (HCV)-infected hepatocytes in liver biopsies taken before and within 7 days of initiating direct-acting antivirals (DAAs) in a double-blinded randomized controlled trial testing 2 (sofosbuvir-velpatasvir) versus 3 (sofosbuvir-velpatasvir-voxilaprevir) DAAs.. We employed thousands of intrahepatic measurements in 10 persons with chronic genotype 1a HCV infection: median proportion of infected hepatocytes declined from 11.3% (range, 1.3%-59%) to 0.6% (range, <0.3%-5.8%), a loss of 75%-95% infected hepatocytes. Plasma viremia correlated with numbers of HCV-infected hepatocytes (r = 0.77; P < .0001). Second-phase plasma dynamics and changes in infected hepatocytes were indistinct (P = .16), demonstrating that second-phase viral dynamics derive from loss of infected cells. DAAs led to a decline in intracellular HCV RNA and interferon-stimulated gene expression (P < .05 for both).. We proved that second-phase viral dynamics reflect decay of intrahepatic burden of HCV, partly due to clearance of HCV RNA from hepatocytes.. NCT02938013.

Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Kinetics; Lactams, Macrocyclic; RNA, Viral; Sofosbuvir; Viremia

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.

Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Sofosbuvir; Treatment Outcome

The combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is recommended for the retreatment of patients with HCV infection in whom previous direct-acting antiviral (DAA) treatment failed. However, whether ribavirin further increases the therapeutic efficacy of SOF/VEL/VOX retreatment remains unclear. We aimed to test this hypothesis in a randomized-controlled trial.. We randomly assigned 315 patients with DAA treatment failure from five Egyptian sites into two groups. Group A (n = 158) received SOF/VEL/VOX for 12 weeks, and group B (n = 157) received SOF/VEL/VOX + weight-based ribavirin for 12 weeks. Therapeutic efficacy was defined as SVR12 (sustained virologic response 12 weeks after treatment end). Safety and tolerability were evaluated by monitoring treatment-related adverse events (AEs) and laboratory abnormalities.. Males comprised 53.9% of group A and 57.1% of group B (p = 0.58); mean ages were 51.8 and 47.3 years in group A and B, respectively. Seventeen patients in each group were lost to follow-up. SVR12 rates were 87.3% (138/158) by intention-to-treat analysis and 97.8% (138/141) by per-protocol analysis in group A; and 87.9% (138/157) and 98.5% (138/140), respectively, in group B (p = n.s. for intention-to-treat and per-protocol analyses). Both regimens were well-tolerated, with no deaths and only one serious AE (anemia) in group B, which required ribavirin discontinuation. Fifty-five patients in group A vs. 77 in group B experienced any AE (p = 0.002).. This randomized-controlled trial showed equal, high efficacy of both regimens for the retreatment of previous DAA failures, although ribavirin was associated with more AEs. Therefore SOF/VEL/VOX monotherapy should be the preferred retreatment strategy. CLINCIALTRIALS.. NCT04695769.. HCV treatment guidelines recommend retreatment of direct-acting antiviral (DAA) treatment failures with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) for 12 weeks. However, whether ribavirin exerts an additional/synergistic effect remains unclear. The present study confirmed that SOF/VEL/VOX without ribavirin is the best regimen for retreatment of DAA treatment failures, and thus will help guide clinicians caring for patients who are not cured with a first course of DAA therapy.

Topics: Antiviral Agents; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Retreatment; Ribavirin; Sofosbuvir; Treatment Outcome

Hepatitis C virus (HCV) is a common cause of liver cirrhosis and hepatocellular carcinoma. Globally, nearly 71 million people have chronic HCV infection, and approximately 399,000 dies annually. In patients without cirrhosis, HCV infection is treated with 12 weeks of sofosbuvir/velpatasvir combination. Results from available small, single-centre observational studies suggest that the sofosbuvir/velpatasvir combination given for 8 weeks may be as effective as the standard 12 weeks of treatment. We propose to compare the treatment response of 12 weeks versus 8 weeks of sofosbuvir/velpatasvir in non-cirrhotic people with chronic HCV infection.. This multicentric, randomized, open-label, non-inferiority trial will include 880 (2 arms x 440) treatment naïve, viraemic (HCV RNA >10,000 IU/mL), non-cirrhotic adults (age >18 years) with chronic hepatitis C. People who are at high-risk for HCV reinfection such as haemophiliacs, people who inject drugs, those on maintenance hemodialysis or having HIV will be excluded. The presence or absence of cirrhosis will be determined with a combination of history, examination, ultrasound, liver stiffness measured with transient elastography, APRI, FIB-4, and esophagogastroduodenoscopy. Participants will be randomized to receive either 8- or 12-week sofosbuvir/velpatasvir treatment. A blood specimen will be collected before starting the treatment (to determine the HCV genotype), after 4 weeks of treatment (for early virological response), and at 12 weeks after treatment discontinuation for SVR12.. The study will provide data on the efficacy of 8 weeks of treatment as compared to the standard of care (12 weeks) in non-cirrhotic patients with chronic HCV infection. Treatment for a shorter duration may improve treatment compliance, reduce the cost of treatment, and ease the treatment implementation from a public health perspective.. Registered with Clinical Trial Registry of India (http://ctri.nic.in) Registration No. CTRI/2022/03/041368 [Registered on: 24/03/2022]-Trial Registered Prospectively.

Topics: Adolescent; Adult; Antiviral Agents; Equivalence Trials as Topic; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Sofosbuvir; Treatment Outcome

Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in HCV-infected Korean adults.. This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir-velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment.. Of 53 participants receiving sofosbuvir-velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir-velpatasvir-voxilaprevir achieved SVR 12. Overall, sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported.. Treatment with sofosbuvir-velpatasvir or sofosbuvir-velpatasvir-voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Republic of Korea; Sofosbuvir; Treatment Outcome

Disparities persist in testing and treatment for hepatitis C virus (HCV), leaving socially marginalized populations less likely to benefit from curative treatment. Linkage services are often insufficient to overcome barriers to navigating the medical system and contextual factors.. To determine the feasibility, acceptability, and safety of HCV treatment at the point of HCV infection diagnosis disclosure in a nonclinical community setting.. In this single-arm nonrandomized controlled trial conducted between July 1, 2020, and October 31, 2021, street-outreach recruitment targeted people experiencing homelessness and injecting drugs in an urban US community who were eligible for simplified HCV treatment.. Study procedures were designed to reflect the community environment and services needed to provide HCV testing, disclosure, and treatment in a nonclinical site. The test-and-treat No One Waits (NOW) model of care provided a 2-week starter pack of 400 mg of sofosbuvir and 100 mg of velpatasvir at time of HCV RNA results disclosure. Participants were transitioned to insurance-provided sofosbuvir-velpatasvir when feasible to complete a 12-week treatment course.. The primary end point was sustained virologic response at posttreatment week 12 or later (SVR12). Acceptability end points were treatment initiation and completion. Safety end points were treatment discontinuation because of a late exclusion criterion and adverse events.. Of the 492 people (median [IQR] age, 48 [37-58] years; 62 [71%] male) who underwent anti-HCV testing, 246 (50%) tested anti-HCV positive, and 111 (23%) tested HCV RNA positive and were eligible for simplified HCV treatment. Eighty-nine of the 111 eligible participants (80%) returned for confirmatory RNA results, and 87 (98%) accepted and initiated HCV treatment. Seventy (80%) were currently injecting drugs, 83 (97%) had an income below the poverty line, and 53 (61%) were currently unsheltered. Most had HCV genotype 1a (45 [52%]) or 3 (20 [23%]). Sixty-nine (79%) completed 12 weeks of sofosbuvir-velpatasvir treatment, 2 stopped treatment because of low adherence, and 16 were lost to follow-up. Of the 66 participants who completed treatment and had a successful blood draw, 61 (92%) had undetectable HCV RNA at treatment completion. Of the 87 treated patients, 58 achieved SVR12, leading to a treatment response of 67% (95% CI, 56%-76%) among the intention-to-treat group and 84% (95% CI, 73%-92%) among the per-protocol group. There were no adverse events, late exclusions, or deaths.. In this nonrandomized controlled trial of HCV treatment at the point of diagnosis, the NOW model of care reduced steps between HCV testing and treatment initiation and resulted in high levels of treatment initiation, completion, and cure. The NOW model of care can expand the current HCV test-and-treat toolkit by reaching a broader population of marginalized communities and expediting curative therapy.. ClinicalTrials.gov Identifier: NCT03987503.

Topics: Antiviral Agents; Female; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Middle Aged; RNA; Sofosbuvir; Treatment Outcome

The overall goal of the Kentucky Viral Hepatitis Treatment Study (KeY Treat) is to eliminate hepatitis C transmission from a county in Appalachian Kentucky by removing the barriers to accessing hepatitis C virus (HCV) treatment.. KeY Treat is a phase IV, open-label, single-arm clinical trial of sofosbuvir/velpatasvir (SOF/VEL) for the treatment of viraemic HCV infections. Those eligible for KeY Treat are at least 18 years of age, viraemic and are residents of the target county. Pregnant women are not eligible. Rapid HCV RNA screening is used to determine eligibility, and those with a quantifiable viral load (VL) consenting to participate initiate SOF/VEL on the same day. All pharmacologic treatment and related medical care is provided free of charge using a non-specialist provider model. Follow-up visits occur at 2, 6 and 12 weeks during treatment to assess medication adherence (measured via VL and self-report), side effects and engagement in risk behaviours. Post-treatment visits occur at 12 weeks (sustained virologic response (SVR12) visit), 6 months and 12 months post-treatment completion to assess re-infection. A control county has also been identified, and prevalence and incidence of chronic HCV infections will be compared with the target community longitudinally. The primary outcome to assess elimination is SVR12. However, several outcomes will be measured to assess the effectiveness of removing the barriers to HCV treatment, including treatment entry, completion and re-infection. Analyses will be conducted via a generalised linear model framework that can incorporate flexible covariate adjustment and multiple outcome types with a compatible link function. Mathematical modelling will be completed assessing the impact and cost-effectiveness of the intervention.. KeY Treat has been approved by the Institutional Review Board at the University of Kentucky. Results from KeY Treat will be presented at conferences and published in peer-reviewed journals.. NCT03949764.

Topics: Antiviral Agents; Carbamates; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Kentucky; Pregnancy; Sofosbuvir; Treatment Outcome

Eliminating hepatitis C is hampered by the costs of direct-acting antiviral treatment and the need to treat hard-to-reach populations. Access could be widened by shortening or simplifying treatment, but limited research means it is unclear which approaches could achieve sufficiently high cure rates to be acceptable. We present the statistical aspects of a multi-arm trial designed to test multiple strategies simultaneously and a monitoring mechanism to detect and stop individual randomly assigned groups with unacceptably low cure rates quickly.. The VIETNARMS trial will factorially randomly assign patients to two drug regimens, three treatment-shortening strategies or control, and adjunctive ribavirin or no adjunctive ribavirin with shortening strategies (14 randomly assigned groups). We will use Bayesian monitoring at interim analyses to detect and stop recruitment into unsuccessful strategies, defined by more than 0.95 posterior probability that the true cure rate is less than 90% for the individual randomly assigned group (non-comparative). Final comparisons will be non-inferiority for regimens (margin 5%) and strategies (margin 10%) and superiority for adjunctive ribavirin. Here, we tested the operating characteristics of the stopping guideline for individual randomly assigned groups, planned interim analysis timings and explored power at the final analysis.. A beta (4.5, 0.5) prior for the true cure rate produces less than 0.05 probability of incorrectly stopping an individual randomly assigned group with a true cure rate of more than 90%. Groups with very low cure rates (<60%) are very likely (>0.9 probability) to stop after about 25% of patients are recruited. Groups with moderately low cure rates (80%) are likely to stop (0.7 probability) before overall recruitment finishes. Interim analyses 7, 10, 13 and 18 months after recruitment commences provide good probabilities of stopping inferior individual randomly assigned groups. For an overall true cure rate of 95%, power is more than 90% to confirm non-inferiority in the regimen and strategy comparisons, regardless of the control cure rate, and to detect a 5% absolute difference in the ribavirin comparison.. The operating characteristics of the stopping guideline are appropriate, and interim analyses can be timed to detect individual randomly assigned groups that are highly likely to have suboptimal performance at various stages. Therefore, our design is suitable for evaluating treatment-shortening or -simplifying strategies.. ISRCTN registry: ISRCTN61522291. Registered on 4 October 2019.

Topics: Administration, Oral; Antiviral Agents; Bayes Theorem; Carbamates; Drug Monitoring; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Pyrrolidines; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin; Sofosbuvir; Treatment Outcome; Valine; Vietnam

In both Russia and Sweden, the dominant hepatitis C virus (HCV) is genotype 1, but around one-third of patients have genotype 3 infection. For such countries, HCV genotype testing is recommended prior to therapy. An effective pangenotypic therapy may potentially eliminate the need for genotyping. In this study, we evaluated the efficacy and safety of sofosbuvir/velpatasvir for 12 weeks in patients from Russia and Sweden.. In an open-label, single-arm phase-3 study, patients could have HCV genotype 1-6 infection and were treatment-naïve or interferon treatment-experienced. All patients received sofosbuvir/velpatasvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12).. Of 122 patients screened, 119 were enrolled and treated. Overall, half (50%) were male, 18% had cirrhosis, and 24% had failed prior interferon-based therapy. In total, 66% of patients were infected with HCV genotype 1 (59% 1b and 7% 1a), 6% with genotype 2, and 29% with genotype 3. The overall SVR12 rate was 99% (118/119, 95% confidence interval 95-100%). One treatment-experienced patient infected with HCV genotype 3 experienced virologic relapse after completing treatment. The most common adverse events were headache (16%) and fatigue (7%). Serious adverse events were observed in four patients, but none were related to treatment. No patients discontinued treatment due to adverse events.. Sofosbuvir/velpatasvir as a pangenotypic treatment for 12 weeks was highly effective in patients from Russia and Sweden infected with HCV genotypes 1, 2, or 3. Sofosbuvir/velpatasvir was safe and well-tolerated. Clinical trial number: ClinicalTrials.gov NCT02722837.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Carbamates; Drug Therapy, Combination; Female; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Russia; Sofosbuvir; Sweden; Young Adult

Hearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection.. We conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir-velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation.. A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders.. In patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.).

Topics: Adult; Age Factors; Aged; Antiviral Agents; Carbamates; Female; Graft Rejection; Graft Survival; Heart Transplantation; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Transplantation; Male; Middle Aged; Pilot Projects; RNA, Viral; Sofosbuvir; Tissue Donors

The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients.. In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis].. In the phase I study, plasma exposures (area under the concentration-time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration-time curve over the 24-h dosing interval; AUC. No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Carbamates; Drug Combinations; Drug Therapy, Combination; Female; Hepatic Insufficiency; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Male; Middle Aged; Ribavirin; Sofosbuvir; Uridine; Young Adult

A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1.. This phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least 1 dose of treatment.. Of 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 of 106 (95% [95% confidence interval {CI}, 89%-99%]) patients: 74 of 78 (95% [95% CI, 87%-99%]) with genotype 1; all 11 (100% [95% CI, 72%-100%]) with genotype 2; 11 of 12 (92% [95% CI, 62%-100%]) with genotype 3; and all 5 (100% [95% CI, 48%-100%]) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, 2 were lost to follow-up, and 1 withdrew consent. Two discontinued treatment due to adverse events and 2 had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), upper respiratory tract infection (8%), and arthralgia (8%).. Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1.. NCT02480712.

Topics: Adult; Aged; Antiviral Agents; Carbamates; Coinfection; Female; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Male; Middle Aged; Sofosbuvir; United States

Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.. We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group.. In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.. Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

Topics: Adult; Aged; Aged, 80 and over; Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Combinations; Drug Resistance, Viral; Female; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; Proline; Protease Inhibitors; Quinoxalines; Sofosbuvir; Sulfonamides; Viral Nonstructural Proteins

Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable

Topics: Adult; Animals; Antiviral Agents; Carbamates; Dogs; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Macaca fascicularis; Male; Microsomes, Liver; Middle Aged; Rats; Rats, Sprague-Dawley; Viral Nonstructural Proteins; Virus Replication; Young Adult

The new pan-genotypic regimen [sofosbuvir (SOF) and velpatasvir (VEL)] for hepatitis C virus (HCV) has been associated with high efficacy. The aim of this study was to assess patient-reported outcomes (PROs) of this regimen.. The PRO data (CLDQ-HCV, SF-36, FACIT-F, WPAI) came from the ASTRAL-1 study, a multicenter multinational blinded placebo-controlled phase 3 clinical trial of a fixed dose combination of SOF 400mg and VEL 100mg for patients with genotype 1, 2, 4, 5, and 6 compared to placebo for 12weeks.. 624 patients received active treatment [618 achieved sustained virologic response (SVR)], and 116 received placebo. The baseline PRO scores were similar. By treatment week 4, patients receiving SOF/VEL experienced improvements in general health (on average, +2.3points), emotional well-being (+3.4), FACIT-F (+1.3), and all domains of CLDQ-HCV (+2.1 to +7.3) (all p<0.005). On the other hand, the only PRO that improved in patients receiving placebo was the worry domain of CLDQ-HCV: +4.6 (p=0.002). By the end of treatment, improvement in PRO scores with SOF/VEL continued, and no improvement was noted in the placebo. Improvement in PROs were also noted 12 and 24weeks post-treatment: +3.7, on average, in patients with SVR-12 after SOF/VEL vs. -2.6, on average, in the placebo arm (p<0.005). Multivariate analysis showed that treatment-emergent changes in PROs were predicted by receiving SOF/VEL for some summary PRO score (p<0.005).. This placebo-controlled trial shows that patients treated with SOF/VEL experience significant improvement of their PROs during treatment and after achieving SVR.. In patients with chronic hepatitis C infection, health-related quality of life and work productivity are often impaired due to HCV-related fatigue. Treatment of hepatitis C with interferon-based regimens, which was the standard of care for all HCV patients until recently, had substantial and potentially debilitating side effects. These regimens caused additional impairment in health-related quality of life and work productivity during treatment and shortly after treatment cessation. The newly developed interferon-free combination of sofosbuvir and velpatasvir has been shown to improve health-related quality of life during treatment, and lead to an improvement in a number of indicators of patient-reported outcomes after successful clearance of HCV and achieving sustained virologic response.

Topics: Antiviral Agents; Carbamates; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Patient Reported Outcome Measures; Quality of Life; Ribavirin; Sofosbuvir

We performed a phase 2 trial of the efficacy and safety of 4, 6, and 8 weeks of sofosbuvir, given in combination with the NS5A inhibitor velpatasvir and the NS3/4A protease inhibitor GS-9857, in patients with hepatitis C virus (HCV) infection.. We enrolled 161 treatment-naïve or previously treated patients infected with HCV genotypes 1 or 3 with or without compensated cirrhosis at 2 centers in New Zealand, from September 2014 through March 2015. All patients received sofosbuvir (400 mg) and velpatasvir (100 mg) plus GS-9857 (100 mg) once daily. The primary efficacy end point was sustained virologic response at 12 weeks after therapy (SVR12). The duration of therapy was determined by baseline patient characteristics: 4 or 6 weeks for treatment-naïve patients without cirrhosis, 6 weeks for treatment-naïve patients with cirrhosis, and 6 or 8 weeks for treatment-experienced patients with or without cirrhosis.. Four weeks of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in 4 of 15 (27%) treatment-naïve patients with HCV genotype 1 without cirrhosis. Six weeks of this combination produced a SVR12 in 14 of 15 (93%) treatment-naïve patients with HCV genotype 1 without cirrhosis, in 13 of 15 (87%) treatment-naïve genotype 1 patients with cirrhosis, in 15 of 18 (83%) treatment-naïve patients with HCV genotype 3 with cirrhosis, and in 20 of 30 (67%) patients with HCV genotype 1 who had failed an all-oral regimen of 2 or more direct-acting antiviral agents. Eight weeks of the drug combination produced an SVR12 in 17 of 17 (100%) patients with HCV genotype 1, in 19 of 19 (100%) patients with HCV genotype 3 and cirrhosis who had failed pegylated interferon plus ribavirin, in 25 of 28 (89%) patients with HCV genotype 1 who had failed protease inhibitor-based triple therapy, and in 4 of 4 (100%) patients with HCV genotype 3 who had failed an all-oral regimen of ≥2 direct-acting antiviral agents. The most common reported adverse events were headache, nausea, and fatigue.. Eight weeks of treatment with the combination of sofosbuvir, velpatasvir, and GS-9857 produced an SVR12 in most treatment-naïve or previously treated patients with HCV genotype 1 or 3 infections, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT02202980.

Topics: Adult; Aged; Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Macrocyclic Compounds; Male; Middle Aged; New Zealand; Proline; Protease Inhibitors; Quinoxalines; Serine Proteases; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Viral Nonstructural Proteins; Young Adult

The purpose of this article is to describe a patient with chronic hepatitis C virus (HCV) infection, who had previously taken 2 other direct-acting antiviral (DAA) regimens and undergone Roux-en-Y gastric bypass (RYGB), successfully treated with a sofosbuvir/velpatasvir/voxilaprevir regimen.. A 64-year-old, African American male presented for management of HCV genotype 1a infection after 2 failed courses of treatment. The patient had a history of severe gastroesophageal reflux disease (GERD), and he was unable to discontinue proton pump inhibitor (PPI) use during all treatment regimens. He was originally treated with 12 weeks of ledipasvir/sofosbuvir but relapsed 3 to 4 months post treatment. The patient had undergone RYGB for the treatment of obesity. After surgery, the patient was re-treated with sofosbuvir/velpatasvir plus ribavirin for 24 weeks. The patient again relapsed 3 months after completing therapy. At our clinic, the patient was started on sofosbuvir/velpatasvir/voxilaprevir for 12 weeks. The patient decided on his own to chew the medication, as he was concerned about medication absorption post surgery, and took concurrent once-daily esomeprazole. Confirmatory posttreatment laboratory work showed his HCV RNA viral load remained undetectable, indicating sustained virologic response, and the patient was deemed cured of HCV.. A patient with a history of relapse after previous DAA therapy and RYGB was successfully treated for HCV infection with sofosbuvir/velpatasvir/voxilaprevir tablets, which he chewed. This case report shows sofosbuvir/velpatasvir/voxilaprevir may be an effective treatment option in the RYGB population, although additional research is needed.

Topics: Antiviral Agents; Gastric Bypass; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Middle Aged; Sofosbuvir

Insurers manage the cost of specialty medicines via rebates, however it is unclear if the savings are passed on to patients, and whether reducing rebates may lead to changes in patient out-of-pocket (OOP) costs and medication adherence. This study examined two drug classes to understand the impact of reducing list prices to net prices, via lower-priced national drug codes (NDCs) or authorized generics, on patient OOP costs and adherence.. This retrospective analysis assessed IQVIA PharMetrics ® Plus adjudicated medical and pharmacy claims for commercially insured patients. Patient OOP costs per prescription and payer drug costs were assessed for evolocumab or alirocumab (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9is]) or velpatasvir/sofosbuvir or ledipasvir/sofosbuvir (hepatitis C virus [HCV] medications). For PCSK9is and HCV medications, the original and lower-priced versions were compared. Adherence was estimated based on proportion of days covered (PDC) (PCSK9is) and receipt of full treatment regimen (HCV medications).. In total, 10,640 patients were included (evolocumab, 5,042; alirocumab, 1,438; velpatasvir/sofosbuvir, 2,952; ledipasvir/sofosbuvir,1,208). After list price reductions, mean payer drug costs decreased by over 60%, while patient OOP cost reductions ranged from 14% to 55% (evolocumab: 55%, p < 0.01; alirocumab: 51%, p < 0.01; velpatasvir/sofosbuvir: 30%, p < 0.01; ledipasvir/sofosbuvir: 14%, p = 0.03). Patients with coinsurance as the largest contributor to their OOP costs had the largest reductions in OOP costs, ranging from adjusted, mean values of US$135 to US$379 (>60% reductions). Six-month PDC for PCSK9is and proportion receiving full HCV treatment regimen were high with the original versions and did not substantially differ with the new, lower-priced versions.. Reducing list prices to approximate net prices (as a proxy for reducing rebates) resulted in lower patient OOP costs, particularly for those with coinsurance. Our findings suggest that future reduction of rebates may assist in patient affordability, although additional transparency is needed.

Topics: Drug Costs; Health Expenditures; Hepatitis C; Humans; Medication Adherence; Retrospective Studies; Sofosbuvir

With the advent of efficacious oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV), identification of characteristics associated with adherence is critical to treatment success. We examined correlates of sub-optimal adherence to HCV therapy in a single-arm, multinational, clinical trial.. ACTG A5360 enrolled HCV treatment-naive persons without decompensated cirrhosis from 5 countries. All participants received a 12-weeks course of sofosbuvir/velpatasvir at entry. In-person visits occurred at initiation and week 24, sustained virologic response (SVR) assessment. Adherence at week 4 was collected remotely and was dichotomized optimal (100%, no missed doses) versus sub-optimal (<100%). Correlates of sub-optimal adherence were explored using logistic regression.. In total, 400 participants enrolled; 399 initiated treatment; 395/397 (99%) reported completing at week 24. Median age was 47 years with 35% female. Among the 368 reporting optimal adherence at week 4 SVR was 96.5% (95% confidence interval [CI] [94.1%, 97.9%]) vs 77.8% (95% CI [59.2%, 89.4%]) P value < .001. In the multivariate model age <30 years and being a US participant were independently associated with early sub-optimal adherence. Participants <30 years were 7.1 times more likely to have early sub-optimal adherence compared to their older counterparts.. Self-reported optimal adherence at week 4 was associated with SVR. Early self-reported adherence could be used to identify those at higher risk of treatment failure and may benefit from additional support. Younger individuals <30 years may also be prioritized for additional adherence support. Clinical Trials Registration. NCT03512210.

Topics: Adult; Antiviral Agents; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Middle Aged; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

Topics: Antiviral Agents; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

It is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis.. We examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24).. One patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028).. Achieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.

Topics: Antiviral Agents; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Humans; Hypertension, Portal; Liver Cirrhosis; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

The high HCV infection cure rates achieved with direct-acting antiviral (DAA) treatments could be compromised in the future by the emergence of antiviral resistance. Thus, it is essential to understand the viral determinants that influence DAA resistance, which is most prevalent in genotype 3. We aimed at studying how resistance to protease-, NS5A-, and NS5B-inhibitors influences the activities of glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir in cell culture, and how the HCV genome adapts to selective pressure by successive rounds of treatment failure.. A previously developed in vivo infectious cDNA clone of strain S52 (genotype 3a) was adapted to efficiently replicate and propagate in human hepatoma cells (Huh7.5) using 31 adaptive substitutions. DAA escape experiments resulted in the selection of S52 variants with decreased drug susceptibility (resistance), which was linked to the emergence of known resistance-associated substitutions (RASs). NS5A-inhibitor resistance was sufficient to promote treatment failure with double-DAA but not triple-DAA regimens. Enhanced viral fitness associated with the selection of sofosbuvir resistance accelerated escape from DAAs. After serial DAA treatment failure, HCV genetic evolution led to a complex genome-wide network of substitutions, some of which coevolved with known RASs.. Baseline NS5A-RAS can compromise the efficacy of double-DAA pangenotypic regimens for HCV genotype 3, and enhanced viral fitness can accelerate treatment failure. Persistence of RASs after successive treatment failure is facilitated by the remarkable evolutionary capacity and plasticity of the HCV genome. Proof-of-concept for the potential development of multi-DAA resistance is shown.

Topics: Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Sofosbuvir; Viral Nonstructural Proteins

Hepatitis C virus (HCV) infection is more prevalent in people living with HIV-AIDS (PLHA) and portends a poorer prognosis. Pharmacokinetic studies suggest the absence of significant interaction between velpatasvir and dolutegravir which has been recently recommended as part of preferred first-line antiretroviral therapy (ART) regimens by WHO. However, clinical data on the use of velpatasvir-based regimen in PLHA taking dolutegavir is lacking. Hence, we aimed to assess the efficacy and safety of sofosbuvir and velpatasvir (SOF + VEL) in HCV and HIV coinfected patients on dolutegravir-based ART. Forty-five consecutive PLHA with HCV coinfection on dolutegravir-based ART were prospectively enrolled. All patients were treated SOF + VEL for 12 weeks. Complete haemogram, liver and renal function tests were assessed at baseline, 4 weeks and at end of treatment. Sustained virological response (SVR) was assessed at 12 weeks after end of treatment. The majority were males (95.5%) with a mean age of 32.8 ± 12.3 years. Cirrhosis was present in 6 (13.3%) patients. All patients completed 12 weeks of therapy with SOF + VEL, but SVR could not be assessed in two patients. Forty-two (97.7%) of the remaining 43 patients attained SVR-12. SVR-12 rate was 97.7% and 93.3% by per protocol and intention to treat analysis, respectively. No grade III/IV adverse events were reported, and there was no worsening of blood counts, liver or renal function test parameters. The pan-genotypic regimen of SOF + VEL is safe and effective in PLHA with HCV coinfection who are on dolutegravir-based ART.

Topics: Adult; Antiviral Agents; Coinfection; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; HIV Infections; Humans; Male; Middle Aged; Sofosbuvir; Treatment Outcome; Young Adult

Topics: Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Sofosbuvir; Treatment Outcome

Hepatitis C is a global health issue. Hepatitis C Virus (HCV) induces fibrosis by redox reactions, which involve the deposition of collagen in extracellular matrix (ECM). This study aimed to examine the antifibrotic effect of direct-acting antivirals; Sofosbuvir and Velpatasvir, per se and in combination against carbon tetrachloride (CCl4)-induced fibrosis in rats. Carbon tetrachloride (intraperitoneal; 0.5 ml/kg) twice weekly for six weeks was used to induce hepatic fibrosis in rats. After two weeks of CCl4, oral administration of Sofosbuvir (20 mg/kg/d) and Velpatasvir (10 mg/kg/d) was administered to rats for the last four weeks. Liver function tests (LFTs), renal function tests (RFTs), oxidative stress markers, and the levels of TNF-a, NF-κB, and IL-6 were measured through ELISA and western blotting at the end of the study. CCl4 significantly ameliorated the values of RFTs, LFTs and lipid profiles in the diseased group, which were normalized by the SOF and VEL both alone and in combination. These drugs produced potent antioxidant effects by significantly increasing antioxidant enzymes. From the histopathology of hepatic tissues of rats treated with drugs, the antifibrotic effect was further manifested, which showed suppression of hepatic stellate cells (HSCs) in treated rats, as compared to the disease control group. The antifibrotic effect was further demonstrated by significantly decreasing the levels of TNF-a, NF-κB and IL-6 in serum and hepatic tissues of treated rats as compared to the disease control group. Sofosbuvir and Velpatasvir alone and in combination showed marked inhibition of fibrosis in the CCl4-induced non-HCV rat model, which was mediated by decreased levels of TNF-a/NF-κB and the IL-6 signaling pathway. Thus, it can be concluded that Sofosbuvir and Velpatasvir might have an antifibrotic effect that appears to be independent of their antiviral activity.

Topics: Animals; Antioxidants; Antiviral Agents; Carbon Tetrachloride; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Interleukin-6; Liver Cirrhosis; NF-kappa B; Rats; Sofosbuvir

The high prevalence of hepatitis C virus (HCV) infection among patients on maintenance hemodialysis (MHD) has been reported in India. Due to the strong association of HCV infection with death and cardiovascular disease, it is important to treat the infection. However, treatment poses a challenge since only a few directly acting antivirals recommended in the guidelines for HCV treatment in the dialysis population are available in India. Pangenotypic sofosbuvir has concerns about its safety due to its renal elimination.. This prospective study was undertaken between 2019 and 2020 among patients on hemodialysis with HCV infection. Clinical details, biochemical parameters, viral load, and genotyping were recorded and the outcome of treatment with sofosbuvir in combination with velpatasvir/daclatasvir for 12 weeks was noted. Descriptive and inferential statistical analysis was carried out. The Chi-squared/Fisher exact test was used.. In the present study, 54 hemodialysis patients with HCV were treated with full doses of sofosbuvir and velpatasvir/daclatasvir. Genotype 1 was the most common, seen in 75.9% (n = 41). Around 96.29% (n = 52) of patients achieved sustained virological response (SVR) at the end of the study. None of the patients experienced serious side effects requiring dose reduction or discontinuation of the treatment.. Sofosbuvir combination therapy offers an excellent response in dialysis patients irrespective of the genotype and presence of cirrhosis with minimal monitoring as in non-chronic kidney disease (CKD) patients.

Topics: Antiviral Agents; Drug Therapy, Combination; Hepatitis C; Humans; India; Prospective Studies; Renal Dialysis; Sofosbuvir; Treatment Outcome

Due to concerns over potential interactions between some hepatitis C direct-acting antivirals (DAAs) and opioids, we describe adverse event (AE) reports of concomitant use of opioids and DAAs.. AEs reported (July 28, 2017-December 31, 2021) with the administration of the DAAs glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir/voxilaprevir, and elbasvir/grazoprevir as suspect products were downloaded from the US Food and Drug Administration AE Reporting System Public Dashboard. The number of AE reports containing opioids (fentanyl, hydrocodone, oxycodone) as co-suspect products/concomitant products were counted and summarized by severity, reporting country and whether an outcome of death was reported. Overdose AEs were counted irrespective of opioid use, and changes over time were assessed.. In total, 40 AEs were reported for DAAs and concomitant fentanyl use, 25 (62.5%) were in the USA, 35 (87.5%) were considered serious, and 14 (35.0%) resulted in death; and 626 were reported with concomitant oxycodone/hydrocodone use, 596 (95.2%) were in the USA, 296 (47.3%) were considered serious, and 28 (4.5%) resulted in death. There were 196 overdose AEs (32 [16%] deaths) declining from 2018 (N = 56) to 2021 (N = 29).. Treating people with hepatitis C virus (HCV) infection who use drugs is key to achieving HCV elimination. Low numbers of DAA AE reports with opioids may provide reassurance to prioritize HCV treatment in this population. These data contribute to evidence supporting the continued scale-up of DAA treatment among people who use drugs to achieve HCV elimination goals.

Topics: Analgesics, Opioid; Antiviral Agents; Fentanyl; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Hydrocodone; Oxycodone; Sofosbuvir

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Ribavirin; Sofosbuvir; Treatment Outcome

Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype.. In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients.. All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults.. The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents.

Topics: Adolescent; Adult; Aminoisobutyric Acids; Antiviral Agents; Carbamates; Child; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Proline; Quinoxalines; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome

SARS-CoV-2 is still a health problem worldwide despite the availability of vaccines. Therefore, there is a need for effective and safe antiviral. SARS-CoV-2 and HCV necessitate RNA-dependent RNA polymerase (RdRp) for replication; therefore, it has been hypothesized that RdRp inhibitors used to treat HCV may be effective treating SARS-CoV-2. Accordingly, we evaluated the effect of the sofosbuvir/velpatasvir (SOF/VEL) combination in early SARS-CoV-2 infection. A multicenter case-control study was conducted, enrolling 120 patients with mild or moderate COVID-19, of whom 30, HCV coinfected or not, received SOF/VEL tablets (400/100 mg) once daily for 9 days within a median of 6 days from the beginning of infection and 90 controls were treated with standard care. The primary endpoint was the effect on viral clearance, and the secondary endpoint was the improvement of clinical outcomes. Nasal swabs for SARS-CoV-2 by PCR were performed every 5-7 days. Between 5-14 days after starting SOF/VEL treatment, SAS-CoV-2 clearance was observed in 83% of patients, while spontaneous clearance in the control was 13% (p < 0.001). An earlier SARS-CoV-2 clearance was observed in the SOF/VEL group than in the control group (median 14 vs 22 days, respectively, p < 0.001) also when the first positivity was considered. None of the patients in the SOF/VEL group showed disease progression, while in the control group, 24% required more intensive treatment (high flow oxygen or noninvasive/invasive ventilation), and one patient died (p < 0.01). No significant side effects were observed in the SOF/VEL group. Early SOF/VEL treatment in mild/moderate COVID-19 seems to be safe and effective for faster elimination of SARS-CoV-2 and to prevent disease progression.

Topics: Antiviral Agents; Carbamates; Case-Control Studies; COVID-19 Drug Treatment; Disease Progression; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; RNA-Dependent RNA Polymerase; SARS-CoV-2; Sofosbuvir; Treatment Outcome

Hepatitis C virus (HCV) genotype 6 mainly distributes in Southeast Asia and South China. Because of the low prevalence in developed countries, optimal treatment for HCV genotype 6 in real-world setting remains to be determined. We aimed to evaluate the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) and glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV genotype 6 infection in Taiwan.. A total of 286 patients with chronic hepatitis C (CHC) genotype 6, 161 receiving 12-week SOF/VEL and 125 receiving 8-week GLE/PIB, were enrolled. All patients were followed up for 12 weeks after treatment completion. Demographic information, HCV viral load (VL), profiles of lipid and sugar, and adverse events were recorded and reviewed.. Sustained virological response (SVR) rates of SOF/VEL and GLE/PIB evaluated by intention-to-treat analysis were 99.38% and 100%, respectively. SVR achieved 100%, regardless of cirrhosis or viral load (cutoff: 6 MIU/mL), of both regimens by per-protocol analysis. Skin itching was the most common adverse event, with an overall incidence of 6.64% which was more prevalent in GLE/PIB (12.0%) than SOF/VEL (2.48%). A significant decrease in the estimated glomerular filtration rate was observed in patients receiving SOF/VEL but not in those receiving GLE/PIB at the time of SVR. No patient discontinued treatment due to adverse event.. The high SVR and excellent safety of SOF/VEL and GLE/PIB in real-world setting reveals that the two DAA regimens are favorable options for treatment of HCV genotype 6 in Taiwan and Asia.

Topics: Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Benzopyrans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Lipids; Proline; Pyrrolidines; Quinoxalines; Sofosbuvir; Sugars; Sulfonamides; Treatment Outcome

Direct-acting antivirals (DAAs) allow for successful transplantation of livers from hepatitis C nucleic acid test (NAT)-positive donors to negative recipients. However, limited data exist to support crushing DAAs in patients with multiple absorption concerns or significant drug interactions.. Crushed sofosbuvir/velpatasvir has been successfully used in nontransplant patients with dysphagia, but data in transplant patients with absorption concerns are limited. A 31-year-old hepatitis C-negative female underwent liver transplantation from a hepatitis C NAT-positive donor. Her postoperative course was complicated by a mucormycosis infection, gastrointestinal bleed, and necrotizing pancreatitis requiring treatment with liposomal amphotericin B and pantoprazole 80 mg twice daily. Surgical interventions included an above-the-knee amputation and ileostomy. Hepatitis C treatment was initially delayed because of concern for reduced absorption with crushed DAA administration through the nasogastric (NG) tube, high ileostomy output, gastrointestinal bleed, pancreatitis, and a known drug interaction with pantoprazole. One month after transplantation, the patient's bilirubin level remained elevated and hepatitis C treatment was initiated with sofosbuvir/velpatasvir. Crushed sofosbuvir/velpatasvir was mixed with 30 mL of water and administered through the NG tube daily. Hepatitis C viral loads were obtained weekly during treatment to monitor efficacy. Although the patient died before evaluation of sustained virological response at 12 weeks, hepatitis C viral clearance was observed within 4 weeks of initiating treatment.. A liver transplant patient exhibited viral clearance of hepatitis C following administration of crushed sofosbuvir/velpatasvir in the setting of multiple absorption concerns.

Topics: Adult; Antiviral Agents; Female; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Transplantation; Pancreatitis; Pantoprazole; Sofosbuvir

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Proline; Quinoxalines; Registries; Sofosbuvir; Sulfonamides; Treatment Outcome

Owing to the advent of pangenotypic direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) treatment, utilization of HCV-infected deceased donor kidneys with simplified genotyping/subtyping-free sofosbuvir/velpatasvir (SOF/VEL) treatment strategy is now becoming a promising strategy for expanding the organ donor pool.. This retrospective, comparative, single-center study included HCV viremic donor kidneys that were transplanted to 9 HCV-positive (HCV Ab-positive) recipients (D+/R+ group) and 14 HCV-negative recipients (D+/R- group) from May 2018 to January 2021. Both groups received prophylaxis with SOF/VEL treatment within 1-week posttransplant devoid of HCV genotyping/subtyping. The primary outcomes were sustained virologic response 12 weeks after completion of therapy (SVR12) and graft survival at 1-year posttransplant.. Baseline characteristics were similar between the HCV D+/R- and D+/R+ groups. The mean age of all recipients was 39.09 ± 9.65 (SD) years, and 73.9% were male. A total of 92.9% (13 out of 14) recipients had pretreatment HCV viremia in the D+/R- group. The pretreatment HCV viral load in the D+/R+ group (5.98, log 10 IU/mL; IQR, 5.28-6.53) was significantly higher than that in the D+/R- group (3.61, log 10 IU/mL; IQR, 2.57-4.57). After SOF/VEL treatment, SVR12 was achieved in all recipients, with a 100% 1-year patient and graft survival rates. The D+/R+ group had a higher incidence of abnormal liver function (44.4% vs. 7.1%). No significant difference was observed between the two groups in terms of DGF, acute rejection, ALT, serum creatinine, and eGFR within 1-year posttransplant. No severe adverse events associated with either HCV viremia or SOF/VEL were observed.. Using a simplified genotyping/subtyping-free SOF/VEL treatment strategy, kidneys from hepatitis C viremic donors for both infected and uninfected recipients presented with safe, excellent, and comparable 1-year outcomes, which can safely expand the donor pool. HCV-positive donor kidneys should be utilized regularly, regardless of the recipient's HCV status.

Topics: Adult; Antiviral Agents; Carbamates; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Kidney; Male; Middle Aged; Retrospective Studies; Sofosbuvir; Viremia

SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.

Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19 Drug Treatment; Hepacivirus; Hepatitis C; Humans; Lung; Nucleosides; SARS-CoV-2; Sofosbuvir

Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Humans; Mental Disorders; Sofosbuvir

The sofosbuvir (SOF) / velpatasvir (VEL) / voxilaprevir (VOX) combination has been evaluated in more than 800 patients enrolled in phase II and phase III studies, where it demonstrated excellent safety and efficacy, achieving overall sustained viral response (SVR) rates of more than 95%. We aimed to assess the efficacy and safety of SOF/VEL/VOX in a real-world study, including patients previously treated for genotype 1b hepatitis C virus (HCV) infection that did not obtain a sustained viral response with previous direct-acting antivirals (DAAs) therapy.. In Romania, through a nationwide government-funded program in 2019-2020, 213 patients with chronic hepatitis C non-responders to previous DAAs therapy, received treatment with SOF/VEL/ VOX 400/100/100 mg/day for 12 weeks. We performed a retrospective longitudinal study that included 143 individuals who were treated in Bucharest, Iași, Craiova and Constanța clinics, all with genotype 1b HCV infection. Efficacy was assessed by the percentage of patients achieving SVR 12 weeks post-treatment (SVR12). Serious adverse events (SAE) were registered.. Our cohort comprised 53% males with a median age of 60 years (27÷77); 47% were pre-treated with ombitasvir/paritaprevir/ritonavir+dasabuvir ± ribavirin, 40% with ledipasvir/SOF, 13% with elbasvir/ grazoprevir. 42% of patients associated co-morbidities, 45% had compensated liver cirrhosis, 2% had treated hepatocellular carcinoma (HCC) and 1% had hepatitis B virus co-infection. SVR by intention to treat was reported in 139/143 (97.2%) and per protocol in 141/143 (98.6%). No predictive factors for SVR were identified. Rate of liver decompensation in patients with cirrhosis was 6% and was statistically associated in multivariate analysis with Child-Pugh score (p<0.01) and with severe steatosis (p=0.004). Occurrence of new HCC was reported in 3.6% of all patients with cirrhosis and was associated with poor liver function [higher Child-Pugh score (p=0.001) and low albumin levels (p=0.02)]. Serious adverse events related to therapy were reported in 1/143(0.7%).. SOF/VEL/VOX was highly efficient in our population of patients with a 97.2% SVR. Liver decompensation occurred in 6% of cirrhotic patients at SVR, related to hepatic dysfunction.

Topics: Antiviral Agents; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Romania; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

Our objective was to determine potential drug interactions (DI) between pangenotypic direct-acting antivirals (pDAA) and concomitant central nervous system (CNS) medication in patients with chronic hepatitis C virus (HCV). Transversal design. Patients aged ≥ 18 years on treatment with pDAA during 2017 were included. The variables collected were comorbidity, concomitant CNS medication and potential DI. The pDAA analyzed were a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) and c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Descriptive statistical analysis. We recruited 1,170 patients (mean age 60.1 years, 56.4% male). Mean concomitant drug use was 3.2 per patient/year. The percentages of potential / possible DI between the DAAs and the concomitant drugs on the CNS were: 2.7% contraindications, 11.3% significant and 4.2% weak. By pDAA, the percentages were: SOF/VEL (2.7%; 0.0%; 4.4%), GLE/GDP (2.7%; 26.5%; 1.6%) SOF/VEL/VOX (2.7%; 6.8%; 4.4%), respectively. Concomitant CNS medication was used in one third of HCV patients. It is important to select a pDAA with a low rate of potential DI to simplify treatment. SOF/VEL is a good alternative compared with the other pDAA studied, mainly due to the concomitant use of antipsychotics and analgesics.. El objetivo fue determinar las potenciales interacciones farmacológicas (IF) entre los antivirales de acción-directa pangenotípicos (AADp) y la medicación-concomitante sobre el sistema nervioso central (SNC) asociada a los pacientes portadores del virus de la hepatitis C crónica (VHC). Se realizó un diseño transversal. Se incluyeron pacientes ≥18 años en tratamiento con AADp durante el año 2017. Las variables recogidas fueron: comorbilidad, medicación-concomitante (SNC) y potenciales IF. Los AADp analizados fueron: a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) y c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Análisis-estadístico descriptivo. Se reclutaron 1.170 pacientes; edad-media de 60,1 años y el 56,4% varones. El promedio de medicamentos-concomitantes fue de 3,2 por paciente/año. El porcentaje de potenciales/posibles IF entre los AADp y los medicamentos-concomitantes sobre el SNC fueron: 2,7% contraindicaciones, 11,3% significativas y 4,2% débiles. En función de los AADp, estos porcentajes fueron los siguientes: SOF/VEL (2,7%; 0,0%; 4,4%), GLE/PIB (2,7%; 26,5%; 1,6%) y SOF/VEL/VOX (2,7%; 6,8%; 4,4%), respectivamente. Un tercio de los pacientes con VHC muestran un uso de medicación-concomitante de acción sobre el SNC. Será importante seleccionar un AADp que tenga una baja tasa de potenciales IF para simplificar el tratamiento. SOF/VEL se presenta como una buena alternativa en comparación con los AADp seleccionados, principalmente en el uso concomitante de antipsicóticos y analgésicos.

Topics: Antiviral Agents; Central Nervous System Agents; Female; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Male; Middle Aged; Sofosbuvir

BACKGROUND The aim of this study was to evaluate the efficacy and safety of Sofosbuvir/Velpatasvir prophylaxis in hepatitis C virus (HCV)-negative recipients who received a transplant kidney from HCV-infected donors. MATERIAL AND METHODS This retrospective cohort study enrolled consecutive HCV-negative recipients between January 2019 and February 2021. All the recipients were treated with Sofosbuvir/Velpatasvir (400 mg/100 mg) once daily for 12 weeks after receiving a transplant kidney from HCV-infected donors. We collected data on renal function and liver function and HCV RNA were collected during the study. We also compared the rates of adverse events. RESULTS A total of 26 patients were included in the cohort. All the recipients (100%) completed 12 weeks of treatment and the entire follow-up. All recipients (100%) had negative HCV RNA, but 4 recipients (15.4%) were HCV antibody (Ab)-positive after transplantation. Fifteen adverse events (57.7%) occurred during the study. Three recipients (11.5%) experienced graft rejection, 6 recipients (23.1%) had delayed graft function, and 3 recipients (11.5%) had bleeding. However, none of them were related to study medication. Renal function was stable in all patients. CONCLUSIONS Sofosbuvir/Velpatasvir pre- and post-transplantation treatment was effective and safe in HCV-uninfected recipients who received a transplant kidney from HCV-infected donors.

Topics: Adult; Aged; Antiviral Agents; Carbamates; Female; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Sofosbuvir; Treatment Outcome; Young Adult

Report the real-world experience of the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in chronic hepatitis C virus (HCV) infected patients who have previously experienced a direct-acting antiviral (DAA) containing regimen.. Consecutive patients who have previously failed or did not tolerate a DAA containing regimen for chronic HCV who was treated with SOF/VEL/VOX were studied. Baseline clinical and laboratory data including NS5A RAS mutation testing were collected.. SOF/VEL/VOX resulted in an end of treatment undetectable HCV viral load in all patients and a sustained virologic response 12 rate of 100% despite the presence of NS5A RAS mutation, HIV infection, and cirrhosis. Treatment with SOF/VEL/VOX was well tolerated and there were no adverse events.. SOF/VEL/VOX is well tolerated and effective in treating patients who have been exposed to prior DAA therapy outside of clinical trials. SOF/VEL/VOX should be considered as the first-line regimen in HCV infected patients who have experienced prior DAA failure.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Lactams, Macrocyclic; Leucine; Proline; Quinoxalines; Sofosbuvir; Sulfonamides; Sustained Virologic Response

In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort.. We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE).. Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12.. This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Male; Middle Aged; Proline; Quinoxalines; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome

Organs from hepatitis C virus (HCV)-viremic donors have been used in HCV-uninfected recipients (D+/R-), but the optimal treatment approach has not been defined. We evaluated the kinetics of HCV infection following transplant in D+/R- kidney-transplant (KT) and liver-transplant (LT) recipients when a preemptive antiviral strategy was used.. Despite differing kinetics of early HCV infection in liver versus non-liver recipients, a preemptive antiviral strategy is effective. Vigilance for adverse immunologic events is warranted.

Topics: Antiviral Agents; Carbamates; Drug Administration Schedule; Female; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Kidney; Kidney Transplantation; Linear Models; Liver; Liver Transplantation; Male; Middle Aged; Proof of Concept Study; Prospective Studies; Sofosbuvir; Sustained Virologic Response; Tissue Donors; Transplant Recipients; Viral Load; Viremia

Direct Acting Antivirals (DAA) have changed the landscape of hepatitis C virus (HCV) infection with high cure rates across genotypes. However, the use of these agents in the setting of allogeneic hematopoietic cell transplantation (HCT) has been limited. In this context, we report the outcome of five children (5-12 years) with relapsed and refractory leukemia and active HCV infection (genotype 1b), who underwent urgent haploidentical HCT and were treated with Sofosbuvir and Velpatasvir (Sof-Vel) from initiation of treatment to 24 weeks post-HCT. All achieved complete virologic response (VR) at a median of 2 weeks, with normalization of liver enzymes. There were no adverse events related to the use of Sof-Vel, with no major fluctuations in cyclosporine levels. Two of the patients developed chronic GVHD and one relapsed. Sof-Vel was continued in one of them along with sirolimus without affecting drug levels. With a median follow-up of 15 months, four patients are disease free with sustained VR. Our study shows that combination of Sof-Vel might be effective in inducing rapid complete and sustained VR during HCT without any major untoward drug interaction.

Topics: Antiviral Agents; Carbamates; Child; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Sofosbuvir; Transplantation, Haploidentical; Treatment Outcome

Real-world data regarding the impact of hepatic fibrosis on the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) treatment is limited in the Asian population.. We analyzed data for all 823 patients with hepatitis C virus treated with SOF/VEL from June 2019 to September 2020 at Chang Gung Memorial Hospital in Chiayi, Taiwan. The degree of fibrosis was determined using the fibrosis-4 (FIB-4) index, with advanced fibrosis or cirrhosis defined as a FIB-4 score of > 3.25. The primary treatment outcome was the rate of sustained virologic response 12 weeks after treatment cessation (SVR). Adverse events (AEs) were also evaluated.. SVR rates did not significantly differ (p > 0.05) between patients with FIB-4 scores of ≤ 3.25 and those with scores of > 3.25. In the per protocol analysis, 99.2% (593/598) of the FIB-4 ≤ 3.25 group and 100% (172/172) of the FIB-4 > 3.25 group achieved SVR; in the evaluable population analysis, 93.4% (593/635) of the FIB-4 ≤ 3.25 group and 91.5% (172/188) of the FIB-4 > 3.25 group achieved SVR. Five patients with FIB-4 scores of ≤ 3.25 did not attain SVR: two relapsed and three had no response. The most common AEs were comparable (p > 0.05) for the FIB-4 ≤ 3.25 group and the FIB-4 > 3.25 group and included abdominal discomfort (4.4% vs. 5.9%), fatigue (4.1% vs. 5.9%), and skin itching (3.6% vs. 3.2%). Laboratory abnormalities were more common in the FIB-4 > 3.25 group (p < 0.001). Six patients with FIB-4 scores of > 3.25 had total bilirubin elevation > 3 × the upper normal limit (UNL). Alanine transaminase elevation > 5 × the UNL was observed in two patients with FIB-4 scores of ≤ 3.25 and one patient with a FIB-4 score of > 3.25. No AEs resulted in treatment discontinuation.. SOF/VEL treatment is well tolerated and achieves high SVR rates for patients of Taiwanese ethnicity with HCV, regardless of cirrhosis status.

Topics: Antiviral Agents; Carbamates; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Sofosbuvir; Sustained Virologic Response; Taiwan; Treatment Outcome

Real-world studies assessing the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) plus ribavirin (RBV) for Child-Pugh B/C hepatitis C virus (HCV)-related cirrhosis are limited.. We included 107 patients with Child-Pugh B/C HCV-related cirrhosis receiving SOF/VEL plus RBV for 12 weeks in Taiwan. The sustained virologic response rates at off-treatment week 12 (SVR12) for the evaluable population (EP), modified EP, and per-protocol population (PP) were assessed. Thesafety profiles were reported.. The SVR12 rates in the EP, modified EP and PP were 89.7% (95% confidence interval [CI], 82.5-94.2%), 94.1% (95% CI, 87.8-97.3%), and 100% (95% CI, 96.2-100%). Number of patients who failed to achieve SVR12 were attributed to virologic failures. The SVR12 rates were comparable regardless of patient characteristics. One patient discontinued treatment because of adverse events (AEs). Twenty-four patients had serious AEs and six died, but none were related to SOF/VEL or RBV. Among the 96 patients achieving SVR12, 84.4% and 64.6% had improved Child-Pugh and model for endstage liver disease (MELD) scores. Multivariate analysis revealed that a baseline MELD score ≥15 was associated with an improved MELD score of ≥3 (odds ratio, 4.13; 95% CI, 1.16-14.71; P=0.02). Patients with chronic kidney disease (CKD) stage 1 had more significant estimated glomerular filtration rate declines than patients with CKD stage 2 (-0.42 mL/min/1.73 m2/month; P=0.01) or stage 3 (-0.56 mL/min/1.73 m2/month; P<0.001).. SOF/VEL plus RBV for 12 weeks is efficacious and well-tolerated for Child-Pugh B/C HCV-related cirrhosis.

Topics: Antiviral Agents; Carbamates; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Ribavirin; Sofosbuvir; Treatment Outcome

Recently developed direct-acting antiviral (DAA) treatments for hepatitis C virus (HCV) have been groundbreaking for their high efficacy across disease genotypes and lack of severe side effects. This study uses a cost-of-illness (COI) approach to estimate the net value conferred by this class of drugs using the cost and efficacy of one of these novel drug combinations, sofosbuvir and velpatasvir (SOF/VEL), recently licensed for generic manufacture in India. This study considers COI of lifetime earnings lost by patients and potential secondarily infected individuals due to disability and premature death from HCV infection. Expected net benefits of treatment are substantial for non-cirrhotic (NC) and compensated cirrhotic (CC) patients (ranging from 5,98,003 INR for NC women to 1,05,25,504 INR for CC men). Increased earnings are not sufficient to fully offset cost of treatment for decompensated cirrhotic individuals but treatment may still be justified on the basis of the intrinsic value of health improvements and other treatment benefits.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Carbamates; Cost of Illness; Disability Evaluation; Drugs, Generic; Female; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; India; International Normalized Ratio; Liver Cirrhosis; Male; Middle Aged; Quality of Life; Sofosbuvir; Young Adult

Donor-derived hepatitis C (dd-HCV) infection may increase the risk of renal impairment (RI) among heart transplantation (HT) recipients. Sofosbuvir, an integral component of HCV direct-acting antivirals (DAAs) has also been linked to RI. To date, no study has examined the trends in renal function for HT recipients of dd-HCV infection and assessed safety and efficacy of Sofosbuvir-based DAAs. Between September 2016 and June 2018, 46 HCV-naive patients and one patient with a history of HCV treated pretransplant, underwent HT from HCV-positive donors (follow-up available through October 10, 2018). Patients were treated with Ledipasvir-Sofosbuvir (genotype 1) or Sofosbuvir-Velpatasvir (genotype 3) for 12 or 24 weeks; no dose adjustments were made for renal function. Data on renal function were available for 23 patients who achieved a sustained virologic response at 12 weeks after the treatment (SVR12; cohort A) and 18 patients who completed 1 year of follow-up (cohort B). Treatment of dd-HCV infection was initiated at a median of 6 weeks post-HT. In both cohorts, a nonsignificant reduction in median estimated glomerular filtration rate (eGFR; ml/min/1.73 m) was noted (cohort A: pretransplant eGFR: 62 [interquartile range {IQR}: 1-84] to SVR12 eGFR: 49 [IQR: 37-82]; p = 0.43; cohort B: pretransplant eGFR: 65 [IQR: 54-84] to 1 year post-HT eGFR: 56 [IQR: 39-75]; p = 0.29). Pretreatment renal function had no significant impact on changes in renal function during treatment. All patients tolerated DAAs well with 100% completion rate to the assigned therapy and duration and 100% success at achieving SVR12. In this first and largest reported case series to date of HT recipients with dd-HCV infection, we observed that neither the dd-HCV infection nor its treatment with Sofosbuvir-based DAAs increased the risk of RI. Sofosbuvir-based DAAs appear safe, tolerable, and effective for HCV treatment even in presence of severe RI.

Topics: Adult; Antiviral Agents; Benzimidazoles; Carbamates; Drug Therapy, Combination; Female; Fluorenes; Heart Transplantation; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Kidney Diseases; Male; Middle Aged; Sofosbuvir; Sustained Virologic Response; Tissue Donors; Transplant Recipients; Uridine Monophosphate

Twelve weeks sofosbuvir/velpatasvir (SOF/VEL) is a highly effective pan-genotypic regimen for hepatitis C. Phase 2 data suggest 8 weeks of treatment may be sufficient for previously untreated noncirrhotic patients with genotype 3 (GT3) infection. To maximize the number of patients potentially cured within a fixed treatment budget, we elected to treat such patients locally eligible for treatment (F2/3), with 8 weeks of SOF/VEL. By local protocol, treatment-naive patients with F2 (LSM > 6.9kPa < 9.5kPa) or F3 fibrosis (≥9.5kPa < 12.5kPa) were eligible for 8-week SOF/VEL treatment. Patients commencing treatment before 1 Oct 2017 were identified from the Scottish HCV database. Baseline and treatment outcome data obtained. Ninety patients were included for analysis (72 (80%) male, mean age 45 (IQR ± 8.4), 28 (31.1%) F3 fibrosis). Opioid agonist therapy (OAT) was prescribed in 82 (91.1%) patients. Of 49 patients attending Glasgow city Alcohol and Drug Services, 27 (55.1%) had evidence of recent drug use (< 3 months) including 8 (16.3%) with self-reported intravenous drug use. On an intention-to-treat basis, SVR rates were 86/90 (95.6%, 95% CI 89.0-98.8). Excluding those who prematurely discontinued treatment (n = 4), died prior to SVR testing (n = 1) or whom experienced reinfection (n = 1), per-protocol SVR rate was 84/84 (100%, 95% CI 95.7-100.0). In conclusion, eight-week SOF/VEL is highly effective in treatment-naive GT3 patients with significant fibrosis. This offers a non-protease inhibitor-based 8-week regimen which may be useful for complex drug interactions or where time-limited opportunity for treatment. In limited resource settings, reduction in drug acquisition costs may help achieve progress towards the goal of HCV elimination.

Topics: Adult; Antiviral Agents; Carbamates; Female; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Male; Middle Aged; Scotland; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

NS5A-P32 deletion (P32del) is a resistance-associated amino acid change that has recently gained popularity in direct-acting antiviral treatment for chronic hepatitis C. Although not yet detected in naive patients, it appears in 5 to 10% of hepatitis C genotype 1b patients who fail to respond to daclatasvir/asunaprevir and sofosbuvir/ledipasvir treatments. In contrast to signature resistance-associated substitutions, such as substitutions at the NS5A-L31 and NS5A-Y93 positions, it shows complete resistance to all NS5A inhibitors in replicon and cell culture. Studies of humanized liver mice suggest that P32del retains good replication fitness and requires two classes of antivirals, except NS5A inhibitors, to be suppressed effectively. Patients with the P32del virus do not respond to glecaprevir/pibrentasvir but do respond to sofosbuvir/velpatasvir/voxilaprevir, presumably to sofosbuvir + glecaprevir/pibrentasvir, and at least partially to sofosbuvir/velpatasvir + ribavirin. Attention should be given to P32del in patients who experience failure with any NS5A inhibitor, especially those with genotype 1b infection.

Topics: Aminoisobutyric Acids; Animals; Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Mice; Sofosbuvir

Hepatitis C (HCV) infection is a significant health threat, with increasing incidence rates in the setting of the opioid crisis. Many patients miss appointments and cannot initiate treatment. We implemented financial incentives to improve appointment attendance in a primary care-based HCV treatment setting.. We conducted a systems-level financial incentives intervention at the Adult Primary Care HCV Treatment Program at Boston Medical Center which provides care to many patients with substance use disorders. From April 1 to June 30, 2017, we provided a $15 gift card to patients who attended appointments with an HCV treatment provider. We evaluated the effectiveness of the incentives by 1) conducting a monthly interrupted time series analysis to assess trends in attendance January 2016-September 2017; and 2) comparing the proportion of attended appointments during the intervention to a historical comparison group in the previous year, April 1 to June 30, 2016.. 327 visits were scheduled over the study period; 198 during the intervention and 129 during the control period. Of patient visits in the intervention group, 72.7% were attended relative to 61.2% of comparison group visits (p = 0.03). Appointments in the intervention group were more likely to be attended (adjusted odds ratio 1.94, 95% confidence interval 1.16-3.24). Interrupted time series analysis showed that the intervention was associated with an average increase of 15.4 attended visits per 100 appointments scheduled, compared to the period prior to the intervention (p = 0.01).. Implementation of a financial incentive program was associated with improved appointment attendance at a safety-net hospital-based primary care HCV treatment program. A randomized trial to establish efficacy and broader implementation potential is warranted.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Female; Fluorenes; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Odds Ratio; Primary Health Care; Program Evaluation; Reward; Safety-net Providers; Sofosbuvir; Sustained Virologic Response; Young Adult

The advent of direct-acting antiviral (DAA) therapies has dramatically transformed HCV treatment, with most recent trials demonstrating high efficacy rates (>90%) across all genotypes and special populations, including patients with HIV/HCV coinfection. The efficacy rates of HCV treatment are nearly identical between patients with HCV monofection and patients with HIV/HCV coinfection; however, there are limited studies to compare real-world efficacy with efficacy observed in clinical trials. Using a database from HIV clinics across the United States (US), we identified 432 patients with HIV/HCV coinfection who completed DAA therapy from January 1, 2014 to March 31, 2017 and were assessed for efficacy. Efficacy was evaluated as sustained virologic response (SVR) 12 weeks after DAA completion; furthermore, factors associated with achieving SVR12 were identified. In this analysis, we found DAA therapies to be effective, with 94% of the patients achieving SVR12 and 6% experiencing virologic failure. Baseline variables, including older age, HCV viral load <800K IU/ML, FIB-4 score <1.45, absence of depression, diabetes, substance abuse, and use of DAA regimens without ribavirin were significant predictors of achieving SVR12. Patients with fewer comorbidities, better liver health, and lower HCV viral loads at baseline were more likely to achieve treatment success. Our results were consistent with other real-world studies, supporting the use of HCV therapy in HIV/HCV coinfected patients.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carbamates; Coinfection; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; United States; Uridine Monophosphate; Viral Load

Topics: Adult; Antiviral Agents; Carbamates; Child; Fatty Liver; Female; Hepacivirus; Hepatectomy; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Living Donors; Monitoring, Physiologic; Sofosbuvir; Transplant Recipients; Treatment Outcome; Viral Load

In this study, the authors report the case of a patient diagnosed with hepatitis C virus who was treated with sofosbuvir-velpatasvir (400/100 mg). As the patient was unable to swallow whole tablets, therapeutic drug monitoring was performed to evaluate the effect of crushing sofosbuvir-velpatasvir tablets on drug absorption and global exposure.

Topics: Aged; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Drug Combinations; Drug Monitoring; Female; Half-Life; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Neoplasms; Pyrrolidines; Quinoxalines; Sofosbuvir; Sulfonamides; Tablets

Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real-world analysis to date, the effectiveness of pangenotypic, panfibrotic, single-tablet, sofosbuvir/velpatasvir (SOF/VEL) once-daily for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed.. Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post-treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis.. Overall, 5552 patients were included: 13.3% treatment-experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non-virological reasons (67% lost to follow-up; 26.5% early treatment discontinuation).. In this large cohort, representative of clinical practice, a simple 12-week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.

Topics: Adult; Antiviral Agents; Carbamates; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Ribavirin; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

The hepatitis C virus (HCV) NS5A-P32 deletion (P32del) confers potent resistance to NS5A inhibitors. Chronic hepatitis C patients in whom NS5A-P32del variants had emerged during prior direct-acting antiviral (DAA) therapy with an NS5A inhibitor show poor response to DAA retreatment. Here, we report three patients with HCV NS5A-P32del infection who were treated with sofosbuvir, velpatasvir plus ribavirin (SOF/VEL + RBV) in a real-world setting. The patients developed HCV NS5A-P32del, L31F + P32del, or L31V + P32del variants following failure of daclatasvir plus asunaprevir (DCV/ASV) therapy. One of the patients failed to respond to subsequent DCV/ASV and beclabuvir therapy, and the remaining two patients failed to respond to subsequent glecaprevir and pibrentasvir therapy. All three patients completed 24-week SOF/VEL + RBV therapy. Serum HCV RNA became negative at the end of the therapy in all three patients. Two patients with NS5A-P32del and NS5A-L31F + P32del achieved sustained virological response 12 weeks after completion of treatment (SVR12), but HCV relapsed in the remaining NS5A-L13V + P32del patient. Direct sequence analysis detected no additional variants within either the NS5A or NS5B regions at the time of relapse. In conclusion, three patients with prior NS5A-P32del-associated DAA treatment failure received 24 weeks of SOF/VEL + RBV therapy, and two of the patients achieved SVR12.

Topics: Antiviral Agents; Carbamates; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Ribavirin; Sofosbuvir; Treatment Outcome

Topics: Antiviral Agents; Benzimidazoles; Betacoronavirus; Carbamates; Coronavirus Infections; COVID-19; Drug Repositioning; Fluorenes; Hepatitis B virus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Pandemics; Peptide Hydrolases; Pneumonia, Viral; SARS-CoV-2; Severe acute respiratory syndrome-related coronavirus; Spain

Hepatitis C virus (HCV) is an important human pathogen causing 400 000 chronic liver disease-related deaths annually. Until recently, the majority of laboratory-based investigations into the biology of HCV have focused on the genotype 2 isolate, JFH-1, involving replicons and infectious cell culture systems. However, genotype 2 is one of eight major genotypes of HCV and there is great sequence variation among these genotypes (>30 % nucleotide divergence). In this regard, genotype 3 is the second most common genotype and accounts for 30 % of global HCV cases. Further, genotype 3 is associated with both high levels of inherent resistance to direct-acting antiviral (DAA) therapy, and a more rapid progression to chronic liver diseases. Neither of these two attributes are fully understood, thus robust genotype 3 culture systems to unravel viral replication are required. Here we describe the generation of robust genotype 3 sub-genomic replicons (SGRs) based on the adapted HCV NS3-NS5B replicase from the DBN3a cell culture infectious clone. Such infectious cell culture-adaptive mutations could potentially promote the development of robust SGRs for other HCV strains and genotypes. The novel genotype 3 SGRs have been used both transiently and to establish stable SGR-harbouring cell lines. We show that these resources can be used to investigate aspects of genotype 3 biology, including NS5A function and DAA resistance. They will be useful tools for these studies, circumventing the need to work under the biosafety level 3 (BSL3) containment required in many countries.

Topics: Antiviral Agents; Carbamates; Cell Line, Tumor; Drug Resistance, Viral; Genome, Viral; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Mutation; Phosphorylation; Replicon; Viral Nonstructural Proteins; Virus Replication

Sofosbuvir/velpatasvir (SOF/VEL) is expected to be highly effective, even in patients with decompensated liver cirrhosis. However, portal hypertension can be problematic after achieving a sustained viral response (SVR), especially in patients with hepatic encephalopathy (HE) associated with large portal-systemic shunt. Although balloon-occluded retrograde transvenous obliteration (BRTO) is a useful option, whether BRTO or SOF/VEL therapy should be initially performed in patients with a poor liver function reserve is controversial. We herein report a case of refractory HE caused by decompensated liver cirrhosis due to hepatitis C virus (HCV) classified as Child-Pugh class C that was treated by BRTO after SVR with SOF/VEL. A 64-year-old woman with HCV-associated decompensated cirrhosis developed refractory HE. Dynamic contrast-enhanced computed tomography (CT) revealed large portal-systemic shunt. We treated the patient with 12 weeks of SOF/VEL, and she achieved SVR. Although the serum albumin level, edema, and ascites were improved, intractable HE remained. Her general condition had been improved after SVR, so HE was suspected to have been caused by portal-systemic shunting. We, therefore, treated the patient by BRTO. On dynamic contrast-enhanced CT, partial obstruction of the shunt vessel was confirmed after BRTO. Thereafter, her serum ammonia level rapidly improved, and HE did not recur. Interventional radiology such as BRTO following SOF/VEL therapy may be a useful option even in patients with decompensated HCV-associated cirrhosis accompanied by portal-systemic shunt.

Topics: Balloon Occlusion; Carbamates; Female; Hepacivirus; Hepatic Encephalopathy; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Middle Aged; Sofosbuvir; Treatment Outcome

We undertook this study to assess the incremental cost per quality adjusted life year (QALY) gained with the use of pan-genotypic sofosbuvir (SOF) + velpatasvir (VEL) for HCV patients, as compared to the current treatment regimen under the universal free treatment scheme in Punjab state.. A Markov model depicting natural history of HCV was developed to simulate the progression of disease. Three scenarios were compared: I (Current Regimen)-use of SOF + daclatasvir (DCV) for non-cirrhotic patients and ledipasvir (LDV) or DCV with SOF ± ribavirin (RBV) according to the genotype for cirrhotic patients; II-use of SOF + DCV for non-cirrhotic patients and use of SOF+VEL for compensated cirrhotic patients (with RBV in decompensated cirrhosis patients) and III-use of SOF+VEL for both non-cirrhotic and compensated cirrhotic patients (with RBV in decompensated cirrhosis patients). The lifetime costs, life-years and QALYs were assessed for each scenario, using a societal perspective. All the future costs and health outcomes were discounted at an annual rate of 3%. Finally, the incremental cost per QALY gained was computed for each of scenario II and III, as compared to scenario I and for scenario III as compared to II. In addition, we evaluated the lifetime costs and QALYs among HCV patients for each of scenario I, II and III against the counterfactual of 'no universal free treatment scheme' scenario which involves patients purchasing care in routine setting of from public and private sector.. Each of the scenarios I, II and III dominate over the no universal free treatment scheme scenario, i.e. have greater QALYs and lesser costs. The use of SOF+VEL only for cirrhotic patients (scenario II) increases QALYs by 0.28 (0.03 to 0.71) per person, and decreases the cost by ₹ 5,946 (₹ 1,198 to ₹ 14,174) per patient, when compared to scenario I. Compared to scenario I, scenario III leads to an increase in QALYs by 0.44 (0.14 to 1.01) per person, and is cost-neutral. While the mean cost difference between scenario III and I is-₹ 2,676 per patient, it ranges from a cost saving of ₹ 14,835 to incurring an extra cost of ₹ 3,456 per patient. For scenario III as compared II, QALYs increase by 0.16 (0.03 to 0.36) per person as well as costs by ₹ 3,086 per patient which ranges from a cost saving of ₹ 1,264 to incurring an extra cost of ₹ 6,344. Shift to scenario II and III increases the program budget by 5.5% and 60% respectively.. Overall, the use of SOF+VEL is highly recommended for the treatment of HCV infection. In comparison to the current practice (scenario I), scenario II is a dominant option. Scenario III is cost-effective as compared to scenario II at a threshold of one-time GDP per capita. If budget is an important constraint, velpatasvir should be given to HCV infected cirrhotic patients. However, if no budget constraint, universal use of velpatasvir for HCV treatment is recommended.

Topics: Adult; Antiviral Agents; Carbamates; Cohort Studies; Cost-Benefit Analysis; Disease Progression; Drug Therapy, Combination; Genotype; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; India; Markov Chains; Quality-Adjusted Life Years; Sofosbuvir; Universal Health Insurance

A 30-year-old woman living with HIV was diagnosed with genotype 2b hepatitis C virus (HCV) infection during the second trimester of her pregnancy. She had achieved virologic suppression on an HIV protease inhibitor-based regimen and had recurrent genital herpes simplex virus infection managed with antivirals. Given the risk of perinatal transmission of HCV and to avoid performing a caesarean section, after multidisciplinary consultations and consideration of the limited data on safety on HCV direct-acting antivirals (DAAs) in pregnancy, she consented to and was successfully treated with a 6-week lead-in course of sofosbuvir (SOF) alone followed by a 6-week course of SOF and velpatasvir postpartum. This resulted in cure of her HCV infection. The neonate tested negative for HCV at birth and was healthy without birth defects 2 years postdelivery. Our case highlights a successful HCV treatment approach in a pregnant woman with newer DAAs.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; Carbamates; Female; Hepatitis C; Herpes Genitalis; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Sofosbuvir

Topics: Carbamates; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Sofosbuvir

Topics: Carbamates; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Sofosbuvir

Topics: Asia; Carbamates; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Sofosbuvir

Topics: Carbamates; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Japan; Liver Cirrhosis; Ribavirin; Sofosbuvir

The emergence of a deletion mutant at hepatitis C virus (HCV) NS5A-P32 (P32del) has recently been reported in a subset of chronic hepatitis C patients who experience virologic failure after direct-acting antiviral drug (DAA) treatment. This mutation confers extremely high resistance to NS5A inhibitors. No effective treatment has been established for cases with this mutation.. We used a JFH1-based recombinant virus with NS5A from a genotype 1b strain to introduce a P32del mutation. We inoculated human hepatocyte chimeric mice with sera from a patient with ledipasvir/sofosbuvir therapy failure carrying a genotype 1b HCV with NS5A L31M and P32del or from a DAA-naïve patient carrying wild-type virus.. JFH1-based chimeric viruses with P32del showed sufficient levels of replication for in vitro assay despite the suppression of viral growth and infectious virus production. Variants with P32del exhibited severe resistance to all tested NS5A inhibitors, including daclatasvir, ledipasvir, elbasvir and velpatasvir, but were as susceptible to NS3/4A inhibitors, NS5B inhibitors, interferon alfa-2b, and ribavirin as wild-type viruses in the in vitro assay. The P32del mutant virus caused persistent infection in all inoculated chimeric mice with high viral titer and frequency. The virus was resistant to the ledipasvir/GS-558093 (a nucleotide analog inhibitor of NS5B polymerase) regimen but susceptible to either simeprevir plus GS-558093 or peg-interferon alfa-2b, compared to the wild-type virus.. Therapies combining at least two drugs among NS3/4A inhibitors, NS5B inhibitors and non-selective antiviral agents may be effective for HCV-infected patients with NS5A-P32del.

Topics: Aged; Animals; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cell Line; Chimera; Drug Resistance, Viral; Drug Therapy, Combination; Fluorenes; Guanosine Monophosphate; Hepacivirus; Hepatitis C; Hepatocytes; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interferon alpha-2; Interferon-alpha; Male; Mice; Middle Aged; Polyethylene Glycols; Pyrrolidines; Recombinant Proteins; Ribavirin; Sequence Deletion; Serine Proteases; Simeprevir; Valine; Viral Nonstructural Proteins

Topics: Adult; Antiviral Agents; Carbamates; Female; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Sofosbuvir; Treatment Outcome

Treatments for Hepatitis C virus (HCV) infection have vastly improved over the past few decades with current regimens now offering pangenotypic activity with excellent cure rates reported in clinical trials, including in the HIV-HCV coinfected population. However, there is some concern that stringent inclusion and exclusion criteria in the trials may lead to results that are not achievable in real-world populations.. Our study evaluated a real-world HIV-HCV coinfected population and compared them to the eligibility criteria for trials of two of the most recent approved HCV agents; sofosbuvir/velpatasvir and glecaprevir/pibrentasvir.. Our study included 219 HIV-HCV coinfected patients and found that 89% met exclusion criteria for the sofosbuvir/velpatasvir trial and 90% met exclusion criteria for the glecaprevir/pibrentasvir trial. The majority of patients met more than one exclusion criteria with the most frequent criteria for exclusion being a non-approved ART regimen (58 and 47% respectively), having a psychiatric disorder (52%), active alcohol or injection drug use (27%), having an HIV viral load > 50 copies/ml (15%), a CrCl < 60 ml/min (13%) and a history of decompensated cirrhosis (13%).. Although the newer Hepatitis C treatments are very effective, the real world HIV-HCV coinfected population often have comorbidities and other characteristics that make them ineligible for clinical trials, such that they are barriers to treatment. These barriers need to be recognized and addressed in order to optimize treatment outcomes in the HIV patient population.

Topics: Adult; Aged; Aminoisobutyric Acids; Anti-Retroviral Agents; Antiviral Agents; Benzimidazoles; Carbamates; Coinfection; Cyclopropanes; Drug Interactions; Female; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Male; Middle Aged; Proline; Pyrrolidines; Quinoxalines; Sofosbuvir; Sulfonamides; Treatment Outcome; Viral Load

The pangenotypic single tablet regimen of NS5B inhibitor sofobuvir (SOF) and NS5A inhibitor velpatasvir (VEL) is advised for 12 weeks in HCV-infected patients including those with compensated cirrhosis. Addition of ribavirin (RBV) may be considered in genotype 3 (GT3) with compensated and is recommended in decompensated cirrhosis. Real-life results with SOF/VEL are limited. To evaluate efficacy and safety in a large real-world-cohort including patients with different GTs and various fibrosis stages.. In total, 1429 patients were treated with SOF/VEL 400/100 mg for 12 weeks in the Puglia registry between June 2017 and May 2018. 1319 (92.3%) reached week 12 post-treatment (SVR12) at the moment. Only 41 received RBV. Diagnosis of cirrhosis was based on transient elastography and/or APRI or FIB-4 scores. Sensitivity analysis in the population including all patients except non virological failure was conducted. Primary efficacy endpoint was the percentage of patients with SVR12.. Patients' mean age was 63.8 years, 42.3% had GT1. The majority were naïve and 735 (55.5%) F0/F2. Of the remaining 587, 282 had cirrhosis. SVR12 was 98.5%, 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4. Overall, SVR12 by sensitivity analysis was 99.4%; 99.7% among F0-F1. Among 218 PWID, SVR12 was 94.5%. Discontinuation rates were 3.7% among PWID and 0.7% among non-PWID (p = 0.004).. SOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carbamates; Drug Interactions; Female; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Male; Middle Aged; Safety; Sofosbuvir; Treatment Outcome; Young Adult

On July 18, 2017, the U.S. Food and Drug Administration (FDA) approved sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) (Vosevi) fixed-dose combination (FDC), an interferon-free, complete regimen for adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have: • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing a nonstructural protein 5A (NS5A) inhibitor; and • genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Approval was based on an acceptable safety profile and high sustained virological response rates 12 weeks after the end of treatment (SVR12) in two phase 3 clinical trials in subjects previously treated with a direct-acting antiviral (DAA) regimen. In POLARIS-1, 96% of SOF/VEL/VOX-treated subjects achieved SVR12. In POLARIS-4, 98% of SOF/VEL/VOX-treated subjects achieved SVR12. A key and challenging question in evaluating the data was determining the contribution of VOX to SOF/VEL and how this differed depending on the genotype and patient population. In this article, we provide our perspective on the issues considered in making these determinations, especially regarding the POLARIS-4 data in subjects who have previously been treated with a chronic HCV regimen containing sofosbuvir without an NS5A inhibitor. Conclusion: We seek to provide context as to why a broad indication was given for NS5A inhibitor-experienced patients (HCV genotypes 1-6) while the indication for NS5A inhibitor- naïve patients was limited to HCV genotypes 1a and 3 only. (Hepatology 2018;67:482-491).

Topics: Adult; Aminoisobutyric Acids; Antiviral Agents; Carbamates; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Risk Assessment; Sofosbuvir; Sulfonamides; Sustained Virologic Response; United States; United States Food and Drug Administration; Viral Nonstructural Proteins

The performances of core-shell 2.7 μm and fully porous sub-2 μm particles packed in narrow diameter columns were compared under the same chromatographic conditions. The stationary phases were compared for fast separation and determination of five new antiviral drugs; daclatasvir, sofosbuvir, velpatasvir, simeprevir, and ledipasvir. The gradient elution was done using ethanol as green organic modifier, which is more environmentally friendly. Although both columns provided very good resolution of the five drugs, core-shell particles had proven to be of better efficiency. Under gradient elution conditions, core-shell particles exhibited faster elution, better peak shape, and enhanced resolution adding to lower system backpressure. The column backpressure on sub-2 μm particles was more than twice that on core-shell particles. This gives a chance to use conventional high-performance liquid chromatography conditions without needing special instrumentation as that required for ultra-high performance liquid chromatography. The method was validated for determination of the five drugs by gradient elution using mobile phase composed of organic modifier ethanol and aqueous part containing 0.75 g sodium octane sufonate and 3.0 g sodium dihydrogen phosphate per liter at pH of 6.15. Detection was done using UV-detector set at 210 nm. The linearity, accuracy, and precision were found very good within the concentration range of 2-200 μg/mL.

Topics: Antiviral Agents; Benzimidazoles; Carbamates; Chromatography, High Pressure Liquid; Fluorenes; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Imidazoles; Molecular Conformation; Particle Size; Porosity; Pyrrolidines; Simeprevir; Sofosbuvir; Surface Properties; Valine

Twelve weeks of the pangenotypic direct-acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL-3 approval study. However, presence of resistance-associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response.. To assess the efficacy and safety of SOF/VEL ± ribavirin (RBV) and the impact of NS5A RASs and RBV use on treatment outcome in HCV GT3 infection in a real-world setting.. In this multicentre cohort study, GT3 patients from ten treatment centres across Germany were included. Sustained virological response was assessed 12 weeks after end-of-treatment (SVR12) in modified intention-to-treat (mITT) and per-protocol analysis (PP). NS5A RASs were tested by population-based sequencing.. A total of 293 GT3 patients were included. The median age was 48 years, 70% were male, 25.3% were cirrhotic, 9.2% were HCV/HIV co-infected and 21.8% were treatment-experienced, including 4.1% with DAA experience. Baseline NS5A RASs (Y93H, A30K, L31M) were detected in 11.2%. RBV was added in 5% of noncirrhotic and 58.9% of cirrhotic patients, respectively. SVR12 rates for SOF/VEL±RBV were 95.9% (mITT) and 99.5% (PP), respectively. Only 1 virological relapse occurred in a cirrhotic patient previously treated with SOF/RBV. No treatment-related major adverse events occurred.. Twelve weeks of SOL/VEL±RBV was safe and highly efficient in HCV GT3 across a diverse patient population. Baseline NS5A RASs were rarely observed and presence did not seem to impact SVR, regardless of the use of RBV.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Carbamates; Cohort Studies; Drug Resistance, Viral; Drug Substitution; Drug Therapy, Combination; Female; Genotype; Germany; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Male; Middle Aged; Sofosbuvir; Sustained Virologic Response; Treatment Outcome; Viral Nonstructural Proteins; Young Adult

Topics: Carbamates; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Ribavirin; Sofosbuvir

Topics: Carbamates; Genotype; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Ribavirin; Sofosbuvir

Velpatasvir (VLP) is a new, oral, direct-acting antiviral with potent inhibitory activity against all hepatitis C virus (HCV) genotypes. A highly sensitive, simple, fast and specific one fluorometric method for determination of VLP in the presence of sofosbuvir was developed and validated. The fluorescence behavior of VLP in different organic solvents was examined and explained. Methanol was concluded to be the best sensitizing reagent. The native fluorescence intensity of VLP was accomplished at 383 nm with 339 nm for excitation wavelength. The impacts of experimental variables included pH, various organized media, and time of stability were examined and optimized. A linear relationship was achieved between the VLP concentration and the fluorescence intensity in a range of 5 to 5 × 10

Topics: Antiviral Agents; Carbamates; Drug Stability; Fluorescence; Fluorometry; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Limit of Detection; Sofosbuvir

Topics: Antiviral Agents; Carbamates; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Liver Cirrhosis; Ribavirin; Sofosbuvir; Treatment Outcome

Topics: Antiviral Agents; Carbamates; Cryoglobulinemia; Exanthema; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Immunologic Factors; Male; Middle Aged; Rituximab; Sofosbuvir

Topics: Administration, Oral; Aminoisobutyric Acids; Antiviral Agents; Carbamates; Contraindications, Drug; Cyclopropanes; Drug Approval; Drug Combinations; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 4 or More Rings; Humans; Lactams, Macrocyclic; Leucine; Macrocyclic Compounds; Proline; Quinoxalines; Sofosbuvir; Sulfonamides