Sofosbuvir/velpatasvir/voxilaprevir Research Articles

Hepatitis C Virus Infection in the Elderly in the Era of Direct-Acting Antivirals: Evidence from Clinical Trials and Real Life.

The introduction of direct-acting antiviral agents (DAAs) into clinical practice has revolutionized the therapeutic approach to patients with chronic hepatitis C virus (HCV) infection. According to the most recent guidelines, the first line of treatment for HCV infection involves the use of one of three pan-genotypic DAA combinations, sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). These drugs have been shown to be effective and safe in numerous clinical trials and real-world studies, but special populations have been neglected. Among the special populations to be treated are elderly patients, whose numbers are increasing in clinical practice. The management of these patients can be challenging, in particular due to multiple comorbidities, polypharmacotherapy, and potential drug-drug interactions. This narrative review aims to summarize the current scientific evidence on the efficacy and safety of DAAs in the elderly population, both in clinical trials and in real-life settings. Although there is still a paucity of real-world data and no clinical trials have yet been conducted in the population aged ≥ 75 years old, some considerations about the efficacy and safety of DAAs in the elderly can be made based on the results of these studies. The pan-genotypic associations of DAAs appear to be as efficacious and safe in the elderly population as in the general population; this is both in terms of similar sustained virologic response (SVR) rates and similar frequencies of adverse events (AEs). However, further studies specifically involving this patient population would be necessary to confirm this evidence.

Treatment Outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir in Direct-Acting Antiviral-Experienced Hepatitis C Virus Patients: A Systematic Review and Meta-Analysis.

About 5% of chronic hepatitis C (CHC) patients experienced treatment failure with direct-acting antiviral (DAA) treatment. The global data on the practice and treatment outcomes of Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) in DAA-experienced CHC patients remains sparse. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of SOF/VEL/VOX as a salvage treatment in DAA-experienced CHC patients. We searched five electronic databases from inception to 31 January 2023. The study outcomes were SVR12 and treatment-related adverse effects, with subgroup analysis performed based on genotype, cirrhosis, HCC, prior SOF/VEL exposure, and region. We identified and analyzed data from 24 studies (2877 DAA-experienced CHC patients); 17.2% had prior SOF/VEL exposure, 25% received ribavirin with SOF/VEL/VOX, and 42% had pre-treatment resistance-associated substitution (RAS) testing performed. Eastern Mediterranean had a higher pooled SVR12 than the America and Europe regions (p < 0.05). Predictors of SOF/VEL/VOX failure were genotype 3, active HCC, baseline cirrhosis, and prior SOF/VEL. Baseline RAS mutation and ribavirin supplementation were not associated with higher SVR12. Treatment discontinuation because of drug-related adverse events was uncommon (10 studies, 0.2%). In summary, SOF/VEL/VOX is efficacious and safe for retreatment in DAA-experienced CHC patients, even with RAS mutation. Our findings support SOF/VEL/VOX as a first-line rescue treatment for DAA-experienced CHC patients.

Effectiveness and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir as a Hepatitis C Virus Infection Salvage Therapy in the Real World: A Systematic Review and Meta-analysis

IntroductionSofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) is the first direct-acting antiviral (DAA) therapy approved for patients who have previously failed a DAA-containing regimen including NS5A inhibitors. In clinical trials, SOF/VEL/VOX was associated with high rates of sustained virologic response at post-treatment week 12 (SVR12) and was well tolerated. However, the effectiveness and safety of SOF/VEL/VOX in the real world remained uncertain. We aimed to perform a systematic review and meta-analysis to assess the real world effectiveness and safety of SOF/VEL/VOX.MethodsWe systematically searched the PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases for relevant real world studies published before January 28, 2022. Patients with previous treatment failure who received SOF/VEL/VOX were included. The primary outcome was the percentage of patients achieving SVR12. Secondary outcome included adverse events (AEs) during treatment.ResultsFifteen studies with a total of 1796 HCV-infected patients with previous treatment failure were included. SVR12 rates were 93% (95% CI 91–95) in the ITT populations (n = 1517, 11 cohorts) and 96% (95% CI 95–97) in the PP populations (n = 1187, 10 cohorts). SVR12 rates were significantly higher in non-GT3-infected patients (OR = 2.29, 95% CI 1.23–4.27, P = 0.009) and non-cirrhotic patients (OR = 2.22, 95% CI 1.07–4.60, P = 0.03) than in GT3-infected patients and cirrhotic patients. Furthermore, the SVR12 rates of previous treatment of SOF/VEL were significantly lower than those of other regimens in both ITT and PP populations (P ≤ 0.001). Adverse events (AEs) were reported in 30% (228/760) of patients. Serious AEs (SAEs) were reported in 3.82% (29/760) of patients. The most frequently reported AEs were headache, asthenia, nausea, fatigue, and diarrhea, which were mostly mild in severity. AE-related treatment discontinuations were reported in 0.66% (5/760) of patients.ConclusionsConsistent with clinical trials, the real world evidence indicates that SOF/VEL/VOX is a well-tolerated and highly effective salvage therapy for HCV-infected patients with previous treatment failure. However, there may still be a risk of treatment failure for patients with GT3 infection, cirrhosis, or SOF/VEL treatment failure. The protocol of this study was registered at PROSPERO, registration no. CRD 42022306828.

Safety and efficacy of sofosbuvir–velpatasvir–voxilaprevir for re-treatment of chronic hepatitis C virus infection in patients with previous direct-acting antiviral treatment failure in Rwanda (SHARED-3): a single-arm trial

Hepatitis C virus (HCV) genotype 4 non-a/d subtypes, which frequently have NS5A resistance-associated substitutions, are highly prevalent in sub-Saharan Africa. These subtypes, particularly genotype 4r, have been associated with higher rates of failure of treatment regimens containing the NS5A inhibitors ledipasvir or daclatasvir, which are the most accessible direct-acting antivirals in low-income countries. Clinical evidence regarding the efficacy of re-treatment options for these subtypes is limited. We aimed to evaluate the safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir for the treatment of adults in Rwanda with chronic HCV infection, predominantly of genotype 4, and a history of direct-acting antiviral treatment failure. In this single-arm prospective trial, we enrolled adults (aged ≥18 years) with a HCV RNA titre of at least 1000 IU/mL, and a documented history of direct-acting antiviral failure. Patients were assessed for eligibility at a single study site after referral from hospitals with HCV treatment programmes throughout Rwanda, and participants for whom sofosbuvir-ledipasvir treatment had failed in the previous SHARED trial were also included. Participants with decompensated liver disease or hepatitis B virus co-infection were excluded. Participants were treated once daily with an oral fixed-dose combination tablet containing sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) for 12 weeks. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after completion of treatment (SVR12) in the intention-to-treat population. Viral sequencing of NS3, NS5A, and NS5B genes was done at baseline in all participants and at end of follow-up (week 24) in participants with treatment failure. The study is registered with ClinicalTrials.gov (NCT03888729) and is completed. Between Sept 23, 2019, and Jan 10, 2020, 49 individuals were screened and 40 participants were enrolled. 20 (50%) were female, 20 (50%) were male, median age was 63 years (IQR 56-68), and median HCV viral load was 6·2 log10 IU/mL (5·8-6·5) at baseline. The genotype subtypes identified were 4r (18 [45%] participants), 4k (six [15%]), 4b (five [13%]), 4q (four [10%]), 4l (two [5%]), 4a (one [3%]), 4m (one [3%]), and 3h (one [3%]). One (3%) genotype 4 isolate could not be subtyped, and one (3%) isolate was of unknown genotype. All successfully sequenced isolates (33 [83%]) had at least two NS5A resistance-associated substitutions and 25 (63%) had three or more. 39 (98% [95% CI 87-100]) participants had SVR12. Seven (18%) participants had a total of ten grade 3, 4, or 5 adverse events, including three (8%) cases of hypertension, and one (3%) case each of cataract, diabetes, gastrointestinal bleeding, joint pain, low back pain, vaginal cancer, and sudden death. Four of these events were categorised as serious adverse events resulting in hospitalisation. The one sudden death occurred at home from an unknown cause 4 weeks after the completion of treatment. No serious adverse event was determined to be related to the study drug or resulted in treatment discontinuation. A 12 week course of sofosbuvir-velpatasvir-voxilaprevir is safe and efficacious for the re-treatment of individuals infected with HCV genotype 4 non-a/d subtypes with frequent baseline NS5A resistance-associated substitutions, following failure of previous direct-acting antiviral treatment. Improved affordability and access to sofosbuvir-velpatasvir-voxilaprevir in regions with these subtypes is crucial. Gilead Sciences.

Early post-liver transplant HCV eradication with sofosbuvir/velpatasvir/voxilaprevir in NS5A-inhibitor experienced patients

Introduction: DAA revolutionized HCV treatment landscape. In HCV viremic patients at liver transplant (LT), early post-LT DAA therapy prevents graft damage and extrahepatic HCV involvement. Few data are available regarding patients who are HCV NS5B+NS5A inhibitors experienced at LT. We aimed to describe our first 6 patients treated early post-LT with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks.

Glecaprevir/Pibrentasvir + Sofosbuvir + Ribavirin as a salvage regimen after Sofosbuvir + Velpatasvir + Voxilaprevir re-treatment failure

Antiviral therapy of chronic hepatitis C virus (HCV) achieves sustained virological response (SVR) in the majority of patients. Even after initial virological failure, re-treatment with the combination of sofosbuvir+velpatasvir+voxilaprevir (SOF/VEL/VOX) has been established as an effective second line regimen. However, some patients fail to achieve SVR after a second antiviral course with SOF/VEL/VOX. These patients are considered difficult-to-cure. Currently, the optimal regimen for antiviral re-re-treamtent is a matter of debate and European and American guidelines suggest the combination of SOF+glecaprevir/pibrentasvir (G/P) + Ribavirin as a salvage regimen. However, there is only little evidence to support this. In this study, data of two patients with genotype 3 chronic HCV infection, liver cirrhosis and virological failure after re-treatment with SOF/VEL/VOX that successfully achieved SVR with the combination of SOF+G/P ± RBV. Importantly, one patient had Child B cirrhosis to the time of treatment initiation. No adverse events were reported. Thus, our data support the use of SOF + G/P + RBV as a salvage regimen after re-treatment failure with SOF/VEL/VOX.

Salvage Therapy with Sofosbuvir/Velpatasvir/Voxilaprevir in DAA-experienced Patients: Results from a Prospective Canadian Registry.

Despite the current highly effective therapies with direct-acting antiviral agents (DAAs), some patients with chronic hepatitis C virus (HCV) infection still do not achieve sustained virological response (SVR) and require retreatment. Sofosbuvir/velpatasvir/voxilaprevir (SVV) is recommended as the first-line retreatment option for most patients. The aim of this study was to evaluate the efficacy of SVV as salvage therapy after at least one course of DAA. Data were collected on all HCV-infected patients who failed DAAs and were prescribed SVV from a prospective Canadian registry (CANUHC) including 17 sites across Canada. Factors associated with failure to achieve SVR with SVV therapy and the utility of RAS testing and ribavirin use were evaluated. A total of 128 patients received SVV after non-SVR with DAA treatment: 80% male, median age 57.5 (31-86), 44% cirrhotic, and 17 patients post liver transplant. First line regimens included: sofosbuvir/velpatasvir (27.3%), sofosbuvir/ledipasvir (26.5%), grazoprevir/elbasvir (12.5%), other (33.5%). Ribavirin was added to SVV in 26 patients due to past sofosbuvir/velpatasvir use (n = 8), complex resistance associated substitution profiles (n = 16) and/or cirrhosis (n = 9). Overall SVR rate was 96% (123/128). Of 35 patients who previously failed sofosbuvir/velpatasvir, 31 (88.5%) achieved SVR compared to 92 of 93 (99%) among those receiving any other regimen (P = .01). Similar to reports from phase 3 clinical trials, SVV proved highly effective as salvage therapy for patients who failed a previous DAA therapy. Those who failed SVV had at least 2 of the following factors: genotype 3, presence of cirrhosis, past liver transplantation, past exposure to sofosbuvir/velpatasvir and/or complex resistance profiles.

Concomitant use of direct-acting antivirals (DAA) and central nervous system drugs in patients with hepatitis C virus infection.

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.

S3256 Hyperbilirubinemia in Chronis Hepatitis C Patients Treated With Protease Inhibitors

INTRODUCTION: Sofosbuvir/velpatasvir/voxilaprevir (SVV) and Glecaprevir/pibrentasvir (GP) are direct acting antiviral (DAA) agents used for chronic hepatitis C virus (HCV) infection. Both are pan-genotypic and used for treatment-experienced patients without cirrhosis or with compensated cirrhosis. Additionally, GP is approved in treatment-naïve patients. Hyperbilirubinemia has emerged as a potential adverse effect for these two medications due to significantly elevated NS3/4A protease inhibitor concentration. We aim to assess the incidence of hyperbilirubinemia in patients treated with these medications. METHODS: This is a retrospective study at a single tertiary care center. Patients who were treated with either SVV or GP between August 2017, and February 2020, were included. Patients who lost to follow-up were excluded. Laboratory exams were performed on a monthly basis. The population was analyzed based on treatment received: SVV +/- Ribavirin (RBV) and GP groups. Abnormal total bilirubin (Tbili) was defined as >1.2 mg/dL. Analyzed data included demographics, therapy history, achievement of sustained virologic response (SVR), hyperbilirubinemia incidence during the treatment period, timing and peak of T.bili, and all-cause mortality rate. RESULTS: Of the 229 charts reviewed, 196 met the inclusion criteria. Age ranged from 19 to 89 years old with a mean of 61, and 63% were males. 164 patients received GP, whereas 32 received SVV +/- RBV. Genotype 1 was the most prevalent. 25% of the population had compensated cirrhosis, and 4 patients underwent liver transplant. The incidence of hyperbilirubinemia was 12.8%, with a mean duration between therapy initiation and peak Tbili of 40 days. The highest Tbili measured was 6 mg/dL. 8.6% of patients had a peak Tbili >1.5 mg/dL, 3% had a peak Tbili >2 mg/dL, and only 1.5% had a peak Tbili >3 mg/dL. None of the patients had to stop therapy due to hyperbilirubinemia. The all-cause mortality rate was 2%, and causes were unrelated to hyperbilirubinemia or liver disease. There was no statistically significant difference in mean Tbili at treatment initiation or at peak between patients who received SVV +/- RBV and those who received GP, P = 0.227 and P = 0.129, respectively. CONCLUSION: Hyperbilirubinemia is a common side effect of DAAs containing NS3/4A protease inhibitors. Although it may not be clinically significant, clinicians should be mindful of potential hyperbilirubinemia and closely monitor chronic HCV patients treated with these agents with follow-up labs.

Potential interactions between pangenotypic direct-acting antivirals and concomitant cardiovascular therapies in patients with chronic hepatitis C virus infection.

ObjectiveTo identify potential drug interactions (DIs) between pangenotypic direct-acting antivirals (pDAAs) and concomitant cardiovascular (CV) therapies in patients with chronic hepatitis C (CHC).MethodsA retrospective observational study was carried out. Patients ≥18 years of age diagnosed with CHC and treated with pDAAs during 2017 were included. Information was collected on concomitant CV therapies and potential DIs [www.hep-druginteractions.org]. The pDAAs analyzed were sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). An analysis including lipid-lowering drugs was also performed.ResultsIn total, 1286 patients (mean age 64.9 years, 56.6% men) were recruited. The percentages of potential DIs with CV drugs were 1.9% contraindications, 38.1% clinically significant and 2.4% weak. When lipid-lowering drugs were included, the percentages of potential DIs with CV drugs were 10.3% contraindications, 46.3% clinically significant and 3.2% weak. Potential DIs associated with each pDAA were as follows (contraindications; clinically significant; weak): SOF/VEL (1.4%; 23.0%; 0.9%), GLE/PIB (12.8%; 60.8%; 4.7%) and SOF/VEL/VOX (16.6%; 55.1%; 4.9%).ConclusionsApproximately on third of patients with CHC are concomitantly treated with CV drugs. SOF/VEL may have fewer DIs with CV drugs than other pDAAs.

Efficacy and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus (HCV) NS5A-Inhibitor Experienced Patients With Difficult to Cure Characteristics.

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.

Efficacy of sofosbuvir/velpatasvir/voxilaprevir in direct-acting antiviral experienced patients with hepatitis C virus.

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.

Prevalence of the potential drug–drug interactions between pangenotypic direct-acting antivirals and the concomitant medications associated with patients with chronic hepatitis C virus infection in Spain

Abstract Objective To determine the comorbidity and potential for drug–drug interactions (DDIs) among pangenotypic direct-acting-antivirals (pDAAs) and the concomitant medications associated with chronic hepatitis C (CHC) patients in routine clinical practice in Spain. Methods Retrospective observational study. Included patients were ≥18 years, diagnosed with CHC, on antiviral treatment and required medical attention during 2017. Two groups were differentiated according to age ranges ( www.hep-druginteractions.org ). The pDAAs analysed were: a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) and c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Bivariate statistical analysis, p Results 3430 patients with a mean age of 56.9 years and 60.3% males were enrolled. The average Charlson index was 0.8. Age range distribution: 18–49 years (28.9%) and ≥50 years (71.1%). The average number of medications per patient/year was 3.1 (SD 2.6). The total percentage of potential DDIs was: 8.6% minor DDIs, 40.5% clinically significant DDIs and 10.0% contraindicated medication. These DDIs were greater in patients ≥50 years (8.6%, 43.8% and 12.4%, respectively, p Conclusions Patients with CHC present high comorbidity and concomitant medication use, particularly elderly patients, thus implying a greater exposure to potential DDIs. Although the DDI rate was considerable with the three combinations analysed, SOF/VEL showed a lower number of clinically significant interactions.

Prevalencia de las potenciales interacciones medicamentosas entre los antivirales de acción directa pangenotípicos y la medicación concomitante asociada a los pacientes con infección del virus de la hepatitis C crónica en España

ObjectiveTo determine the comorbidity and potential for drug-drug interactions (DDIs) among pangenotypic direct-acting-antivirals (pDAAs) and the concomitant medications associated with chronic hepatitis C (CHC) patients in routine clinical practice in Spain. MethodsRetrospective observational study. Included patients were ≥18 years, diagnosed with CHC, on antiviral treatment and required medical attention during 2017. Two groups were differentiated according to age ranges (<50 and ≥50 years). The variables collected were: age, gender, general/specific comorbidity, concomitant medication and potential DDIs (www.hep-druginteractions.org). The pDAAs analysed were: a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) and c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Bivariate statistical analysis, P<.05. Results3,430 patients with a mean age of 56.9 years and 60.3% males were enrolled. The average Charlson index was 0.8. Age range distribution: 18–49 years (28.9%) and ≥50 years (71.1%). The average number of medications per patient/year was 3.1 (SD 2.6). The total percentage of potential DDIs was: 8.6% minor DDIs, 40.5% clinically significant DDIs and 10.0% contraindicated medication. These DDIs were greater in patients ≥50 years (8.6%, 43.8% and 12.4%, respectively, P<.001). For all ages, SOF/VEL showed a lower percentage of: minor interactions (1.3% vs. 6.6% and 5.9%, P<.001); clinically significant interactions (53.4%, vs. 77.4% and 66.3%, P<.001) and contraindicated medication (1.7% vs. 8.3% and 10.7%, P<.001) compared to GLE/PIB and SOF/VEL/VOX, respectively. ConclusionsPatients with CHC present high comorbidity and concomitant medication use, particularly elderly patients, thus implying a greater exposure to potential DDIs. Although the DDI rate was considerable with the three combinations analysed, SOF/VEL showed a lower number of clinically significant interactions.

A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY)

Cure rates in response to retreatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are high, but this regimen has not been studied in patients with a history of poor adherence or treatment interruption, nor in patients with HIV/HCV coinfection. Herein, we aimed to assess the safety and efficacy of this combination in patients with genotype 1 HCV infection who had relapsed following combination direct-acting antiviral (DAA) therapy, regardless of HIV infection or previous treatment course. The RESOLVE study was a multicenter, open-label, phase IIb study investigating the safety, tolerability and efficacy of SOF/VEL/VOX in 77 patients with virologic rebound following combination DAA therapy. Efficacy was defined as HCV RNA below the lower limit of detection 12 weeks after the end of treatment (SVR12), while safety endpoints included the incidence of grade 3 and 4 adverse events (AEs) following treatment, and the proportion of patients who stopped treatment prematurely due to AEs. In an intent-to-treat analysis, 70/77 (90.9%, 95% CI 82.1-95.8%) patients achieved SVR12, including 14/17 (82.4%) HIV coinfected participants and 18/22 (81.8%) of those with previous non-completion of DAA therapy. In an analysis of all patients who completed 12 weeks of study medication, 70/71 patients (99%) achieved SVR12. One patient experienced a grade 3 AE, and 4 experienced a grade 4 AE, all unrelated to study participation. Reported AEs were similar in HIV-coinfected patients, and patients receiving dolutegravir-based antiretroviral treatment experienced no clinically significant increases in aminotransferases. Retreatment with 12 weeks of SOF/VEL/VOX was safe and effective in patients with relapsed HCV following initial combination DAA-based treatment. Treatment response was not affected by HIV coinfection or previous treatment course. Twelve weeks of the combination of direct-acting antivirals (SOF/VEL/VOX) was safe and effective in patients with relapsed hepatitis C virus infection who had previously received combination therapy with direct-acting antivirals. Treatment response was not diminished by HIV coinfection, or non-completion of previous direct-acting antiviral-based therapy.

Real-world effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 573 direct-acting antiviral experienced hepatitis C patients.

Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) provides a needed hepatitis C virus (HCV) antiviral option for direct-acting antiviral (DAA)-experienced patients. We evaluated the effectiveness of SOF/VEL/VOX for 12weeks in DAA-experienced patients with genotype 1-4 treated in clinical practice. In this observational cohort analysis from the Veterans Affairs' Clinical Case Registry, 573 DAA-experienced patients initiating SOF/VEL/VOX were included: 490 genotype 1, 20 genotype 2, 51 genotype 3 and 12 genotype 4. Rates of cirrhosis were 32.7%, 30.0%, 49.0% and 58.3%; rates of prior NS5A-experience were 100.0%, 95.0%, 90.2% and 100.0% for genotypes 1-4, respectively. Overall SVR rates were 90.7% (429/473), 90.0% (18/20), 91.3% (42/46) and 100.0% (12/12) for genotypes 1-4, respectively, and were 91.3% (274/300), 88.9% (16/18), 90.2% (37/41) and 100.0% (11/11) for those with prior NS5A+NS5B experience. For genotype 1, SVR rates were similar in patients with prior regimens of ledipasvir/SOF (90.6%, 298/329), elbasvir/grazoprevir (91.2%, 73/80) and ombitasvir/paritaprevir/ritonavir/dasabuvir (90.9%, 70/77). SVR rates in genotype 1, 2 and 3 patients with prior SOF/VEL experience were 78.9% (15/19), 86.7% (13/15) and 84.6% (11/13). In genotype 1-4 patients completing 12weeks of SOF/VEL/VOX, overall SVR rates were 95.1% (409/430), 89.5% (17/19), 93.3% (42/45) and 100% (12/12). In this diverse real-world cohort of heavily NS5A pretreated patients, SOF/VEL/VOX SVR rates in DAA-experienced patients were high across all genotypes. Genotype 1 patients who had prior experience with the most commonly prescribed NS5A regimens achieved similarly high SVR rates when retreated with SOF/VEL/VOX. For genotypes 1, 2 and 3, patients with prior SOF/VEL experience had lower SVR rates.

Sofosbuvir/Velpatasvir/Voxilaprevir for Previous Treatment Failures With Glecaprevir/Pibrentasvir in Chronic Hepatitis C Infection.

Chronic hepatitis C-infected patients who do not respond to nonstructural 5A inhibitor-containing regimens have few treatment options. It is unclear if patients who fail glecaprevir/pibrentasvir (G/P) (Mavyret) can be re-treated with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) (Vosevi) because the latter's registration trials antedated the availability of the former. Adherent virologic failures to G/P were re-treated with 12 weeks of SOF/VEL/VOX, and all subjects underwent resistance testing at baseline and again with subsequent relapse. Ninety-four percent of subjects achieved sustained virologic response with re-treatment, despite 90% of 31 subjects harboring nonstructural 5A inhibitor resistance-associated mutations at baseline. SOF/VEL/VOX is an effective regimen for virologic failures to G/P.

Sofosbuvir/velpatasvir/voxilaprevir in the Treatment of Chronic Hepatitis C Infection

The landscape of HCV treatment has been entirely transformed due to the development of direct-acting antivirals (DAAs), but there are limited data guiding salvage therapy in patients who previously failed an NS5A inhibitor-containing DAA regimen. We review the preclinical and clinical data for sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pan-genotypic treatment for chronic HCV infection. This combination is a highly effective, well-tolerated and safe 12-week treatment regimen for patients with any genotype, including genotype-3 patients with baseline resistance-associated substitutions (RAS). Its most distinctive role is in patients who have previously failed treatment with advanced DAA regimens. Its efficacy is not significantly affected by RASs, and treatment-emergent RASs are uncommon.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Treatment of Recurrent Hepatitis C Virus Infection After Liver Transplantation.

There are limited data on direct‐acting antiviral (DAA) treatment options for previously treated patients with recurrent genotype 3 (GT3) hepatitis C virus (HCV) after liver transplantation. Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is currently approved for treatment of HCV in patients with prior treatment with DAAs. We report the first published experience using SOF/VEL/VOX after liver transplantation for a DAA‐experienced patient with severe hepatitis due to early recurrent GT3 HCV. The patient was treated with SOF/VEL/VOX that was extended to a total duration of 16 weeks and was intensified with ribavirin (RBV) starting at week 8 due to persistent viremia during treatment. Sustained virologic response at 12 weeks (SVR12) after treatment completion was achieved. SOF/VEL/VOX was well tolerated, and immediate drug–drug interaction (DDI) with tacrolimus (TAC) was not evident. Due to improvement in liver metabolic function with increasing TAC clearance, TAC dose adjustment was required throughout the treatment course. Conclusion: SOF/VEL/VOX can be considered for treatment of recurrent HCV after transplantation. Further study is needed to establish safety and efficacy and define treatment duration in difficult‐to‐treat populations.

Review article: novel antivirals for hepatitis C-sofosbuvir/velpatasvir/voxilaprevir, glecaprevir/pibrentasvir.

In 2017, the hepatitis C treatment regimens sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) and glecaprevir/pibrentasvir (G/P) received approval from the U.S. Food and Drug Administration. Although both SOF/VEL/VOX (NS5B polymerase inhibitor/NS5A inhibitor/NS3/4A protease inhibitor) and G/P (NS3/4A protease inhibitor/NS5A inhibitor) are pangenotypic regimens, they are indicated for distinct subsets of patients with hepatitis C. To compare and contrast available safety and efficacy data for SOF/VEL/VOX and G/P and outline their clinical utility. For each of the regimens, this review outlines the indications, safety information, and the major clinical studies in which SOF/VEL/VOX and G/P were evaluated. SOF/VEL/VOX is positioned as a salvage regimen for patients previously treated with NS5A inhibitors and for genotype 1a- and 3-infected patients who had failed other sofosbuvir-containing regimens. G/P is the first pangenotypic regimen with an 8-week duration for treatment-naïve, non-cirrhotic patients, and it is indicated for patients with any genotype who have advanced kidney disease, including those on dialysis. The addition of SOF/VEL/VOX and G/P to existing hepatitis C treatment options will expand the number of patients who are eligible for and responsive to treatment, thus increasing the possibility of eliminating hepatitis C as a public health issue.