Pangenotypic Regimen Research Articles

Comparison of direct sequencing of the NS5B region with the Versant HCV genotype 2.0 assay for genotyping of viral isolates in Mexico

Hepatitis C virus (HCV) infection affects an estimated 71 million people worldwide. HCV is classified into eight genotypes and >70 subtypes. Determination of HCV genotype is important for selection of type and duration of antiviral therapy, and genotype is also a predictor of treatment response. The most commonly used HCV genotyping method in clinical laboratories is a hybridization-based line probe assay (LiPA; Versant HCV Genotype 2.0). However, these methods have a lack of specificity in genotype identification and subtype assignment. Here, we compared the performance of Versant HCV Genotype 2.0 with the gold standard direct sequencing of the NS5B region, in 97 samples from Mexican patients. We found a genotypic concordance of 63.9% between these methods. While 68 samples (70%) were classified into HCV genotype 1 (GT1) by NS5B sequencing, it was not true for 17 samples (17.5%), which were not match HCV subtype by LiPA. Furthermore, nine of the 33 samples classified by NS5B sequencing as GT1a were not identified by LiPA. Use of direct sequencing could improve selection of the optimal therapy, avoid possible failures of therapy and avoid high costs resulting from incorrect genotyping tests in settings without broad access to pangenotypic regimens.

Factores que influyen en la curación de la hepatitis C en la era de los antivirales de acción directa

Direct-acting antiviral agents are highly potent drugs with a strong genetic barrier. Consequently, the factors influencing hepatitis C cure have been reduced and have progressively lost importance. Host factors, such as the presence of cirrhosis, race, and treatment adherence, influence sustained viral response. Adherence, together with treatment errors and drug interactions, are also important, especially in older patients. Viral factors, such as viral load, genotype, and the presence of baseline resistances affect the response rate but their influence can be minimised by using pan-genotypic regimens. Treatment simplification and the high efficacy of new antiviral treatments will allow treatment universalisation and will hopefully enable elimination of the infection in the next few decades.Supplement information: This article is part of a supplement entitled “The value of simplicity in hepatitis C treatment”, which is sponsored by Gilead.© 2019 Elsevier España, S.L.U. All rights reserved.

Viral dynamics among HCV infected patients with different genotypes treated with genotypic specific or pan-genotypic direct-acting antiviral agent combinations.

BackgroundNew hepatitis C virus (HCV) therapies have improved efficacy, allowed pangenotypic applications, increased barriers to drug resistance and shortened therapy duration.MethodsPatients infected with different HCV genotypes were divided into two groups: group 1 included 169 patients receiving genotypic specific regimens (GSR), while group 2 included 186 patients receiving pan-genotypic regimens (PGR). Patient’s HCV RNA was quantified and sequenced.ResultsComparable sustained viral response (SVR) rates were observed in both GSR and PGR treated patients. Nevertheless, even if not significant, a greater proportion of non-detectable levels (NDL) of HCV RNA was observed in patients treated with PGR as compared with GSR. Overall, among patients in the GSR and PGR groups with residual viremia, 124/169 (73.4%) and 125/186 (67.2%) at four weeks, and 66/169 (39.1%) and 58/186 (31.2%) at eight weeks, achieved SVR. No difference was observed in the clinical outcome comparing patients in the GSR and PGR groups according to genotype. While, comparing patients between the two groups, the proportion of patients with NDL HCV RNA at four and eight weeks was higher in patients infected with genotype 1b treated with PGR (p=0.0015). A significantly higher number of patients infected with 1b had RASs at baseline (p=0.0001). In addition, the proportion of patients with treatment failure was higher in patients with RASs at baseline compared with those without (p=0.012). Overall, 2.5% patients failed to achieve SVR after DAA treatment.ConclusionA sharp HCV RNA decrease was observed in patients treated with both GSR and PGR. However, even if comparable, a slightly greater number of patients treated with PGR achieved NDL HCV RNA as compared with GSR. A significant difference was observed in patients with baseline RASs, both in relation to treatment failure and genotype. In conclusion, the use of new DAA combinations helps patients achieve a more rapid virologic response.

Cost-effectiveness of pan-genotypic direct-acting antiviral regimens for treatment of chronic Hepatitis C in the United States

ABSTRACT Objectives Given the goal of hepatitis C virus elimination by 2030, World Health Organization guidelines recommend treatment of chronic hepatitis C (CHC) with pan-genotypic direct-acting antivirals, such as sofosbuvir/velpatasvir (SOF/VEL), SOF/VEL/voxilaprevir (VOX) or glecaprevir/pibrentasvir (GLE/PIB). The study evaluated the cost-effectiveness of pan-genotypic regimens in initial (SOF/VEL or GLE/PIB) and re-treatment (SOF/VEL/VOX or GLE/PIB+SOF+ribavirin (RBV)) of CHC. Methods A Markov state-transition model projected lifetime CHC health and economic outcomes from the US payer perspective. Model inputs were sourced from clinical trials or published literature and validated by hepatologists. Model outcomes included numbers of advanced liver disease events, life-years and quality-adjusted life-years (QALYs) gained, and total lifetime costs. One-way sensitivity analyses were performed on model results. Results SOF/VEL followed by SOF/VEL/VOX resulted in comparable cure rates to the GLE/PIB treatment pathway (99.94% vs. 99.93%, respectively). SOF-based regimens provided similar QALYs at a lower lifetime cost versus a GLE/PIB treatment pathway ($30,749 vs. $36,255), resulting in cost savings of $5,506 per patient. Results were robust in sensitivity analyses. Conclusion SOF/VEL followed by SOF/VEL/VOX leads to comparable cure rates in the overall CHC population relative to the GLE/PIB treatment pathway. Based on wholesale acquisition prices, the SOF/VEL treatment pathway led to lower lifetime costs.

High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in myanmar.

Exclusive HCV therapy clinical trials with genotype 6 patients in high prevalence areas have been sparse. We analysed the safety and efficacy of two generic, pangenotypic NS5A/NS5B combination oral DAA regimens, primarily in genotypes 3 and 6, in a real-world setting: (a) daclatasvir/sofosbuvir (DCV/SOF)±ribavirin (RBV) and (b) Velpatasvir/sofosbuvir (VEL/SOF±RBV). Between December 2015 and November 2017, data from 522 patients were analysed, 311 of whom were treated with DCV/SOF±RBV for 12/24weeks (genotype 3: n=193, genotype 6: n=89) and 211 were treated with VEL/SOF±RBV for 12/24weeks (genotype 3: n=83, genotype 6: n=77). Overall SVR rates were high for both DCV/SOF±RBV (96.1%, n=299/311) and VEL/SOF±RBV (95.3%, n=201/211), and there was a good adverse event profile. Treatment naïve status and inclusion of RBV (in advanced fibrosis/cirrhosis) were significant independent predictors of achieving SVR12, while type of DAA regimen was not predictive. In this large cohort of genotypes 3 (n=276) and 6 (n=166; n=127 unique subtype of 6c-l), high SVR rates of 94.9% (n=262/276) and 95.2% (n=158/166), respectively, were noted. In conclusion, generic and pangenotypic DCV/SOF and VEL/SOF±RBV regimens were highly effective and safe, in genotypes 3 and 6 chronic HCV in Myanmar. These efficacious pangenotypic regimens suggest that baseline genotype testing can be eliminated moving forward. While RBV may still be needed for those with advanced fibrosis/cirrhosis, in a global elimination strategy it would not be practical even if it does compromise SVR in a minority with difficult to treat characteristics.

State of the Art HCV Treatment in Children

Hepatitis C infection is a global issue with an estimated 5 million children with active HCV infection worldwide. The advent of oral direct-acting antiviral (DAA) regimens has revolutionized treatment in adults with excellent efficacy and tolerability. There are limited data and few approved therapies in children. The aim of this review is to discuss the currently approved regimens for children and the recently reported results of clinical trials of DAA in children. DAA regimens are currently approved only for children ≥ 12 years. For most children < 12 years, it is recommended that HCV therapy be deferred until patients are eligible for oral DAA therapies. For treatment-naive adolescents with HCV genotype 1, 4, 5, or 6, treatment with ledipasvir/sofosbuvir for 12 weeks has been reported to have sustained virologic response at 12 weeks of 98%. For treatment-naive adolescents with genotype 2 or 3 HCV, sofosbuvir- ribavirin combination therapy (12 weeks for genotype 2 and 24 weeks for genotype 3) has been reported to have SVR12 of 100% and 97%, respectively. There are promising, recently published studies showing excellent SVR12 rates for ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in adolescents with HCV genotype 1 or 4, and sofosbuvir/daclatasvir in children/adolescents with HCV genotype 4. Finally, ledipasvir/sofosbuvir ± ribavirin for children age 6–12 years with genotypes 1, 3, 4, 5, and 6 treated for either 12 or 24 weeks is reported to have an SVR12 rate of 99%. HCV treatment in children is rapidly evolving. There are now highly effective all-oral, interferon-free regimens for children ≥ 12 years. Clinical trials are on-going for adolescents and children < 12 years with a variety of pangenotypic ribavirin-free regimens, with anticipated approvals in the near future.

SVR12 rates higher than 99% after sofosbuvir/velpatasvir combination in HCV infected patients with F0-F1 fibrosis stage: A real world experience.

Background and objectivesThe 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.DesignIn 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.ResultsPatients’ 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).ConclusionsSOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID.

Discovery of velpatasvir (GS-5816): A potent pan-genotypic HCV NS5A inhibitor in the single-tablet regimens Vosevi® and Epclusa®.

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.

High efficacy of interferon-free therapy for acute hepatitis C in HIV-positive patients.

The treatment of acute hepatitis C (AHC) with direct-acting antiviral agents (DAAs) is considered a cornerstone of hepatitis C virus (HCV) elimination strategies, especially in human immunodeficiency virus (HIV)-infected individuals at high risk of onward transmission. Optimal treatment regimens and duration for AHC in HIV-coinfected patients remain to be established. Thus, we aimed to evaluate the efficacy and safety of DAA treatment regimens in the setting of AHC. All HIV-positive patients with a diagnosis of AHC according to the European AIDS Treatment Network (NEAT) consensus attending our clinic after 2014 were included. DAA treatment regimens and duration were based on current recommendations for chronic hepatitis C (CHC) at treatment initiation. Thirty-eight HIV/AHC patients (median age 42.0 years), mostly men who have sex with men (92%), were started on interferon-free regimens. HCV-genotype (GT) was predominately GT-1a (65%). The following DAA regimens were prescribed: ombitasvir/paritaprevir/ritonavir/dasabuvir (42%; 16/38), glecaprevir/pibrentasvir (29%; 11/38), sofosbuvir/ledipasvir (13%; 5/38), ombitasvir/paritaprevir/ritonavir (5%; 2/38), grazoprevir/elbasvir (5%; 2/38) and sofosbuvir/velpatasvir (5%; 2/38). All HIV/AHC patients achieved sustained virologic response 12 weeks after end of treatment (SVR12) (100%; 38/38). DAA-related adverse events were rare. Interferon-free DAA regimens (including 34% pan-genotypic regimens) yielded 100% SVR12 in HIV/AHC individuals if treatment durations similar to CHC are applied.

Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients

BackgroundHearts 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.MethodsWe 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.ResultsA 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.ConclusionsIn 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.)

Real-world effectiveness and safety of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir hepatitis C treatment in a single centre in Germany.

BackgroundNewer direct-acting antiviral therapies are increasingly becoming the therapy of choice in patients with hepatitis C virus (HCV) infection. Here, we report the safety and effectiveness of sofosbuvir/velpatasvir (SOF/VEL) and ledipasvir/sofosbuvir (LDV/SOF) in real-world cohorts in Germany.MethodsPatients initiated on SOF/VEL 12 weeks or LDV/SOF 8, 12 or 24 weeks regimens in a single German centre were included in this study. Data on treatment outcomes and adverse events (AE) were analysed in patients with available sustained virologic response 12 weeks after cessation of treatment (SVR12) information overall and by subgroups.ResultsThis study included 115 patients who received SOF/VEL from July-2016 to July-2017, and 249 patients who received LDV/SOF from November-2014 to September-2015. Overall, SVR12 was achieved in 99% of patients on SOF/VEL ± ribavirin 12 weeks independent of HCV genotype, treatment history, or cirrhosis status, and in 96% of patients treated with LDV/SOF 8 weeks or LDV/SOF ± ribavirin 12 or 24 weeks. In genotype 1 treatment-naïve, non-cirrhotic patients, ≥99% achieved SVR12 across SOF/VEL and LDV/SOF regimens. Likewise, 100% of genotype 3-cirrhotic patients on SOF/VEL ± ribavirin regimens achieved SVR12. Grade 3/4 AE were reported in 13 (5.2%) patients on LDV/SOF and in 1 (<1%) patient on SOF/VEL.ConclusionOverall, SOF/VEL and LDV/SOF achieved high SVR rates in a broad patient population. We showed the effectiveness of SOF/VEL as a pan-genotypic regimen, and regardless of treatment history or cirrhosis status. Use of such therapies improves outcomes and contributes towards the global efforts to eradicate HCV.

Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C infection: data from the German Hepatitis C-Registry.

Glecaprevir/pibrentasvir is a pangenotypic direct-acting antiviral regimen approved for treating adults chronically infected with hepatitis C virus (HCV). There are limited real-world data on glecaprevir/pibrentasvir to date. To evaluate the effectiveness and safety of glecaprevir/pibrentasvir under real-world conditions in the German Hepatitis C-Registry (DHC-R). The DHC-R is an ongoing, non-interventional, multicentre, prospective, observational cohort study that monitors patients with chronic HCV infection. Data were collected from patients who initiated glecaprevir/pibrentasvir and completed a screening visit on or after 2 August 2017. The primary effectiveness endpoint was sustained virological response at post-treatment Week 12 (SVR12). Safety and tolerability were also assessed. As of 15 July 2018, 586 patients received glecaprevir/pibrentasvir and had documented SVR12 data, treatment discontinuation, loss to follow-up or HCV reinfection. Five hundred and fifty-two patients (94%) received on-label treatment. At baseline, most on-label patients were infected with HCV genotype 1 (53%) or 3 (33%), HCV treatment-naïve (90%), without cirrhosis (94%), and treated for 8weeks (93%). Five hundred and thirty-four patients (96.7%) achieved SVR12 (intention-to-treat [ITT] analysis). By modified ITT analysis (excluding patients who discontinued and did not achieve SVR12 or patients lost to follow-up), the SVR12 rate was 99.4% (n/N=534/537). There was one documented virological failure (relapse) and two documented HCV reinfections. One hundred and forty-two (26%) adverse events (AEs) and 9 (2%) serious AEs occurred; 2 (<1%) AEs led to treatment discontinuation. All patients treated off-label (N=34) achieved SVR12. Glecaprevir/pibrentasvir was highly effective and well tolerated under real-world conditions. Clinical trial number: DRKS00009717 (German Clinical Trials Register, DRKS).

The first patient with hepatitis C genotype 8 infection in Australia

In Australia, hepatitis C is common amongst people who inject drugs, prisoners and migrants from endemic areas. Sequelae of chronic infection include cirrhosis and hepatocellular carcinoma. Treatment has become highly successful using genotype specific and more recently pan-genotypic regimens.

All Oral Interferon-free Direct-acting Antivirals as Combination Therapies to Cure Hepatitis C.

Chronic hepatitis C (CHC) virus infection and associated hepatic diseases are still challenging, and the disease burden remains significant around the world. Overall treatment rates for the chronically infected patients have been "dismally poor" and that treatment completion of dual-therapy- pegylated interferon (PEG-IFN) and ribavirin (RBV) is suboptimal in the real-world clinical settings. The approval of first, second and next-generation direct-acting antivirals (DAAs) represents a major breakthrough in hepatitis C virus (HCV) therapeutics to treat CHC infected individuals. Such therapeutic regimens in a fixed dose combination (FDC) or along with RBV have proven their clinical efficacy against different HCV genotypes, and harder-to-treat special populations. We continue to see the development of novel pan-genotypic anti-HCV regimens with very high sustained virologic response (SVR; undetectable viral load at week 12 or at the end of therapy) rates, high barrier to drug resistance, low frequency of adverse events, and fewer drug-drug interactions as compared to some older RBV based triple DAA therapies. Oral interferon-free DAAs seem highly successful strategic treatment approaches against hepatitis C and impulse health policy makers to establish the treatment priorties and policies to reduce the rate of hepatitis C-related morbidity and mortality. This review article comprehensively overviews interferon-free anti-HCV regimens, which have totally shifted the treatment paradigms for hepatitis C with some additional benefits to galvanize our efforts to achieve the global goal of HCV elimination in near future.

Research progress of hepatitis C in 2018

Up to now, all major direct-acting antiviral agents (DAAs) have been approved, pan-genotypic regimens are recommended globally, simple monitoring strategy is recommended. In 2018, hepatitis C research focused more on accessibility, rather than new regimens. With the joint efforts of government and social groups, more infected people are getting affordable treatment. In addition approval of DAAs from global pharmaceuticals, a variety of DAAs have been on the clinical trial and approved in our country, and more options are/will be available with clinical trials progress. Management of infected fetus, children, and pregnant women will attract researchers' attention.

Sofosbuvir/velpatasvir/voxilaprevir: a highly effective option for retreatment of hepatitis C in difficult-to-treat patients.

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®, a fixed-dose combination pill for treatment of hepatitis C in treatment-experienced patients.

Effectiveness and safety of glecaprevir and pibrentasvir for hemodialysis patients with hepatitis C virus infection at a single center

Background/Aims: Glecaprevir/pibrentasvir (GLE/PIB) is a pan-genotypic regimen for the treatment of hepatitis B virus (HCV) infection. GLE and PIB are direct acting antiviral (DAA) agents that can be used for patients with chronic renal failure who are on hemodialysis (HD) and those with HCV genotype 2 infections. Here, we report the usefulness and safety of GLE/PIB in 13 hemodialysis (HD) patients with HCV infection. Material and Methods: The subjects comprised patients with genotype 1 and 2 (six each) and one unknown genotype patient in whom GLE/PIB therapy was introduced by December 2018. The mean age was 69.2 (59-78) years (seven men and six women). The mean HCV RNA amount prior to treatment initiation was 4.81 (2.1-6.5). The administration periods were 8 and 12 weeks (n = 9 and 4, respectively). Results: Twelve patients received all the doses orally while an increase in total bilirubin (T-BIL) caused administration to be discontinued in one patient. HCV RNA at week 4 after treatment initiation became undetectable in 11 (91.6%) of the 12 patients. All patients achieved rapid viral response (RVR). Concerning adverse effects, although itching occurred in three (25%) patients, the symptom improved following administration of oral medication and the treatment was able to be continued. Conclusion: The results suggest that GLE/PIB can also be safely administered to HD patients. However, the usefulness and safety need to be further studied by examining more cases.

Treatment of chronic hepatitis C virus infection in Rwanda with ledipasvir–sofosbuvir (SHARED): a single-arm trial

Limited treatment data are available for hepatitis C virus (HCV) in sub-Saharan Africa, especially for genotype 4. Our objective was to establish the safety and efficacy of ledipasvir-sofosbuvir for chronic HCV genotype 1 or 4 infection in adults in Rwanda. We did a single-arm trial to evaluate the safety and efficacy of ledipasvir-sofosbuvir in Rwandan adults with chronic HCV infection at a single study site (Rwanda Military Hospital, Kigali, Rwanda). We enrolled individuals aged 18 years or older with HCV genotype 1 or 4 infection and a plasma HCV RNA concentration of more than 1000 IU/mL at screening. All participants were given ledipasvir (90 mg) and sofosbuvir (400 mg) in a single combination tablet once daily for 12 weeks. We established HCV genotype using an Abbott platform, and HCV subtype with PCR amplification. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after therapy (SVR12). All patients enrolled in the study were included in the primary endpoint analyses. This study is registered with ClinicalTrials.gov, number NCT02964091. 300 participants were enrolled between Feb 6, 2017, and Sept 18, 2017, and the follow-up period was completed on March 1, 2018. On genotyping, 248 (83%) participants were reported as having genotype 4, four (1%) genotype 1, and 48 (16%) both genotype 1 and genotype 4. Subsequent viral sequencing showed all participants actually had genotype 4 infection with subtype 4k (134 [45%]), subtype 4r (48 [16%]), subtype 4q (42 [14%]), and subtype 4v (24 [8%]) predominating. Overall, 261 (87%, 95% CI 83-91) participants achieved SVR12. In participants with genotype 4r, SVR12 was observed in 27 (56%, 95% CI 41-71) participants versus 234 (93%, 90-96) individuals with other subtypes. There were no drug-related treatment discontinuations due to ledipasvir-sofosbuvir. The most common adverse events were hypertension (97 [32%]), headache (78 [26%]), dizziness (61 [20%]), and fatigue (56 [19%]). There were six serious adverse events; none were assessed to be due to the study drug. 296 participants had data for pill counts at week 4 and 8; 271 (92%) had 100% adherence and only one (<1%) had an adherence of less than 90%. This is the first large-scale prospective study reporting direct-acting antiviral outcomes in sub-Saharan Africa. The high adherence and treatment success without intensive support measures or highly specialised clinical providers, and lack of treatment discontinuations due to adverse events support the feasibility of HCV treatment decentralisation and scale-up in sub-Saharan Africa. Genotype 4r is uniquely expressed in this region and associated with high rates of treatment failure, suggesting a need for rigorous test-of-cure in clinical practice and consideration of the use of newer pangenotypic direct-acting antiviral regimens in this region. Gilead Sciences.

Treatment of Hepatitis C: State of the Art 2018

Aim of antiviral therapy on an individual patient level is a sustained virologic response, on a population level the elimination of the hepatitis C virus (HCV). The latter is an aim also defined by the WHO. Specific inhibitors of the RNA-dependent RNA-polymerase, the NS3/4A protease, and the NS5A protein as well as ribavirin are available for antiviral therapy of HCV. Typically, two direct antiviral agents are combined, the treatment duration for the majority of patients is between 8 and 12 weeks. Potential drug-drug interactions with patients' basic medications must be assessed. Two pangenotypic regimens are available: sofosbuvir/velpatasvir and glecaprevir/pibrentasvir. In the individual decision between regimens hepatic and renal function as well as drug-drug interactions must be considered. The sustained virologic response rates are above 95 %, safety and tolerability of the treatment regimens are excellent. In patients with decompensated cirrhosis treatment with protease inhibitors is contraindicated. Sofosbuvir is not approved in patients with severe renal insufficiency. Patients who failed an interferon-free therapy should be retreated with sofosbuvir/velpatasvir/voxilaprevir.

Glecaprevir/pibrentasvir in patients with chronic HCV and recent drug use: An integrated analysis of 7 phase III studies

Background: Injection drug use is the primary mode of transmission for hepatitis C virus (HCV), and treatment guidelines recommend treating HCV-infected people who use drugs; however, concerns about adherence, effectiveness, and reinfection have impeded treatment uptake.Methods: Data were pooled from seven phase III trials that evaluated the efficacy and safety of 8 or 12 weeks of glecaprevir/pibrentasvir (G/P) in patients chronically infected with HCV genotypes 1–6. Patients had compensated liver disease, with or without cirrhosis, and were HCV treatment-naïve or -experienced with interferon or pegylated interferon ± ribavirin, or sofosbuvir plus ribavirin ± pegylated interferon. Patients were grouped into recent drug users (injection drug use ≤12 months before screening, positive urine drug screen [UDS], and/or drug-related adverse event), former drug users (>12 months before screening and negative UDS), or non-drug users. Assessments included sustained virologic response at 12 weeks posttreatment (SVR12), treatment adherence, and safety.Results: Among 1819 patients, 5%, 34%, and 61% were recent, former, and non-drug users, respectively. Treatment adherence and completion were high (≥96%) regardless of drug use status. SVR12 was achieved by 93% (n/N = 91/98), 97% (n/N = 591/610), and >99% (n/N = 1106/1111) of recent, former, and non-drug users, respectively (intention-to-treat analysis). The overall rates of virologic failure were ≤1.5% across all three subpopulations, with no HCV reinfections among recent drug users. Drug-related serious adverse events and adverse events leading to treatment discontinuation were experienced by ≤1% of patients.Conclusions: G/P is a well-tolerated and efficacious pangenotypic regimen for chronic HCV-infected people with recent or active drug use.