Management of hepatitis C genotype 4 in the directly acting antivirals era

Hathorn, Emma; Elsharkawy, Ahmed M.

doi:10.1136/bmjgast-2016-000112

Cited by 15 publications

(22 citation statements)

References 69 publications

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“…Fourteen amino acid positions in NS3 were evaluated: 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175. For NS5A, the four amino acid positions (28,30,31, and 93) most commonly seen in elbasvir resistance studies (18,20) were evaluated. As reported in Table 7, there was a high global conservation among Ն187 NS3 sequences obtained from the public databases.…”

Section: Resultsmentioning

confidence: 99%

“…In the phase 3 C-EDGE clinical trials (25)(26)(27), a fixed-dose combination of elbasvir and grazoprevir administered for 12 weeks resulted in a sustained virologic response 12 weeks after treatment (SVR 12 ) of 95% among HCV treatment-naive GT4-infected patients. The elbasvir-grazoprevir combination is a valuable option, among others (4,28), for patients chronically infected with GT4 HCV. [1,2-c] [1,3] (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons

Asante‐Appiah

Curry

McMonagle

et al. 2017

Antimicrob Agents Chemother

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Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For grazoprevir, the 50% effective concentration (EC 50 ) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC 50 for grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n ϭ 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced grazoprevir antiviral activity by 137-and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC 50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC 50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n ϭ 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir. The activity profiles of grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.KEYWORDS HCV, genotype 4, resistance, antiviral, elbasvir, grazoprevir, NS5A, NS3/4A, antiviral agents, drug resistance mechanisms, hepatitis C virus H epatitis C virus (HCV) is a leading cause of chronic liver disease, with an estimated 170 million people infected globally (1, 2). The World Health Organization estimates that more than 350,000 people die every year from hepatitis C-related liver diseases (3). Approximately 20% of individuals chronically infected with HCV can be expected to develop liver cirrhosis and, of these, 6% will decompensate to end-stage liver disease, with an additional 4% developing hepatocellular carcinoma. A number of treatment options are now available with combinations of interferon-free direct-acting

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons

Asante‐Appiah

Curry

McMonagle

et al. 2017

Antimicrob Agents Chemother

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“…Phase II IMPACT study evaluates this combination in addition to Simeprevir in treatment of HCV genotypes 1 and 4 DAA-naïve patients with portal hypertension or decompensated cirrhosis. All patients achieved SVR12 regardless of the presence of baseline detectable resistance-associated mutations in 83% of patients [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Sofosbuvir Plus Daclatasvir in Treatment of Chronic Hepatitis C Genotype 4 Infection in a Cohort of Egyptian Patients: An Experiment the Size of Egyptian Village

Ahmed

Safwat

Khalifa

et al. 2018

International Journal of Hepatology

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Background and Aims As indicated by the World Health Organization (WHO), Egypt is positioned as the country with the world's highest prevalence of Hepatitis C virus (HCV). HCV is transmitted through unexamined blood transfusions, different employments of syringes, and poor cleansing, as per the WHO. Our study aimed at screening and management of chronic hepatitis C genotype 4 infected patients in Bardeen village, Sharkeya Governorate, Egypt, with Sofosbuvir plus Daclatasvir, as well as estimating the safety and efficacy of that regimen. Methods Screening of adult patients in Bardeen village was done from March 2016 till November 2016 using hepatitis C virus antibodies by third-generation ELISA testing. Positive results were confirmed by PCR. Patients eligible for treatment received Sofosbuvir 400 mg and Daclatasvir 60 mg daily for 12 weeks and were assessed for sustained virologic response at 12 weeks following the end of treatment (SVR 12). Results Out of 2047 subjects screened for hepatitis C virus, 249 (12.2%) showed positive results. 221 out of those 249 subjects (88.7%) had detectable RNA by PCR. Treatment of eligible patients (183 patients) with Sofosbuvir plus Daclatasvir for 12 weeks resulted in 96% achievement of sustained virologic response at week 12. Adverse events were tolerable. Conclusion Sofosbuvir plus Daclatasvir regimen is safe and effective for treatment of chronic hepatitis C Genotype 4 infected patients with minimal adverse events. HCV eradication program implemented in Egypt can be a model for other countries with HCV and limited resources. The availability of generic drugs in Egypt will help much in eradication of the virus.

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“…With these therapies, the wide majority (90–95%) of HCV-infected patients can now be successfully cured [ 2 , 3 ]. Less attention was paid to genotype 4 (GT4) HCV in clinical trials and field-practice studies compared with other genotypes [ 4 ]. Current estimates state that this GT accounts for 13% of all HCV infections [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Treatment of hepatitis C virus genotype 4 in the DAA era

Biagio

Taramasso

Cenderello

2018

Virol J

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The recently approved interferon-free DAA (direct antiviral agents) regimens have shown not only to be effective in terms of sustained virological response (SVR) rates (> 90%) but also well tolerated in most hepatitis C virus (HCV) infected patients. Nevertheless HCV genotypes are different and only a small percentage of trials consider genotype 4 (GT4), which was associated with lower rates of SVR compared with other genotypes before the arrival of the DAA’s. In this review, we discuss the efficacy of DAA therapy in GT4 HCV infection with specific reference to more recent studies, including those conducted in a ‘field-practice’ scenario. Overall, DAA-based regimens appear more effective also in the poorly-explored setting of patients with HCV GT4 infection. Despite an overall limited number of patients was evaluated, favorable results are being derived from studies on ombitasvir/paritaprevir/ritonavir, sofosbuvir and velpatasvir, whether or not in association with voxilaprevir, and with the new combined therapy glecaprevir + pibentasvir.

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Management of hepatitis C genotype 4 in the directly acting antivirals era

Cited by 15 publications

References 69 publications

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons

Sofosbuvir Plus Daclatasvir in Treatment of Chronic Hepatitis C Genotype 4 Infection in a Cohort of Egyptian Patients: An Experiment the Size of Egyptian Village

Treatment of hepatitis C virus genotype 4 in the DAA era

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