Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries

Filipe, Ana da Silva; Sreenu, Vattipally B.; Hughes, Joseph; Aranday-Cortes, Elihu; Irving, William L.; Foster, Graham R.; Agarwal, Kosh; Rosenberg, William; MacDonald, Douglas; Richardson, Paul; Aldersley, Mark; Wiselka, Martin; Ustianowski, Andrew; McLauchlan, John; Thomson, Emma C.

doi:10.1016/j.jhep.2017.06.035

Cited by 34 publications

(51 citation statements)

References 11 publications

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“…to have a reduced response to DAA treatment in the National Health Service England Early Access Programme in association with the MPRMP NS5A [28][29][30][31][32] amino acid motif that is associated with high-level resistance in vitro. (9,37) In another meta-analysis of patients with genotype 4 infection treated with ledipasvir and sofosbuvir, treatment failure occurred in two thirds of patients with subtype g4r and in one patient with g4b. These participants had baseline RASs (28M/V+30R+31M), which remained the dominant sequences posttreatment.…”

Section: Discussionmentioning

confidence: 99%

“…g7 HCV has been shown to be mistyped as g2 in other studies using the TRUGENE assay; this could result in errors in therapeutic decision making, and the adoption of full genome sequencing using more sophisticated technologies such as metagenomic and target enrichment-based NGS may reveal other "rare" genotypes as a cause of treatment failure as treatment is rolled out. (9,20,24) Unbiased metagenomic NGS sequencing overcomes the need for specific primers for full genome sequencing and may therefore help to identify new strains that would not have been amplified using PCR-based methodology. It does not appear, however, that diagnosis of HCV is impaired with standard assays.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the NS5A 28L/P and 30R/S variants were present in 83% of sequences (10/12), but the NS5A [28][29][30][31][32] MPRMP motif recently associated with resistance in g4r infection was not detected. (9)…”

Section: Hcv Resistance Analysismentioning

confidence: 99%

“…(8) Encouragingly, pangenotypic combinations of antiviral drugs have recently been licensed; these have wide-ranging activity against the HCV subtypes present in HICs but have been less well assessed in the context of strains present in low-income and middle-income countries, particularly in SSA. (9) The distribution of HCV genotypes varies substantially around the world. (3) g1a, g1b, and g3a have a global distribution, whereas subtypes of g3 and g6 are found predominantly in Southern and South East Asia.…”

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confidence: 99%

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Highly Diverse Hepatitis C Strains Detected in Sub‐Saharan Africa Have Unknown Susceptibility to Direct‐Acting Antiviral Treatments

et al. 2019

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The global plan to eradicate hepatitis C virus (HCV) led by the World Health Organization outlines the use of highly effective direct‐acting antiviral drugs (DAAs) to achieve elimination by 2030. Identifying individuals with active disease and investigation of the breadth of diversity of the virus in sub‐Saharan Africa (SSA) is essential as genotypes in this region (where very few clinical trials have been carried out) are distinct from those found in other parts of the world. We undertook a population‐based, nested case‐control study in Uganda and obtained additional samples from the Democratic Republic of Congo (DRC) to estimate the prevalence of HCV, assess strategies for disease detection using serological and molecular techniques, and characterize genetic diversity of the virus. Using next‐generation and Sanger sequencing, we aimed to identify strains circulating in East and Central Africa. A total of 7,751 Ugandan patients were initially screened for HCV, and 20 PCR‐positive samples were obtained for sequencing. Serological assays were found to vary significantly in specificity for HCV. HCV strains detected in Uganda included genotype (g) 4k, g4p, g4q, and g4s and a newly identified unassigned g7 HCV strain. Two additional unassigned g7 strains were identified in patients originating from DRC (one partial and one full open reading frame sequence). These g4 and g7 strains contain nonstructural (ns) protein 3 and 5A polymorphisms associated with resistance to DAAs in other genotypes. Clinical studies are therefore indicated to investigate treatment response in infected patients. Conclusion : Although HCV prevalence and genotypes have been well characterized in patients in well‐resourced countries, clinical trials are urgently required in SSA, where highly diverse g4 and g7 strains circulate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hcv Resistance Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Highly Diverse Hepatitis C Strains Detected in Sub‐Saharan Africa Have Unknown Susceptibility to Direct‐Acting Antiviral Treatments

et al. 2019

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“…An exception is the S282T RAS, which persists if compensatory mutations are also acquired 16 . Certain HCV subtypes (4r) have been shown to acquire this substitution more readily 9,10 . Furthermore, with the exception of S282T, all sofosbuvir RAS show negligible increases in resistance using in vitro models 11 and patients who were unresponsive to sofosbuvir containing regimens, often do not carry any of these RAS at baseline or post-treatment.…”

Section: Introductionmentioning

confidence: 99%

Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

Smith

Magrì

Bowden

et al. 2020

Preprint

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Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. With the recent development of direct acting antivirals (DAA), treatment of chronically infected patients has become highly effective although a subset of patients do not respond to therapy. Sofosbuvir is a common component of current de novo or salvage combination therapies. We used pre-treatment whole genome sequencing of HCV from 507 patients infected with HCV subtype 3a and treated with sofosbuvir containing regimens to detect viral polymorphisms associated with response to treatment. We found that three common polymorphisms present in HCV NS2 and NS3 proteins (not direct targets of sofosbuvir) were associated with reduced treatment response.These polymorphisms were enriched in post-treatment HCV sequences of patients unresponsive to treatment; they were also associated with lower reductions in viral load in the first week of therapy. The finding of polymorphisms in NS2 and NS3 proteins associated with poor treatment outcomes emphasises the value of more systematic genome-wide analyses of HCV in uncovering indirect but clinically relevant mechanisms of antiviral resistance.

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Hepatitis C

Dusheiko

2018

Sherlock's Diseases of the Liver and Biliary System

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Response to DAA therapy in the NHS England Early Access Programme for rare HCV subtypes from low and middle income countries

Cited by 34 publications

References 11 publications

Highly Diverse Hepatitis C Strains Detected in Sub‐Saharan Africa Have Unknown Susceptibility to Direct‐Acting Antiviral Treatments

Highly Diverse Hepatitis C Strains Detected in Sub‐Saharan Africa Have Unknown Susceptibility to Direct‐Acting Antiviral Treatments

Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

Hepatitis C

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