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

Davis, Chris; Mgomella, George; Filipe, Ana da Silva; Frost, Éric; Giroux, Geneviève; Hughes, Joseph; Hogan, Catherine A.; Kaleebu, Pontiano; Asiki, Gershim; McLauchlan, John; Niebel, Marc; Ocama, Ponsiano; Pomila, Cristina; Pybus, Oliver G.; Pépin, Jacques; Simmonds, Peter; Singer, Joshua B.; Sreenu, Vattipally B.; Wekesa, Clara; Young, Elizabeth H.; Murphy, Donald G.; Sandhu, Manjinder S.; Thomson, Emma C.

doi:10.1002/hep.30342

Cited by 39 publications

(47 citation statements)

References 41 publications

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“…This is concordant with recent data from a cohort from Uganda and the Democratic Republic of Congo, where highly diverse genotype 4 and 7 strains, including unconfirmed novel strains were recently identified. 2 We can speculate that the diversity of HCV observed in this cohort and other studies, if confirmed by larger phylogenetic analyses, perhaps points to an early evolutionary origin of human hepatitis C genotype 1 and 4 in Africa. 13 We observed a high number of resistance-associated polymorphisms in pre-treatment samples from our cohort.…”

Section: Discussionsupporting

confidence: 74%

“…1 Despite this, there have been few clinical trials conducted in African cohorts and data is lacking on the prevalence, geographical distribution and treatment response of African sub-genotypes. 2,3 There are 8 known HCV genotypes which have been classified based on the analysis of HCV genetic sequences. 4 Except for genotypes 5 and 8, each genotype is further divided into a number of subtypes.…”

Section: Introductionmentioning

confidence: 99%

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Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C

Childs

Davis

Cannon

et al. 2019

Journal of Hepatology

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Graphical abstract AuthorsHighlights Unusual genotypes (G1 non 1a/1b or G4 non 4a/4d) were common in African patients.11 previously unclassified HCV subtypes were represented including novel G1p.Patients with unusual G1 subtypes had a lower SVR rate than any other genotype.Failures were driven by patients treated with a first generation NS5A inhibitor.Background & Aims: HCV subtypes which are unusual in Europe are more prevalent in the African region, but little is known of their response to direct-acting antivirals (DAAs). These include non-1a/1b/ non-subtypeable genotype 1 (G1) or non-4a/4d (G4). In this report we aimed to describe the genotype distribution and treatment outcome in a south London cohort of African patients. Methods:We identified all patients born in Africa who attended our clinic from 2010-2018. Information on HCV genotype, treatment regimen and outcome were obtained. Non-subtypeable samples were analysed using Glasgow NimbleGen nextgeneration sequencing (NGS). Phylogenetic analysis was carried out by generating an uncorrected nucleotide p-distance tree from the complete coding regions of our sequences. Results: Of 91 African patients, 47 (52%) were infected with an unusual subtype. Fourteen novel, as yet undesignated subtypes (G1*), were identified by NGS. Three individuals were infected with the same subtype, now designated as subtype 1p. Baseline sequences were available for 22 patients; 18/22 (82%) had baseline NS5A resistance-associated substitutions (RASs). Sustained virological response (SVR) was achieved in 56/63 (89%) overall, yet only in 21/28 (75%) of those with unusual G1 subtypes, with failure in 3/16 G1*, 1/2 G1p and 3/3 in G1l. Six treatment failures occurred with sofosbuvir/ledipasvir compared to 1 failure on a PI-based regimen. The SVR rate for all other genotypes and subtypes was 35/35 (100%). Conclusions: Most individuals in an unselected cohort of African patients were infected with an unusual genotype, including novel subtype 1p. The SVR rate of those with unusual G1 subtypes was 75%, raising concern about expansion of DAAs across Africa. Depending on the regimen used, higher failure rates in African cohorts could jeopardise HCV elimination. Lay summary: Direct-acting antiviral medications are able to cure hepatitis C in the majority of patients. The most common genotype of hepatitis C in Europe and the United States is genotype 1a or 1b and most clinical trials focused on these geno-types. We report that in a group of African patients, most of them had unusual (non-1a/1b) genotype 1 subtypes, and that the cure rate in these unusual genotypes was lower than in genotypes 1a and 1b.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C

Childs

Davis

Cannon

et al. 2019

Journal of Hepatology

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“…Most GT-4 subtype diversity is observed in sub-Saharan Africa, with GT-4r, for example, frequently found in the DRC and Rwanda. [23] Most of our black GT-4 patients originated from these and other African countries, explaining our observed diversity. Other unusual subtypes, e.g.…”

Section: Researchmentioning

confidence: 72%

Direct-acting antiviral therapy for hepatitis C: The initial experience of the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa

et al. 2020

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Globally, ~71 million people are actively viraemic with the hepatitis C virus (HCV), with an estimated 10.15 million chronically infected in sub-Saharan Africa. [1] An estimated 600 000 South Africans have chronic hepatitis C, although the uncertainty intervals are wide. [2] Concomitantly, accurate prevalence data in the general population are generally lacking, although important data are emerging with regard to a high prevalence in high-risk or key populations. [3] The seroprevalence in the general population is thought to be <1%, and data from the blood transfusion services consistently point towards a low seroprevalence. [4] Key risk populations include people who inject/injected drugs (PWID), men who have sex with men (MSM) and the incarcerated population. A prospective study in HIV-positive MSM in Cape Town noted a hepatitis C seroprevalence of 5.6% and 0.5% in the MSM and non-MSM groups, respectively. [5] In a smaller retrospective Cape Town study, 27% of injecting MSM were HCV antibody-positive; 37.5% were HIV co-infected. [6] More recently, a large countrywide seroprevalence study of key populations found a 45% seroprevalence of HCV in PWID; 24.7% were HIV co-infected. [3] Of MSM, 2.7% were anti-HCV-positive and 40% HIV co-infected. Notably, HCV seroprevalence among sex workers was extremely low at 0.1%, but HIV and hepatitis B rates were high. 2019 marked 30 years since HCV was sequenced and cloned for the first time in 1989. [7] In 1991, 3-5 times weekly subcutaneous interferon for HCV demonstrated poor outcomes. Adding ribavirin improved response rates. In 2001, weekly pegylated interferon (Peg-IFN) plus ribavirin showed significantly improved outcomes. [8,9] Overall, the achievement of a sustained virological response (SVR), defined as the absence of detectable HCV RNA at least 24 weeks This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0.

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“…A consistent, unified approach to classification will advance this field, improving consistency of curating, archiving and reporting sequence data. Recent work sampling poorly accessed populations has uncovered numerous new HCV isolates (41,42), and the diversity of sequences generated for HBV may expand in a similar way. The use of a robust and consistent classification system will also be important in screening new populations for potentially novel HBV isolates.…”

Section: Resultsmentioning

confidence: 99%

Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences

McNaughton

Revill

Matthews

et al. 2019

Preprint

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Hepatitis B virus (HBV) is a diverse, partially double-stranded DNA virus, with 9 genotypes (A-I), and a putative 10th genotype (J), thus far characterised. Given the broadening interest in HBV sequencing, there is an increasing requirement for a consistent, unified approach to HBV genotype and subgenotype classification. We set out to generate an updated resource of reference sequences using the diversity of all genomic-length HBV sequences available in public databases. We collated and aligned genomic-length HBV sequences from public databases and used maximum-likelihood phylogenetic analysis to identify genotype clusters. Within each genotype, we examined the phylogenetic support for currently defined subgenotypes, as well as identifying well-supported clades and deriving reference sequences for them. An alignment of these reference sequences and maximum-likelihood phylogenetic trees of the sequences are provided to simplify classification. Based on the phylogenies generated, we present a comprehensive set of HBV reference sequences at the genotype and subgenotype level.

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

Cited by 39 publications

References 41 publications

Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C

Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C

Direct-acting antiviral therapy for hepatitis C: The initial experience of the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa

Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences

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