| |
|
Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C
|
| |
| |
Download the PDF here
Download the PDF here
"Many high-income countries are not expected to achieve HCV elimination before 2050. while the vast majority of low- and middle-income countries have not yet started addressing the issue. Reasons commonly evoked to explain the difficulties in implementing efficient elimination policies include the lack of political will, the absence of national or regional action plans, insufficient funding, the lack of screening policies, poor linkage-to-care strategies, and treatment restrictions.......World Health Organization (WHO) set the goal to eliminate hepatitis C as a major public health threat (i.e. to reduce the incidence of new infections by 90% and HCV-related mortality by 65%) by 2030. However, as of today, only a few countries are on track to eliminate HCV by 2030.......the report by Childs et al. in the present issue of the Journal5 or our own data, to "discover" that patients born in Africa, who by chance immigrated to Europe and had access to HCV drugs, could be naturally resistant to DAA therapy.....it will be essential to assess whether first-line treatment should be based on a triple combination of sofosbuvir, an NS5A inhibitor and a protease inhibitor in regions where a significant proportion of patients are unlikely to respond to a dual combination including an NS5A inhibitor......The WHO goal to eliminate HCV may be achievable, although probably much later than in 2030 at the global level, but this will require that specific objectives and means are tailored to local situations. This will now be the mission of the HCV community. There are many worlds in the global world, and they are equally important. We must take good care of them all."
from main study: "Five patients who failed initial treatment have thus far commenced retreatment: 3 of these patients have completed 16 weeks of glecaprevir and pibrentasvir, 2 of whom have achieved an SVR. One individual with cirrhosis and G1* HCV virus failed to achieve an SVR with 16 weeks of glecaprevir and pibrentasvir. Two other patients were retreated with sofosbuvir, velpatasvir and voxilaprevir and achieved an SVR......The evidence indicates that the future desired expansion of HCV treatment in Africa may risk unacceptable rates of failure if first generation NS5A inhibitors are utilised without appropriate epidemiological and viral sequence data. Global equity of access to curative treatment is required to avoid jeopardising the hepatitis C elimination agenda."
Global timing of hepatitis C virus elimination: estimating the year countries will achieve the World Health Organization elimination targets
Global timing of hepatitis C virus elimination: estimating the year countries will achieve the World Health Organization elimination targets - AASLD/EASL HCV Special Conference Miami 2/1/19
Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C
Editorial
DAA failures in African patients with "unusual" HCV subtypes: Hey! Didn't you know there was another world?
Jean-Michel Pawlotsky1,2,
1National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Universite Paris-Est,
Creteil, France; 2INSERM U955, Creteil, France
Jnl of Hepatology Dec 2019
See Article, pages 1099-1105 - see below
We all agree: the field of hepatitis C has experienced an unprecedented therapeutic revolution. Since the discovery of hepatitis C virus (HCV) in 1989, the rates of cure of the infection have jumped from approximately 6% after 1 year of standard interferon-alpha administered 3 times per week - at the cost of numerous and often serious side effects - to nearly 98% on average after 8 to 16 weeks of oral treatment nowadays.1 Current direct-acting antiviral (DAA) combination regimens are pangenotypic, easy to take (1 to 3 pills once per day), highly efficacious and well tolerated. In this context, the World Health Organization (WHO) set the goal to eliminate hepatitis C as a major public health threat (i.e. to reduce the incidence of new infections by 90% and HCV-related mortality by 65%) by 2030. However, as of today, only a few countries are on track to eliminate HCV by 2030.2, 3, 4 Many high-income countries are not expected to achieve HCV elimination before 2050, while the vast majority of low- and middle-income countries have not yet started addressing the issue.2, 3, 4 Reasons commonly evoked to explain the difficulties in implementing efficient elimination policies include the lack of political will, the absence of national or regional action plans, insufficient funding, the lack of screening policies, poor linkage-to-care strategies, and treatment restrictions.
Insidiously, another danger weighs on the hope for global HCV elimination: our HCV DAA combinations may not be as pangenotypic as claimed. Indeed, in the current issue of the Journal of Hepatology, Childs et al.5 report from a London hospital on suboptimal rates of sustained virological response (SVR) in patients of African origin who were infected with HCV genotype subtypes unusually found in Western Europe. Among 2,211 patients with chronic hepatitis C seen between 2010 and 2018 in their center, the authors identified 91 individuals (4.1%) who were born in (mostly sub-Saharan) Africa. Thirty-five of them (38.5%) were infected with unusual HCV genotype 1 subtypes, including 1e, 1g, 1h, 1l or unassigned genotype 1 (from which 15 new subtypes were identified by full-length HCV open reading frame sequencing). In addition, 12 of the 91 African patients (13.1%) were infected with unusual HCV genotype 4 subtypes, including 4c, 4e, 4f, 4k and 4r5. In contrast, patients not of African origin were infected with HCV genotypes usually found in the area, including 1a, 1b or 3a, except 3.3% infected with an unassigned genotype 1 subtype. After treatment, only 75% of African patients infected with unusual genotype 1 subtypes achieved SVR, whereas a high rate of response was achieved in those infected with usual subtypes. Factors associated with the lack of SVR in patients of African origin in multivariate analysis were unusual HCV genotype 1 subtype and NS5A inhibitor-based vs. protease inhibitor-based treatment regimens.5 Failures of NS5A inhibitor-containing treatments were explained by the frequency of NS5A resistance-associated substitutions (RASs) present as natural polymorphisms at baseline in African subtypes, particularly at amino acid positions 24, 30 and 31. Most patients had been treated before the implementation of last-generation pangenotypic regimens, but all of those who failed had received treatment combinations supposed to carry pan-genotype 1 activity (sofosbuvir/ledipasvir, grazoprevir/elbasvir, or ombitasvir/paritaprevir/ritonavir plus dasabuvir). One of 3 patients retreated
with glecaprevir/pibrentasvir failed to achieve SVR, while 2 patients retreated with sofosbuvir/velpatasvir/voxilaprevir cured the infection.5
These results echo our recent report of frequent antiviral treatment failures in patients of African origin infected with HCV subtype 4r.6 In our experience, out of 537 patients treated with DAAs who experienced a virological failure between 2015 and 2018, 22.5% were infected with genotype 4 (whereas genotype 4 represents only 13.7% of HCV-infected patients in France7), and among them, 22.3% were infected with subtype 4r, a very rare subtype in the French general population. All patients infected with subtype 4r were born in sub-Saharan Africa.6 This overrepresentation of subtype 4r among patients failing to achieve SVR was in keeping with a Rwandan study showing an SVR rate of only 56% in patients infected with subtype 4r treated with sofosbuvir/ledipasvir, significantly lower than the 93% SVR rate in patients infected with other genotype 4 subtypes.8 Low SVR rates in patients infected with genotype 4r receiving sofosbuvir and an NS5A inhibitor were explained by the presence at baseline of multiple NS5A RASs (L28M/V + L30R ± L31M), conferring substantially reduced susceptibility to NS5A inhibitors, and of fit viral populations harboring S282C/T RASs in their polymerase sequence, conferring reduced susceptibility to sofosbuvir.6
The implementation of the most recent pangenotypic regimens did not solve the issue: our laboratory is now receiving samples from patients of African origin infected with unusual subtypes of genotypes 1, 2 or 4 who carried NS5A RASs on their baseline genome sequences and failed to achieve SVR after sofosbuvir/velpatasvir or glecaprevir/pibrentasvir (unpublished).
Sub-Saharan Africa is not the only region where HCV subtypes that are unusual in the Western world have been found to be less responsive to DAA combinations. Genotype 3, subtype 3b is prevalent in South-East Asia, accounting for 9.7% of cases in a recent study from Thailand9 and 8.9% in a report from mainland China including 27 provinces or municipalities across the country.10 In a Chinese single-arm, open-label, phase III trial, 89% of patients infected with subtype 3b without cirrhosis (25/28) and only 50% of those with cirrhosis (7/14 patients) achieved SVR after 12 weeks of sofosbuvir/velpatasvir.11 Resistance analysis indicated that subtype 3b is inherently resistant to NS5A inhibitors, due to the presence at baseline of the A30K + L31M RAS combination that confers high-level resistance to daclatasvir, elbasvir and velpatasvir and intermediate-level resistance to pibrentasvir.12
These findings must make us think more deeply about our biased vision of the world and its influence on the way we develop new medications in the 21st century. The United States and Western Europe are, by far, the biggest markets for the drug industry. As a result, new medications are developed essentially in the United States and Europe to target these highly profitable markets. Treatments for HCV were no exception. Currently approved HCV DAAs are all manufactured by American drug companies. Pangenotypic drugs have been designed and optimized to be efficacious against the HCV genotypes and subtypes most commonly found in these regions, including genotypes 1a, 1b, 2a, 2c, 3a and 4a. Fortunately, they were also active against genotypes 5a and 6a, frequent in South Africa and in some areas in South-East Asia, respectively, allowing them to be called "pangenotypic". The vast majority of clinical trials and real-world studies with the new HCV DAAs have been performed in the United States, Europe and in some selected countries in the Asia-Pacific region (Japan, New Zealand, Australia). The high SVR rates obtained in these studies were considered sufficient to definitively halt HCV drug development several years ago.
Like for many centuries, and although some of us thought these times were over, the Western world keeps thinking that what is good for him will also be good for the "other" world. Nevertheless, this "other world" displays an incredibly rich heterogeneity of human beings and diseases that often have little to do with what is found in the Western world. It should not be a surprise that Africa and Asia harbor a high genetic diversity of HCV strains, as this diversity was described very soon after the virus discovery. In 2005, Simmonds et al. published a consensus proposal for a unified system of nomenclature of HCV genotypes. At that time, subtypes 1a to 1l, 2a to 2q, 3a to 3i, 4a to 4t, 5a, and 6a to 6q were already known.13 In the 2014 update, classification of confirmed HCV subtypes was provided up to 1l, 2r, 3k, 4w, 5a, 6xa and 7a.14 Complete coding region sequences had been obtained for each of the different subtypes from at least 3 independent strains; they included sequences from genome regions targeted by current HCV DAAs, i.e. NS3 protease, NS5A and NS5B polymerase.14 Thus, it has been well known for decades that, in many parts of the world, HCV strains carrying RASs conferring high-level resistance to DAAs as natural polymorphisms are circulating and unlikely to respond to at least several of the available DAA regimens. Was this considered during the long HCV drug development process? No, never...
Epidemiological studies describing the prevalence of the different HCV genotypes and subtypes in low- and middle-income countries of Africa and Asia are lacking. Precise subtyping requires technologies that are generally not available in these regions. Almost no clinical trials have been performed in these areas. In real-world studies, scarce data from these areas have been reported, generally with old-generation drug combinations, sometimes using generics. It is ironic that we had to wait for studies performed in Western Europe, such as the report by Childs et al. in the present issue of the Journal5 or our own data, to "discover" that patients born in Africa, who by chance immigrated to Europe and had access to HCV drugs, could be naturally resistant to DAA therapy. Sadly, HCV drug development has now been halted as the needs of the Western world have been fulfilled. Thus, no new HCV drugs will be commercialized.
What should we do? First, we must think of the world as global and diverse, with consideration for all needs, wherever they come from. Secondly, it is key to identify funding mechanisms by which profits made in the West benefit those who live elsewhere. Thirdly, we must treat the "other" world like ours, perform careful epidemiological studies to establish the prevalence of the different HCV genotypes and subtypes and perform clinical trials to define simplified first-line therapeutic strategies that allow for optimal access to care and high efficacy in any region. In this respect, it will be essential to assess whether first-line treatment should be based on a triple combination of sofosbuvir, an NS5A inhibitor and a protease inhibitor in regions where a significant proportion of patients are unlikely to respond to a dual combination including an NS5A inhibitor. Finally, access to cheap generic drugs that fit with the local needs, i.e. that provide equal efficacy against usual and "unusual" HCV subtypes present in the area, must be provided as part of local elimination strategies.
One size never fits all. The WHO goal to eliminate HCV may be achievable, although probably much later than in 2030 at the global level, but this will require that specific objectives and means are tailored to local situations. This will now be the mission of the HCV community. There are many worlds in the global world, and they are equally important. We must take good care of them all.
------------------------
"Five patients who failed initial treatment have thus far commenced retreatment: 3 of these patients have completed 16 weeks of glecaprevir and pibrentasvir, 2 of whom have achieved an SVR. One individual with cirrhosis and G1* HCV virus failed to achieve an SVR with 16 weeks of glecaprevir and pibrentasvir. Two other patients were retreated with sofosbuvir, velpatasvir and voxilaprevir and achieved an SVR."
Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C
Highlights
• 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.
• The majority of unusual G1 subtypes had baseline NS5A resistance mutations.
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 next-generation 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 genotypes. 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.
Introduction
Direct-acting antiviral therapy (DAA) therapy has revolutionised hepatitis C (HCV) treatment. High cure rates with short courses of treatment make global eradication of HCV feasible; consequently, the World Health Organisation has promulgated a call for elimination of viral hepatitis as a public health threat by 2030.1
With 11 million people infected, HCV has an estimated prevalence of 1% in the African region.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. A genome-wide nucleotide sequence difference of 31-33% is considered sufficient to differentiate a genotype and a difference of 12-15% is sufficient to distinguish a sub-genotype (or subtype), although these boundaries are not strict and phylogeny is also considered.
Clinical trial and real-life data routinely report sustained virological response (SVR) rates in excess of 95% for genotype 1a, (G1a) 1b, 3 and 4. There are fewer data available on less prevalent genotypes such as 5 or 6, nor are unusual subtypes well represented. In an analysis of over 1,700 patients with genotype 1 HCV, who had been enrolled in clinical trials of NS5A inhibitors, less than 1% had subtypes of genotype 1 other than 1a or 1b.5 The available evidence suggests that other genotype 1 subtypes are common in Africa but less frequent in the industrialised countries where clinical trials have been centred.6, 16 In this paper we refer to these as "unusual genotypes". We choose this nomenclature for clarity as these genotypes are unusual in Europe, but not unusual in Africa, as we will discuss. However, there is a paucity of data as to whether the treatment response in patients with these less well characterised subtypes is comparable to more common subtypes. This has led to calls for more treatment outcome data in well characterised cohorts of patients.7, 8
Our institution serves a population of high ethnic diversity with a high prevalence of chronic hepatitis C infection. In this analysis we report the distribution of HCV genotypes and subtypes according to country of birth and treatment outcomes in an immigrant population cohort of patients born in Africa.
Patients and methods
Patients
This is a retrospective cohort study of all patients with hepatitis C at our centre who originate from the continent of Africa. We performed a search of our clinical database to identify all patients who were born in Africa, were infected with HCV and who accessed care between 2010 and 2018. For comparison, we also collected available information on the ethnicity and/or country of birth of all patients attending our clinic with HCV infection during the same time period. The study was approved by the Health Research Authority of England and Wales.
Clinical data
We report on the genotypes, subtypes and treatment outcome in this group. The choice of hepatitis C treatment for all patients was discussed at a hepatitis multidisciplinary meeting and based on NHS England guidance. Data was gathered on the DAA regimen used including the use of ribavirin, the degree of hepatic fibrosis and the individuals's HIV status. SVR was defined as an undetectable HCV RNA by sensitive polymerase chain reaction 12 and 24 weeks after cessation of treatment.
Virological assays
HCV RNA was determined by the Roche COBAS® AmpliPrep/COBAS® TaqMan™ HCV Test, v2.0 assay with a sensitivity of 15 IU/ml.
For all patients, HCV genotyping was performed using the VERSANT HCV Geno 2.0 assay at our in-house tertiary viral hepatitis laboratory. Where samples could not be subtyped beyond belonging to genotype 1, they were designated 'unassigned genotype 1'. These were sent to the MRC-University of Glasgow Centre for Virus Research, Glasgow for next-generation sequencing (NGS) with the aim of identifying the subtypes.
In this paper, we refer to all non-1a/1b/unassigned genotype 1 or non-4a/4d genotype 4 samples as "unusual African subtypes". We use this term for want of a more precise label, as the epidemiological association with the region has been established. Many but not all of the identified sequences have been provisionally assigned genotypes; the majority of which have been given a notation based on sequences isolated from sub-Saharan, or North Africa. The word unusual refers to the low frequency with which these subtypes are seen in European treatment centres.
Next-generation sequencing
NGS was carried out using a target enrichment sequencing protocol as previously described.9 Briefly, RNA was extracted from 200 μl plasma using the Agencourt RNAdvance Blood kit (Beckman Coulter) and reverse transcribed using SuperScript III (Invitrogen) with random hexamers and a NEB Second Strand Synthesis kit (New England Biolabs). Adapter-ligated DNA was amplified in real-time on an ABI 7500 cycler, using a KAPA Hifi Real-time library amplification kit. Index tags were added using NEBnext multiplex oligos (New England BioLabs). Pooled libraries were enriched using the NimbleGen SeqCap EZ system (Roche). Amplified DNA was purified using AMPure XP beads and eluted in a final volume of 15 μl. AnAgilent 2200 TapeStation was used to verify the final size profile of amplified library DNA. DNA libraries with appropriate index tags were pooled and paired end sequencing carried out on an Illumina MiSeq instrument using 300-cycle v2 reagents. De novo assembly was carried out using dipSPAdes and mapping with Tanoti (http://www.bioinformatics.cvr.ac.uk/tanoti.php). Sequence data were submitted to GenBank (accession numbers to follow).
Phylogenetic analysis
An uncorrected nucleotide p-distance tree was generated using MEGA 7.0 from the complete coding regions of our sequences after alignment using MAFFT with a reference set of subtypes, including unassigned genotype 1 sequences. Maximum likelihood phylogenetic analysis was carried out using RaxML and the best fit model (GTR+G+I).
Statistical analysis
Continuous variables were reported as median (interquartile range). Categorical univariate analysis was carried out using Chi Square and Fishers exact test. Analysis was performed using SPSS Statistics v25. When performing multivariate analysis, the small numbers led to issues of separation in the data therefore bias-reduced penalized-likelihood logistic regression (Firth 1993) was used.10 This was implemented in the 'logistf' R package and penalized-likelihood ratio tests were used to assess significance.11 Variables with a p value of <0.05 in univariate analysis were included in multivariate analysis.
Results
Sub-genotypes prevalent in African patients
The total number of patients with HCV seen at our centre between 2010 and 2018 was 2,211, of whom we identified 91 (4.1%) patients who were born in Africa, the majority from sub-Saharan Africa (Table 1). The ethnicity or country of birth of the whole HCV cohort are shown in Fig. 1. Amongst the African patients 20/91 (22%) patients were infected with genotype 1a or 1b, 35 (39%) patients had unusual African genotype 1 subtypes, including sub-genotypes 1e, 1g, 1h, 1l, and 23 patients had unassigned genotype 1. Five patients (5.6%) were infected with genotype 2; 3 (3.3%) were infected with genotype 3; 14 (15.6%) had genotype 4; 12 (13.1%) were infected with unusual subtypes of genotype type 4, including 4c, 4e, 4f, 4k, 4r; 2 patients had genotype 5 and 6 infection. The frequency of HCV genotypes of the whole cohort compared to the African group are shown in Fig. 2. Of the non-African patients, who were predominantly British born, but also included Asian, Caribbean and other European backgrounds, 38.7% were infected with genotype 1a, 15.2% with G1b, 30.4% with G3a and only 3.3% with unassigned G1.
In the African cohort, HCV genotypes according to country of birth are shown in Table 1 and Fig. 3. Of the 23 unassigned genotype 1 samples that underwent NGS, 18 complete open reading frame sequences from 15 novel unassigned subtypes were identified. Formal HCV sub-genotype assignment and classification requires at least 3 epidemiologically unrelated isolates.4 We met this recognised criterion with samples from 3 individuals from Nigeria, shown on the p-distance tree as Patient (P)15, P17, and P38. Two of the patients were a married couple, however phylogenetic analysis indicated that they were infected with different variants of the same subtype. This novel subtype has been assigned as 1p. It should be noted that 1 of our patients who failed treatment with sofosbuvir and ledipasvir, P17, was infected with the newly identified genotype 1p.
Treatment response
To date, 63 patients have completed DAA treatment and follow-up. Fifty-six of these patients have achieved an SVR, while 7 failed treatment, giving an overall SVR rate of 89%. As expected, response rates in genotypes 1a or 1b were uniformly high. Similarly, all patients infected with genotype 2, 3, 4 and 5 achieved an SVR. In those patients with unusual G1 and G4 African subtypes, treatment response according to genotype and choice of treatment regimen are shown in Table 2. An SVR was observed in only 21 of the 28 (75%) patients infected with unusual African genotype 1.
Five patients who failed initial treatment have thus far commenced retreatment: 3 of these patients have completed 16 weeks of glecaprevir and pibrentasvir, 2 of whom have achieved an SVR. One individual with cirrhosis and G1* HCV virus failed to achieve an SVR with 16 weeks of glecaprevir and pibrentasvir. Two other patients were retreated with sofosbuvir, velpatasvir and voxilaprevir and achieved an SVR.
Factors associated with lack of SVR
A univariate categorical analysis was carried out to investigate which factors were associated with response. The presence of an unusual genotype 1 African subtype or the use of an NS5A inhibitor-based regimen were both significantly associated with a lack of SVR in univariate analysis, no other factors were. The results are shown in Table 3.
In multivariate analysis with SVR as the outcome variable, unusual genotype 1 remained highly significant with a p value of 0.016 (Chi-Squared: 5.78, df = 1), treatment regimen (NS5A inhibitor-based vs. protease inhibitor) was close to significant with a p value of 0.054 (Chi-Squared: 3.69, df = 1).
HCV sequence results
Baseline sequence data was available for 22 patients, 14 who achieved SVR, 6 treatment failures, 2 who have not yet been treated. There were numerous NS5A polymorphisms present at baseline in patients with unusual G1 subtypes, particularly at positions 24, 30 and 31. Resistance-associated substitutions (RASs) listed in the EASL 2018 HCV guidelines as conferring reduced susceptibility to NS5A inhibitors or being associated with reduced treatment response were seen at baseline in 18/22 (82%) patients. All the treatment failures had either M28 polymorphisms (L and S) (2 failures) or L31M (4 failures). Five SVR patients had M28 (L and V), 3 patients (2 with 1* and 1 with 1g) who achieved SVR had Y93 (F/H/N) at baseline. These data are expanded in Table 4. The individual patient with 1* who has failed treatment with both sofosbuvir/ledipasvir and then glecaprevir/pibrentasvir had Q62E, L31M at baseline and Q62D, L31M following SOF/LDV. Following glecaprevir/pibrentasvir treatment Q30H, H58S and Y93H were also accumulated.
| |
| |
| |
|
|
|
