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Research Needs Editorial - Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub Saharan Africa and South East Asia About the absolute need to keep active research on the efficacy of direct-acting antiviral drugs against the hepatitis C virus
 
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Research Needs Editorial - Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub Saharan Africa and South East Asia
 
About the absolute need to keep active research on the efficacy of direct-acting antiviral drugs against the hepatitis C virus
 
Editorial Jnl of Hepatology
July 27, 2020 Jean-Michel Pawlotsky
 
These findings provide a rational to select effective strategies based on dual or triple first-line therapy for unusual HCV subtypes inherently resistant to NS5A inhibitors commonly found in sub-Saharan Africa and South-East Asia.
 
This is the condition to achieve the World Health Organization HCV elimination goals within a reasonable time frame. The study by Nguyen et al. provides an excellent contribution to this endeavor.
 
The clear message from these studies is that it is not the time to discard the models, stop funding and close the shop. HCV research is not over, but it must be targeted.
 
New resistance profiles continuously emerge while access to therapy progresses.
 
it is mandatory to maintain industry-independent cell culture-based phenotypic HCV platforms harboring the expertise and a number of different infectious and self-replicating models covering all possible HCV genotypes and subtypes, that can address questions related to treatment efficacy and failure, including antiviral drug effectiveness, viral resistance, variant fitness, the role of RASs, etc.
 
Beyond screening and access to care, the key to HCV elimination as a public health threat (90% reduction in incidence, 65% reduction in mortality by 2030) is to administer the right first-line treatment, including dual or triple therapy, to as many patients as possible.
 
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There has been major progress in the treatment of chronic hepatitis C over the past 10 years. It is now accepted that the vast majority of patients with HCV infection will eliminate the virus after an 8- to 12-week course of therapy combining 2 or 3 direct-acting antiviral (DAA) drugs. Inhibitors of the HCV nonstructural 5A (NS5A) protein are the backbone of any DAA combination, because of their potency and speed of action that results from their dual antiviral mechanism, including inhibition of viral replication through disorganization of replication complexes and inhibition of viral assembly and release.1,2 NS5A inhibitors are used in combination with a nucleotide analogue, an NS3-4A protease inhibitor, or both. Recent clinical practice guidelines recommend the use of either the pangenotypic fixed-dose combination of the nucleotide analogue sofosbuvir with the NS5A inhibitor velpatasvir, or of the NS3-4A protease inhibitor glecaprevir with the NS5A inhibitor pibrentasvir, as first-line treatment in patients with chronic hepatitis C.3,4 The pangenotypic combination of sofosbuvir and the NS5A inhibitor daclatasvir is also widely used, especially in low- and middle-income countries. Finally, the fixed-dose combination of the NS3-4A inhibitor grazoprevir and the NS5A inhibitor elbasvir remains indicated in some patients infected with HCV genotype 1.3,4
 
Although the rates of HCV cure are very high with these combinations, some patients fail to eliminate the virus. Treatment failure is associated with the selection of preexisting viral subpopulations carrying resistance-associated substitutions (RASs) in the NS5A region that reduce their susceptibility to NS5A inhibitors.5 With the aforementioned pangenotypic DAA regimens, treatment failures are rare in patients infected with the most frequent HCV genotypes and subtypes, including subtypes 1a, 1b, 2a, 2c, 3a, 4a, 5a and 6a. However, classification of HCV includes a much larger number of distinct subtypes, up to 1l, 2r, 3k, 4w, 6xa, 7a and 8a,6 and many more HCV genotypes and subtypes probably exist. Some of these subtypes, that are ‘unusual’ in regions where most of the research is done, account for important proportions of the HCV-infected population in certain low- and middle-income countries and in immigrants from these areas living in Europe or North America. Some HCV subtypes, such as 1l, 4r, 3b or 3g or others, which are prevalent in certain countries, have been reported to be inherently resistant to several NS5A inhibitors, due to the presence of natural polymorphisms conferring medium- to high-level resistance to these DAAs.7, 8, 9
 
HCV treatment guidelines must be applicable to any group of HCV-infected patients. Thus, it is mandatory to be in a capacity to explore the in vitro effectiveness of the different HCV DAAs available in clinical practice against all known HCV genotypes and subtypes, and to characterize the presence of RASs prior to therapy and their selection by treatment, as well as the level of drug resistance they confer in diverse genetic backgrounds. Most of the information available has been generated and published by the drug industry as part of their preclinical and clinical developments. These studies used different model systems, frequent genotypes/subtypes from the list above, and a non-exhaustive panel of compounds for comparison. Fortunately, 2 key industry-independent, complementary studies have recently been published that fill many of our knowledge gaps about the intrinsic antiviral characteristics of NS5A inhibitors used in the everyday treatment of HCV infection: the first by Gottwein et al. in Gastroenterology in 2018,10the second by Nguyen et al. in the present issue of the Journal of Hepatology.11
 
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Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub Saharan Africa and South East Asia
 
May 26, 2020 - Dung Nguyen1, David Smith1, Alun Vaughan-Jackson2, Andrea Magri3, STOP-HCV Consortium, Eleanor Barnes1*, Peter Simmonds1*
 
http://www.natap.org/2020/HCV/061220_01.htm
 
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The study by Gottwein et al. measured the effectiveness of different concentrations of daclatasvir, ledipasvir, ombitasvir, elbasvir, ruzasvir (an NS5A inhibitor that was not approved), velpatasvir and pibrentasvir in cultured hepatoma cell lines infected with HCV recombinants expressing subtype-specific NS5A proteins, with or without engineered RASs.10 The in vitro antiviral effectiveness of the NS5A inhibitors was tested against HCV subtypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a and 7a. Their findings supported current recommendations to use dual combinations including either velpatasvir or pibrentasvir as first-line HCV treatment in areas where the subtypes tested in the study are dominant.10 Gottwein et al. also characterized the in vitro susceptibility to NS5A inhibitors of a large number of infectious HCV variants of the same 9 genotypes/subtypes carrying 1 of 2 engineered RASs in their NS5A sequence.10 RASs at NS5A positions 28 and 93 conferred high-level resistance to velpatasvir, whereas velpatasvir was more active than other NS5A inhibitors (except pibrentasvir) against RASs at positions 30 and 31. No resistance to pibrentasvir was conferred by RASs at positions 28, 30 and 31, whereas low-level resistance was conferred by RASs at position 93. The combination of a RAS at position 93 and a deletion at position 32 conferred high-level resistance to pibrentasvir. Together, these results indicated that pibrentasvir had the highest barrier to resistance of all NS5A inhibitors tested.10
 
The results generated by Gottwein et al. were very helpful to better understand HCV treatment outcomes and draw clinical practice guidelines applicable to patients infected with genotypes/subtypes that are frequent in Western Europe, North America and parts of Asia. Nevertheless, this study provided no information on ‘difficult-to-cure’ HCV subtypes commonly found in sub-Saharan Africa and South-East Asia or in migrant populations from these regions known to be inherently resistant to NS5A inhibitors.8,9,1, 13, 14 Hopefully, this gap has now been filled by the excellent article by Nguyen et al. in the present issue of the Journal of Hepatology.11
 
In their study, Nguyen et al. used an SGR-JFH1 genotype 2a replicon backbone with cloned NS5A sequences from ‘unusual’ subtypes 1l, 3b, 3g, 4r, 6u and 6v in a hepatoma cell line to measure the antiviral effectiveness of daclatasvir, elbasvir, ledipasvir, velpatasvir and pibrentasvir.11 These subtypes were selected because their NS5A sequences are known to harbor amino acid residues reported as RASs in other subtypes.6 In addition, lower rates of cure have been reported with NS5A inhibitor-containing regimens in patients infected with subtypes 1l, 4r and 3b in clinical trials or retrospective cohort studies.8,9,12,14 The study suggests that subtypes 3b and 3g are inherently resistant to daclatasvir, ledipasvir, elbasvir and velpatasvir, whilst subtypes 1l, 4r, 6u and 6v are sensitive to elbasvir and velpatasvir, but resistant to daclatasvir and ledipasvir. Only pibrentasvir had high activity against all tested subtypes.11
 
These results would support the use of the fixed-dose, single-pill combination of glecaprevir and pibrentasvir as first-line therapy in regions or groups of patients with a substantial prevalence of HCV subtypes inherently resistant to other NS5A inhibitors. However, this recommendation goes with the condition that these subtypes are also inherently sensitive to the NS3-4A protease inhibitor glecaprevir. No experimental data were provided by Nguyen et al. to address this point, which was studied in silico. The authors analyzed sequences from the 6 subtypes available in public databases, looking for the presence of RASs known to confer reduced susceptibility to glecaprevir in the most closely related common HCV subtypes. They found only the A166S RAS in 3.1% (3/98) and 100% (4/4) of NS3 sequences from subtypes 3b and 3g, respectively. A166S appears to confer low-level (if any) resistance to glecaprevir in vitro and has been selected in some patients infected with genotype 3a with virologic failure.15,16 The impact of the presence of this RAS at baseline in patients infected with subtypes 3b and 3g receiving glecaprevir/pibrentasvir is unknown. Together, these findings provide a rational to select effective strategies based on dual or triple first-line therapy for unusual HCV subtypes inherently resistant to NS5A inhibitors commonly found in sub-Saharan Africa and South-East Asia.
 
The clear message from these studies is that it is not the time to discard the models, stop funding and close the shop. HCV research is not over, but it must be targeted. Many patients remain to be treated worldwide. Most of them live in low- or middle-income countries or belong to under-served communities in areas where treatment has been broadly offered. New resistance profiles continuously emerge while access to therapy progresses. Unusual subtypes, including those that are inherently resistant to current HCV DAAs, account for substantial proportions of the HCV-infected populations in many regions of the world, especially in places where the most recent drug combinations are not yet available. For all these reasons, it is mandatory to maintain industry-independent cell culture-based phenotypic HCV platforms harboring the expertise and a number of different infectious and self-replicating models covering all possible HCV genotypes and subtypes, that can address questions related to treatment efficacy and failure, including antiviral drug effectiveness, viral resistance, variant fitness, the role of RASs, etc. Several such platforms that collaborate on a regular basis and exchange models and expertise should exist in different countries and continents. Most importantly, they should be publicly funded.
 
Beyond screening and access to care, the key to HCV elimination as a public health threat (90% reduction in incidence, 65% reduction in mortality by 2030) is to administer the right first-line treatment, including dual or triple therapy, to as many patients as possible. This remains a challenge in countries where HCV subtypes inherently resistant to the locally available DAA regimens, that are often generic, account for a substantial proportion of the infected population in the absence of precise description of their frequency. The combination of careful epidemiological studies mapping the distribution of HCV genotypes and subtypes in all areas and of regularly updated, exhaustive, industry-independent in vitro studies on HCV DAA efficacy and viral resistance is mandatory to inform international, national and local treatment guidelines and make them truly universal. This is the condition to achieve the World Health Organization HCV elimination goals within a reasonable time frame. The study by Nguyen et al. provides an excellent contribution to this endeavor.

 
 
 
 
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