IFNL4 Genotype Frequencies in Asian Populations Support Shorter Duration Therapy with Sofosbuvir-Based Hepatitis C Virus Regimens to Increase the Number Cured

Abstract

Globally, ∼56.8 million people are chronically infected with hepatitis C virus (HCV), with about half residing in Asia. The cost and efficiency of delivering regimens based on direct-acting antiviral agents for HCV are important considerations in implementing these curative treatments. For sofosbuvir-based regimens, most patients are treated for 12 weeks; however, treatment for 8 weeks has been shown to cure HCV infection in 95% of patients without cirrhosis. Furthermore, virological failure after 8-week treatment occurs in only 1%–2% of individuals without cirrhosis, who have a favorable IFNL4 genotype, which is present in >50% of South Asians and >80% of East Asians. We propose that sofosbuvir-based treatment for 8 weeks, or perhaps shorter, would yield high response rate regimens in Asian countries and markedly increase the number of patients who could be cured for a given cost of the medication. We propose that a noninferiority trial in an East Asian population be conducted to test this hypothesis.

Chronic infection with hepatitis C virus (HCV) is a global public health problem of large proportions. Worldwide, ∼56.8 million people have chronic hepatitis C, of whom about half reside in Asia (Blach et al., 2022). HCV infection is a major cause of hepatocellular carcinoma, cirrhosis, and end-stage liver disease. Fortunately, successful treatment greatly reduces the risk of those outcomes, especially if the infection is cleared before advanced hepatic fibrosis develops. In 2014, treatment for HCV based on the highly effective direct-acting antiviral agent (DAA) sofosbuvir became available and this compound remains the backbone of several widely used DAA regimens. Compared to treatment with pegylated-IFN-α, regimens based on sofosbuvir and other DAAs markedly improve cure rates with fewer adverse effects. Market competition has led to a drop in the price of sofosbuvir-based regimens; however, cost remains a major barrier to fuller implementation of these therapies.

The World Health Organization has set an aggressive goal of reducing viral hepatitis mortality by 65% by 2030 (https://www.who.int/hepatitis/publications/hep-elimination-by-2030-brief/en). A key determinant for reducing HCV-associated mortality will be how many individuals are successfully treated for HCV infection (the product of the number of patients treated and the proportion of those treated who are cured). Meeting this goal will require innovative approaches to scale up delivery of successful treatment of chronic hepatitis C. In many countries, the cost of drugs and the available medical/public health work force will limit the number of patients who can be treated.

Shortening the duration of treatment could reduce pharmaceutical costs and improve treatment efficiency, facilitating treatment of more patients for the same cost. The duration of treatment affects the probability of treatment success as well as treatment costs; therefore, these effects must be weighed in considering an optimal treatment strategy. Here, we propose that reducing the duration of treatment with sofosbuvir-based regimens could increase the number of individuals who can be cured of HCV infection at a given cost. Regional differences in host genetic factors that affect treatment response suggest this strategy might be especially effective in Asian countries.

Current guidelines for treating noncirrhotic HCV-infected individuals with sofosbuvir-based regimens may not be optimal for maximizing the total number of people who are cured. Standard therapy with these regimens is for 12 weeks; however, among individuals who do not have cirrhosis, effectiveness is only marginally lower for an 8-week therapy. In the ION-3 trial of treatment with the ledipasvir/sofosbuvir, per protocol sustained virological response (SVR) rates were 98.6% in the 12-week arm and 95.3% in those treated for 8 weeks (Kowdley et al., 2014). In the POLARIS-2 trial of the pan-genotypic sofosbuvir/velpatasvir/voxilaprevir regimen, those per protocol SVR rates were 99.3% and 95.8%, respectively (Jacobson et al., 2017). Thus, observed differences in cure rates between 8 and 12 weeks treatment with these regimens are 3%–4%. On a population basis, the marginal benefit of treating patients for 12 weeks is small. Assuming 99% efficacy for 12 weeks and 95% efficacy for 8 weeks, a 12-week strategy increases pharmaceutical drug costs by 50% to successfully treat 4% more individuals. Stated differently, an 8-week strategy would cure 44% more HCV-infected individuals for the same pharmaceutical cost.

Marked regional population-specific differences in the frequency of IFNL4 alleles might impact response to shorter duration treatment with sofosbuvir-based regimens. IFNL4-ΔG/TT (rs368234815) is the primary functional variant for spontaneous clearance of HCV and response to HCV treatment (Aka et al., 2014; O'Brien et al., 2015; Prokunina-Olsson et al., 2013). The IFNL4-ΔG allele, which is associated with impaired viral clearance, generates the interferon lambda 4 (IFN-λ4) protein, whereas IFNL4-TT is a “knockout” allele that abrogates expression and production of the functional protein. Before the discovery of IFNL4, genome-wide association studies demonstrated strong associations between single nucleotide polymorphisms (SNPs) in the interferon lambda chromosomal region at chromosome 19 and HCV clearance (Ge et al., 2009; O'Brien, 2009; Suppiah et al., 2009; Tanaka et al., 2009). Based on those findings, genotype for the rs12979860 SNP (commonly called “IL28B”) was developed as a clinical test to predict response to HCV treatment. The subsequent discovery of IFNL4 revealed that rs12979860 lies in intron 1 of IFNL4 and that rs12979860 is in strong linkage disequilibrium with IFNL4-ΔG/TT, especially in individuals of European or Asian ancestry (Prokunina-Olsson et al., 2013). Thus, rs12979860 is a surrogate for the functional IFNL4-ΔG/TT variant, with the rs12979860-C allele linked to IFNL4-TT and rs12979860-T linked to IFNL4-ΔG.

Response to sofosbuvir-based treatment differs by IFNL4 genotype. In patients treated with sofosbuvir plus ribavirin, IFNL4-ΔG allele associated with slower early viral decay, due to slower loss of free virus and decreased drug efficacy (as determined by a viral kinetic–pharmacokinetic model) (Meissner et al., 2014). Among individuals without cirrhosis who received the 8-week therapy with ledipasvir/sofosbuvir in the ION-3 trial, IFNL4 rs12979860 genotype associated with treatment failure due to virological relapse, with only 1.8% of patients with the rs12979860-CC genotype suffering relapse (compared to 4.9% for those with rs12979860-CT genotype and 9.1% of those with rs12979860-TT) (O'Brien et al., 2014). Ledipasvir/sofosbuvir is indicated primarily for HCV genotype 1; however, the sofosbuvir/velpatasvir/voxilaprevir combination is designed to be effective for all HCV genotypes. Among patients without cirrhosis who were randomized to an 8-week treatment with this regimen in the POLARIS 2 trial, only 2/166 (1.2%) patients with rs12979860-CC genotype relapsed compared to 19/335 (5.7%) of those with the rs12979860-CT or -TT genotypes (O'Brien et al., 2017). Although rs12979860 marks the functional IFNL4-ΔG/TT variant, the latter is a better predictor of treatment response, especially in African American patients (Prokunina-Olsson et al., 2013); therefore, analyses based on rs12979860 may underestimate the strength of true associations between IFNL4 genotype and virological relapse. These findings show that IFNL4 genotype predicts response to sofosbuvir-based regimens and suggest that only 1%–2% of noncirrhotic patients with a favorable IFNL4 genotype will relapse if treated for 8 weeks with regimen appropriate for the viral genotype.

Strong evolutionary selection for the IFNL4-TT allele led to marked racial differences in genotype frequencies for the IFNL4-ΔG/TT and rs12979860 variants (Key et al., 2014; Prokunina-Olsson et al., 2013; Thomas et al., 2009). IFNL4-ΔG is the major form in Africans, but the minor allele in Europeans and Asians, with an almost 10-fold difference in frequency of the favorable IFNL4-TT/TT genotype between African (8.9%) and East Asian (84.3%) populations included in the 1,000 Genomes Project (Table 1). The 47.9% frequency of IFNL4-TT/TT in European populations lies amid that range; therefore, response rates from trials conducted among populations of European ancestry will, all else being equal, underestimate efficacy in Asian populations and overestimate efficacy in African populations. In Asian populations, the 8-week treatment with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir/voxilaprevir might yield even higher overall cure rates than those observed in ION-3 and POLARIS-2. It is also possible that a treatment duration of <8 weeks could yield suitably high cure rates in Asian patients.

Table 1.

Frequencies of Genotype for the IFNL4-ΔG/TT (rs368234815) Polymorphism in Populations from the 1,000 Genomes Project

Population	TT/TT	TT/ΔG	ΔG/ΔG
African	8.9%	40.7%	50.4%
European	47.9%	41.9%	10.1%
South Asian	56.9%	38.4%	4.7%
East Asian	84.3%	15.1%	0.6%

http://grch37.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=19:39738654-39739654;v=rs11322783;vdb=variation;vf=584506463 Accessed January 25, 2023.

IFNL4-ΔG/TT (rs368234815) is a dinucleotide polymorphism that is represented by the rs11322783 single nucleotide polymorphism in the 1,000 Genomes Project database.

The best approaches to reducing HCV-related mortality treatment will need to be tailored to the specific epidemic and challenges in each region and country. In addition to cost, the distribution of HCV viral genotypes is an important consideration in selecting appropriate treatment regimens for a country. Although our present focus is on the public health goal of maximizing the number of patients who might be cured for a given cost, a strategy of universal short duration treatment with retreatment of the small percentage of patients with virological failure might yield very high cure rates at lower cost than a 12-week treatment strategy. For example, among patients who relapsed after initial treatment with 8 weeks of ledipasvir/sofosbuvir, 80% responded to retreatment with 24 weeks of the same regimen (Lawitz et al., 2015). Combining that retreatment rate to the ∼95% efficacy seen after initial treatment of 8 weeks in ION-3 would yield an overall response rate of ∼99%, achieved after considerably fewer “treatment weeks” than required for an initial course of 12 weeks alone (O'Brien et al., 2016). More recent studies indicate retreatment with the sofosbuvir/velpatasvir/voxilaprevir regimen for 12 weeks yields rates of HCV cure exceeding 95% (Bourlière et al., 2017). On that basis, we calculate that a strategy under which short course treatment that cured 95% of patients was followed by retreatment of the remaining 5% of patients with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir would cure 99.8% of HCV-infected patients.

Based on these considerations, we hypothesize that a treatment duration of 8 weeks, or perhaps less, might yield very high response rates for sofosbuvir-based regimens in Asian populations. Our hypothesis could be tested in a noninferiority trial of a viral genotype-appropriate sofosbuvir regimen in an East Asian country. Patients without evidence of cirrhosis would be randomized to 3 arms of differing treatment duration (12, 8, or 6 weeks). To replicate the type of simplified and streamlined process that may be needed to diagnose and treat as many HCV patients as possible, neither viral genotype nor IFNL4-ΔG/TT genotype would be considered for study entry or randomization, although both might be measured for research purposes, as might viral genome sequences. Patients who suffered virological failure would be offered longer duration retreatment with an appropriate DAA regimen. Thresholds for noninferiority would be based on the aim of achieving virological cure for the maximum number of patients at a given cost.

In wealthier countries with higher treatment costs, IFNL4 genotype might be determined for individual patients, perhaps using a point of care IFNL4 genotyping assay (Duffy et al., 2017; Trickey et al., 2023), and the appropriate duration of therapy could be based on IFNL4 genotype and other variables. In lower resource countries, generic DAAs may be affordable, but individualized IFNL4 genotyping might be cost prohibitive. In such settings, national treatment strategies might consider the overall frequency of favorable IFNL4 genotypes in that population. Consideration of these relationships might improve global strategies to reduce mortality from HCV infection.

Footnotes

Disclaimer

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research was supported by the Intramural Research Program of the National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics).

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