Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection

doi:10.1016/j.jhep.2018.07.002

Journal of Hepatology

Volume 69, Issue 5, November 2018, Pages 1178-1187

https://doi.org/10.1016/j.jhep.2018.07.002 Get rights and content

Summary

Treatment of chronic hepatitis C virus infection has been revolutionised by the development of direct-acting antivirals (DAAs). All-oral, once-daily, 8- to 12-week treatment regimens are now standard of care, with viral eradication possible in >95% of patients across different populations. Despite these advances, several unresolved issues remain, including treatment of patients with hepatitis C virus genotype 3, chronic kidney disease, and those in whom DAA therapy has previously failed. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Herein, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

Introduction

Hepatitis C virus (HCV) infection is a major global health concern, affecting approximately 70 million people or 1% of the world population according to recent estimates.¹ Moreover, chronic HCV infection is associated with substantial morbidity and mortality, with liver-related complications including cirrhosis, liver failure and hepatocellular carcinoma (HCC).¹ The goal of antiviral therapy is to prevent these complications by achieving viral eradication. This is defined as undetectable HCV RNA 12 weeks after treatment cessation, also called a sustained virologic response (SVR).[2], [3]

The recent introduction of direct-acting antivirals (DAAs) has revolutionised HCV therapy and made viral cure, which is associated with improved quality of life, a reality in the vast majority of patients.[4], [5] Even in patients in whom interferon-based treatment has traditionally been difficult or contraindicated, including those with decompensated cirrhosis or severe kidney disease, HCV can now be eradicated with minimal toxicity and good overall tolerability.[6], [7], [8] Moreover, large-scale post-marketing studies have shown that data from clinical trials can be replicated in the real-world setting with high overall efficacy and few safety concerns.[9], [10], [11]

Finally, there is increasing evidence that viral eradication following DAA therapy is associated with a significant decrease in liver-related morbidity and mortality, and the adverse extrahepatic sequelae of HCV infection, while being associated with an increase in health-related quality of life.[12], [13], [14], [15] Despite these overwhelming advances, there remain challenges to eliminating HCV in some patient subgroups, including those in whom previous DAA-based therapies have failed.

The recent approval of pangenotypic DAA regimens has addressed the remaining gaps in the HCV treatment portfolio (Fig. 1). These regimens include the NS3/4A protease inhibitor pibrentasvir plus the NS5A inhibitor glecaprevir (GLE/PIB; AbbVie, North Chicago, IL, USA) and the NS5B polymerase inhibitor sofosbuvir in combination with the NS5A inhibitor velpatasvir plus the NS3/4A protease inhibitor voxilaprevir (SOF/VEL/VOX; Gilead Sciences, Foster City, CA, USA).

In this review, we will discuss the limitations of previous DAA regimens and how these have been overcome with the advent of recently approved DAA regimens (Table 1, Table 2).

Section snippets

Genotype inclusivity of existing DAA regimens

There are eight major HCV genotypes and several dozens of subtypes that show a high degree of genetic variability.[16], [17] Worldwide, genotype 1 is the most prevalent HCV genotype, followed by genotypes 3, 2 and 4.¹⁸ Interestingly, some genotypes show a high degree of endemicity, particularly genotype 3 in India and Pakistan and genotype 4 in Egypt and the Middle East.[18], [19] The natural course of HCV infection may vary among genotypes. For example, genotype 3 is associated with increased

Glecaprevir/pibrentasvir clinical trials

Both glecaprevir and pibrentasvir (GLE/PIB) have very limited metabolic activity in the liver or kidney, and have potent antiviral activity in vitro against all major HCV genotypes. PIB has a high barrier to common RASs identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, and 93 of the NS5A gene.⁶²

A number of phase III trials evaluated an 8–16-week treatment duration in non-cirrhotic patients across genotypes 1–6. In the ENDURANCE-1 study, 8 or 12 weeks

Sofosbuvir/velpatasvir/voxilaprevir clinical trials

The SOF/VEL/VOX regimen is approved in Europe, Canada and the United States for the treatment of patients with chronic HCV infection without cirrhosis or with compensated cirrhosis who have previously been treated with an NS5A inhibitor. The recommended treatment duration is 12 weeks. In Europe, 8–12 weeks of SOF/VEL/VOX is also approved for DAA-naïve patients, with and without compensated cirrhosis. As with the major GLE/PIB trials, the four POLARIS phase III trials, which evaluated the safety

Pangenotypic therapies

From a global perspective, HCV elimination can only be achieved with DAA regimens that are highly active in all known HCV genotypes, while having excellent tolerability profiles and few drug-drug interactions. The two direct-acting antiviral drug combinations GLE/PIB and SOF/VEL, with SOF/VEL/VOX as a backup, have the ability to address most, if not all, existing therapeutic challenges and limitations associated with HCV therapy. This is particularly true for the treatment of HCV genotypes 4,

Remaining challenges

As with all other regimens containing HCV NS3/4A protease inhibitors, GLE/PIB and SOF/VEL/VOX, which both contain an NS3/4A protease inhibitor, are not recommended in patients with decompensated cirrhosis (Child-Turcotte-Pugh stage B or C). Thus, patients with decompensated cirrhosis and prior DAA failure have no explicit treatment options at this time. For these patients, alternative treatment options, including off label DAA combinations without an NS3/4A inhibitor such as SOF/VEL ± ribavirin

Conflict of interest

J.V. reports personal fees from AbbVie, Gilead, Merck, outside the submitted work. I.J. reports personal fees from AbbVie, Bristol-Myers Squibb, Intercept; grants and personal fees from Gilead, Merck, Janssen, outside the submitted work. J.S.P. reports personal fees from Gilead, outside the submitted work. S.Z. reports personal fees from AbbVie, Gilead, Merck, Janssen, Falk, Intercept, outside the submitted work.

Please refer to the accompanying ICMJE disclosure forms for further details.

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The combination of pegylated interferon (Peg-IFN) and ribavirin has provided a “cure” for a considerable proportion of patients with chronic hepatitis C infection (CHC), particularly in patients with the favorable interferon λ 3 (IFNL3) genotype.1 These cure rates were further improved by replacing interferon-based therapy with potent, direct-acting antiviral agents (DAAs),1 and the sustained virological response (SVR) rate to DAA in HCV-infected patients is approaching 100%.15 However, some HCV-associated metabolic events cannot be reversed, even after viral clearance.1
Whether hepatitis C virus (HCV) infection is associated with breast cancer risk remains elusive, and we aimed to elucidate it. A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database (TNHIRD) was conducted. Additionally, breast cancer risk factors, and HCV core expression were surveyed in breast cancer patients of a tertiary care center. Three TNHIRD cohorts (1:4:4, propensity score-matched, 2003–2012), including HCV-treated (3646 HCV-infected females with interferon-based therapy ≥6 months), HCV-untreated (n = 14,584) and HCV-uninfected (n = 14,584) cohorts, were enrolled. The HCV-untreated cohort had the highest 9-year breast cancer cumulative incidence (2.017%; 95% confidence interval [CI]: 1.382%–2.846%), while the HCV-treated (1.073%; 0.414%–2.356%), and HCV-uninfected (1.453%; 0.785%–2.486%) cohorts showed no difference. Untreated HCV infection (hazard ratio [HR]: 1.701; 95% CI: 1.205%–2.400), urban residency (1.658, 1.183–2.323), and baseline cardiovascular events (1.920; 1.005–3.668) were associated with incident breast cancers. The interaction analysis showed that particularly among patients <49 years, HCV infection was associated with breast cancer development (2.193; 1.097–4.384). Of 12,170 hospitalized breast cancer patients, 4.90% were HCV Ab-positive. HCV Ab-positive patients were older (60.92+/-10.82 vs 53.91+/-11.38 years, P < 0.0001) and had a higher body mass index (25.39+/-5.1 vs 24.5+/-4.3 kg/m², P = 0.007), rates of diabetes (30.60 vs 19.98%, P < 0.0001), hypertension (46.9 vs 30.39%, P < 0.0001), dyslipidemia (25.52 vs 20.28%, P = 0.031), and hyperuricemia (11.38 vs 5.52%, P < 0.0001) than their counterparts. No HCV core-positive cells were demonstrated in breast cancer tissues. Conclusions: Untreated HCV infection, urbanization, and cardiovascular events were potential risk factors for breast cancer. The HCV-associated risk was most prominent among patients <49 years, might not be associated with in situ HCV core-related oncogenesis but with metabolic alterations, and was reversed by anti–HCV therapy.
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Hepatitis C virus (HCV) has caused a considerable threat to human health. To date, no treatments are without side effects. The proteins and RNA associated with HCV have specific functions during the viral life cycle. The vulnerabilities to virus are associated with those proteins or RNA. Thus, targeting these proteins and RNA is an efficient strategy to develop anti-HCV therapeutics. The treatment for HCV-infected patients has been greatly improved after the approval of direct-acting antivirals (DAAs). However, the cost of DAAs is unusually high, which adds to the economic burden on patients with chronic liver diseases. So far, many efforts have been devoted to the development of small molecules as novel HCV inhibitors. Investigations on the inhibitory activities of these small molecules have involved the target identification and the mechanism of action. In this mini-review, these small molecules divided into four kinds were elaborated, which focused on their targets and structural features. Furthermore, we raised the current challenges and promising prospects. This mini-review may facilitate the development of small molecules with improved activities targeting HCV based on the chemical scaffolds of HCV inhibitors.
Redesigning of the cap conformation and symmetry of the diphenylethyne core to yield highly potent pan-genotypic NS5A inhibitors with high potency and high resistance barrier
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Despite the fact that DAA therapy options continue to increase and develop, efficacy of DAAs varies against different genotypes, this is mainly a consequence of the fact that DAA drug development was initially focused on HCV genotype 1, partly because interferon showed the lowest efficacy in this genotype and partly because it is the most common genotype worldwide. On the other hand, genotype 3 appears to be more difficult to cure with DAAs than other genotypes [2]. HCV genotype 3 (GT3) is the second-most prevalent genotype, accounting for 25% of all infections.
Herein, we report the discovery of several NS5A inhibitors with potency against HCV genotype 1b in the picomolar range. Compounds (15, 33) were of extremely high potency against HCV genotype 1b (EC₅₀ ≈ 1 pM), improved activity against genotype 3a (GT 3a) and good metabolic stability. We studied the impact of changing the cap conformation relative to the diphenylethyne core and/or compound symmetry on both potency and metabolic stability. The analogs obtained exhibited improved potency against HCV genotypes 1a, 1b, 3a and 4a compared to the clinically approved candidate daclatasvir with EC₅₀ values in the low picomolar range and SI₅₀s > 7 orders of magnitude. Compound 15, a symmetrically m-, m’-substituted diphenyl ethyne analog, was 150-fold more potent than daclatasvir against GT 3a, while compound 33, an asymmetrically m-, p-substituted diphenyl ethyne analog, was 35-fold more potent than daclatasvir against GT 3a. In addition, compound 15 exhibited a higher resistance barrier than daclatasvir against genotype 1b.
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Use of these DAAs eliminated the side-effects of previous interferon therapy and improved the quality of life of HCV infected patients. Treatment using DAAs achieves sustained virologic response (SVR) in about 92–95% cases [8]. However, DAA therapy is quite costly and fails in about 5–10% cases due to pre-existing or new generation of resistance-associated substitutions (RAS) [9 10].
Hepatitis C virus (HCV) infection causes viral hepatitis leading to hepatocellular carcinoma. Despite the clinical use of direct-acting antivirals (DAAs) still there is treatment failure in 5–10% cases. Therefore, it is crucial to develop new antivirals against HCV. In this endeavor, we developed the “Anti-HCV” platform using machine learning and quantitative structure–activity relationship (QSAR) approaches to predict repurposed drugs targeting HCV non-structural (NS) proteins. We retrieved experimentally validated small molecules from the ChEMBL database with bioactivity (IC₅₀/EC₅₀) against HCV NS3 (454), NS3/4A (495), NS5A (494) and NS5B (1671) proteins. These unique compounds were divided into training/testing and independent validation datasets. Relevant molecular descriptors and fingerprints were selected using a recursive feature elimination algorithm. Different machine learning techniques viz. support vector machine, k-nearest neighbour, artificial neural network, and random forest were used to develop the predictive models. We achieved Pearson’s correlation coefficients from 0.80 to 0.92 during 10-fold cross validation and similar performance on independent datasets using the best developed models. The robustness and reliability of developed predictive models were also supported by applicability domain, chemical diversity and decoy datasets analyses. The “Anti-HCV” predictive models were used to identify potential repurposing drugs. Representative candidates were further validated by molecular docking which displayed high binding affinities. Hence, this study identified promising repurposed drugs viz. naftifine, butalbital (NS3), vinorelbine, epicriptine (NS3/4A), pipecuronium, trimethaphan (NS5A), olodaterol and vemurafenib (NS5B) etc. targeting HCV NS proteins. These potential repurposed drugs may prove useful in antiviral drug development against HCV.
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Background/aims: We performed a systematic review and meta-analysis addressing community-based assessment and treatment of hepatitis C virus (HCV)-related liver disease, injecting drug use (IDU) and alcohol use amongst people who are homeless (PWAH). Methods: Using systematic review methodology, databases were searched (MEDLINE/EMBASE/CINAHL) for studies combining PWAH, HCV-related liver disease and community assessment until December 2019. Studies with a sample size ≥ 30, with PWAH constituting at least 30% of the cohort were included and a quality assessment performed. Pooled estimates of key indicators were analysed using meta-analysis. Results: We identified 39 studies (n = 13,918), 37 categorised as poor quality (Newcastle-Ottawa Scale). Prevalence of homelessness ranged between 30%-100% (37 studies). Eight studies provided all of the following: HCV screening, alcohol/substance use/liver fibrosis assessment and HCV treatment. No study provided interventions for alcohol use, with two providing opioid substitution treatment. Alcohol use prevalence (24 studies) was 4%-97%, being 59% (95% CI 20%-92%) in four studies that included only PWAH. Recent IDU prevalence (16 studies) was 7%-73%, being 21% (95% CI 17%-26%) in four studies that included only PWAH. HCV seroprevalence (25 studies) was 2.5% - 58%; in 13 studies that included only PWAH, this was 20% (95% CI 12%-30%). Prevalence of F4 fibrosis (nine studies) was 6%-28%, being 7% and 16% in two studies that included only PWAH. Direct acting antiviral-based intention-to-treat sustained virological response (SVR) rates (five studies) were 82%-92%, being 92% in the one study that included only PWAH. In the only two randomised controlled trials (RCT) identified, community-based interventions (mental health/peer mentor) significantly increased linkage to care (p = 0.04), HCV treatment (p = 0.005) and SVR rates (p = 0.018).Conclusion: The burden from alcohol/IDU and HCV, and consequently liver disease in PWAH needs addressing. RCT trials assessing community-based interventions to improve liver health in PWAH are needed.
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ReviewChallenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection

Summary

Introduction

Section snippets

Genotype inclusivity of existing DAA regimens

Glecaprevir/pibrentasvir clinical trials

Sofosbuvir/velpatasvir/voxilaprevir clinical trials

Pangenotypic therapies

Remaining challenges

Conflict of interest

Clin Liver Dis

Lancet

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Curr Opin Virol

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Lancet Gastroenterol Hepatol

Kidney Int

Gastroenterology

J Hepatol

J Hepatol

J Hepatol

J Hepatol

J Hepatol

Clin Gastroenterol Hepatol

Lancet Infect Dis

Gastroenterology

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EASL recommendations on treatment of hepatitis C 2018

J Hepatol

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Nat Rev Dis Prim

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Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis

N Engl J Med

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Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment

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Aliment Pharmacol Ther

Identification of novel HCV genotype and subtypes in patients treated with sofosbuvir based regimens

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Liver Int

Review
Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection