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In theory, any step of the hepatitis C virus (HCV) lifecycle can be a target for direct-acting antiviral (DAA) drugs (drugs that directly block a viral function), and/or host-targeted agents (HTA, drugs that block a cellular function essential to the viral lifecycle). Four classes of HCV DAAs and two classes of HTAs have reached late clinical development. The HCV DAAs include: inhibitors of the NS3/4A protease that block HCV polyprotein processing; inhibitors of the RNA-dependent RNA polymerase (RdRp), including nucleoside/nucleotide analogues and non-nucleoside inhibitors that block viral replication; and NS5A inhibitors that block viral replication, virion assembly and release. The HCV HTAs in development interact with cellular factors required for HCV replication; they include cyclophilin A inhibitors and microRNA-122 antagonists.1
In 2014, three drugs were approved in the European Union, including the nucleotide analogue sofosbuvir, the protease inhibitor simeprevir and the NS5A inhibitor daclatasvir. They can be used in combination with pegylated interferon α (IFNα) and ribavirin, or as part of sofosbuvir-based IFN-free combinations.1 Other compounds will likely be approved before the end of 2014, including the NS5A inhibitor ledipasvir in combination with sofosbuvir in a single tablet, and the triple combination of the ritonavir-boosted protease inhibitor ABT-450 and the NS5A inhibitor ombitasvir in one tablet plus the non-nucleoside RdRp inhibitor dasabuvir. A number of other drugs from the same classes currently are in Phase II or III clinical development.
In vitro studies showed that other steps of the HCV lifecycle, such as entry, fusion, polyprotein translation, assembly, virion maturation or viral particle release can be blocked by means of specific or non-specific antiviral approaches. Viral entry appears as an attractive target, as suggested by the experience in other chronic viral infections. Two HIV entry inhibitors, maraviroc and enfuvirtide, have been approved and numerous other compounds have reached early to late clinical developmental stages. They include: inhibitors of attachment that interact with gp120 binding to CD4; postattachment inhibitors that do not prevent gp120 binding but hinder access of CD4-bound gp120 to C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4); CCR5 antagonists, such as maraviroc; CXCR4 antagonists; and fusion inhibitors, such as enfuvirtide.2 These compounds reduce viral replication and they are active on viruses that are resistant to other antiretroviral drug classes, thus representing an attractive second line of therapy in HIV-infected patients.2
Entry inhibition also proved to be useful in hepatitis B virus (HBV) infection. Polyclonal antibodies to hepatitis B surface (HBs) antigen derived from pooled human plasma (hepatitis B immunoglobulins, HBIg) are used to neutralise HBV virions in order to prevent infection of the graft in chronic HBV carriers receiving liver transplantation.3 Nowadays, HBIg are systematically used together with nucleoside or nucleotide analogue therapy. Recent data suggest that HBIg may not be absolutely required when either entecavir or tenofovir is used.4 Although this position has not reached a consensus, HBIg infusion, a cumbersome and expensive procedure, could be abandoned and replaced by lifelong nucleoside/nucleotide analogue therapy in the post-transplant setting in HBV-infected patients.
In this issue of Gut, Xiao et al 5 report their experience of combining inhibitors of HCV entry with different HCV DAAs and HTAs in various in vitro and in vivo models. The entry inhibitors tested included monoclonal antibodies directed to components of the HCV receptor complex (claudin-1, scavenger receptor B1 (SR-B1) and CD81) and the tyrosine kinase inhibitors acting on the epidermal growth factor receptor, erlotinib and dasatinib. The DAAs and HTA tested included: the NS3/4A protease inhibitors, telaprevir, boceprevir, danoprevir and simeprevir; the nucleoside/nucleotide analogue inhibitors of HCV RdRp, mericitabine and sofosbuvir; the NS5A inhibitor, daclatasvir and the cyclophilin inhibitor, alisporivir. Synergy was observed with all entry inhibitors in combination with all other DAAs, with the HTA alisporivir and with IFNα in cellular models of acute and persistent HCV infection in cell culture. In humanised, liver-chimeric urokinase plasminogen activator (uPA)/severe combined immunodeficiency (SCID) mice persistently infected with HCV, the combination of telaprevir and the anti-SR-B1 monoclonal antibody resulted in a greater antiviral effect than each compound alone. No cell toxicity was observed with these combinations.
This nicely performed study demonstrates that HCV entry inhibition is a valuable IFN-free approach in combination with compounds that block other steps of the HCV lifecycle, at least in experimental models. It raises the question as to whether there still is room for the clinical development of anti-HCV strategies based on entry inhibition. In their discussion, the authors state ‘there is an unmet medical need for novel strategies for the prevention of HCV graft infection following liver transplantation, and a need to develop more efficient and better tolerated combination therapies for chronic infection for certain patient subgroups and patients with resistance.’5 These three statements deserve discussion.
Is prevention of HCV graft infection after liver transplantation an unmet need? In the absence of therapy, HCV recurrence due to graft infection is universal and reduces the life of the graft. In a recent exploratory study,6 44 patients infected with HCV genotypes 1–4 on the liver transplant list for hepatocellular carcinoma on compensated cirrhosis were treated with the combination of sofosbuvir and ribavirin until transplantation (up to 48 weeks); 41 of them (93%) were HCV RNA undetectable at the time of transplantation. Among them, 64% were HCV RNA undetectable off therapy 12 weeks after transplantation (25/39 patients who reached week 12 post-transplant), that is, achieved a sustained virological response (SVR) with no recurrence of HCV infection on the graft. Only one of the patients with undetectable HCV RNA for more than 30 continuous days infected his liver graft.6 Although no data has been generated yet with other drug combinations, accumulating experience suggests that adding a second DAA to sofosbuvir, with or without ribavirin, will yield even more efficient prevention of post-transplant HCV recurrence. Additionally, promising preliminary results have been reported in patients with post-transplant HCV recurrence treated with IFN-free regimens. Thus, prevention of HCV graft infection after liver transplantation is no longer an unmet need, and HCV entry inhibitors are unlikely to find an indication in this setting.
Are more efficient and better tolerated combinations of anti-HCV drugs needed for certain patient subgroups? Recent Phase II and III clinical trials showed that the combination of a nucleotide analogue with one or two drugs with a low barrier to resistance, or the triple combination of three drugs with a low barrier to resistance, yielded SVR rates in the order of 95% in treatment-naive and experienced patients, with an excellent tolerance over 6–24 weeks of administration.6 – 12 Although not all regimens are effective against all HCV genotypes, several already or soon-to-be approved drugs have pangenotypic activity. Additionally, drug–drug interactions appear to be easy to handle with most of the new DAAs. Very high SVR rates were reported in groups previously considered as difficult to cure, such as prior non-responders to IFN-based treatment, patients with compensated cirrhosis or HIV-coinfected patients who should no longer be considered a ‘special population’. Our current understanding of the mechanisms of HCV clearance on IFN-free therapies indicates that most, if not all, HCV-infected patients can achieve SVR with the existing or in-development combinations. Optimisation of current treatment regimens is possible in more difficult-to-cure patients, for instance, by increasing the number of drugs from different classes in the combination, prolonging treatment duration and/or adding ribavirin. Thus, even though being able to use more drug classes could be interesting in principle, there is no pressing need for the clinical development of entry inhibitors in the HCV field.
Will more efficient combinations be needed for patients with resistance? This question is unanswered. In clinical trials, 5%–10% of patients failed to eliminate HCV.6 – 12 This may translate into 10%–20% in real life, especially in the most difficult-to-cure populations. All patients exposed to protease inhibitors, NS5A inhibitors and/or non-nucleoside inhibitors of HCV RdRp who will fail to eradicate infection will select HCV variants resistant to the DAA(s) they received, that may remain as a dominant viral population for months to years. Whether such patients can be re-treated efficiently with combinations of the available drug classes is not yet known. Re-treatment of patients who failed on the triple combination of pegylated IFNα, ribavirin and a protease inhibitor with sofosbuvir plus daclatasvir yielded a 100% SVR rate in a small Phase II trial.12 A case was reported of a patient who failed on 8 weeks of the combination of sofosbuvir and ledipasvir and selected viruses resistant to both drugs. Infection was cured after the patient was re-treated 24 weeks with the same drug combination plus ribavirin. Our current understanding of the mechanisms of HCV response to IFN-free therapy again suggests that most, if not all, failing patients will find a re-treatment option, with eventually more of the existing classes of drugs in the combination and/or longer administration, susceptible to eliminate HCV without the need for alternative mechanisms of action.
In summary, there is no unmet clinical need unlikely to be solved in the short term to mid-term with the classes of HCV drugs currently approved or at the late clinical developmental stages. It is, nevertheless, safe to keep active ongoing research, in the (unlikely) case broad exposure to the new anti-HCV drugs results in a major clinical problem related to the selection and spread of multidrug-resistant viruses. There are many other viral infections in human, animal and plant medicine. They sometimes represent important public health or economical problems, but no active drug development programmes exist. Some of these infections could benefit from approaches based on viral entry inhibition. The fine study by Xiao et al brings a proof of concept that entry inhibitors can be combined with other antiviral agents, including virus-specific and/or HTAs, to treat and eventually cure various kinds of viral infections. HCV research and drug development can now be used as a valuable model for this endeavour.
Competing interests The author has received research grants from Gilead Sciences. He has served as an advisor for Abbvie, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Idenix, Janssen, Merck, Novartis, and Roche.
Provenance and peer review Commissioned; internally peer reviewed.
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