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NS3/NS4A protease inhibitors block the hepatitis C virus (HCV) NS3/NS4A protease enzymatic cleavage of the HCV C-terminal polyprotein into discrete nonstructural proteins. Telaprevir and boceprevir represent the first wave of HCV protease inhibitors. The second wave (simeprevir, ABT-450, asunaprevir) have improved pharmacokinetics and allow once-daily dosing with more tolerable side effects. Each of these agents has similar genotype and subtype coverage (less efficacious against 1a than 1b because of a lower barrier to selection for resistance) and resistance profiles. The true second-generation protease inhibitors (MK-5172) are in earlier stages of development and likely provide close to pan-genotypic antiviral activity and a higher genetic barrier to resistance.
NS5A inhibitors block viral production at two steps: the HCV replication complex and the virion assembly stage. Representative drugs in development include daclastavir, ledipasvir, ABT-267, and MK-8742.
Nucleos(t)ide NS5B Polymerase Inhibitors
Nucleos(t)ide NS5B polymerase inhibitors inhibit HCV RNA-dependent RNA-polymerase activity by binding to the active site and causing early chain termination. These agents (sofosbuvir) have broad potency and a very high barrier to resistance. Because of the critical function of the highly conserved active site, mutations in this site result in crippled replication fitness. This barrier to resistance stands in stark contrast to the nonnucleoside NS5B inhibitors, which bind to the enzyme outside the active site (allosteric inhibitors) and induce conformational changes that limit access of nucleotides to the growing viral RNA.
Figure 1 shows the HCV genome, which is a small, positive-sense, single-stranded RNA virus with a 9.6-kb genome. The virus circulates as a highly lipidated molecule that closely resembles host lipoproteins. Once inside the cell, the viral genome is exposed and translated into a polypeptide of about 3000 amino acids. This polypeptide is cleaved by a combination of host and viral proteases into 10 viral proteins. These include 3 structural proteins (C, E1, E2) and 7 non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B).
Host Targeting Agents
Cyclophilin inhibitors inhibit cyclophilin A and disrupt its interaction with NS5A and the HCV replication complex, which results in impaired replication.
MicroRNA antagonists exert inhibitory effect on HCV replication by blocking a key microRNA essential for HCV RNA replication.
Mechanism of Action
Sofosbuvir is a nucleotide analog inhibitor of HCV NS5B polymerase, targeting the HCV NS5B polymerase active site and becoming incorporated into the growing viral RNA, causing early chain termination. It exerts potent antiviral activity against HCV genotypes 1 through 6.
The US Food and Drug Administration (FDA) approved the use of sofosbuvir in patients with HCV genotype 1 to 4 infections. It is also approved for use in human immunodeficiency virus (HIV)/HCV coinfection and patients with hepatocellular carcinoma awaiting liver transplantation who are within Milan criteria and have a Model for End-Stage Liver Disease (MELD) score of <15.
In HCV genotype 1 treatment-naïve patients, the combination of sofosbuvir, pegylated interferon (PEG-IFN) and ribavirin (RBV) for 12 weeks yielded a sustained virologic response (SVR) of 89%; in those with multiple unfavorable baseline factors, the SVR was 71%. Patients with genotype 2 who were treated with sofosbuvir and RBV for 12 weeks had a SVR of 95%-97% in treatment-naïve patients and 82%-90% in treatment-experienced patients. In patients with genotype 3, an extended duration of 24 weeks with sofosbuvir and RBV produced a SVR rate of 93% in treatment-naïve populations and 77% in treatment-experienced populations.[3-5]
The PHOTON-1 study, in which HCV/HIV-1-coinfected patients were treated with sofosbuvir and RBV for 12-24 weeks, yielded a SVR of 76% in genotype 1, 88% in genotype 2, and 92% in genotype 3 with a good safety profile and minimal drug interaction with highly active anti-retroviral therapy (HAART).
Table 1 summarizes the approved uses of sofosbuvir.
Table 1. Recommended Sofosbuvir Regimens
Sofosbuvir is given orally at 400 mg daily with or without food. PEG-IFN is given at 180 μg subcutaneously once per week. RBV is given orally, is weight-based (<75 kg = 1000 mg and >75 kg = 1200 mg), and is given in two divided doses daily with food. Patients with renal impairment require an RBV dose reduction.
Up to 48 weeks (or until time of liver transplantation)
Use Outside the Approved Indications
Patients with HCV genotype 1 who are ineligible for or intolerant of PEG-IFN-based regimens should consider 1) sofosbuvir and simeprevir for 12 weeks, particularly in patients with compensated cirrhosis, or 2) sofosbuvir and ribavirin for 24 weeks.
Patients with mild to moderate renal impairment and/or anemia should consider sofosbuvir and simeprevir for 12 weeks.
Patients who failed first-generation protease inhibitors and who are therefore not candidates for simeprevir-based therapy and require immediate treatment should consider sofosbuvir and PEG-IFN/RBV therapy for 12 weeks.
Patients with posttransplantation-recurrent HCV infection may be considered for sofosbuvir and simpeprevir for 12 weeks in genotype 1; sofosbuvir and RBV with or without PEG-IFN for 24 weeks in genotypes 2, 3, and 4; or sofosbuvir and RBV for up to 48 weeks in decompensated disease or fibrosing cholestatic hepatitis C.
Mechanism of Action
Simeprevir is a macrocyclic NS3/4A protease inhibitor that inhibits the HCV NS3/4A protease's cleavage of the HCV polyprotein, preventing viral replication in infected cells.
The FDA approved the use of simeprevir in combination with PEG-IFN and RBV for HCV genotype 1 infection in treatment-naïve and treatment-experienced patients with noncirrhotic and compensated cirrhotic disease.
A pooled analysis of phase 3 studies of HCV treatment-naïve patients treated with simeprevir for 12 weeks and PEG-IFN/RBV for 24 weeks showed a SVR of 80%. This was reduced to 61% and 60% in patients with interleukin−28B TT genotype and cirrhosis, respectively. The efficacy was also significantly lower among those with genotype 1a who harbor the Q80K polymorphism (SVR 58%).[8, 9]
Prior PEG-IFN/RBV relapsers treated with simeprevir for 12 weeks and PEG-IFN/RBV for 24 weeks had a SVR of 79%. Prior partial- and null-responders treated with simeprevir for 12 weeks and PEG-IFN/RBV for 48 weeks had a SVR of 65% and 53%, respectively.
Table 2 summarizes the approved uses of simeprevir.
Table 2. Recommended Simeprevir Regimens for HCV Genotype 1 Patients
Prior Treatment Status
Medications and Duration
Simeprevir is given orally at 150 mg daily. PEG-IFN is given at 180 μg subcutaneously once per week. RBV is given orally, is weight-based (<75 kg = 1000 mg and >75kg = 1200 mg), and is given in two divided doses daily with food. Patients with renal impairment require an RBV dose reduction.
Simeprevir 12 weeks + PEG/RBV 24 weeks
Simeprevir 12 weeks + PEG/RBV 24 weeks
Simeprevir 12 weeks + PEG/RBV 48 weeks
Simeprevir 12 weeks + PEG/RBV 48 weeks
Use Outside the Approved Indications and Conditions
The “Use Outside the Approved Indications” section for sofosbuvir discusses combination therapy of simeprevir with sofosbuvir for patients who are ineligible for PEG-IFN-based therapy, who have renal impairment, or who have recurrent allograft HCV.
Patients who have HIV/HCV coinfection, have genotype 1b, have genotype 1a without Q80K polymorphism, and are on compatible HAART regimens (permitted antiretroviral therapy with simeprevir: raltegravir, rilpivirine, maraviroc, tenofovir, emtricitabine, lamivudine, and abacavir) may consider the following: 1) if no cirrhosis, simeprevir and PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV for 12 or 36 weeks based on response-guided therapy criteria; or 2) if cirrhosis, simeprevir and PEG-IFN/RBV for 12 weeks followed by 36 weeks of PEG-IFN/RBV.
The challenges associated with the use of these agents include cost of treatment, third-party reimbursement for off-label use, use in special populations, and drug resistance.
Combining direct-acting antiviral agents (DAAs) in an off-label manner may be an attractive option for patients who are unwilling or unable to undergo PEG-IFN-based therapy. While the sofosbuvir/simeprevir strategy relies on phase 2 data supporting safety and efficacy compared with the FDA-approved regimen, these data were derived from exactly those patients who necessitate more urgent treatment (patients with either cirrhosis and bridging fibrosis). It will be of great interest to assess the willingness of third-party payers to support this regimen, especially in the setting of the most recent American Association for the Study of Liver Diseases-Infections Diseases Society of America HCV guidance document, http://www.hcvguidelines.org/ which supports its use.
The optimal use of these medications in special populations such as patients with decompensated cirrhosis, first-generation protease inhibitor failures, recipients of solid organ transplants, and patients with end-stage kidney disease is not clear, because data are much more limited and may be challenging to obtain. Thus, use of these and other DAAs in these populations will likely be off-label and will require justification based on their risk/benefit comparison.
Resistance issues will be clarified as different drugs and combinations are evaluated. One case of sofosbuvir resistance (S282T) was reported in the LONESTAR trial with sofosbuvir and ledipasvir. Although the resistant variant persisted during the retreatment phase with sofosbuvir/ledipasvir/RBV, the patient nonetheless achieved SVR with longer duration of therapy. The efficacy of simeprevir/PEG-IFN/RBV is significantly diminished in patients with genotype 1a who had a baseline Q80K polymorphism; thus, routine baseline Q80K testing should be performed and alternative treatment offered to those with the polymorphism. For those patients treated in the COSMOS trial with sofosbuvir/simeprevir, the baseline Q80K had an insignificant impact on SVR.
Will Sofosbuvir and/or Simeprevir Replace the Previous Generation of Antiviral Agents?
Although there is no head-to-head trial comparison, it appears that simeprevir is at least as effective as telaprevir and boceprevir. Simeprevir has the advantage of once-daily dosing, more tolerable side effects, shorter treatment duration, less intense monitoring, and no requirement to be administered food or a high-fat meal, and this has led to the American Association of the Study of Liver Diseases advising against the use of the first-generation protease inhibitors. In addition, simeprevir is a weak inhibitor of P-glycoprotein and CYP3A4 in the gut; thus, no dose adjustment is required for cyclosporine or tacrolimus, making it a useful treatment agent in the liver transplant recipient.
Sofosbuvir is a potent NS5B polymerase inhibitor that is effective across all HCV genotypes and in difficult-to-treat populations. It is given once daily and is associated with minimal adverse effects. These drugs have the highest barrier to resistance among the current classes and are effective both with and without PEG-IFN. Sofosbuvir has also been associated with promising treatment outcomes as part of an all-oral regimen with other DAAs (e.g., ledipasvir) now completing phase 3 trials.
Overall, sofosbuvir and simeprevir represent a major advance in HCV treatment and will undoubtedly supplant telaprevir and boceprevir based on their efficacy, safety, tolerability, and convenience. While the earliest such drugs are still approved as add-ons to PEG-IFN-based therapy in genotype 1 HCV, all-oral PEG-IFN-free regimens will become available within the next year and will advance HCV treatment even further. (See Table 3 for a summary of key points.)
Table 3. Key Points
Sofosbuvir and simeprevir, each approved as add-on therapy with PEG-IFN/RBV, have surpassed the previous generation of direct antiviral agents (telaprevir, boceprevir) based on their effectiveness, safety, convenience, and resistance profiles.
Sofosbuvir is a nucleotide NS5 polymerase inhibitor with pan-genotypic activity and a very high barrier to viral resistance. It has been shown to be effective in treatment-naïve, treatment-experienced, and difficult-to-treat populations such as those with HCV/HIV coinfection, cirrhosis, and patients with mild to moderate impaired renal function and anemia.
Sofosbuvir is not recommended in patients with severe renal impairment/ESRD or hemodialysis, because no dosing data are currently available for this patient population.
Simeprevir is a second-wave, macrocyclic NS3/4A protease inhibitor and is effective against HCV genotype 1; however, its clinical efficacy is limited by the Q80K polymorphism in genotype 1a patients.
Based on phase 2 data, strong rationale exists for the use of sofosbuvir and simeprevir in genotype 1 treatment-naïve or experienced patients with advanced fibrosis who are intolerant of or ineligible for PEG-IFN.
Sofosbuvir and simeprevir each have minimal to no interaction with cyclosporine and tacrolimus; thus, a combination of sofosbuvir and simeprevir may be considered in the setting of recurrent allograft HCV.
Given the overall effectiveness and safety of the new HCV therapies, treatment should be strongly considered in each patient to mitigate long-term risks such as disease progression, change in health status making future treatment impossible, and risk of HCV transmission.