Hepatitis C is the leading cause of liver-related mortality and liver transplant worldwide, and it is estimated that approximately 185 million people are infected with Hepatitis C virus (HCV).[1] The prevalence of HCV infection in India is about 1.5% indicating that more than 18 million Indians are infected with HCV.[2]. In the past decade of this century, the treatment of HCV infection has been limited to pegylated interferon α2 (peg-IFN) along with ribavirin (RBV) with a sustained virological response (SVR) of 40% to 50% in HCV genotype 1 (GT1) and about 70%-80% in HCV genotype 2/3 (GT2/3) patients.[3-5] However, the combination is associated with numerous side-effects and treatment contraindications (decompensated cirrhosis for peg-IFN and renal failure for RBV).The poor safety profile of the combination therapy along with a deeper understanding of the HCV structure has led to the development of a number of direct-acting antiviral agents (DAAs) for the treatment of HCV infection. In recent years, DAA regimens that do not contain peg-IFN and/or RBV have revolutionised the treatment of chronic HCV infection.
HCV is an RNA virus that replicates in the cytoplasm. Its genome contains three major structural proteins (e.g., core, E1 and E2 proteins) and at least six nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B that exert functions in the replication cycle of the virus (Figure 1). Sequencing studies in patient populations have revealed six major genotypes with clear differences in global geographic distribution and racial preferences.[6] For example, GT1 is the most common and is responsible for 46.2% cases of HCV infection across the world.[7] In India, the GT3 is more common (54.4% cases) followed by GT1[8, 9] These genotypes demonstrate striking differences in susceptibility to antiviral drugs, thereby allowing individualisation of therapy depending on patient genotype.
In 2011, the use of first-generation NS3 protease inhibitors telaprevir and boceprevir, in combination with peg-IFN and RBV for HCV GT1 indicated for the first time that DAAs could increase SVR rates and shorten the duration of treatment. The downside of these regimens was the occurrence of serious systemic side effects and a high daily pill burden.[3] This in turn lead to poor patient compliance to therapy and disappointing SVR rates in previous non-responders to dual therapy. Since then a number of DAAs that target non-structural HCV proteins, such as NS3 and NS5A/B have been developed as these proteins perform crucial functions in the viral replication process. This review focuses on the pharmacology of four new DAAs namely, sofosbuvir, ledipasvir, daclatasvir and velpatasvir that have been recently approved for the treatment of HCV infection. Except for velpatasvir, all the rest have recently been marketed in India.
Sofosbuvir:
Sofosbuvir (SOF) is a HCV specific nucleotide inhibitor and inhibits the HCV NS5B RNA dependent RNA polymerase. It is a pro-drug of uridine monophosphate and is phosphorylated to the active uridine triphosphate in the hepatocytes. It competes with endogenous uridine triphosphate for incorporation into the growing viral RNA chain. Once it is bound it prevents further addition of nucleotides, and terminates chain elongation leading to inhibition of viral replication. [10, 11] SOF has shown pangenotypic activity against the HCV genotypes. Clinical trials did not reveal the presence of resistance-associated variants (mutation in NS5B or S282T) in patients treated with SOF and RBV, with or without peg-IFN, indicating that SOF has a high genetic barrier to resistance. The active triphosphate has a long intracellular half-life.[12] SOF is dephosphorylated to a metabolite (GS-331007) which has no activity against HCV. The important pharmacokinetic features of SOF are mentioned in table 1. SOF is available as a 400 mg tablet to be administered orally once daily, with or without food.[13]
SOF has a favourable safety profile and is well tolerated in patients with chronic hepatitis C. Adverse events (AEs) encountered while evaluating an interferon-free regimen of SOF plus RBV for 12 or 24 weeks, included fatigue, headache, nausea, insomnia, pruritus, irritability, anaemia and asthenia and were consistent with those expected with RBV. Additional side effects such as pyrexia, chills, pruritus, neutropenia and influenza-like illness were observed in patients who had received peg-IFN along with SOF and RBV for 12 weeks. [13] A fall in the haemoglobin level and a raised bilirubin level as is expected with RBV and a fall in neutrophil counts as is observed with peg-IFN were also reported in these trials.[14]
SOF is a substrate of P-glycoprotein (P-gp). [12, 15] Thus, it is expected that SOF concentrations may be reduced when it is coadministered with potent intestinal P-gp inducers such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifampicin or Hypericum perforatum (St John’s wort).[16] In addition, coadministration of SOF with rifabutin, rifampicin, rifapentine and tipranavir/ritonavir is not recommended as they can reduce SOF concentrations and hence decrease its therapeutic effect [12]. SOF should be administered cautiously with amiodarone, and whenever required with cardiac monitoring, as serious symptomatic bradycardia has been reported. [13, 16]
SOF is approved for the treatment of HCV infection in combination with RBV, with or without peg-IFN both in treatment naïve (TN) or treatment experienced (TE) patients. Clinical trials conducted with SOF have revealed that SOF plus RBV achieves high SVR12 rates in patients with HCV GT2 or GT3 infections: FISSION (TN)-67%; POSITRON (IFN intolerant, unwilling or ineligible)-78%; FUSION (TE)-50%; VALENCE (TN or TE)-93%.[16, 17] SOF plus RBV and peg-IFN achieves high SVR12 rates in HCV GT 1, 4, 5 or 6 infections: NEUTRINO (TN)-91%; ATOMIC (TN)-90 to 93%. In HCV patients co-infected with HIV-1, SOF plus RBV showed an SVR12 of 75% in TN patients of HCV GT2 or GT3 and an SVR12 of 76% in TN patients of HIV GT1 and SVR12 of 93% in TE patients of GT2 or GT3 respectively (PHOTON-1).[18] SOF plus RBV administered before liver transplantation prevented recurrent HCV infection (SVR12 of 69%) in patients with HCV RNA levels below the limit of quantification. [16]
Ledipasvir:
Ledipasvir (LDV) acts against HCV by inhibiting its NS5A RNA dependent RNA polymerase. Like NS5B, NS5A is essential for viral replication. In addition NS5A also helps in the virion assembly. LDV, is not used as monotherapy because unlike SOF, it has a low barrier to resistance. In fact, a 3 day monotherapy with LDV selects mutations and confers resistance in all patients treated with therapeutic doses. Since SOF has a high barrier to resistance and its mechanism of action also differs from LDV, it appeared that the LDV could be used with benefit in combination with SOF. [19] Hence clinical trials were designed to evaluate the safety and efficacy of LDV/SOF combination. Table 1 states the pharmacokinetic features of LDV.
LDV has shown an excellent safety profile when studied as monotherapy in clinical trials. All AEs reported were mild or moderate, with headache being the most common and was reported in 10% subjects.[19] In a pooled analysis of the ION-1, ION-2 and ION-3 trials which evaluated the effect of LDV/SOF or LDV/SOF plus RBV regimens, the incidence of treatment related AEs was 45% versus 71%. [20] The most common AEs in patients who received LDV/SOF were fatigue, headache, nausea, diarrhoea and insomnia.[21] The AEs which are commonly associated with RBV (e.g. fatigue, insomnia) were higher in patients who received the LDV/SOF plus RBV regimen. Increase in bilirubin levels to >1.5 x ULN and transient asymptomatic increases in lipase levels to >3 x ULN occurred in ≤ 3 % patients. No deaths were reported in any of the trials. [22]
H2 receptor antagonists like famotidine and proton pump inhibitors like omeprazole can be administered simultaneously with LDV at a dose that does not exceed the equivalent of 40 mg of famotidine twice daily and 20 mg/day of omeprazole. Antacids (e.g. aluminium and magnesium hydroxide) should be separated from the dosing of LDV by 4 hours. As LDV is a substrate of P-gp, it is likely that its concentration may be reduced when it is coadministered with the potent intestinal P-gp inducers mentioned above. Administration of LDV with HMG-CoA reductase inhibitors (e.g. rosuvastatin) is not recommended as it increases the statin concentration and is associated with a high risk of myopathy, including rhabdomyolysis. [23, 24]
A fixed dose combination (FDC) tablet of LDV/SOF (90 mg/400mg) to be taken orally once daily has been approved in India for the management of TN or TE patients of HCV GT1, with or without cirrhosis.[23] The approval is based on the data available from the phase III ION trials which included TN (ION-1 and ION-3) or TE (ION-2) patients with chronic HCV GT1 infection. Approximately 20 % of patients in ION-1 and ION-2 had cirrhosis, whereas no patient in ION-3 had cirrhosis. The SVR12 for LDV/SOF without and with RBV were 99% and 97% (ION-1), 94% and 96% (ION-2) and 95% and 93% (ION-3) respectively. [25] The FDC has shown promising results in chronic HCV GT4 infection (SYNERGY trial, SVR12- 95%) and in HCV and HIV co-infection (ION-4, SVR12- 96%; ERADICATE trial, SVR12-100% in TN and 97% in TE patients). [22] LDV/SOF in combination with RBV in HCV GT1 or GT4 infections (SOLAR-1 trial) has shown encouraging results in patients with decompensated cirrhosis (SVR12 – 87% and 89%) or liver transplantation (SVR12 – 96% and 98%).[26] Patients with HCV GT3 infection also showed a promising response to LDV/SOF based regimens in the ELECTRON-2 trial (SVR12: 64% in TN and 100% in TE).[22]
Daclatasvir:
Daclatasvir (DCV), is also an NS5A replication complex inhibitor like LDV. It not only inhibits the intracellular HCV RNA synthesis but also inhibits the virion assembly and secretion. DCV causes a rapid initial decline of HCV RNA which is followed by a more gradual decrease. [27] DCV (30 mg or 60 mg) has been recommended to be used with SOF (400 mg), with or without RBV, for the management of HCV GT3 infection. [28] Like SOF, DCV is pangenotypic and has potent anti-viral activity. However, resistant variants have emerged in patients with genotype 1a and 1b receiving DCV monotherapy and hence, as in the case of LDV, DCV should be used with SOF. [29] The pharmacokinetic features of DCV have been stated in table 1.
DCV has a good safety profile with none of the patients in the clinical trials stopping its intake due to an AE. The most common AEs observed in patients who received DCV plus SOF and DCV plus SOF and RBV were headache (18.5% vs 27.2%), nausea (14.4% vs 15.8%) and fatigue (2.8% vs 15.3%).[30] AEs commonly associated with RBV use (anaemia, insomnia) were seen in higher frequency in patients receiving DCV plus SOF regimens containing RBV. DCV plus SOF was tolerated well by the HCV infected patients having a co-infection with HIV-1, with their mean CD4+ counts remaining stable.[31]
Daclatasvir is a substrate of CYP3A4, P-gp and organic cation transporter 1. The coadministration of DCV with strong inducers of CYP3A4 such as rifampicin, St. John’s Wort, systemic prednisolone, carbamazepine, phenytoin, phenobarbital and oxcarbazepine is not recommended. The dose of DCV should be increased to 90 mg per day if coadministered with moderate CYP3A4 inducers like bosentan, dexamethasone, modafinil, nafcillin and rifapentine. [28] Similarly the dose needs to be reduced to 30 mg/day if coadministered with strong CYP3A4 inhibitors such as clarithromycin, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin and voriconazole. [28] Like LDV its coadministration with P-gp inducers is not recommended. The plasma concentration of digoxin and HMG-CoA inhibitors (statins) are increased when coadministered with DCV, and their concentrations need to be monitored. [29] No dose adjustment is needed for buprenorphine or naloxone when coadministered with DCV, but patients should be monitored for occurrence of adverse events. Dose adjustments of DCV are needed when it is coadministered with antiretroviral agents. The dose of DCV should be reduced to 30 mg per day when given with ritonavir, cobicistat containing regimens, indinavir, nelfinavir and saquinavir. The DCV dose needs to be increased to 90 mg per day when coadministered with efavirenz, etravirine and nevirapine. [28]
DCV (30 mg/60 mg tablets) is prescribed with SOF, with or without RBV. SVR12 rates achieved with DCV plus SOF-based regimens in chronic HCV GT1 TN or TE patients without cirrhosis were nearly 100% and about 89% in few GT3 TN patients without cirrhosis (AI444040 trial). [32] DCV plus SOF combination was found to be effective in patients with advanced liver disease (ALLY-3 trial, SVR12 – 86 to 92%), post-transplant recurrence (ALLY-1 trial, SVR12 – 83 to 100%) and HIV-1 co-infection (ALLY-2 trial, SVR12 – 67 to 100%). [29]
Velpatasvir:
Velpatasvir (VPV) is a HCV NS5A protein inhibitor that has been recently approved in the USA, EU and Canada for treatment of chronic HCV infection. Its mechanism of action is similar to LDV and DCV. VPV has activity against all the 6 important genotypes of HCV. [33] Although resistance-associated variants of NS5A and NS5B were present at baseline the combination of SOF/VPV showed high SVR12 rates. The salient pharmacokinetic features of VPV are mentioned in table 1.
VPV/SOF based regimens were generally well tolerated by patients in clinical trials. A collective analysis of the clinical trials which assessed SOF/VPV revealed that 79% of the HCV infected patients who received the FDC alone for 12 weeks experienced an AE. The most common AEs (> 10% incidence) reported in these clinical trials were headache, fatigue, nasopharyngitis, nausea, insomnia and pruritus. [34] No deaths have been attributed to VPV in studies assessing its safety. [33]
VPV, like SOF, is a substrate of P-gp and thus, its concomitant use with potent or moderate P-gp or CYP inducers mentioned above is not recommended. [34] VPV/SOF combinations have been studied with some of the HIV treatment regimens. Tenofovir concentrations may be increased when given with the VPV/SOF regimen, so its monitoring is recommended. Coadministration of efavirenz or tipranavir/ritonavir is not recommended because they cause decrease in the VPV concentrations. [33] The solubility of VPV is significantly decreased when coadministered with drugs which increase the gastric pH, causing its decreased absorption. Hence, it is recommended that antacid administration be separated by 4 hours from VPV while the H2 receptor antagonists dosing should be given 12 hours apart from VPV dosing. Administration of PPIs is not recommended, and if necessary then they should be given at least 4 hours before VPV administration. [35] Similar to LDV/SOF, coadministration of VPV/SOF with HMG-CoA reductase inhibitors like rosuvastatin and atorvastatin is expected to cause an increase in the statin levels and is associated with an augmented risk of myopathy, including rhabdomyolysis. All potential drug interactions that can occur with SOF can occur with this VPV/SOF fixed dose combination.
SOF/VPV (400 mg/100mg) is available as an FDC tablet to be taken orally once daily with or without food. Clinical trials have shown that SOF/VPV combination is highly effective in patients with chronic HCV (GT1 to 6) infection without cirrhosis or compensated cirrhosis (ASTRAL-1 trial, SVR12 – 99%; ASTRAL-2 trial, SVR12- 99%; ASTRAL-3 trial, SVR12- 95%). [36] In patients with decompensated cirrhosis, SOF/VPV in combination with RBV was effective across HCV genotypes 1,2,3,4,6 (ASTRAL-4 trial, SVR12 – 94%). [37] SOF/VPV has shown promising results in patients with HCV GT 1, 2, 3 or 4 infection with HIV co-infection (ASTRAL 5 trial, SVR12- 95% ). [36]
Conclusion:
HCV infection remains an important health issue attributing to high morbidity and mortality. However, the recent approval of the new DAAs against HCV infection marks a major milestone in the management of this infection, especially those who are cirrhotic or co-infected with HIV. The new DAAs also have a good safety profile which will help in the betterment of the quality of life of the HCV infected patients.