The management of hepatitis C virus (HCV) infection in special populations is challenging. The efficacy and safety data of the currently approved all-oral direct-acting antiviral combinations, including sofosbuvir, ledipasvir, daclatasvir, paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D), and ribavirin, is compelling for use in special HCV populations, as has recently been recommended by expert guidelines. The treatment regimens and sustained virological response rates for special populations are nearly similar to those of the general HCV population. Sofosbuvir is not recommended in patients with severe renal impairment, and simeprevir and 3D regimen are not recommended for those with decompensated liver disease.
Key points
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The management of hepatitis C virus (HCV) infection in special populations, including patients with decompensated cirrhosis, liver transplantation, human immunodeficiency virus coinfection, and end-stage renal disease, is challenging.
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Interferon-based therapy had reduced efficacy, increased side effects, altered pharmacokinetics, and the potential for drug-drug interactions (DDI), via CYP3A, with boceprevir and telaprevir.
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New-generation direct-acting antivirals (DAA) with high potency and no to minimal DDI are preferred, especially as interferon-free regimens. The efficacy and safety data of the currently approved all-oral DAA combinations, containing sofosbuvir, ledipasvir, daclatasvir, paritaprevir/ritonavir/ombitasvir plus dasabuvir, and ribavirin, is compelling for use is special HCV populations, as has recently been recommended by the AASLD/IDSA and EASL guidelines.
Introduction
Chronic hepatitis C virus (HCV) infection is a worldwide leading cause of chronic liver disease that affects more than 170 million individuals. Treatment of HCV has been evolving rapidly over the past few years, shifting from a combination of pegylated-interferon (PEG-IFN) plus ribavirin (RBV) to an all-oral combination of direct-acting antivirals (DAA) targeting NS3/4A, NS5A, and NS5B HCV proteins. Experiences have shown that the epidemiology, the natural history, and the response to treatment of HCV vary among certain patient populations, especially in those with decompensated cirrhosis, liver transplantation (LT), human immunodeficiency virus (HIV) coinfection, and end-stage renal disease (ESRD). The management of HCV in these populations is challenging, particularly with IFN-based therapy, because of reduced efficacy of treatment, increased treatment-related side effects, altered pharmacokinetics, and the potential for significant drug-drug interactions (DDI) with early-generation protease inhibitors, such as boceprevir, telaprevir, and simeprevir. Accordingly, new-generation DAA with high potency and minimal DDI, especially the IFN-free/RBV-free regimens, are preferred. Recently, the safety and efficacy data of the currently approved all-oral DAA combinations in special HCV populations have been increasingly reported. Although the number of patients is still limited in clinical trials, these data are convincing, which has led to a recommendation for their use in special HCV populations in guidelines published by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), and the European Association for the Study of the Liver (EASL).
This review focuses on the DAA-based management of HCV patients with decompensated cirrhosis, post-LT, HIV coinfection, and ESRD, using the currently available regimens in the United States and Europe. In addition, unique clinical features of these HCV populations and the use of IFN-based therapy are briefly reviewed. Important pharmacokinetic and metabolic properties of the currently available DAA are summarized in Table 1 . In addition, at this evolving stage of HCV management, it is suggested that continuous updates on the more recent recommendations for HCV treatment be obtained from the AASLD and the EASL Web sites.
| Drug | Metabolism/Excretion Route | Interaction with CYP and Substrate Transporters | Dosage Adjustment in Patients with Renal Impairment | Dosage Adjustment in Patients with Liver Impairment |
|---|---|---|---|---|
| NS3/4A Protease Inhibitors | ||||
| Telaprevir | Hepatic (CYP3A) | Strong CYP3A inhibitor, moderate P-gp inhibitor | No dose adjustment is required for any degree of RI (clinical data limited) | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class B/C |
| Boceprevir | Hepatic (CYP3A, aldoketo-reductase) | Moderate CYP3A inhibitor, weak P-gp inhibitor | No dose adjustment is required for any degree of RI (clinical data limited) | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class B/C |
| Simeprevir | Hepatic (CYP3A) | Mild CYP1A2 and CYP3A inhibitor, inhibitor of OATP1B1 and MRP2 | No dose adjustment is required for mild-severe RI; no data in ESRD | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class C |
| Paritaprevir (ABT-450)/ritonavir | Hepatic (CYP3A) | Strong CYP3A inhibitor (ritonavir), inhibitor of OATP1B1, substrate of P-gp and BCRP | No dose adjustment is required for mild-moderate RI; no data in severe RI/ESRD | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class C |
| Asunaprevir | Hepatic (CYP3A) | Weak CYP3A4 inducer, moderate CYP2D6 inhibitor, inhibitor of P-gp and OATP1B1 | No dose adjustment is required for any degree of RI (clinical data limited) | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class B/C |
| NS5A Replication Complex Inhibitors | ||||
| Daclatasvir | Hepatic (CYP3A) | Not a CYP3A inducer/inhibitor, moderate inhibitor of P-gp and OATP1B1 | No dose adjustment is required for any degree of RI (clinical data is limited) | No dose adjustment is required in compensated cirrhosis; Not recommended for CTP class C |
| Ledipasvir | Feces (major); hepatic and renal (minor) | Not a CYP inducer/inhibitor, weak inhibitor of P-gp and OATP1B1 | No dose adjustment is required for mild-moderate RI; no data in severe RI/ESRD | No dose adjustment is required for any degree of liver impairment |
| Ombitasvir (ABT-267) | Amide hydrolysis and oxidative metabolism | Not a CYP inducer/inhibitor, substrate of P-gp and BCRP | No dose adjustment is required for mild-moderate RI; no data in severe RI/ESRD | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class C |
| NS5B Nucleotide Polymerase Inhibitors | ||||
| Sofosbuvir | Renal | Not a CYP inducer/inhibitor, substrate of P-gp | No dose adjustment is required for mild-moderate RI; no data in severe RI/ESRD | No dose adjustment is required for any degree of liver impairment |
| NS5B Non-Nucleoside Polymerase Inhibitors | ||||
| Dasabuvir (ABT-333) | Hepatic (CYP2C8 60%, CYP3A4 30%, CYP2D6 10%) | Not a CYP inducer/inhibitor, substrate of P-gp and BCRP | No dose adjustment is required for mild-moderate RI; no data in severe RI/ESRD | No dose adjustment is required in compensated cirrhosis; not recommended for CTP class C |
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