DÄ internationalArchive1-2/2017Treatment Options in Hepatitis C

cme

Treatment Options in Hepatitis C

The current state of the art

Dtsch Arztebl Int 2017; 114(1-2): 11-21; DOI: 10.3238/arztebl.2017.0011

Zeuzem, S

Background: Among patients with chronic hepatitis C, 20–30% develop hepatic cirrhosis and its complications within 30 years. The antiviral treatment of hepatitis C, previously interferon-based, has recently become interferon-free, with resulting improvements in sustained virological response rates, safety, and tolerability and a shorter duration of treatment.

Methods: This review is based on relevant publications retrieved by a selective literature search, and particularly on studies and reviews concerning the course and treatment of hepatitis C.

Results: The available drugs for interferon-free antiviral treatment of hepatitis C include inhibitors of the RNA-dependent RNA polymerase, NS3/4A protease, and NS5A protein of the hepatitis C virus (HCV), and ribavirin. Typically, two specific inhibitors are given in combination; the usual duration of treatment is 12 weeks.The antiviral drugs differ in their genotypic antiviral effectiveness and resistance barriers. The appropriate drug(s) should be chosen in consideration of the patient’s hepatic and renal function and potential drug interactions. These drugs are safe and well-tolerated and result in sustained virological response rates between 90% and 100%.

Conclusion: All patients with hepatitis C, whatever their disease stage, can derive a sustained eradication of HCV from a combination of drugs with direct antiviral activity. Viral eradication is associated with a better quality of life and with lower morbidity and mortality.

LNSLNS

More than 100 million persons worldwide are infected with the hepatitis C virus (HCV). The prevalence of HCV in Germany is estimated at 0.3–0.5% (e1, e2). It is transmitted parenterally. Transmission via the transfusion of whole blood and blood products has been minimized through the use of serological and molecular testing procedures. The risk of transmission of HCV now arises mainly from needle sharing among intravenous drug abusers, homosexual contacts between men, and, in countries with poor adherence to hygiene guidelines, iatrogenic transmission (e3).

Acute hepatitis C takes a chronic course in 50–70% of cases. Hepatic fibrosis progresses is dependent on the age of the patient at the time of infection. On average, 20–30% of patients develop cirrhosis within 30 years (e3, e4). The progression of fibrosis is modulated by cofactors such as the amount of alcohol consumed or viral coinfections (e.g., with HIV) (e3, e4). Patients with HCV-associated cirrhosis have a 3–6% incidence of hepatocellular carcinoma (e5).

The treatment of HCV has been revolutionized by the recent introduction of potent direct antiviral agents (DAA).

Interferon-free treatment now gives patients an excellent chance of long-lasting virus eradication, i.e., a sustained virological response (SVR) (e6).

Learning objectives

The goals of this article are to:

  • give the reader knowledge of the genotypic antiviral effectiveness, safety, and tolerability of the available inhibitors of RNA-dependent RNA polymerase, NS3/4A protease, and the NS5A protein;
  • explain the treatment schemes recommended for different patient populations;
  • discuss the importance of hepatic and renal function and potential drug interactions for the choice of antiviral drugs.

Methods

For this review, we evaluated publications about the antiviral treatment of hepatitis C from the years 2003 (first publication on the effective use of a direct antiviral agent in humans [e7]) to 2016 that were retrieved by a selective search in PubMed, with special attention to phase 2 and 3 trials and reviews on the course and treatment of hepatitis C. We also considered all abstracts of presentations on this subject within this time period that were given at the meetings of the German (DGVS), European (EASL), and American (AASLD) specialty societies, as well as these societies’ HCV treatment guidelines.

Sustained viral response: a patient-relevant endpoint

The molecular demonstration of the absence of HCV-RNA twelve weeks after the end of a course of antiviral treatment confirms the sustained eradication of the virus. The likelihood of a late recurrence is well under 1% (e8, e9), and most such events are actually not recurrences but reinfections (e10). The eradication of HCV does not generate protective immunity (e11).

A meta-analysis of 129 studies involving a total of 34 563 patients who had undergone interferon-based treatment revealed that a sustained virological response was associated with a 62% to 84% reduction of mortality, a 68% to 79% reduction of the risk of hepatocellular carcinoma (HCC), and a 90% reduction of the risk of needing liver transplantation (e12). As interferon-based treatment was contraindicated in patients with decompensated cirrhosis, these data are uninformative with respect to any potential clinical benefit, for these patients, of sustained viral eradication with direct antiviral agents (DAA). Initial studies have yielded clinical and laboratory evidence of improvement mainly for patients with a MELD (“model of end-stage liver disease”) score below 16–18 points (13). In large-scale cohort studies, sustained viral eradication was associated both with lower liver-associated mortality and with substantially lower extrahepatic mortality (although no causal link was demonstrated) (e13). Sustained viral eradication eliminates the risk of individual transmission and is associated with a better quality of life (4, e14).

Because of the residual risk of HCC even after successful viral eradication, patients with hepatic cirrhosis (regardless of the possible regression of fibrosis) should undergo lifelong surveillance with hepatic ultrasonography and alpha-fetoprotein measurement every six months, as recommended in the German guideline (5). Esophageal varices are very unlikely to arise once HCV has been eradicated, because viral eradication is associated with the regression of hepatic fibrosis and portal hypertension (as reflected in the hepatovenous portal pressure gradient [HVPG]) (e15).

HCV genotypes

The genetic variability of the hepatitis C virus is high. There are at least six different genotypes (HCV-1, 2, 3, and others) with multiple subtypes (e.g., HCV-1a, 1b and more). The precise diagnosis can be established either by direct sequencing or by a reverse hybridization assay. Infection with HCV genotype 3 is associated with more rapid progression of fibrosis than infection with other HCV genotypes (e16). There are conflicting data on associations of specific HCV genotypes with the incidence of hepatocellular carcinoma (e17, e18).

Antiviral drugs

The basis of current, interferon-free treatment is a combination of directly acting antiviral drugs (Table 1) with high antiviral efficacy, resistance barriers, and different sites of attack (Figure) (6, 7).

The replication cycle of the hepatitis C virus, with points of attack of antiviral drugs
The replication cycle of the hepatitis C virus, with points of attack of antiviral drugs
Figure
The replication cycle of the hepatitis C virus, with points of attack of antiviral drugs
Antiviral drugs for the treatment of hepatitis C (HCV)
Antiviral drugs for the treatment of hepatitis C (HCV)
Table 1
Antiviral drugs for the treatment of hepatitis C (HCV)

RNA-dependent RNA polymerase inhibitors are categorized as either nucleotide inhibitors (NI) or non-nucleoside inhibitors (NNI). NI are phosphorylated within cells by the activity of cellular kinases, bind as triphosphates to the active center of the HCV-specific NS5B polymerase, and abort the construction of the growing viral RNA chain. NNI cause allosteric inhibition of NS5B polymerase. The generic names of all HCV polymerase inhibitors end in “-buvir.” Protease inhibitors are directed against HCV-NS3/4A serine protease (splitting of the HCV polyprotein); their generic names end in “-previr.” The HCV-NS5A protein plays a role in HCV replication and the modulation of cellular functions. Various NS5A inhibitors have been developed; these have generic names ending in “-asvir.” (6). Ribavirin, a drug whose antiviral mechanism of action is still incompletely understood, continues to play an important role in various antiviral drug regimens (e19).

The treatment of acute hepatitis C

In the multicenter German “Acute HCV IV” trial, six weeks of treatment with sofosbuvir/ledipasvir resulted in a sustained viral eradication rate of 100% in patients acutely infected with HCV genotype 1 (8). It should be noted, however, that the combination of sofosbuvir and ledipasvir is available in Germany only in packages of 28 tablets, so that taking a single tablet per day for six weeks (i.e., 42 tablets total) is unreasonable in terms of drug economics. Until further data are available, patients with acute hepatitis C should be treated for eight weeks, analogously to the recommendations for previously untreated (non-cirrhotic) patients with acute hepatitis C. As the rate of HCV transmission to health care workers via needle stick injury is very low, no post-exposure prophylaxis is recommended in this situation (9).

Treatment options

For previously untreated patients with chronic hepatitis C

Various drug combinations have been approved for the treatment of HCV genotype 1 infection, including both fixed co-formulations (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, paritaprevir/ombitasvir with dasabuvir, grazoprevir/elbasvir) and combinations in which the doses of the two agents can be freely chosen (sofosbuvir plus simeprevir, sofosbuvir plus daclatasvir) (Table 2) (1017). All combinations result in sustained virological response rates above 95% in this patient population and are generally very well tolerated. The duration of treatment is twelve weeks but can be shortened to eight in the case of sofosbuvir/ledipasvir for a previously untreated, non-cirrhotic patient with an HCV-RNA viral load under 6 million IU/mL, or paritaprevir/ombitasvir/dasabuvir for a previously untreated, non-cirrhotic patient with an HCV genotype 1b infection (10, 18, e20).

Approved antiviral treatment regimens*
Approved antiviral treatment regimens*
Table 2
Approved antiviral treatment regimens*

The administration of ribavirin in addition to paritaprevir/ombitasvir/dasabuvir is recommended for the treatment of patients who are infected with HCV genotype 1a, but not for those infected with HCV genotype 1b (12, 13, 19). Only limited evidence is now available on the possible role of ribavirin as an addition to the freely combinable regimens.

The European approval for the treatment of patients with HCV-1a infection with grazoprevir/elbasvir contains the recommendation that treatment for 16 weeks, with ribavirin given in addition, should be considered for patients whose initial viral load exceeds 800 000 IU/mL, in order to lower the risk of treatment failure. Alternatively, the decision to modify the treatment in this way can be based on testing for resistance-associated variants (RAVs) of the NS5A gene, which lower the activity of elbasvir by at least a factor of 5 (14).

The standard treatment of HCV genotype 2 infection is with sofosbuvir/ribavirin (20), and that of HCV genotype 3 infection is with sofosbuvir/daclatasvir, for twelve weeks in both cases (21). Effective drug combinations for the treatment of HCV genotype 4 infection include sofosbuvir/ledipasvir (e21), paritaprevir/ombitasvir (without dasabuvir, but with ribavirin) (22), grazoprevir/elbasvir (23), sofosbuvir/daclatasvir (e22), and sofosbuvir/simeprevir (e23) (Table 2).

The first approved pangenotypic drug combination is that of sofosbuvir with velpatasvir, which yields virus eradication rates of 97–100% in infections with HCV genotype 1, 2, 3, 4, 5, or 6 (24, 25).

Patients previously treated with (peg-)interferon/ribavirin

The sustained virological response rates obtainable with all of the approved drug regimens are essentially the same in non-cirrhotic patients infected with HCV genotype 1 regardless of whether they are treatment-naïve or have been previously treated with (peg-)interferon/ribavirin (1017). Nonetheless, there is an important distinction between patients infected with HCV genotype 1 who have been previously treated with a (peg-)interferon/ribavirin in combination with, or without, a direct antiviral agent (usually a first-generation NS3/4A protease inhibitor, such as telaprevir or boceprevir). Patients previously treated with a triple combination of peginterferon, ribavirin, and an NS3/4A protease inhibitor can be treated anew with sofosbuvir/ledipasvir (26), sofosbuvir/velpatasvir (24), or sofosbuvir/daclatasvir (27) without any compromise of the likelihood of a sustained virological response.

It is unusual (<10–15%) for a non-cirrhotic patient with an HCV genotype 2 infection to fail to respond to treatment with (peg-)interferon/ribavirin. Retreatment options for such patients include sofosbuvir/ribavirin for 12–16 weeks (28) and sofosbuvir/velpatasvir for 12 weeks (25). In a comparative trial, sofosbuvir/velpatasvir yielded a higher sustained virological response rate than sofosbuvir/ribavirin (99% versus 94%), and this difference was statistically significant (25). In patients from Eastern Europe in particular, the possibility of an HCV-2k/1b chimera must be considered: this is a virus isolate with the characteristics of HCV genotype 2 at the 5’ end (leading to classification as HCV genotype 2 in HCV typing assays), but those of HCV genotype 1 at the 3’ end (and therefore also at the target area of all direct antiviral agents) (e24). For such chimeras, the sustained virological response rates are 30% with sofosbuvir/ribavirin (for twelve weeks) and more than 90% with sofosbuvir/NS5A inhibitor (for twelve weeks) (e24, e25) (personal communication from Dr. David Metreveli, European Limbach Diagnostic Group, Tbilisi, Georgia).

The treatment options for patients infected with HCV genotype 3 who have been previously treated with (peg-)interferon/ribavirin are the following:

  • sofosbuvir/ribavirin for 24 weeks (sustained virological response rates, 71–87 %) (20, 25)
  • sofosbuvir/daclatasvir or sofosbuvir/velpatasvir, for 12 weeks in both cases (sustained virological response rates of 86% and 91%, respectively) (21, 25).

The currently approved NS3/4A protease inhibitors simeprevir, paritaprevir and grazoprevir have no antiviral activity against HCV genotype 3 at the doses in which they are used. For patients who tolerated initial treatment with (peg-)interferon/ribavirin well, the combination (peg-)interferon/ribavirin/sofosbuvir is an alternative regimen for retreatment, with a sustained virological response rate of 94% (29).

Numerous drug regimens have been approved for the retreatment of patients infected with HCV genotype 4 (Table 2), while less evidence is available for the treatment of HCV genotypes 5 and 6 (e26, e27). In the latter situation, the pangenotypic combination sofosbuvir/velpatasvir can be given (24).

Virological relapse after interferon-free treatment with direct antiviral agents

Treatment failure during or after the administration of direct antiviral agents (DAA) is presumed to be due to the selection of resistance-associated viral variants (RAVs). The demonstrability of the different kinds of RAV by population-based sequencing, and their persistence rates, differ depending on the time of testing and the DAA substance class. RAVs in the NS5A gene generally persist longer than RAVs in the NS3/4A gene (30). All currently approved DAAs, with the exception of the nucleoside polymerase inhibitor sofosbuvir, have a relatively low resistance barrier, and there are relevant cross-resistances between the individual NS3/4A proteases and the NS5A inhibitors (30, e28).

Treatment failures in combination therapy with multiple DAAs often reflect a complex virological situation. A new treatment can be initiated in a specialized center on the basis of HCV resistance analysis (e29, 31).

Fixed double and triple drug combinations (a second-generation NS3/4A protease inhibitor plus a second-generation NS5A inhibitor, each with antiviral activity covering selected RAVs as well, with or without a nucleoside polymerase inhibitor) (e30e32) are now in an advanced stage of clinical development. They can achieve high rates of sustained viral eradication even in patients who have previously experienced a DAA treatment failure. These combinations are expected to be approved in 2017.

Compensated hepatic cirrhosis

Fibrosis in patients with chronic hepatitis C is now staged non-invasively by means of biochemical algorithms (the APRI score, FIB4, and others) or elastographic techniques (e33, e34). The sensitivity and specificity of transient elastography for the diagnosis of hepatic cirrhosis (threshold value of liver stiffness, 12.5 kPa) are 83–87% and 89–95%, respectively (e34).

In patients infected with HCV genotype 1 who have not been previously treated, the following approved antiviral treatment regimens can be used regardless of whether the patient has or does not have compensated hepatic cirrhosis:

  • sofosbuvir/ledipasvir (10, 32)
  • sofosbuvir/velpatasvir (11, 24)
  • grazoprevir/elbasvir (14, 23)
  • paritaprevir/ombitasvir/dasabuvir in HCV genotype 1b infection (33, e35)

In cirrhotic patients with HCV genotype 1a infection, it is recommended that treatment with paritaprevir/ombitasvir/dasabuvir should be prolonged from 12 to 24 weeks, with the concomitant administration of ribavirin (12, 13, 33). The phase 3 trials of sofosbuvir/simeprevir did not include the concomitant administration of ribavirin. In patients infected with HCV genotype 1a with a polymorphism at position 80 of the NS3/4A protease (Q80K), the antiviral efficacy of simeprevir is reduced; the sustained virus eradication rate for sofosbuvir/simeprevir without ribavirin in this patient group is only 74% (e36). There are conflicting data on the combination of sofosbuvir/daclatasvir with ribavirin (1, e37).

For previously treated patients infected with HCV genotype 1 who have compensated hepatic cirrhosis, it is recommended that sofosbuvir/ledipasvir should be given for the usual duration of 12 weeks, but with concomitant ribavirin administration. If ribavirin is not tolerated, the treatment should be prolonged to 24 weeks (10, e38e41). For the grazoprevir/elbasvir treatment regimen in patients infected with HCV genotype 1a, concomitant ribavirin treatment and a prolongation of the treatment from 12 to 16 weeks should be considered (e42). For other treatment regimens, the recommendations are no different for previously untreated and previously treated patients with cirrhosis.

The highest sustained virological response rates in cirrhotic patients infected with HCV genotype 2 were achieved with sofosbuvir/velpatasvir independently of previous treatment (25). For patients infected with HCV genotype 3, data from a trial on patients with decompensated hepatic cirrhosis (34) make it seem reasonable to give ribavirin concomitantly to patients with compensated hepatic cirrhosis as well; the approval text is formulated in such a way as to permit this option (11). An alternative treatment regimen is sofosbuvir/daclatasvir, but the evidence from phase 3 trials on the duration of treatment and the concomitant administration of ribavirin is currently incomplete (21, e43). For patients infected with HCV genotype 3 who have compensated hepatic cirrhosis, a further therapeutic option is the combination peginterferon/ribavirin/sofosbuvir for 12 weeks (with a sustained viral eradication rate of 91% in previously untreated patients, 86% in previously treated patients) (29).

The spectrum of available treatments for patients infected with HCV genotype 4 largely corresponds to that of patients infected with HCV genotype 1 (Table 2). Sofosbuvir/velpatasvir has been approved for the treatment of patients infected with HCV genotypes 5 and 6 with compensated hepatic cirrhosis, although the evidence base is inadequate for more specific recommendations in relation to previous treatment (11, 24).

Decompensated hepatic cirrhosis

Precirrhosis and compensated cirrhosis can be hard to distinguish on clinical grounds, but decompensated cirrhosis is well defined. In patients with decompensated cirrhosis, NS3/4A protease inhibitors and non-nucleoside polymerase inhibitors should not be used, as their pharmacokinetic characteristics may cause further liver damage (1214, 16). This consideration limits the antiviral treatment options for such patients to sofosbuvir and the combinable NS5A inhibitors (1, 2, 34, 35).

There is a clear indication for antiviral treatment in all patients for whom liver transplantation can be avoided in the intermediate or long term. The issue is more complex in patients for whom liver transplantation is already held to be indicated. The advantages of viral eradication before transplantation (more favorable perioperative course, prevention of reinfection of the transplanted organ) must be weighed against the potential adverse effects of antiviral drugs in patients with decompensated cirrhosis (possible higher infection rate, lactic acidosis) and the potential influence of successful viral eradication on organ allocation priorities (improved MELD, and thus lower priority, in a patient still needing liver transplantation) (3, e44, e45). Thus, the decision to give antiviral treatment to patients on the waiting list for liver transplantation should only be made after consultation with the transplant center. Ribavirin should be given concomitantly to optimize antiviral efficacy, but at a lower initial dose (600 mg/day) in patients with decompensated cirrhosis.

HCV-associated hepatic cirrhosis with hepatocellular carcinoma (HCC)

Any treatment of HCC with curative intent should be accompanied by antiviral treatment with the goal of viral eradication. Although there is a role for antiviral suppression therapy in the palliative treatment of hepatitis-B–associated HCC (e46), there are no analogous data regarding the palliative treatment of HCV-associated HCC. The decision to give antiviral treatment should be made in an experienced center on an individual basis, in consideration of the overall treatment concept and the patient’s life expectancy (3).

After liver transplantation

The progression of fibrosis due to chronic hepatitis C is accelerated in patients who are immune-suppressed after liver transplantation; thus, as a rule, antiviral treatment is indicated. Patients with fibrosing cholestatic hepatitis have a higher mortality and should therefore be started on antiviral treatment immediately. In transplant recipients with a mild HCV (re-)infection, antiviral treatment can be initiated after glucocorticoids have been discontinued (3). Antiviral treatment can also be clinically indicated for the differential diagnosis of an acute rejection reaction. The antiviral treatment options correspond to those of patients who are not transplant recipients (1, 35, e47, e48), but the antiviral drugs should be selected with due regard to potential interactions (immunosuppressants), comorbidities, and ribavirin side effects (36).

End-stage and near-end-stage renal failure

The safety of sofosbuvir for patients with severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2) or patients receiving hemodialysis because of end-stage renal failure has not been adequately demonstrated. A single dose of 400 mg of sofosvir in such patients leads to a marked rise in the plasma level of sofosvir and of its metabolite GS-331007 (15).

Approved antiviral treatment regimens for patients with severe renal insufficiency include paritaprevir/ombitasvir with or without dasabuvir (for patients with HCV genotype 1 or 4 infection, respectively) and grazoprevir/elbasvir for patients with HCV genotype 1 or 4 infection (1214, 37, 38). Ribavirin is recommended in analogy to patient groups with normal renal function, but at a lower dose (200 mg/day).

Because of the lack of approved options for antiviral treatment, patients infected with HCV genotype 3 have also been treated off-label with combinations containing sofosbuvir, with very good virological response rates. No severe side effects have been noted in the small patient cohorts published to date (e49, e50).

Coinfected patients

Patients with an HCV monoinfection and those with an HCV/HIV coinfection do not differ with respect to their sustained viral eradication rates or side-effect profiles with interferon-free DAA treatment (e51e54). Prescribing physicians should note potential drug interactions between the various HCV treatment regimens (in particular, those involving NS3/4A protease inhibitors) and the antiretroviral drugs given to treat HIV (36). In HBV/HCV coinfection, the hepatitis virus with the higher viral load is treated with higher priority. The sustained virus eradication rates in the treatment of chronic hepatitis C are not lessened by the simultaneous presence of hepatitis B (e55). There are no clinically relevant drug interactions between DAAs against HCV on the one hand, and tenofovir and entecavir on the other.

Antiviral treatment in pregnancy

The risk of vertical transmission in mothers with an HCV monoinfection is 5% and is not diminished by cesarean section (e56). Mothers are not advised against breastfeeding either. Vertically acquired hepatitis C takes a mild course in childhood, with very slow progression of hepatic fibrosis (e57). Antiviral treatment during pregnancy cannot be recommended, as there are insufficient data on the potential teratogenicity of DAAs.

Antiviral treatment in childhood

In an initial clinical trial, 12 weeks of treatment with sofosbuvir/ledipasvir (400 mg / 90 mg) yielded sustained virus eradication rates of 96% and 100% in patients aged 12 to 17 (body weight 33–128 kg) with chronic HCV infection of genotypes 1 and 4, respectively. The pharmacokinetic parameters of both substances were analogous to those seen in adults (e58). Further cohorts of children aged 6–11 (17–44 kg) and 3–5 (<17 kg) are now under evaluation, with drug doses of 33.75–45 mg (ledipasvir) and 150–200 mg (sofosbuvir) (e59). The findings are expected to become available in 2017.

Preemptive HCV treatment before immunotherapy or chemotherapy

There is an urgent indication for preemptive antiviral treatment in patients with a chronic hepatitis B infection before they undergo certain types of immunotherapy or chemotherapy (in particular, before treatment with anti-CD20 antibodies) (e60). There is insufficient evidence at present for any recommendation of an analogous procedure for patients with chronic hepatitis C.

Important side effects and drug interactions

Sofosbuvir is generally well tolerated; its more common side effects include mild nausea, headache, and insomnia (15). The combination of sofosbuvir with amiodarone can cause life-threatening bradycardia (39). The addition of NS5A inhibitors (ledipasvir, daclastasvir, velpatasvir) does not lessen tolerability to any clinically relevant extent (10, 11). Therapeutic elevation of the gastric pH lessens the bioavailability of ledipasvir, and thus the concomitant administration of sofosbuvir/ledipasvir with a proton pump inhibitor in a high dose is not recommended (e61).

The side-effect profile and drug-interaction spectrum of the NS3/4A protease inhibitors are more complex. Simeprevir can evoke both nonspecific side effects (nausea, headache, fatigue) and photosensitivity reactions; patients should be advised to avoid direct exposure to sunlight and to use a topical sunscreen (16). All of the approved NS3/4A protease inhibitors (simeprevir, paritaprevir, grazoprevir) can mildly or moderately elevate bilirubin and transaminase levels (12, 14, 16). A simultaneous, clinically relevant rise of both the bilirubin concentration and the transaminase concentrations is rare but presumably reflects hepatotoxicity and must be followed by discontinuation of the the protease inhibitor. The characteristic side effects of ribavirin are (dose-dependent) hemolytic anemia, dyspnea, an irritative cough, reduced exercise tolerance, and skin rash (40). As hemolysis elevates the bilirubin concentration as well, rises in bilirubin levels are more pronounced when ribavirin and NS3/4A protease inhibitors are given simultaneously.

All drugs taken for concurrent illnesses should also be checked for possible interactions with antiviral drugs against HCV (see the relevant package inserts and the website maintained by the pharmacology department at the University of Liverpool, www.hep-druginteractions.org) (36). Particularly critical classes of drugs include anticonvulsants, anti-arrhythmic drugs, antimycobacterial drugs, St. John’s wort, and—in combination with NS3/4A protease inhibitors—immunosuppressant drugs, antibiotics, antimycotic drugs, antiretroviral drugs, HMG-CoA reductase inhibitors, sedatives, antidepressants, and antipsychotic drugs (36).

Confict of interest statement

Prof. Zeuzem has received third-party funding for clinical trials from AbbVie, BMS, Boehringer Ingelheim, Gilead, Janssen-Cilag, Merck/MSD, Novartis, RochePharma, Santaris, Vertex, and ZymoGenetics. He serves as a scientific advisor for Abbvie, Bristol-Myers Squibb, Gilead, Janssen, and Merck/MSD for questions concerning the treatment of hepatitis C and receives honoraria from these companies for lectures at continuing medical education events, as well as reimbursement of travel and accommodation expenses.

Manuscript submitted on 22 August 2016, revised version accepted on 3 November 2016.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. Stefan Zeuzem
Medizinische Klinik 1
Universitätsklinikum Frankfurt
Theodor-Stern-Kai 7
D-60590 Frankfurt am Main, Germany
Zeuzem@em.uni-frankfurt.de

Cite this as:
Zeuzem S: Treatment options in hepatitis C—the current state of the art. Dtsch Arztebl Int 2017; 114: 11–21. DOI: 10.3238/arztebl.2017.0011

@Supplementary material:
eReferences:
www.aerzteblatt-international.de/ref0117

1.
Poordad F, Schiff ER, Vierling JM, et al.: Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016; 63: 1493–1505 CrossRef MEDLINE PubMed Central
2.
Charlton M, Everson GT, Flamm SL, et al.: Ledipasvir and Sofosbuvir plus Ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015; 149: 649–59 CrossRef MEDLINE
3.
Zimmermann T, Beckebaum S, Berg C, et al.: Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation. Z Gastroenterol 2016; 54: 665–84 CrossRef MEDLINE
4.
Younossi ZM, Stepanova M, Feld J, et al.: Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: Results from ASTRAL-1 placebo-controlled trial. J Hepatol 2016; 65: 33–9 CrossRef MEDLINE
5.
Sarrazin C, Berg T, Ross RS, et al.: Prophylaxe, Diagnostik und Therapie der Hepatitis C Virus (HCV) Infektion: German guidelines on the management of HCV infection. Z Gastroenterol 2010; 48: 289–351 CrossRef MEDLINE
6.
Lange CM, Jacobson IM, Rice CM, Zeuzem S: Emerging therapies for the treatment of hepatitis C. EMBO Mol Med 2014; 6: 4–15. CrossRef MEDLINE PubMed Central
7.
Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM: Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56 (Suppl 1): 88–100 CrossRef
8.
Deterding K, Spinner C, Schott E, et al.: Six weeks of ledipasvir/sofosbuvir treatment of acute hepatitis C virus genotype 1 monoinfection: The HepNet Acute HCV IV Study. Lancet Infect Dis 2016; http://dx.doi.org/10.1016/S1473–3099(16)30408-X CrossRef
9.
Robert-Koch-Institut-Ratgeber für Ärzte: Hepatitis C. www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_HepatitisC.html (last accessed on 20 August 2016).
10.
Zusammenfassung der Merkmale des Arzneimittels Harvoni (Fachinformation): http://ec.europa.eu/health/documents/community-register/2014/20141117130011/anx_130011_de.pdf (last accessed on 20 August 2016).
11.
Zusammenfassung der Merkmale des Arzneimittels Epclusa (Fachinformation): http://ec.europa.eu/health/documents/community-register/2016/20160706135323/anx_135323_de.pdf (last accessed on 20 August 2016).
12.
Zusammenfassung der Merkmale des Arzneimittels Viekirax (Fachinformation): http://ec.europa.eu/health/documents/community-register/2015/20150115130406/anx_130406_de.pdf (last accessed on 20 August 2016).
13.
Zusammenfassung der Merkmale des Arzneimittels Exviera (Fachinformation): http://ec.europa.eu/health/documents/community-register/2015/20150115130446/anx_130446_de.pdf (last accessed on 20 August 2016).
14.
Zusammenfassung der Merkmale des Arzneimittels Zepatier (Fachinformation): http://ec.europa.eu/health/documents/community-register/2016/20160722135308/anx_135308_de.pdf (last accessed on 20 August 2016).
15.
Zusammenfassung der Merkmale des Arzneimittels Sovaldi (Fachinformation): www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/002798/WC500160597.pdf (last accessed on 20 August 2016).
16.
Zusammenfassung der Merkmale des Arzneimittels Olysio (Fachinformation): http://ec.europa.eu/health/documents/community-register/2014/20140514128513/anx_128513_de.pdf (last accessed on 20 August 2016).
17.
Zusammenfassung der Merkmale des Arzneimittels Daklinza (Fachinformation): www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/003768/WC500172848.pdf (last accessed on 20 August 2016).
18.
Kowdley KV, Gordon SC, Reddy KR, et al.: Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–88 CrossRef MEDLINE
19.
Ferenci P, Bernstein D, Lalezari J, et al.: ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370: 1983–92 CrossRef MEDLINE
20.
Zeuzem S, Dusheiko GM, Salupere R, et al.: Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370: 1993–2001 CrossRef MEDLINE
21.
Nelson DR, Cooper JN, Lalezari JP, et al.: All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61: 1127–35 CrossRef MEDLINE PubMed Central
22.
Hézode C, Asselah T, Reddy KR, et al.: Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; 385: 2502–9. CrossRef
23.
Zeuzem S, Ghalib R, Reddy KR, et al.: Grazoprevir-Elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: A randomized trial. Ann Intern Med 2015; 163: 1–13 CrossRef MEDLINE
24.
Feld JJ, Jacobson IM, Hézode C, et al.: Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373: 2599–07 CrossRef MEDLINE
25.
Foster GR, Afdhal N, Roberts SK, et al.: Sofosbuvir and Velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373: 2608–17 CrossRef MEDLINE
26.
Afdhal N, Reddy KR, Nelson DR, et al.: Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–93 CrossRef CrossRef
27.
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.: Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370: 211–21 CrossRef MEDLINE
28.
Jacobson IM, Gordon SC, Kowdley KV, et al.: Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867–77 CrossRef MEDLINE
29.
Foster GR, Pianko S, Brown A, et al.: Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. Gastroenterology 2015; 149: 1462–70 CrossRef MEDLINE
30.
Sarrazin C, Zeuzem S: Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138: 447–62 CrossRef MEDLINE
31.
Poordad F, Bennett M, Sepe TE, et al.: Ombitasvir/paritaprevir/r, dasabuvir, and sofosbuvir treatment of patients with HCV genotype 1-infection who failed a prior course of DAA therapy: the Quartz study. J Hepatol 2016; 64: 767–8 CrossRef
32.
Afdhal N, Zeuzem S, Kwo P, et al.: Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–98 CrossRef CrossRef MEDLINE
33.
Poordad F, Hezode C, Trinh R, et al.: ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370: 1973–82 CrossRef MEDLINE
34.
Curry MP, O’Leary JG, Bzowej N, et al.: Sofosbuvir and Velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015; 373: 2618–28. CrossRef MEDLINE
35.
Manns M, Samuel D, Gane EJ, et al.: Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis 2016; 16: 685–97 CrossRef
36.
University of Liverpool: HEP drug interaction. www.hep-druginteractions.org (last accessed on 20 August 2016).
37.
Pockros PJ, Reddy KR, Mantry PS, et al.: Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 2016; 150: 1590–8 CrossRef MEDLINE
38.
Roth D, Nelson DR, Bruchfeld A, et al.: Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet 2015; 386: 1537–45 CrossRef
39.
Fontaine H, Lazarus A, Pol S, et al.: Bradyarrhythmias associated with sofosbuvir treatment. N Engl J Med 2015; 373: 1886–8 CrossRef
40.
Zusammenfassung der Merkmale des Arzneimittels Ribavirins (Fachinformation): www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/001185/WC500094137.pdf (last accessed on 20 August 2016).
e1.
Platt L, Easterbrook P, Gower E, et al.: Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. Lancet Infect Dis 2016; 16: 797–808 CrossRef
e2.
Bruggmann P, Berg T, Øvrehus AL, et al.: Historical epidemiology of hepatitis C virus (HCV) in selected countries. J Viral Hepat 2014; 21(Suppl 1): 5–33.
e3.
Webster DP, Klenerman P, Dusheiko GM: Hepatitis C. Lancet 2015; 385: 1124–35 CrossRef
e4.
Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349: 825–32 CrossRef
e5.
Fattovich G, Stroffolini T, Zagni I, Donato F: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127(Suppl 1): 35–50 CrossRef
e6.
Zeuzem S: Decade in review-HCV: hepatitis C therapy-a fast and competitive race. Nat Rev Gastroenterol Hepatol 2014; 11: 644–5 CrossRef MEDLINE
e7.
Lamarre D, Anderson PC, Bailey M, et al.: An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426: 186–9 CrossRef MEDLINE
e8.
Swain MG, Lai MY, Shiffman ML, et al.: A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010; 139: 1593–601 CrossRef MEDLINE
e9.
Simmons B, Saleem J, Hill A, Riley RD, Cooke GS: Risk of late relapse or reinfection with hepatitis C virus after achieving a sustained virological response: A systematic review and meta-analysis. Clin Infect Dis 2016; 62: 683–94 CrossRef MEDLINE PubMed Central
e10.
Svarovskaia E, Martin R, Chodavarapu K, et al.: HCV reinfection cases in phase 3 studies of sofosbuvir. J Hepatol 2015; 62: 222–3 CrossRef
e11.
Grebely J, Prins M, Hellard M, et al.: Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of injecting drug users: towards a vaccine. Lancet Infect Dis 2012; 12: 408–14 CrossRef
e12.
Hill AM, Saleem J, Heath KA, Simmons B: Effects of sustained virological response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and re-infection: meta-analysis of 129 studies in 23,309 patients with Hepatitis C infection. Hepatology 2014; 60: 218–19.
e13.
Lee MH, Yang HI, Lu SN, et al.: Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012; 206: 469–77 CrossRef MEDLINE
e14.
Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F: Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005; 41: 790–800 CrossRef MEDLINE
e15.
Afdhal N, Asselah T, Everson GT, et al.: HCV eradication results in reduction of hepatic venous pressure gradient 48 weeks after end of treatment. Final results of the study of sofosbuvir plus ribavirin in patients with cirrhosis and portal hypertension. J Hepatol 2016; 64: 221–2 CrossRef
e16.
Bochud PY, Cai T, Overbeck K, et al.: Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol 2009; 51: 655–66 CrossRef MEDLINE
e17.
Di Bisceglie AM: Hepatitis C and hepatocellular carcinoma. Hepatology 1997; 26 (Suppl 1): 34–8 CrossRef
e18.
Roffi L, Redaelli A, Colloredo G, et al.: Outcome of liver disease in a large cohort of histologically proven chronic hepatitis C: influence of HCV genotype. Eur J Gastroenterol Hepatol 2001; 13: 501–6 CrossRef MEDLINE
e19.
Hofmann WP, Herrmann E, Sarrazin C, Zeuzem S: Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms. Liver Int 2008; 28: 1332–43. CrossRef MEDLINE
e20.
Welzel TM, Zeuzem S, Dumas EO, et al.: GARNET: High SVR rates following 8-week treatment with ombitasvir/paritaprevir/ritonavir + dasabuvir in patients with HCV genotype 1b infection. Presented at the European Association for the Study of the Liver Special Conference: New Perspectives in Hepatitis C Virus Infection –The Roadmap for Cure, Paris, France on September 23–24, 2016: https://news.abbvie.com/news/abbvie-presents-data-on-eight-week-treatment-viekirax-ombitasvirparitaprevirritonavir-tablets-exviera-dasabuvir-tablets-in-patients-with-genotype-1b-chronic-hepatitis-c.htm (last accessed on 9 October 2016)
e21.
Abergel A, Metivier S, Samuel D, et al.: Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection. Hepatology 2016; 64:1049–56 CrossRef MEDLINE
e22.
Hézode C, Abergel A, Chas J, et al.: Sustained virologic response to daclatasvir and sofosbuvir, with or without ribavirin, among patients in the French daclatasvir ATU programme infected with HCV genotypes 4, 5 and 6. J Hepatol 2016; 64: 755 CrossRef
e23.
Buti M, Calleja JL, Forns X, et al.: Simeprevir plus sofosbuvir for hepatitis C virus genotype 4 infection: a phase 3, open-label study. J Hepatol 2016; 64: 220–1 CrossRef
e24.
Hedskog C, Doehle B, Chodavarapu K, et al.: Characterization of hepatitis C virus intergenotypic recombinant strains and associated virological response to sofosbuvir/ribavirin. Hepatology 2015; 61: 471–80 CrossRef MEDLINE
e25.
Susser S, Dietz J, Barak M, et al.: Prevalence and clinical importance of hepatitis C virus genotype 2k/1b chimeras. J Hepatol 2016: 64: 136.
e26.
Abergel A, Asselah T, Metivier S, et al.: Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis 2016; 16: 459–64 CrossRef
e27.
Gane EJ, Hyland RH, An D, et al.: Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015; 149: 1454–61 CrossRef MEDLINE
e28.
Sarrazin C: The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 2016; 64: 486–504 CrossRef MEDLINE
e29.
Vermehren J, Susser S, Dietz J, et al.: Retreatment of patients who failed DAA-combination therapies: real-world experience from a large hepatitis C resistance database. J Hepatol 2016; 64: 188 CrossRef
e30.
Gane E, Poordad F, Wang S, et al.: High Efficacy of ABT-493 and ABT-530 in patients with HCV genotype 1 or 3 infection and compensated cirrhosis. Gastroenterology 2016; 151: :651–9.
e31.
Gane EJ, Schwabe C, Hyland RH, et al.: Efficacy of the combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in treatment-naïve or previously treated patients with hepatitis C virus genotype 1 or 3 infections. Gastroenterology 2016; 151: 448–56 CrossRef CrossRef
e32.
Gane EJ, Pianko S, Roberts SK, et al.: High efficacy of an 8-week 3-drug regimen of grazoprevir/MK-8408/MK-3682 in HCV genotype 1, 2 and 3-infected patients: SVR24 data from the phase 2 C-CREST 1 and 2 studies. J Hepatol 2016; 64: 759 CrossRef
e33.
Poynard T, Morra R, Ingiliz P, et al.: Biomarkers of liver fibrosis. Adv Clin Chem 2008; 46: 131–60 CrossRef
e34.
Friedrich-Rust M, Poynard T, Castera L: Critical comparison of elastography methods to assess chronic liver disease. Nat Rev Gastroenterol Hepatol 2016; 13: 402–11 CrossRef MEDLINE
e35.
Feld JJ, Moreno C, Trinh R, et al.: Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks. J Hepatol 2016; 64: 301–7 CrossRef MEDLINE
e36.
Lawitz E, Matusow G, DeJesus E, et al.: Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2). Hepatology 2016; 64: 360–9 CrossRef MEDLINE
e37.
Welzel T, Petersen J, Herzer K, et al.: Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virologic response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut 2016 [epub ahera of print].
e38.
Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS): Therapie der chronischen Hepatitis C – Addendum zur S3 Leitlinie Februar 2015. www.dgvs.de/leitlinien/therapie-der-chronischen-hepatitis-c/ (last accessed on 20 August 2016).
e39.
European Association for the Study of the Liver (EASL): EASL recommendations on treatment of Hepatitis C 2016. www.easl.eu/medias/cpg/HCV2016/English-report.pdf (last accessed on 9 October 2016).
e40.
American Association for the Study of Liver Disease (AASLD) and Infectious Diseases Society of America (IDSA): HCV guidance— recommendations for testing, managing, and treating Hepatitis C. www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed (last accessed on 20 August 2016).
e41.
Reddy KR, Bourlière M, Sulkowski M, et al.: Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis. Hepatology 2015; 62: 79–86 CrossRef MEDLINE
e42.
Kwo P, Gane E, Peng C-Y, et al.: Effectiveness of Elbasvir and Grazoprevir combination, with or without Ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology 2016; [epub ahera of print].
e43.
Leroy V, Angus P, Bronowicki JP, et al.: Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology 2016; 63: 1430–41 CrossRef MEDLINE PubMed Central
e44.
Bunchorntavakul C, Reddy KR: Treat chronic hepatitis C virus infection in decompensated cirrhosis – pre- or post-liver transplantation? The ironic conundrum in the era of effective and well-tolerated therapy. J Viral Hepat 2016; 23: 408–18 CrossRef MEDLINE
e45.
Welker M, Luhne S, Lange CM, et al.: Lactic acidosis in patients with hepatitis C virus cirrhosis and combined ribavirin/sofosbuvir treatment. J Hepatol 2016; 64: 790–9 CrossRef MEDLINE
e46.
Zhang YQ, Guo JS: Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2015; 21: 3860–6 CrossRef MEDLINE PubMed Central
e47.
Kwo PY, Mantry PS, Coakley E, et al.: An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med 2014; 371: 2375–82 CrossRef MEDLINE
e48.
Pungpapong S, Aqel B, Leise M, et al.: Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant. Hepatology 2015; 61: 1880–6 CrossRef MEDLINE
e49.
Saxena V, Koraishy FM, Sise ME, et al.: Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function. Liver Int 2016; 36: 807–816 CrossRef MEDLINE
e50.
Desnoyer A, Pospai D, Lê MP, et al.: Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C. J Hepatol 2016; 65: 40–7 CrossRef
e51.
Naggie S, Cooper C, Saag M, et al.: Ledipasvir and Sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373: 705–13 CrossRef MEDLINE PubMed Central
e52.
Wyles DL, Ruane PJ, Sulkowski MS, et al.: Daclatasvir plus Sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373: 714–25 CrossRef MEDLINE
e53.
Sulkowski MS, Eron JJ, Wyles D, et al.: Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA 2015; 313: 1223–31 CrossRef MEDLINE
e54.
Rockstroh JK, Nelson M, Katlama C, et al.: Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV 2015; 2: e319–27. Erratum in: Lancet HIV 2015; 2: e416. Lancet HIV 2015; 2: e316.
e55.
Gane EJ, Hyland RH, An D, Svarovskaia ES, Brainard D, McHutchison JG: Ledipasvir and sofosbuvir for HCV-infection in patients coinfected with HBV. Antivir Ther 2016; Jul 1. [Epub ahead of print].
e56.
Yeung CY, Lee HC, Chan WT, Jiang CB, Chang SW, Chuang CK: Vertical transmission of hepatitis C virus: Current knowledge and perspectives. World J Hepatol 2014; 6: 643–51 CrossRef MEDLINE PubMed Central
e57.
Jara P, Resti M, Hierro L, et al.: Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003; 36: 275–80 CrossRef MEDLINE
e58.
Schwarz K, Murray KF, Rosenthal P, et al.: High rates of SVR12 in adolescents treated with the combination of ledipasvir/sofosbuvir. J Hepatol 2016, 64: 184.
e59.
Gilead Sciences: Safety and efficacy of Ledipasvir/Sofosbuvir fixed dose combination +/-Ribavirin in adolescents and children with chronic HCV-infection. https://clinicaltrials.gov/ct2/show/NCT02249182 (last accessed on 20 August 2016).
e60.
Shouval D, Shibolet O: Immunosuppression and HBV reactivation. Semin Liver Dis 2013; 33: 167–177 CrossRef MEDLINE
e61.
Afdhal N, Bacon B, Curry M, et al.: No effect of proton pump inhibitor (PPI) use on SVR with ledipasvir/sofosbuvir (LDV/SOF): Real world data from 2034 genotype 1 patients in the Trio network. J Hepatol 2016: 64: 222–3.
Medical Clinik I, Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt/Main: Prof. Dr. med Zeuzem
The replication cycle of the hepatitis C virus, with points of attack of antiviral drugs
The replication cycle of the hepatitis C virus, with points of attack of antiviral drugs
Figure
The replication cycle of the hepatitis C virus, with points of attack of antiviral drugs
Antiviral drugs for the treatment of hepatitis C (HCV)
Antiviral drugs for the treatment of hepatitis C (HCV)
Table 1
Antiviral drugs for the treatment of hepatitis C (HCV)
Approved antiviral treatment regimens*
Approved antiviral treatment regimens*
Table 2
Approved antiviral treatment regimens*
1. Poordad F, Schiff ER, Vierling JM, et al.: Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016; 63: 1493–1505 CrossRef MEDLINE PubMed Central
2. Charlton M, Everson GT, Flamm SL, et al.: Ledipasvir and Sofosbuvir plus Ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015; 149: 649–59 CrossRef MEDLINE
3.Zimmermann T, Beckebaum S, Berg C, et al.: Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation. Z Gastroenterol 2016; 54: 665–84 CrossRef MEDLINE
4.Younossi ZM, Stepanova M, Feld J, et al.: Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: Results from ASTRAL-1 placebo-controlled trial. J Hepatol 2016; 65: 33–9 CrossRef MEDLINE
5.Sarrazin C, Berg T, Ross RS, et al.: Prophylaxe, Diagnostik und Therapie der Hepatitis C Virus (HCV) Infektion: German guidelines on the management of HCV infection. Z Gastroenterol 2010; 48: 289–351 CrossRef MEDLINE
6.Lange CM, Jacobson IM, Rice CM, Zeuzem S: Emerging therapies for the treatment of hepatitis C. EMBO Mol Med 2014; 6: 4–15. CrossRef MEDLINE PubMed Central
7.Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM: Antiviral strategies in hepatitis C virus infection. J Hepatol 2012; 56 (Suppl 1): 88–100 CrossRef
8.Deterding K, Spinner C, Schott E, et al.: Six weeks of ledipasvir/sofosbuvir treatment of acute hepatitis C virus genotype 1 monoinfection: The HepNet Acute HCV IV Study. Lancet Infect Dis 2016; http://dx.doi.org/10.1016/S1473–3099(16)30408-X CrossRef
9.Robert-Koch-Institut-Ratgeber für Ärzte: Hepatitis C. www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_HepatitisC.html (last accessed on 20 August 2016).
10.Zusammenfassung der Merkmale des Arzneimittels Harvoni (Fachinformation): http://ec.europa.eu/health/documents/community-register/2014/20141117130011/anx_130011_de.pdf (last accessed on 20 August 2016).
11.Zusammenfassung der Merkmale des Arzneimittels Epclusa (Fachinformation): http://ec.europa.eu/health/documents/community-register/2016/20160706135323/anx_135323_de.pdf (last accessed on 20 August 2016).
12.Zusammenfassung der Merkmale des Arzneimittels Viekirax (Fachinformation): http://ec.europa.eu/health/documents/community-register/2015/20150115130406/anx_130406_de.pdf (last accessed on 20 August 2016).
13.Zusammenfassung der Merkmale des Arzneimittels Exviera (Fachinformation): http://ec.europa.eu/health/documents/community-register/2015/20150115130446/anx_130446_de.pdf (last accessed on 20 August 2016).
14.Zusammenfassung der Merkmale des Arzneimittels Zepatier (Fachinformation): http://ec.europa.eu/health/documents/community-register/2016/20160722135308/anx_135308_de.pdf (last accessed on 20 August 2016).
15.Zusammenfassung der Merkmale des Arzneimittels Sovaldi (Fachinformation): www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/002798/WC500160597.pdf (last accessed on 20 August 2016).
16.Zusammenfassung der Merkmale des Arzneimittels Olysio (Fachinformation): http://ec.europa.eu/health/documents/community-register/2014/20140514128513/anx_128513_de.pdf (last accessed on 20 August 2016).
17.Zusammenfassung der Merkmale des Arzneimittels Daklinza (Fachinformation): www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/003768/WC500172848.pdf (last accessed on 20 August 2016).
18.Kowdley KV, Gordon SC, Reddy KR, et al.: Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–88 CrossRef MEDLINE
19.Ferenci P, Bernstein D, Lalezari J, et al.: ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370: 1983–92 CrossRef MEDLINE
20.Zeuzem S, Dusheiko GM, Salupere R, et al.: Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370: 1993–2001 CrossRef MEDLINE
21.Nelson DR, Cooper JN, Lalezari JP, et al.: All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61: 1127–35 CrossRef MEDLINE PubMed Central
22.Hézode C, Asselah T, Reddy KR, et al.: Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; 385: 2502–9. CrossRef
23.Zeuzem S, Ghalib R, Reddy KR, et al.: Grazoprevir-Elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: A randomized trial. Ann Intern Med 2015; 163: 1–13 CrossRef MEDLINE
24.Feld JJ, Jacobson IM, Hézode C, et al.: Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015; 373: 2599–07 CrossRef MEDLINE
25.Foster GR, Afdhal N, Roberts SK, et al.: Sofosbuvir and Velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373: 2608–17 CrossRef MEDLINE
26.Afdhal N, Reddy KR, Nelson DR, et al.: Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–93 CrossRef CrossRef
27.Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al.: Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370: 211–21 CrossRef MEDLINE
28.Jacobson IM, Gordon SC, Kowdley KV, et al.: Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867–77 CrossRef MEDLINE
29.Foster GR, Pianko S, Brown A, et al.: Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. Gastroenterology 2015; 149: 1462–70 CrossRef MEDLINE
30.Sarrazin C, Zeuzem S: Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology 2010; 138: 447–62 CrossRef MEDLINE
31.Poordad F, Bennett M, Sepe TE, et al.: Ombitasvir/paritaprevir/r, dasabuvir, and sofosbuvir treatment of patients with HCV genotype 1-infection who failed a prior course of DAA therapy: the Quartz study. J Hepatol 2016; 64: 767–8 CrossRef
32.Afdhal N, Zeuzem S, Kwo P, et al.: Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–98 CrossRef CrossRef MEDLINE
33.Poordad F, Hezode C, Trinh R, et al.: ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370: 1973–82 CrossRef MEDLINE
34.Curry MP, O’Leary JG, Bzowej N, et al.: Sofosbuvir and Velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015; 373: 2618–28. CrossRef MEDLINE
35.Manns M, Samuel D, Gane EJ, et al.: Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis 2016; 16: 685–97 CrossRef
36.University of Liverpool: HEP drug interaction. www.hep-druginteractions.org (last accessed on 20 August 2016).
37. Pockros PJ, Reddy KR, Mantry PS, et al.: Efficacy of direct-acting antiviral combination for patients with hepatitis C virus genotype 1 infection and severe renal impairment or end-stage renal disease. Gastroenterology 2016; 150: 1590–8 CrossRef MEDLINE
38.Roth D, Nelson DR, Bruchfeld A, et al.: Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet 2015; 386: 1537–45 CrossRef
39.Fontaine H, Lazarus A, Pol S, et al.: Bradyarrhythmias associated with sofosbuvir treatment. N Engl J Med 2015; 373: 1886–8 CrossRef
40.Zusammenfassung der Merkmale des Arzneimittels Ribavirins (Fachinformation): www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/001185/WC500094137.pdf (last accessed on 20 August 2016).
e1.Platt L, Easterbrook P, Gower E, et al.: Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. Lancet Infect Dis 2016; 16: 797–808 CrossRef
e2. Bruggmann P, Berg T, Øvrehus AL, et al.: Historical epidemiology of hepatitis C virus (HCV) in selected countries. J Viral Hepat 2014; 21(Suppl 1): 5–33.
e3.Webster DP, Klenerman P, Dusheiko GM: Hepatitis C. Lancet 2015; 385: 1124–35 CrossRef
e4.Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349: 825–32 CrossRef
e5.Fattovich G, Stroffolini T, Zagni I, Donato F: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004; 127(Suppl 1): 35–50 CrossRef
e6.Zeuzem S: Decade in review-HCV: hepatitis C therapy-a fast and competitive race. Nat Rev Gastroenterol Hepatol 2014; 11: 644–5 CrossRef MEDLINE
e7.Lamarre D, Anderson PC, Bailey M, et al.: An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426: 186–9 CrossRef MEDLINE
e8.Swain MG, Lai MY, Shiffman ML, et al.: A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010; 139: 1593–601 CrossRef MEDLINE
e9.Simmons B, Saleem J, Hill A, Riley RD, Cooke GS: Risk of late relapse or reinfection with hepatitis C virus after achieving a sustained virological response: A systematic review and meta-analysis. Clin Infect Dis 2016; 62: 683–94 CrossRef MEDLINE PubMed Central
e10.Svarovskaia E, Martin R, Chodavarapu K, et al.: HCV reinfection cases in phase 3 studies of sofosbuvir. J Hepatol 2015; 62: 222–3 CrossRef
e11.Grebely J, Prins M, Hellard M, et al.: Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of injecting drug users: towards a vaccine. Lancet Infect Dis 2012; 12: 408–14 CrossRef
e12.Hill AM, Saleem J, Heath KA, Simmons B: Effects of sustained virological response (SVR) on the risk of liver transplant, hepatocellular carcinoma, death and re-infection: meta-analysis of 129 studies in 23,309 patients with Hepatitis C infection. Hepatology 2014; 60: 218–19.
e13. Lee MH, Yang HI, Lu SN, et al.: Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012; 206: 469–77 CrossRef MEDLINE
e14.Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F: Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005; 41: 790–800 CrossRef MEDLINE
e15.Afdhal N, Asselah T, Everson GT, et al.: HCV eradication results in reduction of hepatic venous pressure gradient 48 weeks after end of treatment. Final results of the study of sofosbuvir plus ribavirin in patients with cirrhosis and portal hypertension. J Hepatol 2016; 64: 221–2 CrossRef
e16.Bochud PY, Cai T, Overbeck K, et al.: Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol 2009; 51: 655–66 CrossRef MEDLINE
e17.Di Bisceglie AM: Hepatitis C and hepatocellular carcinoma. Hepatology 1997; 26 (Suppl 1): 34–8 CrossRef
e18.Roffi L, Redaelli A, Colloredo G, et al.: Outcome of liver disease in a large cohort of histologically proven chronic hepatitis C: influence of HCV genotype. Eur J Gastroenterol Hepatol 2001; 13: 501–6 CrossRef MEDLINE
e19.Hofmann WP, Herrmann E, Sarrazin C, Zeuzem S: Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms. Liver Int 2008; 28: 1332–43. CrossRef MEDLINE
e20.Welzel TM, Zeuzem S, Dumas EO, et al.: GARNET: High SVR rates following 8-week treatment with ombitasvir/paritaprevir/ritonavir + dasabuvir in patients with HCV genotype 1b infection. Presented at the European Association for the Study of the Liver Special Conference: New Perspectives in Hepatitis C Virus Infection –The Roadmap for Cure, Paris, France on September 23–24, 2016: https://news.abbvie.com/news/abbvie-presents-data-on-eight-week-treatment-viekirax-ombitasvirparitaprevirritonavir-tablets-exviera-dasabuvir-tablets-in-patients-with-genotype-1b-chronic-hepatitis-c.htm (last accessed on 9 October 2016)
e21.Abergel A, Metivier S, Samuel D, et al.: Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection. Hepatology 2016; 64:1049–56 CrossRef MEDLINE
e22.Hézode C, Abergel A, Chas J, et al.: Sustained virologic response to daclatasvir and sofosbuvir, with or without ribavirin, among patients in the French daclatasvir ATU programme infected with HCV genotypes 4, 5 and 6. J Hepatol 2016; 64: 755 CrossRef
e23.Buti M, Calleja JL, Forns X, et al.: Simeprevir plus sofosbuvir for hepatitis C virus genotype 4 infection: a phase 3, open-label study. J Hepatol 2016; 64: 220–1 CrossRef
e24. Hedskog C, Doehle B, Chodavarapu K, et al.: Characterization of hepatitis C virus intergenotypic recombinant strains and associated virological response to sofosbuvir/ribavirin. Hepatology 2015; 61: 471–80 CrossRef MEDLINE
e25.Susser S, Dietz J, Barak M, et al.: Prevalence and clinical importance of hepatitis C virus genotype 2k/1b chimeras. J Hepatol 2016: 64: 136.
e26.Abergel A, Asselah T, Metivier S, et al.: Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis 2016; 16: 459–64 CrossRef
e27.Gane EJ, Hyland RH, An D, et al.: Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015; 149: 1454–61 CrossRef MEDLINE
e28.Sarrazin C: The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 2016; 64: 486–504 CrossRef MEDLINE
e29.Vermehren J, Susser S, Dietz J, et al.: Retreatment of patients who failed DAA-combination therapies: real-world experience from a large hepatitis C resistance database. J Hepatol 2016; 64: 188 CrossRef
e30. Gane E, Poordad F, Wang S, et al.: High Efficacy of ABT-493 and ABT-530 in patients with HCV genotype 1 or 3 infection and compensated cirrhosis. Gastroenterology 2016; 151: :651–9.
e31.Gane EJ, Schwabe C, Hyland RH, et al.: Efficacy of the combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in treatment-naïve or previously treated patients with hepatitis C virus genotype 1 or 3 infections. Gastroenterology 2016; 151: 448–56 CrossRef CrossRef
e32.Gane EJ, Pianko S, Roberts SK, et al.: High efficacy of an 8-week 3-drug regimen of grazoprevir/MK-8408/MK-3682 in HCV genotype 1, 2 and 3-infected patients: SVR24 data from the phase 2 C-CREST 1 and 2 studies. J Hepatol 2016; 64: 759 CrossRef
e33.Poynard T, Morra R, Ingiliz P, et al.: Biomarkers of liver fibrosis. Adv Clin Chem 2008; 46: 131–60 CrossRef
e34.Friedrich-Rust M, Poynard T, Castera L: Critical comparison of elastography methods to assess chronic liver disease. Nat Rev Gastroenterol Hepatol 2016; 13: 402–11 CrossRef MEDLINE
e35.Feld JJ, Moreno C, Trinh R, et al.: Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks. J Hepatol 2016; 64: 301–7 CrossRef MEDLINE
e36.Lawitz E, Matusow G, DeJesus E, et al.: Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2). Hepatology 2016; 64: 360–9 CrossRef MEDLINE
e37.Welzel T, Petersen J, Herzer K, et al.: Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virologic response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut 2016 [epub ahera of print].
e38.Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS): Therapie der chronischen Hepatitis C – Addendum zur S3 Leitlinie Februar 2015. www.dgvs.de/leitlinien/therapie-der-chronischen-hepatitis-c/ (last accessed on 20 August 2016).
e39.European Association for the Study of the Liver (EASL): EASL recommendations on treatment of Hepatitis C 2016. www.easl.eu/medias/cpg/HCV2016/English-report.pdf (last accessed on 9 October 2016).
e40.American Association for the Study of Liver Disease (AASLD) and Infectious Diseases Society of America (IDSA): HCV guidance— recommendations for testing, managing, and treating Hepatitis C. www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed (last accessed on 20 August 2016).
e41.Reddy KR, Bourlière M, Sulkowski M, et al.: Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis. Hepatology 2015; 62: 79–86 CrossRef MEDLINE
e42.Kwo P, Gane E, Peng C-Y, et al.: Effectiveness of Elbasvir and Grazoprevir combination, with or without Ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology 2016; [epub ahera of print].
e43.Leroy V, Angus P, Bronowicki JP, et al.: Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology 2016; 63: 1430–41 CrossRef MEDLINE PubMed Central
e44.Bunchorntavakul C, Reddy KR: Treat chronic hepatitis C virus infection in decompensated cirrhosis – pre- or post-liver transplantation? The ironic conundrum in the era of effective and well-tolerated therapy. J Viral Hepat 2016; 23: 408–18 CrossRef MEDLINE
e45. Welker M, Luhne S, Lange CM, et al.: Lactic acidosis in patients with hepatitis C virus cirrhosis and combined ribavirin/sofosbuvir treatment. J Hepatol 2016; 64: 790–9 CrossRef MEDLINE
e46.Zhang YQ, Guo JS: Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2015; 21: 3860–6 CrossRef MEDLINE PubMed Central
e47.Kwo PY, Mantry PS, Coakley E, et al.: An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med 2014; 371: 2375–82 CrossRef MEDLINE
e48.Pungpapong S, Aqel B, Leise M, et al.: Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant. Hepatology 2015; 61: 1880–6 CrossRef MEDLINE
e49.Saxena V, Koraishy FM, Sise ME, et al.: Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function. Liver Int 2016; 36: 807–816 CrossRef MEDLINE
e50.Desnoyer A, Pospai D, Lê MP, et al.: Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C. J Hepatol 2016; 65: 40–7 CrossRef
e51.Naggie S, Cooper C, Saag M, et al.: Ledipasvir and Sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373: 705–13 CrossRef MEDLINE PubMed Central
e52.Wyles DL, Ruane PJ, Sulkowski MS, et al.: Daclatasvir plus Sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373: 714–25 CrossRef MEDLINE
e53.Sulkowski MS, Eron JJ, Wyles D, et al.: Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA 2015; 313: 1223–31 CrossRef MEDLINE
e54. Rockstroh JK, Nelson M, Katlama C, et al.: Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV 2015; 2: e319–27. Erratum in: Lancet HIV 2015; 2: e416. Lancet HIV 2015; 2: e316.
e55.Gane EJ, Hyland RH, An D, Svarovskaia ES, Brainard D, McHutchison JG: Ledipasvir and sofosbuvir for HCV-infection in patients coinfected with HBV. Antivir Ther 2016; Jul 1. [Epub ahead of print].
e56.Yeung CY, Lee HC, Chan WT, Jiang CB, Chang SW, Chuang CK: Vertical transmission of hepatitis C virus: Current knowledge and perspectives. World J Hepatol 2014; 6: 643–51 CrossRef MEDLINE PubMed Central
e57.Jara P, Resti M, Hierro L, et al.: Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children. Clin Infect Dis 2003; 36: 275–80 CrossRef MEDLINE
e58.Schwarz K, Murray KF, Rosenthal P, et al.: High rates of SVR12 in adolescents treated with the combination of ledipasvir/sofosbuvir. J Hepatol 2016, 64: 184.
e59.Gilead Sciences: Safety and efficacy of Ledipasvir/Sofosbuvir fixed dose combination +/-Ribavirin in adolescents and children with chronic HCV-infection. https://clinicaltrials.gov/ct2/show/NCT02249182 (last accessed on 20 August 2016).
e60.Shouval D, Shibolet O: Immunosuppression and HBV reactivation. Semin Liver Dis 2013; 33: 167–177 CrossRef MEDLINE
e61.Afdhal N, Bacon B, Curry M, et al.: No effect of proton pump inhibitor (PPI) use on SVR with ledipasvir/sofosbuvir (LDV/SOF): Real world data from 2034 genotype 1 patients in the Trio network. J Hepatol 2016: 64: 222–3.