A clinical textbook

Hepatology 2018

12. Standard therapy of chronic hepatitis C virus infection

Markus Cornberg, Christoph Höner zu Siederdissen, Benjamin Maasoumy, Michael P. Manns

Preface

In the next years we will hopefully see a dramatic and universal impact on end-stage liver disease due to the introduction of potent oral drug regimens against hepatitis C virus (HCV) infection. Thanks to a colossal and decade-long effort by medical researchers and pharmaceutical companies around the world, the vast majority of the 64-103 million people living with chronic HCV infection (Gower 2014, Cornberg, 2011, Polaris, 2017) can now potentially be cured by the oral anti-HCV drugs that have been approved over the last five years. One remaining obstacle that has to be solved is the global access to these therapies. The following chapter gives you an overview of today’s standard of care.

Goal of antiviral therapy

The prevalence of HCV has already peaked or is starting to decline in some countries due to the implementation of blood-donor screening and treatment uptake; however, globally, HCV-related complications such as cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) are expected to increase in several countries over the course of the next decade with today's treatment paradigm (Razavi 2014). In 2015, approximately 400,000 people died from HCV associated diseases (http://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/). Importantly, chronic HCV infection not only increases liver-related mortality but also mortality from extrahepatic diseases (Negro 2015, EASL 2018).

The goal of antiviral therapy is to cure hepatitis C via a sustained elimination of the virus. A sustained elimination of HCV is achieved, if the HCV RNA remains negative three to six months after the end of treatment (sustained virologic response, SVR-12 or SVR-24). Follow-up studies documented that more than 99% of patients who achieved an SVR-24 after interferon alfa (IFN) based therapies remain HCV RNA negative 4-5 years after the end of treatment and no signs of hepatitis have been documented (Swain 2010, Manns 2013, EASL 2018). In 2011, the FDA accepted SVR12 (HCV RNA negativity 12 weeks after end of treatment) as endpoint for future trials because HCV relapse usually occurs within the first 12 weeks after the end of treatment. The first long-term follow-up studies after therapy with direct-acting antiviral agents (DAA) confirm the durability of SVR-12 in more than 99% of treated patients (Reddy 2018). For DAA treatment regimens even HCV RNA negativity four weeks after therapy has been shown to be highly predictive for achieving long term viral clearance (positive predictive value >98%) (Yoshida 2015). Late virologic relapses at time points beyond 24 weeks after the end of therapy may appear in rare cases but reinfection should always be considered in this situation (Midgard 2016).

Importantly, long-term benefits of SVR are the reduction of HCV-related hepatocellular carcinoma (HCC) and overall mortality (Veldt 2007, Backus 2011, van der Meer 2012). Most data are available after IFN based therapy but first data confirm that eradication of HCV with DAA reduces the risk of HCC by more than 70% (Ioannou 2017). Mathematical modeling forecasts that an increase in SVR by new DAAs and increase in treatment uptake will result in a decline of HCC, decompensated and compensated cirrhosis and consecutive liver-related deaths by 75% in the next 15 years (Wedemeyer 2014). It has been shown that patients with SVR (treated with IFN) have a similar life expectancy compared with the general population (van der Meer 2014, Bruno 2016). In patients with advanced and decompensated cirrhosis, SVR can lead to improvement of liver function (Deterding 2015) and may reduce the need for liver transplantation (Pascasio 2017, Belli 2016). However, the risk to develop HCC is not zero in patients achieving SVR if cirrhosis is already present (El-Serag 2016). In addition to liver disease, several other hepatic manifestations such as cryoglobulinaemia, non-Hodgkin’s lymphoma, membranoproliferative glomerulonephritis or porphyria cutanea tarda have been reported in the natural history of HCV infection. Antiviral therapy with IFN can reduce extrahepatic manifestations related to HCV, especially when SVR is achieved (Cacoub 2018a). First data for the newer IFN-free DAA regimens show similar results (Saadoun 2017) (see also chapter 15).

Therapeutic concepts and medication

Development of antiviral treatment

Before the identification of HCV as the infectious agent for non-A, non-B hepatitis (Choo 1989), interferon alfa (IFN) led to a normalisation of transaminases and an improvement of liver histology in some patients (Hoofnagle 1986). After the identification of HCV it became possible to measure success of therapy as the long-lasting disappearance of HCV RNA from serum, the SVR. Since then, SVR rates have increased from 5-20% with IFN monotherapy, and up to 40-50% with the combination of IFN + ribavirin (RBV) to now close to 100% with direct-acting antiviral agents (DAA) (Figure 1). In between, the development and approval of pegylated interferon alfa (PEG-IFN) improved the pharmacokinetics of IFN, allowing more convenient dosing intervals and resulting in higher SVR, especially for HCV genotype 1 (GT1). Two PEG-IFNs were available: PEG-IFN α-2b (PEG-Intron®, Merck) and PEG-IFN α-2a (PEGASYS®, Roche). Although smaller trials from southern Europe have suggested slightly higher SVR rates in patients treated with PEG-IFN α-2a (Ascione 2010, Rumi 2010), a large US multicentre study did not detect any significant difference between the two PEG-IFNs + RBV regarding SVR (McHutchison 2009). For further details regarding pegylated interferons, see Hepatology 2015.

The development of DAA against HCV has revolutionised the treatment of chronic hepatitis C. The main targets for DAAs are the NS3/4A protease, NS5B polymerase and the NS5A replication complex. Combinations of different DAAs from these different classes allow very potent treatments. In 2011, the first selective protease inhibitors (PI) were approved for patients with HCV GT1. Boceprevir (BOC) (Victrelis®) and telaprevir (TLV) (Incivek®; Incivo®) improved SVR rates to up to 75% in naïve HCV GT1 patients and 29-88% in treatment-experienced HCV GT1 patients (Manns 2012, Sarrazin 2012). However, both PIs required combination with PEG-IFN + RBV because monotherapy would result in rapid emergence of drug resistance. Also, these two PIs cannot be combined as they have the same target and cross-resistance. Either of the two PIs can be combined with PEG-IFN α-2a or PEG-IFN α-2b (Sarrazin 2012). TLV had to be administered at least twice daily (Buti 2012) and BOC three times daily and both PIs are associated with severe side effects, especially anaemia (Maasoumy 2013b, Hezode 2014a). In 2014, new DAAs were approved. Simeprevir (SMV) (Olysio®, Sovriad®) was the first once-daily PI. The SVR rates for treatment-naïve GT1 patients increase to 80-81% with PEG-IFN+RBV plus SMV (Jacobson 2014, Manns 2014). However, this was not a major improvement over BOC or TLV triple therapy (Reddy 2015b). However, with SMV more patients achieve an early treatment response and qualify for shorter treatment duration of 24 weeks compared with the first wave PIs. Importantly, SMV also has significantly less side effects (Reddy 2015b).

Sofosbuvir (SOF) (Sovaldi®) was the first available once-daily NS5B polymerase inhibitor (approved 12/2013 by FDA and 1/2014 by EMA). For genotype 1, PEG-IFN+RBV + SOF for just 12 weeks leads to 89% SVR in treatment-naïve patients (Lawitz 2013). The resistance barrier of SOF is much higher compared to the available PIs. Very few individuals have developed a confirmed selection of SOF-resistant variants. Thus, a combination of only SOF + RBV was sufficient for a substantial propotion of patients. Valid data were first published for genotypes 2 and 3 (Zeuzem 2014a) with SVR rates of 85-100% for treatment-naïve GT2/3 patients. SOF can also be combined with a PI or a NS5A inhibitor, i.e. treatment with SOF+SMV resulted in 92% SVR in GT1 (Lawitz 2014) also later confirmed in large real-world cohorts (Sulkowski 2016).

The combination of SOF with the NS5A inhibitor daclatasvir (DCV, Daklinza®) or ledipasvir (LDV) were the first NS5A based IFN free combination therapies that have also shown >90% SVR (Sulkowski 2014, Kowdley 2014, Afdhal 2014a; Afdhal 2014b). Importantly, the combination SOF+DCV (approved by EMA in 8/2014) and the fixed dose single tablet combination of SOF/LDV (Harvoni® approved in 10/2014 by FDA and 11/2014 by EMA) showed >95% SVR in GT1 patients with treatment failure on PEG-IFN+RBV/PI triple therapies (Sulkowski 2014, Afdhal 2014a). SOF in combination with DCV or LDV also has some activity against other genotypes including GT3 (Cornberg 2017). The so-called 3D regimen, ombitasvir (OBV), paritaprevir/r (PTV/r) (Viekirax®), and dasabuvir (DSV, Exviera®) (approved in 12/2014 by FDA and 1/2015 by EMA for GT1 and GT4 patients) was the first combination that includes DAAs against all three targets (Ferenci 2014, Poordad 2014, Zeuzem 2014b, Feld 2014). In 2016, the fixed dose combinations elbasvir (EBR) plus grazoprevir (GZR) (Zepatier®) was approved and was the first single tablet regimen for GT1 and GT4 patients with chronic kidney disease (CKD) (Zeuzem 2015, Kwo 2017, Roth 2015). The first pangenotypic DAA combinations SOF plus velpatasvir (VEL) (Curry 2015b, Feld 2015, Foster 2015) and glecaprevir (GLE) plus pibrentasvir (Zeuzem 2018, Puoti 2018) were approved in 2016 and 2017. Finally, the triple fixed dose combination SOF/VEL plus plus voxilaprevir (VOX) was approved in 8/2017 and allows retreatment of patients who failed DAA therapy (Bourlière 2017). In 2018, most patients can be treated with DAA therapy, except maybe non-GT1/4 patients with decompensated cirrhosis plus CKD. SVR rates are above 95% for all patients and RBV is only necessary in decompensated cirrhosis.

Figure 1. Development of chronic hepatitis C therapy. The sustained virologic response rates have improved from around 5% with interferon monotherapy in the early 90s to >95% today with DAA combinations (data for treatment-naïve GT1 patients). Indicated trials are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds. Table 1. Approved medication for the treatment of chronic hepatitis C (5/2018). Not all medication is still available or recommended. Generics are not considered.
Medication Dosing Comment
Type I interferons Subcutaneous injection IFNs are not recommended if DAA combinations are available (EASL, 2018)
Pegylated interferon α-2a (Pegasys®) 180 µg once weekly
Pegylated interferon α-2b (PEG-Intron®) 1.5 µg/kg once weekly
Interferon α-2a (Roferon®) 3 - 4.5 Mill IU three times weekly
Interferon α-2b (Intron A®) 3 Mill IU three times weekly
Consensus Interferon (Infergen®) 9 µg three times weekly
Ribavirin Oral Ribavirin should be avoided if possible (EASL, 2018)
Ribavirin (Copegus®) 800 - 1200 mg daily (200 mg or 400 mg tablets)
Ribavirin (Rebetol®) 600 - 1400 mg daily (200 mg tablets or solution)
HCV NS3/4A protease inhibitors Oral
Boceprevir (Victrelis®) 800 mg (4 x 200 mg tablets) every 7-9 hours Boceprevir and Telaprevir are no longer available since 2014/2015
Telaprevir (Incivek®, Incivo®) 750 mg (2 x 375 mg tablets) every 7-9 hours*
*3 x 375 mg every 12 hours in treatment-naïve patients
Simeprevir (Olysio® (US, EU), Sovriad® (Japan), Galexos® (Canada)) 150 mg (1 x 150 mg tablets) once daily
100 mg in Japan
Olysio® is no longer available since 5/2018
Paritaprevir (coformulated with ritonavir and ombitasvir as Viekirax®) 150 mg once daily (2 x 75 mg, 2 tablets once daily) Paritaprevir is no longer available in some countries such as Germany since 2018
Asunaprevir (Sunvepra® (Japan)) 100 mg (1 tablet) twice daily Asunaprevir is only available in Japan in combination with Daclatasvir
Grazoprevir (coformulated with elbasvir as Zepatier®) 100 mg (1 tablet) once daily
Glecaprevir (coformulated with pibrentasvir as Maviret® or Mavyret®) 300 mg once daily (3 tablets a 100 mg) once daily
Voxilaprevir (coformulated with sofosbuvir and velpatasvir as Vosevi®) 100 mg once daily (1 tablet) once daily
HCV NS5B polymerase inhibitors Oral
Sofosbuvir (Sovaldi®) (Nucleotide analogue) 400 mg (1 tablet) once daily
Dasabuvir (Exviera®) (Non-Nucleoside analogue) 250 mg (1 tablet) twice daily Dasabuvir is no longer available in some countries such as Germany since 2018
HCV NS5A replication complex inhibitor Oral
Daclatasvir (Daklinza®) 60 mg (1 tablet) once daily
(dose adjustments if coadminstered with CYP3A4 inhibitor (30 mg/d) or inducer (90 mg/d))
Ledipasvir (coformulated with sofosbuvir as Harvoni®) 90 mg (1 tablet) once daily
Ombitasvir (coformulated with paritaprevir/ritonvavir as Viekirax®) 25 mg once daily (2 x 12.5 mg, 2 tablets once daily) Ombitasvir is no longer available in some countries such as Germany since 2018
Elbasvir (coformulated with grazoprevir as Zepatier®) 100 mg (1 tablet) once daily
Velpatasvir (coformulated with sofosbuvir as Epclusa® or with sofosbuvir and voxilaprevir as Vosevi®) 100 mg (1 tablet) once daily
Pibrentasvir (coformulated with glecaprevir as Maviret® or Mavyret®) 120 mg (3 tablets a 40 mg) once daily
Table 2. Fixed dose DAA combinations used* for the treatment of chronic hepatitis C in 2018 and discussed in this document. Generics are not considered.
Name DAA Dosing
Harvoni® sofosbuvir/ledipasvir
(SOF/LDV)
1 tablet once daily (with or without food)
Zepatier® grazoprevir/elbasvir
(GZR/EBR)
1 table once daily (with or without food)
Epclusa® sofosbuvir/ledipasvir
(SOF/VEL)
1 tablet once daily (with or without food)
Maviret® glecaprevir/pibrentasvir (GLE/PIB) 3 tablets once daily (with food)
Vosevi® sofosbuvir/ledipasvir/voxilaprevir (SOF/VEL/VOX) 1 tablet once daily (with food)

Treatment indication

In general, every patient with chronic hepatitis C should receive antiviral therapy, because patients who are cured of their HCV infection benefit as indicated above, i.e., reduction in the risk of hepatocellular carcinoma (HCC), liver-related mortality and even all-cause mortality. DAA regimens, ideally IFN-free and RBV-free regimens, should be preferred (EASL 2018). However, if resources are limited and DAA therapies are not easily accessible, treatment should not be delayed in patients with advanced fibrosis and high risk for liver-related complications. These patients should be treated with high priority with the best available treatment option. Also, patients with severe extrahepatic hepatitis C manifestations should be given high priority for immediate treatment. The timing of treatment in patients with mild liver disease can be individualised; waiting for IFN-free therapies with low risk for side effects - if so far not available - should be considered.

Another reason for early treatment is the prevention of further transmission of the virus in individuals at high risk of transmitting HCV (PWIDs, men who have sex with men (MSM) with high-risk sexual practices, women of childbearing age, hemodialysis patients, prison inmates) (EASL 2018). However, the risk of re-infection is high in risk groups (PWIDs and MSM) (Midgard 2016, Ingiliz 2017) and preventive measures to reduce this risk after successful treatment should be implemented.

Patients with decompensated cirrhosis and an indication for liver transplantation with a MELD score above 18-20 may be treated after transplantation, because the probability of significant improvement in liver function and delisting is low (EASL 2018). Treatment is generally not recommended in patients with limited life expectancy because of non-HCV-related comorbidities (EASL 2018).

Predictors of treatment response and pre-therapeutic assessment

Over the last decade, tailoring treatment duration and dosing with interferon-based therapies according to individual parameters associated with response has improved SVR. Predicting SVR before the start of antiviral treatment helps in making treatment decisions. Important baseline factors associated with SVR to PEG-IFN+RBV are the HCV genotype, the degree of liver fibrosis and steatosis, baseline viral load, presence of insulin resistance, age, gender, body mass index, ethnicity, and HIV coinfection (see Hepatology 2015). Many of these factors may have less relevance for DAA therapy. For IFN-free therapies other parameters seem to be more important such as HCV subtypes 1a and 1b or antiviral resistance (for antiviral resistance see extra section below) and in many countries the cost of therapy. Still, liver disease severity is important to assess.

Genotype

The HCV genotype (GT), including GT1 subtype (1a or 1b) is still important to tailor the treatment regimen (duration or decision to add RBV). GT3 is now the most difficult to treat genotype and not all available regimens (e.g. grazoprevir/elbasvir) are effective (EASL 2018). Patients with HCV GT1a have a higher risk of developing resistance on a first wave PI-based therapy compared to HCV GT1b because HCV GT1a requires an exchange of only one nucleotide versus two for HCV GT1b at position 155 in order to develop resistance. For SMV, a GT1a variant with the Q80K mutation is important (reviewed in Sarrazin and Zeuzem 2010)). GT1a versus GT1b also plays a role with NS5A inhibitor-based therapies. Efficacy of daclatasvir (DCV) in combination with PEG-IFN+RBV was significantly higher in GT1b compared with GT1a patients (Hezode 2014b). The IFN-free regimen of the protease inhibitor (PI) asunaprevir with DCV is approved in Japan but only for GT1b patients as success rates in GT1a patients were rather low (Lok 2012). Also for the “3D” regimen ombitasvir/paritaprevir/r + dasabuvir there are notable differences between HCV GT1a and GT1b. While the addition of RBV seems to be necessary for all GT1a patients, GT1b does not require RBV (Ferenci 2014). For grazoprevir/elbasvir there seem to be slightly lower SVR rates in genotype 1a. This is mainly due to baseline NS5A resistant associated substitutions (RAS) specific to elbasvir in genotype 1a (Zeuzem 2015). In contrast, no obvious difference has been documented with SOF/LDV or SOF/VEL therapy (Kowdley 2014, Feld 2015). Although SOF has a high barrier for resistance, low-frequency NS5B substitutions may be potentially associated with reduced response rates in HCV GT1b but not GT1a patients (Donaldson 2014). Interestingly, 8 weeks SOF/VEL/VOX was not as effective in GT1a versus GT1b because of the Q80K variant, which were more prevalent in US patients (Jacobson 2017).

However, for the easy to treat non-cirrhotic patients determination of the genotype may be dispensable because pangenotypic therapies are available. This simplified treatment algorithm would be important to accelerate treatment uptake.

Genotype 2k / genotype 1b hybrid

Patients can be infected with hepatitis C viruses that are hybrids of different genotypes. Some patients that are infected with such hybrids can be misclassified as GT2a/c with standard genotype assays, which is specific for the structural HCV GT2 proteins. However, the virus has a GT2k sequence in the structural HCV proteins and a GT1b sequence in the non-structural (NS) HCV proteins. This can only be detected by sequencing or with certain assays that also analyses this region (De Keukeleire 2015b, De Keukeleire 2015a). This specific subtype is predominantly prevalent in patients from Eastern Europe (i.e. Georgia) (Karchava 2015). However, the GT2k/GT1b can also be found in other countries due to immigration. If GT2k/GT1b is present, patients can be successfully treated with a GT1 specific therapy because DAA target the NS proteins (Susser 2017, Todt 2017). Thus, we recommend testing for GT2k/GT1b in patients with origin from Eastern Europe and other parameter, which could hint towards this issue, such as treatment failure in a GT2 patient, if patients have no access to pangenotypic therapies.

HCV RNA

Quantitative HCV RNA kinetics during treatment was (and is) the strongest on-treatment SVR predictor for most PEG-IFN+RBV-based regimens. However, nowadays this issue is less relevant if potent DAA combinations are being used. Due to the excellent tolerance and the rare cases of virological breakthroughs a response guided strategy or stopping criteria have not been implemented for IFN-free regimens. According to the prescribing information all patients are treated for a fixed treatment duration and SVR rates are in general high. However, the current AASLD/IDSA guidance still recommend testing for quantitative HCV RNA at week 4 of DAA therapy mainly to monitor patient compliance (https://www.hcvguidelines.org/evaluate/monitoring). However, so far data are rather limited on how on-treatment HCV RNA levels have to be interpreted. For the majority of patients on treatment HCV RNA during IFN-free DAA therapy does not seem to have any predictive value (Maasoumy 2016). Some studies demonstrated that detectable HCV RNA may be found frequently even at the end of therapy, in particular if highly sensitive assays are used for HCV RNA quantification. However, the vast majority of these patients still achieve SVR (Maasoumy 2016). Therefore, treatment extension cannot be recommended in these cases.

In an Asian proof-of-concept study with GT1b patients without cirrhosis, all patients who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received only 3 weeks of treatment achieved SVR. This study suggests that HCV RNA measurements at very early points in time during treatment could guide treatment duration (Lau 2016). Despite this interesting data, on-treatment HCV RNA monitoring is not recommended to shorten or prolong treatment with modern IFN-free DAA therapies and should only be used to monitor patient compliance (https://www.hcvguidelines.org/evaluate/monitoring). EASL has diminished the need for any viral load testing for the first time in their current version of HCV treatment recommendations. Viral load testing is only recommended before and 12 or 24 weeks after the end of antiviral therapy. Instead of HCV RNA also HCV core antigen can be performed if HCV RNA tests are not available or affordable (EASL 2018).

Genetic polymorphisms

Genome-wide association studies have identified host genetic polymorphisms (i.e., rs12979860, rs8099917) located on chromosome 19 upstream of the region coding for IL28B (or IFN λ3) associated with spontaneous HCV clearance and SVR to treatment with PEG-IFN+RBV (Ge 2009, Rauch 2010, Tanaka 2009, Suppiah 2009). Recently, a new dinucleotide variant ss469415590 (TT or ΔG) upstream of IL28B (or IFN λ3), which is in high linkage disequilibrium with IL28B rs12979860 was discovered (Prokunina-Olsson 2013). Compared to the IL28B SNP, the IFN λ4 DNP is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians (Prokunina-Olsson 2013). So far, screening for genetic variants has not been shown to be useful for modern IFN-free DAA regimens. Given the high overall response rates of DAA combination therapies it is in general difficult to identify statistically significant predictive markers.

Others

For SOF plus RBV or LDV, female sex and to a lesser degree baseline viraemia of <6 log10 IU/mL and a body weight <30 kg/m2 are associated with numerically higher SVR rates. As discussed above, GT1b patients generally respond better to some of the approved DAA regimens (i.e. GZR/EBR). An important response predictor remains the stage of liver disease and interestingly previous treatment with PEG-IFN+RBV.

Antiviral resistance

The development of DAA leads to the emerging problem of drug resistance due to so-called resistance-associated amino acid substitutions (RAS) of the virus. Patients who received monotherapy with certain DAAs, i.e., the 1st generation PIs BOC or TLV developed resistance within a few days (Sarrazin 2007). If RAS emerge, it is not completely known for how long they persist and if this has any significant consequences for future therapies. Some studies suggest that the majority of PI resistant variants revert to wild type within 1-2 years after the end of therapy. This may be different for NS5A RASs (reviewed in Sarrazin 2016).

At this stage there is no recommendation to routinely analyse HCV sequences either before therapy or during DAA treatment, because it has no practical consequence up to now. One exception was the testing for the Q80K variant in GT1a patients treated with PEG-IFN+RBV plus SMV. The combination of different DAA classes should overcome the problem of resistance and allow IFN-free combinations. SOF has a very high resistance barrier and even SOF plus the weak antiviral RBV lead to high SVR rates and treatment failure is mainly related to relapse and not breakthrough (Osinusi 2013). SOF combined with a PI (SOF+SMV) or an NS5A inhibitor (SOF+DCV or SOF/LDV or SOF/VEL) shows SVR rates >90%. However, based on some studies NS5A RASs may become an issue in clinical practice. The frequency of baseline NS5A RAS was approximately 16% in the SOF/LDV studies (reviewed in (Sarrazin 2016) and 20% in GZR/EBR studies (Jacobson et al., 2015) based on population Sanger sequencing (PopSeq) with a threshold of >25% for minor variant detection. With next generation deep sequencing (NGS) and a sensitivity threshold of 1%, the frequency of detectable NS5A RASs is much higher but minor populations that are now detected may have less clinical relevance (Jacobson et al., 2015). Drug specific NS5A variants detected with PopSeq have the highest impact on SVR but these RASs are not frequent. This has been systematically analysed for GZR/EBR (Table 3).

Table 3. Relevance of baseline NS5A RASs. Efficacy of 12 weeks GZR/EBR in genotype 1a patients with baseline NS5A RASs (Jacobson et al., 2015).
All NS5A RAVs EBR specific RAVs No NS5A RAVs
Sequencing method RAS prevalence SVR12 RAS prevalence SVR12 Prevalence SVR12
PopSeq n=438 86/438 (20%) 74/86 (86%) 24/438 (5%) 14/24 (58%) 352/438 (80%) 389/396 (98%)
NGS 1% sensitivity n=439 150/439 (34%) 136/150 (91%) 43/439 (10%) 31/43 (72%) 289/439 (66%) 284/289 (98%)

In the case of GZR/EBR, NS5A RASs had no impact on SVR in GT1b patients. The NS5A RASs may be of more importance in GT1a and especially if other negative predictors (previous non-responder, advanced cirrhosis) are present. Baseline NS5A RAS testing may therefore be important in certain patient groups (i.e. GT1a and GT3) to optimise treatment, especially because NS5A RAS do not vanish over time (reviewed in (Sarrazin 2016).

In the case of potent NS5A regimens, baseline RAS testing may not be necessary prior to first-line therapy (EASL 2018). However, this topic may deserve more attention in the future when we need to select the ideal salvage therapy for patients after treatment failure on DAA combinations.

Treatment in 2018

We will only review the fixed dose combinations that are listed in table 2. For previous DAA therapies (i.e. sofosbuvir + daclatasvir or ombitasvir/paritaprevir/r + dasabuvir see Hepatology 2016). In countries where the DAA combinations listed in table 2 are available and reimbursable, these therapies replace the older regimens. As a consequence of the rapid development of new DAAs, the marketing and production of boceprevir and telaprevir was terminated in the US by the respective pharmaceutical company in 2014/2015. In 2018, Janssen Pharmaceuticals Inc. (Janssen) has decided to terminate the license that it holds for simeprevir due to their assessment of market demand. Daclatasvir is not used anymore in several countries such as Germany because it has to be combined with sofosbuvir and this combination is more expensive than any other DAA regimen listed in table 2. However, the combination of sofosbuvir + daclatasvir is still frequently used in countries where these drugs are generic. Due to the approval of Maviret® (glecaprevir/pibrentasvir), Abbvie decided to withdraw the 3D combination (ombitasvir/paraitaprevir/r + dasabuvir) in some countries (i.e. Germany). The new EASL recommendations do not recommend interferon alfa anymore and suggest avoiding ribavirin if possible (EASL 2018). The combination of at least two of the three major drug classes (protease inhibitors, polymerase inhibitors and NS5A inhibitors) results in SVR ≥95% with just 8-12 weeks treatment. Most of efficacy data of the DAA combinations have been confirmed in real-world by large registries.

However, treatment options can be different around the world as not all new treatment options will be accessible in all countries at the same time and in some countries, generics are available (Zeng 2017). Thus, for detailed information regarding older treatment options such as dual treatment with PEG-IFN+RBV or triple treatment regimens including PEG-IFN+RBV plus protease inhibitors we refer you to the previous edition of the textbook dating from 2015. For DAA combinations sofosbuvir + ribavirin, sofosbuvir + simeprevir, sofosbuvir + daclatasvir and for the 3D combination (ombitasvir/paraitaprevir/r + dasabuvir) we refer you to the textbook dating from 2016.

All approved IFN-free DAA regimens have an excellent safety profile and a similar efficacy. Table 4 & 5 give an overview of the treatment schedules with SOF/LDV, GZR/EBR, SOF/VEL, GLE/PIB and SOF/VEL/VOX based on the data discussed below. Due to the high efficacy, good tolerability and wider eligibility it is very likely that these regimens will also prove to have a high population-based effectiveness, which was in the end disappointing for the first-generation PI-based triple therapies (Maasoumy 2014).

Table 4. Treatment of patients with chronic hepatitis C without cirrhosis.
GT Pretreatment SOF/LDV GZR/EBR GLE/PIB SOF/VEL SOF/VEL/VOX
1a No (naïve) 8 weeks6 12 weeks2 8 weeks 12 weeks 8# weeks
PEG-IFN+RBV ± SOF or SOF+RBV 12 weeks3,5 12 weeks2,3 8 weeks8 12 weeks3 8*,#-12 weeks
DAA-Tx with NS5A Inhibitor no no 16 weeks7 no 12 weeks
1b No (naïve) 8 weeks6 12 weeks4 8 weeks 12 weeks 8 weeks
PEG-IFN+RBV ± SOF or SOF+RBV 12 weeks3 12 weeks3 8 weeks8 12 weeks3 8*-12 weeks
DAA-Tx with NS5A Inhibitor no no 16 weeks7 no 12 weeks
2 No (naïve) no no 8 weeks 12 weeks 8 weeks
PEG-IFN+RBV ± SOF or SOF+RBV no no 8 weeks 12 weeks 8*-12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
3 No (naïve) no no 8 weeks 12 weeks 8 weeks
PEG-IFN+RBV ± SOF or SOF+RBV no no 16 weeks1 12 weeks 8*-12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
4 No (naïve) 12 weeks 12 weeks2 8 weeks 12 weeks 8 weeks
PEG-IFN+RBV ± SOF or SOF+RBV 12 weeks3,5 12 weeks2,3,5 8 weeks 12 weeks3 8*-12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
5, 6 No (naïve) 12 weeks no 8 weeks 12 weeks 8 weeks
PEG-IFN+RBV ± SOF or SOF+RBV no no 8 weeks 12 weeks 8*-12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
  SVR≥95%, RBV free
  Ribavirin may be required in some patients
  SVR ≥95% but not recommended as first line treatment
  SVR <95%, or no sufficient data.
PEG-IFN: pegylated Interferon alfa; RBV: ribavirin; GLE: Glecaprevir; PIB: Pibrentasvir; GZR: Grazoprevir; EBR: Elbasvir; SOF: Sofosbuvir; VEL: Velpatasvir; LDV: Ledipasvir;
VOX: Voxilaprevir
* DAA naive. # lower response in GT1a patients in the US (Q80K). 1 EASL recommends 12 weeks. 2 HCV RNA ≤800.000 IU/mL at baseline or exclusion of NS5A RAS. 3 Treatment experience with PEG-IFN+RBV+PI (Simeprevir, Telaprevir or Boceprevir) was analysed. 4 8 weeksif F0-2 (fibroscan ≤9.5kPA). 5 not recommended as RBV free treatment option by EASL 2018. 6 Female and male with HCV RNA <6 million IU/mL at baseline. 7 prior therapy with NS5A-Inhibitor but without protease inhibitor (FDA label, not recommended by EMA). 8 12 weeksif pretreatment with protease-Inhibitor but without NS5A inhibitor (FDA label, not recommended by EMA). Table 5. Treatment of patients with chronic hepatitis C with compensated cirrhosis.
GT Pretreatment SOF/LDV GZR/EBR GLE/PIB SOF/VEL SOF/VEL/VOX
1a No (naïve) 12 weeks5 12 weeks1 12 weeks 12 weeks 12 weeks
PEG-IFN+RBV ± SOF or SOF+RBV 12 weeks3,5 12 weeks1,2 12 weeks7 12 weeks2 12 weeks
DAA-Tx with NS5A Inhibitor no no 16 weeks6 no 12 weeks
1b No (naïve) 12 weeks5 12 weeks 12 weeks 12 weeks 12 weeks
PEG-IFN+RBV ± SOF or SOF+RBV 12 weeks3,5 12 weeks2 12 weeks7 12 weeks2 12 weeks
DAA-Tx with NS5A Inhibitor no no 16 weeks6 no 12 weeks
2 No (naïve) no no 12 weeks 12 weeks 12weeks
PEG-IFN+RBV ± SOF or SOF+RBV no no 12 weeks 12 weeks 12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
3 No (naïve) no no 12 weeks 12 weeks3,4 8 weeks
PEG-IFN+RBV ± SOF or SOF+RBV no no 16 weeks 12 weeks3,4 8*-12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
4 No (naïve) 12 weeks 12 weeks1 12 weeks 12 weeks 12 weeks
PEG-IFN+RBV ± SOF or SOF+RBV 12 weeks3,5 12 weeks1,2,3 12 weeks 12 weeks2 12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
5, 6 No (naïve) 12 weeks no 12 weeks 12 weeks 12 weeks
PEG-IFN+RBV ± SOF or SOF+RBV no no 12 weeks 12 weeks 12 weeks
DAA-Tx with NS5A Inhibitor no no no no 12 weeks
  SVR≥95%, RBV free
  Ribavirin may be required in some patients
  SVR ≥95% but not recommended as first line treatment
  SVR <95%, or no sufficient data.
PEG-IFN: pegylated Interferon alfa; RBV: ribavirin; GLE: Glecaprevir; PIB: Pibrentasvir; GZR: Grazoprevir; EBR: Elbasvir; SOF: Sofosbuvir; VEL: Velpatasvir; LDV: Ledipasvir;
VOX: Voxilaprevir
* DAA naive. 1 HCV RNA ≤800.000 IU/mL at baseline or exclusion of NS5A RAS. 2 Treatment experience with PEG-IFN+RBV+PI (Simeprevir, Telaprevir or Boceprevir) was analysed. 3 not recommended as RBV free treatment option by EASL 2018. 4 If NS5A RAS (Y93H) detected additional RBV recommended. 5 If platelets <75.000/μl ribavirin should be added or/and treatment may be extended to 24 weeks. 6 pretreatment with NS5A-Inhibitor but without protease inhibitor (FDA label, not recommended by EMA). 7 prior therapy with protease-Inhibitor but without NS5A inhibitor (FDA label, not recommended by EMA).

Sofosbuvir and Ledipasvir (SOF/LDV)

The combination of SOF and LDV is available as a single-tablet fixed-dose combination (Harvoni®, Gilead Sciences). The single pill contains the NS5B polymerase inhibitor SOF (400 mg) and the NS5A inhibitor LDV (90 mg). SOF/LDV is recommended for patients infected with genotype 1, 4-6. Some data (phase 2 and real-world) are available for GT3 patients (Cornberg 2017), but as better treatment options for GT3 are available, SOF/LDV is not recommended for GT3 (EASL 2018). SOF/LDV is not recommended for patients with chronic kidney disease (CKD with GFR<30 ml/min), but can be used without restrictions in patients with decompensated cirrhosis.

Genoytpe 1

SOF/LDV was studied in the ION-1 (Afdhal 2014b) and ION-3 (Kowdley 2014) trials in treatment-naive patients (Table 6). ION-1 studied 12 vs. 24 weeks SOF/LDV in 865 patients, including cirrhotic patients, and ION-3 investigated 8 vs. 12 weeks in 647 non-cirrhotic patients. In non-cirrhotic patients, SOF/LDV demonstrated an SVR12 of >99.5% irrespective of the use of RBV or a 12 or 24-week treatment duration (Afdhal 2014b). Shortening treatment duration to 8 weeks was evaluated in the ION-3 trial, which showed an SVR of 93% and 94% with and without RBV, respectively (Kowdley et al., 2014). Relapse occurred more frequently in patients with baseline viral load >6 million IU/mL (relapse 10% versus 2% without RBV) and male patients (relapse 8% versus 1%). In real-world data, excellent SVR rates are confirmed with 8 weeks SOF/LDV in patients who fall into this category but the cut-off of 6 million IU/mL may not be so important (Buggisch2017). However, SVR was slightly diminished to 90% in patients taking proton pump inhibitors (PPI) (Terrault 2016). The timing of PPI dosing needs consideration. Based on the approvals of FDA and EMA, treatment can be shortened to 8 weeks in treatment-naive non-cirrhotic patients with a baseline viral load <6 million IU/mL (Table 4). AASLD/IDSA does only recommend 8 weeks SOF/LDV in naïve GT1 patients without cirrhosis who are non-black, HIV-uninfected, and whose HCV RNA level is <6 million IU/mL (https://www.hcvguidelines.org/treatment-naive/gt1a/no-cirrhosis).

Cirrhotic patients had an SVR of 100% if SOF/LDV was combined with RBV for 12 or 24 weeks. Without the concomitant use of RBV, an SVR of 97% was achieved with 12 or 24 weeks of treatment (Afdhal 2014b). Based on these results, the FDA recommends 12 weeks of treatment in treatment-naïve patients with cirrhosis, while the EMA recommends 24 weeks of treatment, which may be shortened to 12 weeks in patients with a slow disease progression and the option for retreatment. The concomitant use of RBV is not recommended in naïve patients with compensated cirrhosis. A retrospective analysis of >500 patients with cirrhosis confirmed that naïve patients with compensated cirrhosis can be treated for 12 weeks with SOF/LDV without RBV (Reddy 2015a). SOF/LDV plus RBV over 12 or 24 weeks has been investigated in patients with decompensated liver cirrhosis (Child-Pugh B and C) before or after liver transplantation. SVR12 was around 75% in Child-C patients and more than 80% in Child-B patients. Some patients died during the study period mainly because of complications related to hepatic decompensation (Charlton 2015, Manns 2016) (see section cirrhosis below). Due to limited data at the time of approval in patients with advanced or decompensated cirrhosis EMA recommended 24 weeks SOF/LDV + RBV for decompensated cirrhosis pre-/post liver transplant.

The use of IFN-free SOF/LDV in PEG-IFN+RBV treatment-experienced patients was investigated in the ION-2 trial in cirrhotic and non-cirrhotic patients (Afdhal 2014a). Previous treatment was either with PEG-IFN+RBV or PEG-IFN+RBV + TLV or BOC. Overall, no marked difference could be shown between the treatment duration of 12 or 24 weeks and the addition of RBV to the SOF/LDV combination in non-cirrhotic patients. 12 weeks of SOF/LDV achieved an SVR of 95%, whereas 24 weeks achieved 99%. The addition of RBV to 12 weeks of SOF/LDV demonstrated an SVR of 100% and 99% for 24 weeks of treatment. In cirrhotic patients the SVR rates decreased to 86% for 12 weeks of SOF/LDV and 82% for SOF/LDV+RBV. Treatment for 24 weeks achieved an SVR of 100% regardless of the use of RBV (Table 7). However, each study arm consisted of only 22 treatment-experienced cirrhotic patients. Based on these findings the FDA recommended a duration of 12 weeks for treatment-experienced non-cirrhotic patients and 24 weeks for treatment-experienced cirrhotic patients with SOF/LDV. Of note, a retrospective analysis of >500 patients with cirrhosis treated within all Gilead SOF/LDV Phase 2 and Phase 3 trials revealed that SVR after 12 weeks SOF/LDV was 5-9% lower in the treatment-experienced patients compared to naïve patients (Reddy 2015a). The addition of RBV to a 12 weeks regimen of SOF/LDV demonstrates SVR rates of 96% and is comparable with the 24 weeks regimen in treatment-experienced patients with compensated cirrhosis. Although the addition of RBV is not part of the EMA or FDA label, it may be considered in treatment-experienced patients with compensated cirrhosis as an option to shorten treatment, while maintaining a reasonable SVR rate. The EASL IFN and RBV free recommendations recommend 12 weeks SOF/LDV only in treatment-experienced GT1b patients (EASL 2018).

The efficacy of SOF/LDV in patients with prior exposure to a PI has been investigated in the ION-2 and the SIRIUS trial (Afdhal 2014a, Bourlière 2015). Overall, response rates were similar to the response rates in patients who were treated with PEG-IFN+RBV. In total, 231 patients in the ION-2 trial had previous exposure to a PI. LDV/SOF for 12 weeks led to an SVR of 94%, and for 24 weeks 97%. The addition of RBV resulted in SVR rates of 97% and 100%, respectively (Afdhal 2014a). In the SIRIUS trial 155 GT1 patients with previous PEG-IFN+RBV+PI non-response and compensated cirrhosis have been treated either with SOF/LDV + RBV for 12 weeks or SOF/LDV + placebo for 24 weeks. 12 weeks SOF/LDV + RBV or SOF/LDV for 24 weeks provided similarly high SVR12 rates of 96-97% (Bourlière 2015).

Genotypes 2 and 3

SOF/LDV is not recommended for GT2 (EASL 2018). There are limited data for SOF/LDV in naïve patients with GT3. 51 patients were treated either with SOF/LDV or with SOF/LDV+RBV for 12 weeks in the ELECTRON-2 study. 64% of patients treated with SOF/LDV achieved SVR while 100% of patients achieved SVR with SOF/LDV plus RBV. SOF/LDV+RBV for 12 weeks has been studied in 50 treatment-experienced patients with GT3. SVR was 89% for patients without cirrhosis and 73% for patients with cirrhosis (Gane 2015). EMA (not FDA) approved SOF/LDV + RBV for 24 weeks for GT3 patients with cirrhosis. Thus, some real-world data are available. For example, in Germany SOF/LDV + RBV for 24 weeks achieved 89-93% in cirrhotic patients (Cornberg 2017). Despite these data we will not recommend SOF/LDV + RBV for 24 weeks for GT3 because alternative treatment options are available (see below).

Genotype 4

SOF/LDV is approved for GT4 although data were limited at that time. SOF/LDV given for 12 weeks resulted in 95% SVR in 21 GT4 patients (Kapoor 2014). A phase 3 study from Egypt has investigated SOF/LDV in 255 patients. Treatment-naive patients showed 95% and 90% SVR with 8 weeks of SOF/LDV and SOF/LDV + RBV, respectively, and 98% for 12 weeks SOF/LDV ± RBV. Among PEG-IFN-experienced patients, SVR rates were 94% for 12 weeks SOF/LDV and 100% for SOF/LDV + RBV (Shiha 2018) (Table 8).

Real-world studies have shown >90% SVR in GT4 infected patients (Ahmed 2018).

Genotype 5-6

Data with IFN free regimens are still rare for GT5 and 6. SOF/LDV for 12 weeks has been studied in 41 GT5 and 25 naïve GT6 patients. SVR for GT5 and GT6 are 95-96% (Abergel 2016, Gane 2015) (Table 8).

Table 6. Pivotal phase 3 studies with SOF/LDV treatment regimens in treatment-naïve patients with HCV genotype 1. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ION-1
(Afdhal 2014b)
N=865
a) 400/90 mg SOF/LDV 12 weeks No cirrhosis: 100%
Cirrhosis: 97%
b) 400/90 mg SOF/LDV + 1000–1200 mg RBV 12 weeks No cirrhosis: 100%
Cirrhosis: 100%
c) 400/90 mg SOF/LDV 24 weeks No cirrhosis: 99.5%
Cirrhosis: 96.9%
d) 400/90 mg SOF/LDV + 1000–1200 mg RBV 24 weeks No cirrhosis: 100%
Cirrhosis: 100%
ION-3
(Kowdley 2014)
N=647
No cirrhosis
a) 400/90 mg SOF/LDV 8 weeks 94%
b) 400/90 mg SOF/LDV + 1000–1200 mg RBV 8 weeks 93%
c) 400/90 mg SOF/LDV 12 weeks 95%
SOF: sofosbuvir, LDV: ledipasvir, RBV: ribavirin Table 7. Pivotal phase 2-3 studies with DAA treatment regimens in PEG-IFN+RBV based treatment-experienced patients infected with HCV genotype 1. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ION-2
(Afdhal et al., 2014a)
n=440 (treatment-experienced, incl. n=231 pts with failure to previous PI -based therapy)
a) 400/90 mg SOF/LDV 12 weeks No cirrhosis: 95%
Cirrhosis: 86%
b) 400/90 mg SOF/LDV + 1000-1200 mg RBV 12 weeks No cirrhosis: 100%
Cirrhosis: 82%
c) 400/90 mg SOF/LDV 24 weeks No cirrhosis: 99%
Cirrhosis: 100%
d) 400/90 mg SOF/LDV + 1000-1200 mg RBV 24 weeks No cirrhosis: 99%
Cirrhosis: 100%
SIRIUS
(Bourlière et al., 2015)
n=155 pts with failure to previous PI -based therapy and compensated cirrhosis
63% HCV GT1a
a) 400/90 mg SOF/LDV + 1000-1200 mg RBV 12 weeks 96%
b) 400/90 mg SOF/LDV 24 weeks 97%
SOF: sofosbuvir, LDV: ledipasvir, RBV: ribavirin Table 8. Pivotal phase 2-3 studies with DAA treatment regimens in HCV GT4-6 infection. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
(Kapoor 2014)
n=21 GT4
400/90 mg SOF/LDV 12 weeks 95%
(Shiha et al., 2018)
n=255 GT4
400/90 mg SOF/LDV 8 weeks 95% (naïve)
400/90 mg SOF/LDV + RBV 8 weeks 90% (naïve)
400/90 mg SOF/LDV 12 weeks 94% (IFN-Exp.)
400/90 mg SOF/LDV + RBV 12 weeks 100% (IFN-Exp.)
400/90 mg SOF/LDV + RBV 12 weeks (SOF exp.) 100% (SOF-Exp.)
(Abergel et al., 2016)
n=41 GT5
400/90 mg SOF/LDV 12 weeks 95%
Cirrhosis 89%
(Gane et al., 2015)
n=25 GT6, 92% naïve
400/90 mg SOF/LDV 12 weeks 96%
SOF: sofosbuvir, LDV: ledipasvir, RBV: ribavirin, Exp.: treatment experienced patients

Grazoprevir and Elbasvir (GZR/EBR)

The combination of GZR and EBR is available as a single-tablet fixed-dose combination (Zepatier®, MSD). GZR is a second-generation PI (Summa 2012). EBR is a selective inhibitor of the HCV NS5a replication complex (Coburn 2013). The combination of GZR/EBR (Zepatier ®) is a fixed dose single tablet regimen. The FDA and EMA approved GZR/EBR (Zepatier®) in 2016 for genotype 1 and 4. GZR/EBV can be used in patients with CKD including hemodialysis. GZR/EBR is not recommended for patients with decompensated cirrhosis based on pharmacokinetic data (EASL 2018).

Genotype 1

Treatment naïve GT1 patients have been treated in phase 2 (C-WORTHY) and phase 3 (C-EDGE) trials (Table 9) (Sulkowski 2015, Zeuzem 2015, Cornberg and Manns 2015). Based on this data, naïve patients with GT1 with or without cirrhosis should receive 12 weeks GZR/EBR (Table 4 & 5). Patients with GT1a (naïve as well as PEG-IFN+RBV experienced) who have baseline NS5A RASs have demonstrated lower SVR rates (Table 3). However, this was only relevant for patients with baseline HCV RNA <800,000 IU/mL. It is recommended that GT1a patients with baseline NS5A RASs or a baseline viral load >800,000 IU/mL should be treated for 16 weeks plus RBV. One study analysed if 8 weeks GZR/EBR with or without RBV is sufficient in naïve GT1b patients without cirrhosis. The SVR rate was 93-94% (Vierling 2015). Interim data from a phase 3 study (STREAGER) indicate even higher SVR rates of 98% in GT1b patients with F0-2 fibrosis (Abergel 2018). Thus, the EASL recommendations suggested using 8 weeks GZR/EBR in treatment naïve GT1b patients with F0-2 fibrosis (EASL 2018). However, 8 weeks GZR/EBR is so far only approved in Switzerland and Canada.

GZR/EBR has also been evaluated in PEG-IFN+RBV treatment-experienced GT1 patients in the C-EDGE study (Kwo 2017). 35% of the study cohort had cirrhosis. Patients were randomised to receive 12 weeks GZR/EBR, 12 weeks GZR/EBR plus RBV, 16 weeks GZR/EBR or 16 weeks GZR/EBR plus RBV (SVR by intention-to-treat analysis is shown in Table 10). All patients who had a previous relapse and all patients with GT1b achieved SVR with 12 weeks GZR/EBR in the per protocol analysis. GT1a patients with previous non-response to PEG-IFN+RBV had lower SVR rates with 12 weeks GZR/EBR (91%) and may benefit from 16 weeks GZR/EBR plus RBV (100% SVR). However, the reason for relapse was most likely due to baseline NS5A RASs.

The open-label C-SALVAGE study investigated 12 weeks GZR/EBR plus RBV in 79 patients with GT1 and failure to PEG-IFN+RBV plus either BOC, TLV or SMV (Forns 2015). Overall 96% of patients achieved SVR12. There was no significant difference between GT1a and GT1b with 93% versus 96%, respectively. Patients with baseline NS3 RASs had 91% SVR.

A retrospective pooled analysis of all GT1b patients from 11 trials conformed the high efficacy of 12 weeks GZR/EBR. Only 15 out of 1077 (1.4%) treated patients experienced a virological failure (Zeuzem 2018).

Several real-world cohorts confirm the excellent safety and efficacy profile of 12 weeks GZR/EBR with 95-99% SVR rates in GT1 (Flamm 2018, Kramer 2018). Interestingly, in real world patients with GT1a have been treated with 12 weeks GZR/EBR without RAS testing. The SVR in those patients was 98% in the TRIO network analysis (Flamm 2018).

Genotype 3

GZR/EBR was investigated in combination with SOF in treatment naïve and experienced patients with GT3 and compensated liver cirrhosis. Treatment naïve patients were treated for 8 or 12 weeks and achieved 91% and 96% SVR, respectively, Treatment experienced patients were treated 12 weeks, 16 weeks and 12 weeks plus RBV and achieved 100%, 94% and 94% SVR, respectively (Foster 2018). SVR was 100% in the per protocol analysis. Thus, 12 weeks GRZ/EBR + SOF could be an option for GT3. Actually this is recommended by AASLD as one of two first line treatment options in interferon treatment experienced GT3 patients with cirrhosis (https://www.hcvguidelines.org/treatment-experienced/gt3/p-r/compensated-cirrhosis). However, this combination is not approved and other options are available.

Genotype 4

GZR/EBR is also effective against genotype 4. The integrated analysis of the phase 2-3 trials showed SVR12 rates of 96% (97/101) for treatment-naïve patients treated with 12 weeks and 100% (8/8) in treatment-experienced participants treated with 16 weeks GZR/EBR plus ribavirin (Asselah 2018b) (Table 11). Baseline NS5A RAS did not impact SVR in this analysis. Based on the data treatment naïve GT4 patients without cirrhosis may be treated with 12 weeks GZR/EBR. However, EASL recommends 12 weeks GZR/EBR in GT4 (no cirrhosis and cirrhosis) if baseline HCV RNA is <800.000 IU/mL.

Other genotypes

The phase 2 C-SCAPE study evaluated GZR/EBR, with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infections. GT2 patients received 12 weeks GZR + RBV ± EBR. SVR was suboptimal with 73-80%. Those with genotype 4, 5 or 6 infections were randomised to receive EBR/GZR ± RBV for 12 weeks. SVR in GT4 was 90-100%. GT5 SVR was 25% without and 100% with RBV. GT 6 SVR was 75% irrespective of RBV (Brown 2018). Thus, GZR/EBR is not recommended for GT 2, 5 and 6 (EASL 2018).

Treatment regimens with sofosbuvir and daclatasvir

Daclatasvir (DCV) is an inhibitor of the HCV NS5A replication complex (Gao 2010). DCV is given once-daily at a standard dose of 60 mg (Table 1). DCV has been tested in combination regimens with PEG-IFN + RBV as well as with other DAAs including asunaprevir (Lok 2012, Suzuki 2013) and sofosbuvir (Sulkowski 2014a). We will focus on the combination with sofosbuvir because asunaprevir is only available in Japan and the IFN-based combination with DCV is not a first-line option.

The combination SOF + DCV was approved in 8/2014 by EMA based on a phase 2 trial (Sulkowski 2014a). The study enrolled 211 patients, including 126 naïve GT1 patients (Table 4), 41 GT1 patients who previously failed PEG-IFN + RBV/PI triple therapy and 44 GT2/3 patients. Naïve GT1 patients were treated 12 or 24 weeks with or without RBV. All but two patients achieved SVR12. One patient was lost to follow-up after he achieved SVR4 and the other patient with missing data at week 12 post-treatment achieved SVR24. Cirrhosis was an exclusion criterion of the study. Nevertheless, some patients were classified as cirrhotics by fibrotest (Sulkowski 2014a). The EMA label recommends treatment of 12 weeks SOF + DCV without RBV for naïve patients without cirrhosis. Patients with cirrhosis should be considered for 24 weeks of therapy due to the limited data available. Shortening treatment to 12 weeks may be considered for previously untreated patients with cirrhosis and positive prognostic factors (Figure 2C). Ribavirin may be considered for patients with very advanced liver disease or with other negative prognostic factors. There are additional data from the phase 3 ALLY-2 trial, which assessed the efficacy and safety of 12 weeks SOF + DCV in GT1-4 patients coinfected with HIV (Wyles 2015) (see section HIV). The phase 3 ALLY-1 trial investigated SOF + DCV plus RBV (initial dose of 600 mg, then titrated) in 60 patients with advanced cirrhosis (Poordad 2016). GT1a patients had 76% SVR and GT1b patients had 100% SVR. Real-world data are available (Pol 2017, Welzel 2016). Data from compassionate use programmes suggest that 24 weeks SOF + DCV with or without RBV should be given in patients with advanced cirrhosis (Pol 2017, Welzel 2016). The results of non-responders to PEG-IFN + RBV/PI and GT2/3 patients will be discussed later.

Table 9. Pivotal phase 2-3 studies with GZR/EBR/ treatment regimens in treatment-naïve patients with HCV genotype 1. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
C-EDGE TN
(Zeuzem et al., 2015)
n=288 / 94 (treatment-naïve GT1, 22% cirrhosis)
a) 50/100 mg GZR/EBR 12 weeks
(n=288 GT1)
GT1a: 92%
No NS5A RAS: 98%
b) Deferred / placebo
(n=94 GT1)
GT1b: 99%
C-WORTHY, part C
(Vierling et al., 2015)
n=61 (treatment-naïve GT1b, no cirrhosis)
a) 50/100 mg GZR/EBR 8 weeks 94%
b) 50/100 mg GZR/EBR + 1000-1200 mg RBV 8 weeks 93%
STREAGER
(Abergel et al., 2018)
n=90 (treatment-naïve GT1b, no cirrhosis, fibroscan <9.5kPa)
a) 50/100 mg GZR/EBR 8 weeks 97%
RBV: ribavirin, GZR: grazoprevir, EBR: elbasvir Table 10. Pivotal phase 2-3 studies with GZR/EBR in PEG-IFN+RBV based treatment-experienced patients infected with HCV genotype 1. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
C-EDGE TE
(Kwo et al., 2017)
n=374 (PEG-IFN+RBV treatment-experienced, 35% cirrhosis GT1)
a) 50/100 mg GZR/EBR 12 weeks GT1a: 90.2%
GT1b: 100%
b) 50/100 mg GZR/EBR + 1000-1200 mg RBV 12 weeks GT1a: 93.3%
GT1b: 96.6%
c) 50/100 mg GZR/EBR 16 weeks GT1a: 93.8%
GT1b: 95.8%
d) 50/100 mg GZR/EBR + 1000-1200 mg RBV 16 weeks GT1a: 94.8% (mITT 100%)
GT1b: 100%
C-SALVAGE
(Forns et al., 2015)
n=79 pts. with failure to previous PI based therapy, 43% cirrhosis
50/100 mg GZR/EBR + 1000-1200 mg RBV 12 weeks 96.2%, cirrhosis 94.1%
GT1a: 93.3%
GT1b: 95.5%
NS3 RASs: 91.2%
NS5A RASs: 75%
RBV: ribavirin, GZR: grazoprevir, EBR: elbasvir, mITT: modified ITT excluding virological failures Table 11. Pivotal phase 2-3 studies with GZR/EBR/ treatment regimens in patients with HCV genotype 4. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
C-EDGE TN
(Zeuzem et al., 2015)
n=18 GT4
50/100 mg GZR/EBR 12 weeks GT4: 100%
Pooled analysis
(Asselah et al., 2018)
n=155, N=111 naïve (13.5% cirrhosis), n=44 exp (41% cirrhosis).
50/100 mg GZR/EBR 12 weeks (naïve, n=101) 96%
50/100 mg GZR/EBR + RBV 12 weeks (naïve, n=10) 100%
50/100 mg GZR/EBR 12 weeks (exp., n=16) 89%
50/100 mg GZR/EBR + RBV 12 weeks (exp., n=15) 93%
50/100 mg GZR/EBR ± RBV 16 weeks (exp., n=13) 60-100%
RBV: ribavirin, GZR: grazoprevir ,EBR: elbasvir, Exp.: treatment (PEG-IFN + RBV) experienced patients

Glecaprevir and Pibrentasvir (GLE/PIB)

The combination of GLE and PIB is available as a fixed-dose combination (Maviret®, Mavyret®, Abbvie). GLE is a NS3/4A protease inhibitor. PIB is a selective second-generation inhibitor of the HCV NS5a replication complex.

The combination of GLE/PIB (Maviret ®, Mavyret®) was approved in 2017. All genotypes can be treated with GLE/PIB. GLE/PIB can be used in patients with CKD and hemodialysis but is not recommended in patients with decompensated cirrhosis.

Genotype 1

The integrated analysis of all phase 2 and 3 studies showed that 8 or 12 weeks GLE/PIB resulted in ≥99% SVR in GT1 patients without cirrhosis. There was only one treatment failure in the 8-week group (Puoti 2018). Thus, there were no differences in naïve or treatment-experienced patients. The EXPEDITION-1 trial investigated 12 weeks GLE/PIB in 87 GT1 patients with compensated cirrhosis. Only one GT1a patients had a relapse (Forns 2017) (Table 12). International guidelines recommend 8 weeks GLE/PIB for non-cirrhotic GT1 and 12 weeks for patients with compensated cirrhosis (EASL 2018).

Genotype 2

The integrated analysis of all phase 2 and 3 studies showed that 8 or 12 weeks GLE/PIB resulted in ≥98% SVR in GT2 patients without cirrhosis. There were two treatment failure in the 8-week group (Puoti et al., 2018). Thus, there were no differences in naïve or treatment-experienced patients. The EXPEDITION-1 trial investigated 12 weeks GLE/PIB in 31 GT2 patients with compensated cirrhosis. SVR was 100% (Forns 2017) (Table 13). A Japanese study (CERTAIN-2) confirmed 100% SVR in 18 patients (Toyoda 2017). International guidelines recommend 8 weeks GLE/PIB for non-cirrhotic GT2 and 12 weeks for patients with compensated cirrhosis (EASL 2018).

Genotype 3

The ENDURANCE-3 study analysed >500 naïve GT3 patients without cirrhosis. 12 weeks GLE/PIB were compared with 12 weeks SOF + DCV. In addition, the study contained an additional arm testing 8 weeks GLE/PIB. SVR was ≥95% in all treatment arms (Table 14). There were numerically more treatment failures in the eight week group (Zeuzem 2018). Most of the patients treated in the phase 3 ENDURANCE-3 trial had mild F0-F2 fibrosis and only 17% had F3 fibrosis. The integrated analysis of all phase 2 and 3 GT3 studies showed that 8 or 12 weeks GLE/PIB resulted in 95% SVR in treatment-naïve GT3 patients without cirrhosis, respectively (Puoti 2018). The SURVEYOR-II - Part 3 trial investigated 12 or 16 weeks GLE/PIB in treatment-experienced (PEG-IFN + RBV ± SOF) without cirrhosis. In addition, treatment-naïve patients with cirrhosis were treated for 12 weeks and treatment-experienced patients with cirrhosis for 16 weeks. SVR was 91-98% (Wyles 2017) (Table 14). Based on the results, the EMA label recommends 8 weeks GLE/PIB for naïve non-cirrhotic GT3 patients and 12 weeks for treatment naïve patients with cirrhosis. For treatment experienced patients with or without cirrhosis, 16 weeks are recommended. EASL recommends for treatment-experienced patients without cirrhosis only 12 weeks GLE/PIB (EASL 2018), while AASLD/IDSA recommends 16 weeks (https://www.hcvguidelines.org/treatment-experienced/gt3/p-r/without-cirrhosis).

Genotype 4-6

The integrated analysis of all phase 2 and 3 studies showed that 8 or 12 weeks GLE/PIB resulted in 92-100% SVR in GT4-6 patients without cirrhosis. However, no virological failure was documented (Puoti 2018) (Table 15). So far there are only limited data for GT4-6 in patients with cirrhosis. However, no relapse has been documented with 12 weeks GLE/PIB (Gane 2017b). Thus, the treatment recommendations for GT4-6 are the same as for GT1, which is 8 weeks for patients without cirrhosis and 12 weeks for patients with cirrhosis (Table 4 & 5).

Table 12. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 1. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
Integrated analysis of phase 2 and 3 studies
(Puoti et al., 2018)
N=875 GT1, no cirrhosis
(naïve and exp.)
a) 300/120 mg GLE/PIB 8 weeks 99% ITT, 99.8% mITT
b) 300/120 mg GLE/PIB 12 weeks 99.8% ITT, 100% mITT
EXPEDITION-1
(Forns et al., 2017)
N=87 GT1, cirrhosis
300/120 mg GLE/PIB 12 weeks GT1a: 98%
GT1b: 100%
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN) experienced patients,
ITT: intention-to-treat analysis, mITT: modified ITT excluding virological failures
Table 13. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 2. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
Integrated analysis of phase 2 and 3 studies
(Puoti et al., 2018)
N=436 GT2, no cirrhosis
(naïve and exp.)
a) 300/120 mg GLE/PIB 8 weeks 98% ITT, 99% mITT
b) 300/120 mg GLE/PIB 12 weeks 99% ITT, 100% mITT
EXPEDITION-1
(Forns et al., 2017)
N=31 GT2, cirrhosis
300/120 mg GLE/PIB 12 weeks 100%
CERTAIN-2
(Toyoda et al., 2017)
N=18 GT2, cirrhosis
300/120 mg GLE/PIB 12 weeks 100%
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN + RBV) experienced patients, mITT: modified intention-to-treat excluding non-virological failures Table 14. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 3. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ENDURANCE-3
(Zeuzem et al., 2018)
N=505 GT3, naïve, no cirrhosis
a) 300/120 mg GLE/PIB 8 weeks 95% (149/157)
b) 300/120 mg GLE/PIB 12 weeks* 95% (222/233)
c) 300/120 mg SOF + DCV 12 weeks* 97% (111/115)
* 2:1 randomisation
SURVEYOR-2, part 3
(Wyles et al., 2017)
N=131 GT3, Exp. without cirrhosis, naïve and exp. with cirrhosis
a) Naïve cirrhosis: 300/120 mg GLE/PIB 12 weeks 98%
b) Exp. no cirrhosis 300/120 mg GLE/PIB 12 weeks 91%
c) Exp. no cirrhosis 300/120 mg GLE/PIB 16 weeks 95%
d) Exp. cirrhosis 300/120 mg GLE/PIB 16 weeks 96%
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN + RBV ± SOF) experienced patients Table 15. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 4-6. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
Integrated analysis of phase 2 and 3 studies
(Puoti et al., 2018)
N=174 GT4 | n=30 GT5 | n=43 GT6, no cirrhosis
(naïve and exp.)
a) 300/120 mg GLE/PIB 8 weeks GT4: 95% ITT, 100% PP
GT5: 100% ITT, 100 PP
GT6: 92% ITT, 100% PP
b) 300/120 mg GLE/PIB 12 weeks GT4: 99% ITT, 100% PP
GT5: 100% ITT, 100% PP
GT6: 100% ITT, 100% PP
Integrated analysis of phase 2 and 3 studies
(Gane et al., 2017b)
N=22 GT4 | n=2 GT5, | n=7 GT6, cirrhosis
(naïve and exp.)
300/120 mg GLE/PIB 12 weeks GT4: 100% ITT, 100% PP
GT5: 100% ITT, 100 PP
GT6: 100% ITT, 100% PP
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN + RBV) experienced patients, PP: per-protocol population

Sofosbuvir and velpatasvir (SOF/VEL)

The combination of SOF and VEL is available as a fixed-dose combination (Epclusa®, Gilead Sciences). VEL is a selective inhibitor of the HCV NS5a replication complex. SOF/VEL was approved in 2016 as the first regimen that is effective in all genotypes. Based on the phase 3 studies (Feld 2015, Curry 2015b), treatment duration of 12 weeks is the standard for all GT1,2,4-6 patients and GT3 patients without cirrhosis (Table 4 & 5). For genotype 3 patients with cirrhosis, baseline RASs may be relevant. SOF/VEL is not recommended for patients with CKD (GFR<30 ml/min). SOF/VEL can be used in patients with decompensated cirrhosis (see below).

Genotype 1

The efficacy of 12 weeks SOF/VEL in previously treated patients with GT1 with or without cirrhosis was investigated in the ASTRAL-1 trial. In the ASTRAL-1 trial, 32% of the SOF/VEL treated patients were treatment experienced. A small number of 56 SOF/VEL treated patients were PEG-IFN+RBV+PI treatment-experienced. As the SVR rate was 98-99% for all GT1 (Table 16), there was no obvious difference between treatment-experienced and naïve patients (Feld 2015).

An integrated analysis of patients with advanced fibrosis and cirrhosis showed 98% SVR and 99% SVR, respectively (Asselah 2018a). Patients with CHILD-B cirrhosis were treated in the ASTRAL-4 study. Here 12 weeks SOF/VEL was compared with 12 weeks SOF/VEL + RBV and 24 weeks SOF/VEL. SVR rates were 88-100%. There was a numerically higher SVR rate with 12 weeks SOF/VEL + RBV (Curry 2015b).

Thus, 12 weeks SOF/VEL is recommended for all GT1 patients, including cirrhosis or PEG-IFN+RBV+PI treatment-experienced. RBV may be added in patients with decompensated cirrhosis or treatment duration can be extended to 24 weeks if patients are ineligible for RBV (EASL 2018) (https://www.hcvguidelines.org/unique-populations/decompensated-cirrhosis).

Genotype 2

The ASTRAL-2 and 3 trials (Foster 2015) investigated 12 weeks SOF/VEL versus SOF+RBV in 266 GT2 patients. SVR was 99% with 12 weeks SOF/VEL and 94% with 12 weeks SOF+RBV (Table 17). In addition, the ASTRAL-4 study analysed the responses to 12 weeks SOF/VEL in decompensated cirrhosis (Curry 2015b). However, the study enrolled only 12 decompensated patients with GT2. All patients achieved SVR. 12 weeks SOF/VEL is recommended for all GT2 patients, including compensated cirrhosis. RBV may be added in patients with decompensated cirrhosis or treatment duration can be extended to 24 weeks if patients are ineligible for RBV, as data are limited for this specific group of patients (EASL 2018) (https://www.hcvguidelines.org/unique-populations/decompensated-cirrhosis).

Genotype 3

The ASTRAL-2 and 3 trials (Foster 2015) investigated 12 weeks SOF/VEL versus SOF+RBV in 552 GT3 patients. For GT3, the additional benefit for SOF/VEL was higher (SVR 95% versus 80%) (Table 18). The integrated analysis of patients with fibrosis and cirrhosis showed 99% SVR in patients with fibrosis but only 91% SVR in patients with cirrhosis (Asselah 2018a). Treatment-experienced patients with advanced fibrosis and cirrhosis showed 90% SVR versus 97% in naïve patients (Asselah 2018a). Patients with baseline RAS in GT3 and advanced fibrosis and cirrhosis achieved SVR in only 79% with 12 weeks SOF/VEL (Asselah 2018a). This was one reason that EASL does not recommend 12 weeks SOF/VEL without RBV in GT3 cirrhosis, if RAS testing is not available (EASL 2018). In the POLARIS-3 study, 109 GT3 patients with cirrhosis received SOF/VEL. The only 2 virological treatment failures were prior PEG-IFN + RBV non-responder (Jacobson et al., 2017). AASLD/IDSA guidance recommends 12 weeks SOF/VEL in naïve GT3 patients with cirrhosis and 12 weeks SOF/VEL/VOX or SOF/VEL + RBV in treatment-experienced patients with cirrhosis, if RAS test is not available (https://www.hcvguidelines.org/treatment-experienced/gt3/p-r/compensated-cirrhosis). A randomised trial in 204 GT3 patients with cirrhosis showed 91% SVR with 12 weeks SOF/VEL and 96% with 12 weeks SOF/VEL + RBV. In this study, treatment-experienced GT3 patients with cirrhosis had even better responses with 12 weeks SOF/VEL compared with naïve patients. The impaired SVR was related to NS5A RAS (Table 18). Patients without NS5A RAS (Y93H) had 96% SVR with or without RBV (Buti 2018). The frequency of baseline NS5A RAS (Y93H) may impact the response to 12 weeks SOF/VEL in patients with GT3 cirrhosis. Thus, in areas with a high frequency of NS5A RAS, GT3 patients with cirrhosis should either receive additional RBV or RAS testing should be performed. Otherwise alternative treatment options should be preferred.

In contrast, patients with mild fibrosis may require only 8 weeks SOF/VEL. 8 weeks SOF/VEL in 90 patients receiving opiate substitution therapy (OST) showed 93% SVR but no patients had a virological failure (Boyle 2018) (Table 18). However, in 2018 8 weeks SOF/VEL are not recommended by international guidelines.

The ASTRAL-4 study analysed the responses to 12 weeks SOF/VEL in decompensated cirrhosis (Curry 2015b). SVR with 12 weeks SOF/VEL in GT3 patients was low with 50%. The addition of RBV increased SVR rate to 85% (Table 18). Thus, RBV needs to be added in patients with decompensated cirrhosis and GT§ infection. For patients with decompensated cirrhosis who are RBV ineligible, SOF/VEL for 24 weeks is currently recommended, although this did not result in higher SVR rates compared to 12 weeks in the ASTRAL-4 trial. However, the number of patients analysed was quite small. (EASL 2018) (https://www.hcvguidelines.org/unique-populations/decompensated-cirrhosis).

Genotype 4-6

ASTRAL-1 included 116 GT4 treatment-naive patients without cirrhosis or with compensated cirrhosis, all of whom achieved SVR12 (100%) (Feld 2015). In the POLARIS-2 study, 57 patients with GT4 received 12 weeks SOF/VEL and 98% achieved SVR (Table 19) (Jacobson 2017).

ASTRAL-1 included 35 GT5 and 41 GT6 treatment-naive patients without cirrhosis or with compensated cirrhosis. 97% of GT5 and 100% of GT6 patients achieved SVR with 12 weeks SOF/VEL (Feld 2015).

Treatment recommendations are the same as for GT1 patients (EASL 2018).

Table 16. Pivotal phase 3 studies with SOF/VEL treatment regimens in treatment-naïve patients with HCV genotype 1. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ASTRAL-1
(Feld et al., 2015)
n=393 (GT1, 19% cirrhosis, 68-72% naive)
a) 400/100mg SOF/VEL 12 weeks
(n=328)
GT1a: 98%
b) placebo
(n=65)
GT1b: 99%
ASTRAL-4
(Curry et al., 2015)
n=207(GT1, decompensated cirrhosis, 36-53% naive)
a) 400/100mg SOF/VEL 12 weeks
(n=90)
GT1a: 88%
GT1b: 89%
b) 400/100mg SOF/VEL + 1000-1200 mg RBV 12 weeks
(n=87)
GT1a: 94%
GT1b: 100%
c) 400/100mg SOF/VEL 24 weeks
(n=90)
GT1a: 93%
GT1b: 88%
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir,
Exp.: treatment-experienced patients
Table 17. Pivotal phase 3 studies with SOF/VEL treatment regimens in HCV GT2 infection (naïve and treatment-experienced). Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ASTRAL-2
(Foster et al., 2015)
GT2: 266
14-30% cirrhosis
a) 400/100 mg SOF/VEL 12 weeks 99%
b) 400 mg SOF + 1000-1200 mg RBV 12 weeks 94%
Pooled analysis
(Asselah et al., 2018)
n=155, N=111 naïve (13.5% cirrhosis), n=44 exp (41% cirrhosis).
a) 400/100mg SOF/VEL 12 weeks
(n=90)
100%
b) 400/100mg SOF/VEL + 1000-1200 mg RBV 12 weeks
(n=87)
100%
c) 400/100mg SOF/VEL 24 weeks
(n=90)
75% (3/4)
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir,
Exp.: treatment-experienced patients
Table 18. Pivotal phase 3 with SOF/VEL treatment regimens in HCV GT3 infection (naïve and treatment-experienced). Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ASTRAL-3
(Foster et al., 2015)
n=552
14-30% cirrhosis
a) 400/100 mg SOF/VEL 12 weeks 95%
exp. cirrhosis 89%
b) 400 mg SOF + 1000-1200 mg RBV 24 weeks 80%
exp. cirrhosis 58%
ASTRAL-4
(Curry et al., 2015)
n=39
with decompensated cirrhosis
a) 400/100mg SOF/VEL 12 weeks
(n=90)
50%
b) 400/100mg SOF/VEL + 1000-1200 mg RBV 12 weeks (n=87) 85%
c) 400/100mg SOF/VEL 24 weeks
(n=90)
50%
POLARIS-3
(Jacobson et al., 2017)
n=109, cirrhosis, n=32 exp.
400/100 mg SOF/VEL 12 weeks (control group) 96%, mITT 98%
Naïve: 100% mITT
Exp.: 93.75% mITT
(Pianko et al., 2015)
n=105 GT3 treated with 400/100 mg SOF/VEL, n=52 with cirrhosis
a) 400/100 mg SOF/VEL 12 weeks 100% no cirrhosis
92% (24/26) cirrhosis
b) 400/100 mg SOF/VEL weeks + 1000-1200 mg RBV 12 weeks 100% no cirrhosis
96% (25/26) cirrhosis
(Buti et al., 2018)
N=204 with cirrhosis, 27% exp., 19-22% NS5A RAS
a) 400/100 mg SOF/VEL 12 weeks 91% (5 relapser)
Naïve 89%, exp. 96%
NS5A-RAS 84%
b) 400/100 mg SOF/VEL weeks + 1000-1200 mg RBV 12 weeks 96% (2 relapser)
Naïve 96%, exp. 96%
NS5A-RAS 96%
(Boyle et al., 2018)
n=90 GT3, F0-F3 (31% F3), mainly OST patients
400/100 mg SOF/VEL 8 weeks 93% ITT, 100 mITT
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir, Exp.: treatment-experienced patients, mITT: modified intention-to-treat excluding non-virological failures Table 19. Pivotal phase 3 with SOF/VEL treatment regimen in HCV GT4-6 infection. Studies are not head-to-head and SVR between studies are difficult to compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Treatment SVR
ASTRAL-1
(Feld et al., 2015)
n=116 GT4 | 35 GT5 | 41 GT6
400/100 mg SOF/VEL 12 weeks GT4: 100%
GT5: 97%
GT6: 100%
ASTRAL-4
(Curry et al., 2015)
n=8 GT4 | 1 GT6 with decompensated cirrhosis
a) 400/100 mg SOF/VEL 12 weeks GT4: 4/4
b) 400/100 mg SOF/VEL weeks + 1000-1200 mg RBV 12 weeks GT4: 2/2
c) 400/100 mg SOF/VEL 24 weeks GT4: 2/2, GT6: 1/1
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir,
Exp.: treatment-experienced patients

Sofosbuvir and velpatasvir and voxilaprevir (SOF/VEL/VOX)

Voxilaprevir (VOX) is an HCV N3/4A protease inhibitor (Rodriguez-Torres 2016) that is combined with SOF/VEL in a single tablet (Vosevi®). SOF/VEL/VOX was approved in 2017. It is the first approved RBV free DAA therapy for patients who failed an NS5A-containing DAA regimen (see Treatment of patients with prior DAA treatment failure below). SOF/VEL/VOX has also been approved for DAA naive patients by EMA (not FDA) but as other options are available SOF/VEL/VOX should be restricted to patients with DAA failure.

Treatment of DAA naïve patients

Two phase 3 studies investigated SOF/VEL/VOX in DAA naïve patients. POLARIS-2 compared the efficacy of 8 weeks of SOF/VEL/VOX to 12 weeks of SOF/VEL. The study included 941 patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis. POLARIS-3 enrolled 219 GT3 patients with cirrhosis (Jacobson 2017). 8 weeks SOF/VEL/VOX missed the pre-specified non-inferiority criteria, mainly because of a lower SVR in GT1a patients (Table 20). The lower SVR in GT1a patients was associated with the Q80K variant. However, 8 weeks SOF/VEL/VOX showed a similar SVR compared with 12 weeks SOF/VEL in GT3 patients with and without compensated cirrhosis. At least, 29% of GT3 patients treated with SOF/VEL/VOX had platelets <100/nl. Thus, 8 weeks SOF/VEL/VOX can be an option for all GT3 patients according to the EMA label. However, EASL recommends 12 weeks SOF/VEL/VOX for GT3 patients with cirrhosis (EASL 2018). AALSD/IDSA considers also 12 weeks SOF/VEL/VOX but specifically only for naïve GT3 patients with cirrhosis if baseline Y93H is present (https://www.hcvguidelines.org/treatment-naive/gt3/compensated-cirrhosis) or in PEG-IFN+RBV experienced GT3 patients with cirrhosis (https://www.hcvguidelines.org/treatment-experienced/gt3/p-r/compensated-cirrhosis).

Table 20. Pivotal phase 3 studies with SOF/VEL/VOX treatment regimens in DAA naive patients with HCV genotype 1-6. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
POLARIS-2
(Jacobson et al., 2017)
n=941 GT1-6, 23-24% exp., 18-19% cirrhosis (GT3 only no cirrhosis)
a) 400/100mg SOF/VEL 12 weeks
(n=440)
GT1a: 99%
GT1b: 97%
GT2: 100%
GT3: 97%
GT4: 98%
GT5: -
GT6: 100%
b) 400/100/100mg SOF/VEL/VOX 8 weeks
(n=501)
GT1a: 95%
GT1b: 97%
GT2: 97%
GT3: 99%
GT4: 94%
GT5: 94
GT6: 100%
POLARIS-3
(Jacobson et al., 2017)
n=219 GT3
with cirrhosis
a) 400/100mg SOF/VEL 12 weeks
(n=109)
GT3: 96%
b) 400/100/100mg SOF/VEL/VOX 8 weeks
(n=110)
GT3: 96%
GT: genotype, SOF: sofosbuvir, VEL: velpastasvir, VOX: voxilaprevir

Treatment of patients with prior DAA treatment failure

As more patients are treated, the size of the population of patients who fail to achieve SVR with DAA-including regimens might expand in the future. Retreatment of patients with previous treatment failure is one important topic in the treatment of chronic hepatitis C. RAS testing may be performed (Dietz 2018) to select the therapy based on susceptibility to the corresponding drug class.

However, the only EMA approved RBV free treatment for patients with DAA treatment failure in 2018 is SOF/VEL/VOX.

The POLARIS-4 study investigated patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor. Patients received either SOF/VEL/VOX or SOF/VEL for 12 weeks. An additional 19 GT4 patients were treated with SOF/VEL/VOX. Overall, SVR was 98% with SOF/VEL/VOX and 90% with SOF/VEL (Bourlière 2017) (Table 21).

NS5A inhibitors are part of all currently used DAA combinations. NS5A RAS, unlike NS3 and NS5B RAS, appear to maintain the viability of the virus after unsuccessful treatment with an NS5A inhibitor containing therapy. Thus, NS5A remain at high frequency in the majority of patients for more than five years after the end of treatment (Pawlotsky 2016). As a result, retreatment of patients after NS5A failure is of special importance. The POLARIS-1 trial investigated 263 patients who failed previous NS5A based therapy. Overall, the SVR was 96% with 12 weeks SOF/VEL/VOX (Bourlière 2017) (Table 21). SVR was 99% in patients without cirrhosis and 93% in patients with cirrhosis. 147 of the 152 patients in the placebo group have been treated later with 12 weeks SOF/VEL/VOX and 97% achieved SVR (Bourlière 2018). The recommended treatment duration for SOF/VEL/VOX for DAA experienced patients is 12 weeks. However, GT3 patients with cirrhosis (especially those with NS5A RAS) may be considered for additional RBV to minimise the relapse risk (https://www.hcvguidelines.org/treatment-experienced/gt3/daa). In the POLARIS-4 study, all 4 GT3 patients who experienced a relapse had cirrhosis (Bourlière 2017).

In patients with contraindications for SOF/VEL/VOX (i.e. decompensated cirrhosis), SOF/VEL + RBV for 24 weeks could be an alternative and is not off-label use according to the EMA label.

However, not all patients with previous DAA therapy must be treated with SOF/VEL/VOX. Data for retreatment of patients with HCV GT1 infection and failure to previous therapy with PEG-IFN+RBV + TLV or BOC are available for SOF/LDV, GZR/EBR and SOF/VEL regimens (see above). Thus, these combinations can be used for these patients.

Also patients that failed a SOF + SMV retreatment do not necessarily require SOF/VEL/VOX.

Retreatment with GLE/PIB for 12 weeks could be an option. In the MAGELLAN-1 Part 2 study, GLE/PIB was investigated in patients who failed previous NS3/4A protease and/or NS5A inhibitor-containing therapy. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks GLE/PIB, respectively (Poordad 2018) (Table 22). Patients with failure to NS3/4A inhibitor-based therapy showed 100% SVR even with 12 weeks therapy. However, there were only 3 patients enrolled who failed SOF + SMV but all were treated for 16 weeks. In another study, patients who failed NS5A inhibitor-based therapy were treated 12 (with ribavirin in cirrhosis) or 16 weeks with GLEB/PIB. Based on the results, patients with cirrhosis require 16 weeks therapy (Lok 2018).

Of note, GLE/PIB is only approved for DAA failures in the FDA label and not in EMA.

Finally, the combination of GLE/PIB + SOF + RBV would be the most powerful therapy because it combines SOF with GLE and the second-generation NS5A inhibitor PIB, which has a higher barrier to NS5A resistance. This combination has been used in the MAGELLAN-3 study in patients who failed prior GLE/PIB therapy. Only one of 23 patients showed a relapse after 12 weeks or 16 weeks therapy (Wyles 2018). EASL recommends 12 weeks GLE/PIB + SOF for patients after DAA failure with complex NS5A RAS profiles or in combination with RBV for patients who failed multiple DAA therapies (EASL 2018).

Table 21. Phase 3 studies with SOF/VEL/VOX treatment regimens in DAA treatment-experienced patients with HCV genotype 1-6. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
POLARIS-1
(Bourlière et al., 2017)
n=388 NS5A failure
34-46% cirrhosis
a) 400/100/100mg SOF/VEL/VOX 12 weeks
(n=236)
GT1a: 96%, GT1b: 100%
GT2: 100%
GT3: 95%
GT4: 91%
GT6: 100%
b) Placebo (n=152)
POLARIS-4
(Bourlière et al., 2017)
n=333 non-NS5A failure
46% cirrhosis
c) 400/100mg SOF/VEL 12 weeks
(n=151)
GT1a: 89%, GT1b: 95%
GT2: 97%
GT3: 85%
d) 400/100/100mg SOF/VEL/VOX 12 weeks
(n=182)
GT1a: 98%
GT1b: 96%
GT2: 100%
GT3: 96%
GT4: 100%
deferred treatment group of POLARIS-1
(Bourlière et al., 2018)
n=147 NS5A failure
400/100/100mg SOF/VEL/VOX 12 weeks 97% (3% relapse, all GT1a)
GT: genotype, SOF: sofosbuvir, VEL: velpastasvir, VOX: voxilaprevir Table 22. Phase 2-3 studies with GLE/PIB treatment regimens in DAA treatment-experienced patients with HCV genotype 1-6. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
MAGELLAN-1
(Poordad et al., 2018)
n=91 with GT1, 4
a) 300/120 mg GLE/PIB 12 weeks PI failure: 100% (14/14)
NS5Ai failure 88% (14/16)
PI + NS5Ai failure 79% (11/14)
b) 300/120 mg GLE/PIB 16 weeks PI failure: 100% (13/13)
NS5Ai failure 94% (17/18)
PI + NS5Ai failure 81% (13/16)
(Lok et al., 2018)
n=167 NS5A failure
27% cirrhosis
a) 300/120 mg GLE/PIB 12 weeks No cirrhosis 96%
b) 300/120 mg GLE/PIB 16 weeks No cirrhosis 96%
c) 300/120 mg GLE/PIB 12 weeks + RBV Cirrhosis 86% (enrollment stopped)
d) 300/120 mg GLE/PIB 16 weeks Cirrhosis 100%
MAGELLAN-3
(Wyles et al., 2018)
n=23 GT1-6, GLE/PIB failure
61% F4
a) 300/120 mg GLE/PIB + SOF + RBV 12 weeks 100%
b) 300/120 mg GLE/PIB + SOF + RBV 16 weeks (prior NS5Ai and/or PI or cirrhosis or GT3) 95% (1 relapse GT1)
GT: genotype, GLE: glecaprevir, PIB: pibrentasvir, SOF: sofosbuvir, RBV: ribavirin,
NS5Ai: NS5A inhibitor, PI: NS3/4A protease inhibitor

Optimisation of HCV treatment

Adherence to therapy

Adherence to therapy is one of the most important factors associated with the success of antiviral treatment. The definition of adherence used in the PEG-IFN era was the “80/80 rule”, that is, patients who receive more than 80% of the medication and are treated for more than 80% of the planned duration of treatment are considered adherent. One of the first studies investigating the effect of adherence in PEG-IFN+RBV treatment demonstrated that patients who fulfilled the 80/80 rule had a 63% SVR compared to 52% of those with less than 80% adherence (McHutchison et al., 2002). For the IFN free DAA therapies, adherence to the DAA may be even more important because irregular intake bears the risk of rapid emergence of drug resistance. It will important to collect more real-world data in difficult-to-treat patient cohorts if the SVR is >90% under “normal” non-standardised study conditions. For some patient populations it may be important to treat patients under DOT (directly observed therapy) condition to guarantee adherence (Schütz 2018). Another important and new issue is drug-drug interactions (DDI) that can diminish the effectiveness of the DAAs or induce toxicity of concomitant medications, which may lead to discontinuation of all drugs. Knowledge about DDI is therefore important for the optimal management of patients receiving DAA (Honer Zu Siederdissen 2016).

Management of side effects and complications

Severe side effects may reduce adherence to therapy and may result in dose modifications that result in a less-than-optimal response (see Chapter 14). This was the main problem in the IFN era with IFN-induced bone marrow suppression, flu-like symptoms, neuropsychiatric disorders, and autoimmune syndromes. The main problem of RBV is hemolytic anaemia (Manns 2006). First generation PIs BOC and TLV were associated with additional side effects such as rash or dysgeusia and additionally an increase of anaemia that resulted in frequent treatment discontinuations. Thus, many patients could not be treated before the availability of IFN free DAA combinations (Maasoumy 2013b).

In contrast, IFN free DAA therapies are in general very well tolerated (Younossi 2016). If RBV can be omitted, DAA treatment can even improve patient-reported outcomes (PROs) (Höner Zu Siederdissen 2018). With the better tolerability and safety profile of DAAs, eligibility for HCV treatment expanded broadly, including patients with decompensated cirrhosis (Höner Zu Siederdissen 2015). However, studies in patients with decompensated cirrhosis have reported higher rates of serious adverse events and also mortality, which has to be considered (Maan 2016) (see section cirrhosis). In addition, patients with advanced cirrhosis remain at high risk to develop HCC despite HCV eradication (El-Serag 2016). Thus, long-term surveillance of HCV cured patients with cirrhosis is mandatory (EASL 2018).

Drug-drug interactions

With the introduction of DAAs a completely new challenge had to be faced: drug-drug interactions (DDI). First generation PIs underwent extensive hepatic metabolism via the CYP3A pathway (Maasoumy 2013a, Burger 2012). Consequently, up to 49% of hepatitis C patients were at risk for DDI if treated with TLV or BOC due to their co-medication (Maasoumy 2013a).

The next generation PIs SMV and PTV/r as well as the NS5A inhibitors DCV, OBV and LDV have fewer relevant DDIs, but are also metabolised by CYP3A, although to a lesser degree (Kiser 2013). However, DDIs are not limited to the CYP3A pathway. Interactions may also occur with the p-glycoprotein (P-gp) transport or the organic anion transporting polypeptide 1B1 (OATP1B1, OATP1B3 and OATP2B1) as well as other pathways such as CYP2C19, CYP2C9, CYP2D6, UGT1A1 (Kiser 2013).

Currently, 2 or 3 DAAs are used in therapy, each of them with the potential to cause DDIs. In one publication that has assessed the risk for significant interaction with the concomitant medication and OBV/PTV/r + DSV, LDV/SOF, DCV/SOF, SMV + SOF or TLV or BOC a significant amount of interactions occurred (Höner Zu Siederdissen 2016). Potentially significant interactions could be expected in 66% of the patients taking OBV/PTV/r + DSV, in 31% of SOF + SMV patients, 37% of SOF + DCV patients, and 40% of SOF/LDV patients. PPI, thyroid hormones and dihydropyridine derivates were most frequently involved in possible DDIs. Importantly, the risk for DDIs was higher in patients with advanced cirrhosis due to polypharmacy affecting between 39% and 92% of patients treated with a combination of 2 or more DAAs.

DDIs needs to be considered also while using the newer DAA regimens such as SOF/VEL/VOX, GRZ/EBR and GLE/PIB. For optimal therapeutic management, it is essential to specifically ask patients about concomitant medications and assess if those drugs might interact with the DAAs. In some cases, closer monitoring or slight dose modifications may be sufficient while in other cases some drugs should be strictly avoided especially, if alternatives are available that do not cause interactions. Furthermore, the patient has to be informed that self-medication may also be a problem since interactions are not limited to approved drugs. Even herbals and foods have to be considered. Examples are St. John’s Wort, which is a potent inducer of CYP3A and P-gp or naringin, a flavinoid of grapefruit, which is an inhibitor of CYP3A. Drug interactions are usually considered significant if the area under the plasma concentration time curve (AUC) is altered by more than 30%. It is also important to note, that potentially life-threatening interactions are not known yet and only detected after careful observation after market approval. This was the case for the combination of amiodarone and SOF which led to severe bradycardia (Fontaine 2015). If the patient has no pacemaker, it is recommended to wait at least 3 months before starting a SOF containing regimen after withdrawal of amiodarone.

As the effect of DDI may vary depending on which drugs are used, no strict recommendation or rule can be given regarding the concomitant use of various medications. Therefore it is strongly advised to consider the recommendations in the product label. Supportive online tools or apps for mobile devices are available. One example is the very comprehensive drug interaction resource provided by the University of Liverpool (http://www.hep-druginteractions.org). The website provides clinically useful and evidence-based information which is updated when new drug interactions are analysed and published.

The following recommendations are based on the product label and the current EASL guidelines (EASL 2018).

SOF/LDV is affected by and may affect drugs transported or metabolised by intestinal P-gp, breast cancer resistance protein (BCRP) and hepatic organic anion transporting polypeptide (OATP). Interactions may be possible with the following drugs: digoxin, dabigatran, amlodipine, buprenorphine, carvedilol, cyclosporine and rosuvastatin. Patients with concomitant statin therapy should be monitored for statin side effects.

The solubility of LDV is depended on the gastric pH. Thus, PPIs may lead to decreased LDV concentrations with subsequently reduced SVR rates. Concomitant use should be generally avoided. If not possible, intake should be 4 hours apart and the equivalent PPI dosage should not surpass 20 mg omeprazole or pantoprazole. Co-administration with amiodarone should be strictly avoided as mentioned above. For antiretrovirals see Chapter 17.

GRZ/ERB are weak inhibitors of CYP3A and P-gp, therefore coadministration with other drugs metabolised by a similar pathway should be avoided or monitored cautiously (e.g. tacrolimus, statins, dabigatran, ticagrelor, quetiapine). Coadministration with cyclosporine is not recommended.

SOF/VEL interact with CYP2B6, CYP2C8, CYP3A4, P-gp, BCRP and OATP1B1. Concomitant intake of potent P-gp or CYP inducers should be strictly avoided (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital, phenytoin, St John’s wort). The solubility is also depended on the gastric pH, therefore, the considerations regarding PPI intake for SOF/LDV do also apply for SOF/VEL. Co-administration with amiodarone should be strictly avoided.

GLE/PIB interact with OATP1B1, OATP1B3, P-gp, BCRP and CYP3A. Co-administration with dabigatran, aliskiren, lovastatin, atorvastatin or simvastatin for example is not recommended. Rosuvastatin may need a dose reduction. Contrary, strong inducers of P-gp and CYP3A may reduce GLE/PIB concentrations (e.g. rifampicin, carbamazepine, St. John’s wort, phenytoin, oxcarbazepine or eslicarbazepine). Co-administration of GLE/PIB with ethinylestradiol-containing contraception has led to ALT elevations, therefore co-administration is contraindicated. Instead, progesterone-containing contraception is allowed.

SOF/VEL/VOX has the same interaction potential as SOF/VEL with additional interactions caused by the PI voxilaprevir, which is mainly metabolised by CYP3A4. Strong inhibitors of CYP3A (e.g. azole antifungals, antiretrovirals with boosted protease inhibitors) should not be co-administered. This also applies to most statins except pravastatin. It should be evaluated, if the statin-therapy can be stopped during HCV treatment. Co-administration with dabigatran, edoxaban, cyclosporine, aliskiren and amiodarone is not recommended.

Treatment of hepatitis C in special populations

Patients with acute hepatitis C

The goal of acute hepatitis C treatment is the prevention of persistent HCV infection. Spontaneous clearance of acute hepatitis C occurs in 10-50% (Maasoumy and Wedemeyer 2012). Early treatment with interferon based therapy was more effective, than treating patients with chronic hepatits C (Jaeckel 2001, Wiegand 2006, Deterding 2013).

This strategy seems obsolete as DAA regimens have a very high efficacy in patients with chronic hepatitis C. Treating patients with acute hepatitis C is today mainly motivated by breaking the transmission chain in people with high risk behaviors.

Several studies have now provided data that short-term treatment of 6-8 weeks with DAA combination therapy (i.e. SOF/LDV) is highly effective in patients with acute (Deterding 2017) or recent (Martinello 2018) HCV infection. However, so far the data are limited to define distinct treatment regimen and treatment duration for patients with acute HCV infection. HIV infected patients with acute or recent HCV infection may need a different approach than monoinfected patients, if ultrashort therapies are applied. For example, 6 weeks SOF/LDV has been investigated in 20 GT1 patients with acute HCV monoinfection (Deterding 2017) and in 26 HIV GT1 and GT4 patients with acute hepatitis C (Rockstroh 2017). All HCV monoinfected patients achieved SVR (Deterding 2017) while three HIV patients relapsed after the end of therapy, two additional with SVR4 were lost to follow up and one patient had a reinfection resulting in only 77% SVR (Rockstroh 2017).

Symptomatic patients in particular with jaundice have a good chance of clearing HCV spontaneously (Gerlach 2003, Hofer 2003), occurring usually in the first 12 weeks after the onset of symptoms. Given the high SVR in patients with chronic hepatitis C with new DAA therapies, the decision to monitor the natural course may be easier. Thus, monitoring HCV RNA levels at 4 and 12 weeks following diagnosis of acute infection provides an opportunity to assess the likelihood of spontaneous clearance without compromising outcome.

However, treatment of acute or early HCV infection may be important in risk groups to prevent transmission and new infections. The unrestricted DAA availability in the Netherlands and the increase uptake of treatment of acute and early HCV infection was followed by a 51% decrease in acute HCV infections among HIV positive MSM (Boerekamps 2018).

At this stage, a pangenotypic treatment regimen given for 8 weeks may be the best approach for patients with acute hepatitis C (EASL 2018). However, treatment of acute hepatitis C has to be considered an off-label use.

Patients with normal aminotransferase levels

Approximately 30% of patients with chronic hepatitis C maintain persistently normal alanine aminotransferase (ALT) levels despite having detectable HCV RNA in serum. These patients have generally mild liver disease and show a slow progression to cirrhosis. However, up to one third of patients with normal ALT can present with significant liver fibrosis necessitating an effective treatment (Bacon 2002). In current guidelines, ALT elevation is not a prerequisite to start antiviral therapy and the assessment of liver fibrosis stage should be made regardless of ALT (EASL 2018).

Patients with compensated versus decompensated liver cirrhosis

Successful therapy of patients with advanced fibrosis and liver cirrhosis is associated with decreased incidence of HCC, decompensation and liver-related mortality (Morgan, 2010, Veldt 2007, Ioannou 2017). In addition, in patients awaiting liver transplantation, successful therapy prevents graft reinfection (Forns 2003). Thus, patients should be considered for immediate therapy if no contraindications are present. Efficacy data for patients with compensated liver cirrhosis are well defined in several hundred patients. Based on the findings of several Phase 3 trials for the evaluation of IFN-free regimens, patients with compensated liver cirrhosis are expected to have SVR rates ≥95% (EASL 2018). However, SVR rates are lower in patients with decompensated cirrhosis and not all DAA combinations can be administered due to contraindications. NS3/4A protease inhibitors are not recommended or even contraindicated in patients with decompensated cirrhosis because of substantially higher drug exposure with the dose used in compensated liver disease (EASL 2018). Thus, GZR/EBR, GLE/PIB and SOF/VEL/VOX are not recommended in decompensated liver cirrhosis (EASL 2018) (https://www.hcvguidelines.org/unique-populations/decompensated-cirrhosis).

Nevertheless, several studies and real-world data have demonstrated that IFN-free PI free DAA therapy is reasonably safe even in patients with advanced liver disease, but these patients still have an increased risk for hospitalisation during treatment, mostly due to complications from liver disease (Höner Zu Siederdissen 2015, Manns 2016, Poordad 2016, Curry 2015b).

The SOLAR-2 study evaluated the use of SOF/LDV + RBV in 329 patients with decompensated cirrhosis for 12 and 24 weeks including patients after liver transplantation (Manns 2016). SVR12 rates were ranging between 87% and 96% for patients with Child-Pugh-Turcotte score (CPT) B patients and 72-85% for CPT C patients in GT 1 (Table 23). Importantly, although the overall number of severe adverse events ranged between 17% and 30% in the SOLAR-2 and ALLY-I (SOF + DCV study) trial, the number of treatment associated severe adverse events was rather low with about 2-5% in the SOLAR-2 trial, suggesting a good safety of DAAs even in decompensated patients, but a high risk for complications due to the underlying liver disease (Manns 2016, Poordad 2016). However, the rate of treatment discontinuations can be higher in RBV treated patients, thus, the use of RBV is still a concern in these patients and the initial dose should be low (i.e. 600mg) (https://www.hcvguidelines.org/unique-populations/decompensated-cirrhosis).

The combination of SOF/VEL was studied in patients with CPT B (not CPT C) in the ASTRAL-4 study in GT1, GT2, GT3, GT4 and GT6 (Curry 2015b). Only numerically small differences could be seen between 12 and 24 weeks of SOF/VEL for GT1, 2, 4 and 6, suggesting that 12 weeks of therapy was enough. International guidelines recommend the addition of RBV (low initial dose [600mg] of ribavirin, increase as tolerated) or extension to 24 weeks in RBV ineligible patients (EASL 2018) (https://www.hcvguidelines.org/unique-populations/decompensated-cirrhosis). For GT3 the combination of SOF/VEL + RBV for 12 weeks showed the highest response rates with 85% whereas both combinations without RBV showed an SVR12 of only 50%, thus RBV seems important in these difficult-to-treat patients (Table 18).

An important question is, if patients with advanced liver cirrhosis benefit from IFN-free therapies. Early data suggest that patients treated with IFN-free therapies show an improvement of liver function (Deterding 2015). Several study with CPT B and C patients demonstrated that virologic response to DAA therapy for 12-24 weeks was associated with improvements in bilirubin, albumin, MELD and CPT scores (Manns 2016). Recent studies have documented that up to one third of DAA treated HCV patients with decompensated cirrhosis can be delisted as result of clinical improvement, which appears to be remain stable in most patients (Pascasio 2017, Belli 2016). However, the benefit of treatment in decompensated cirrhosis is still not completely clear to date and further follow-up data are needed to see whether successful treatment in these patient population leads to decreased mortality and prevention of liver transplantation in the long-term. For example, patients with high MELD scores are unlikely to benefit from treatment and in one study no patients with a MELD >20 could be delisted (Pascasio 2017). Several studies evaluated prognostic factors that are associated with improvement of liver function after DAA therapy in decompensated cirrhosis. Albumin < 28 g/l was associated with a poor treatment response and age > 65 years and/or an albumin < 35 g/l was associated with an increased rate of adverse events and a lower chance for improvement of liver function in the UK EAP, possibly suggesting a point of no return in these patients (Charlton 2015, Foster 2016). A retrospective analysis of data from 4 clinical trials with SOF-based therapies in patients with decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). Based on the results, the authors developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) which was associated significantly with patient outcomes and was called the “BE3A score” (El-Sherif 2018). It is important that patients with CTP B or C improved to CPT A. However, some patients may achieve a significant decrease of the MELD score but the patient has still a poor prognosis and low quality of life, which has been called the “MELD purgatory” after successful DAA therapy (Tapper 2017).

EASL recommends that patients awaiting liver transplantation should be treated with DAA if the MELD-score is <18-20. Patients with MELD scores ≥18-20 should be transplanted first and treated after liver transplantation (EASL 2018). In certain situations, treatment may be considered before transplantation. However, creatinine and therefore renal function is a main driver of the MELD score, which can be a problem because SOF-based therapies are not recommended, if GFR is <30 ml/min and PIs as well as IFN are contraindicated in decompensated cirrhosis.

Table 23. Pivotal phase 2 and 3 trials with SOF/LDV and SOF/VEL in patients with decompensated cirrhosis. Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Treatment Child B Child C
SOLAR-2 (GT1)
(Manns et al., 2016)
a) 400/90 mg SOF/LDV + RBV 12 weeks 87% (20/23) 85% (17/20)
b) 400/90 mg SOF/LDV + RBV 24 weeks 96% (22/23) 72% (13/18)
ASTRAL-4 (GT1,2,3,4,6)
(Curry et al., 2015)
a) 400/100 mg SOF/VEL 12 weeks 83% (75/68)
b) 400/100 mg SOF/VEL + RBV 12 weeks 94% (82/87)
c) 400/100 mg SOF/VEL 24 weeks 86% (77/90)
GT: genotype, SOF: sofosbuvir, VEL: velpastasvir, VOX: voxilaprevir

Patients with hepatocellular carcinoma (HCC)

The ideal timing of DAA therapy in patient with HCC is debated. There are rationales to treat patients with HCC who have an indication for liver transplantation after transplantation. Some studies have shown lower SVR in patients with active HCC compared with patients without HCC or patients with HCC after transplantation (Beste 2017, Prenner 2017) (Table 24). Several studies have also suggested that rates of HCC recurrence in patients with a history of HCC (i.e. after resection or ablative therapies) can potentially be increased after DAA therapy (Reig, 2016, Conti 2016, El Kassas, 2018), while other studies suggested the opposite (Petta 2017, Huang 2018). The timing of DAA therapy in patients with HCC may be crucial. If patients receive potentially curative treatment for HCC it may be best to wait with DAA therapy for 3-6 months after successful HCC therapy. Importantly, SVR rates seem not to be impaired in patients with successfully treated HCC (Persico 2018a).

Overall, the treatment of patients with HCC is an individualised approach and patients should be managed in specialised centres.

Table 24. Studies with DAA in patients with hepatocellular carcinoma (HCC). Studies are not head-to-head and it is difficult to compare SVR between different studies because the populations had significant differences in genetic and socioeconomic backgrounds.
Study Cohort SVR HCC SVR No HCC
(Beste et al., 2017) DAA therapy: 16,863 non-HCC, 482 HCC, 142 HCC but treatment after LT 74%
After LT 94%
91%
(Prenner et al., 2017) DAA therapy: 284 non-HCC, 137 HCC 79% 88%
LT: liver transplantation, HCC: hepatocellular carcinoma

Patients after liver transplantation

HCV reinfection occurs in almost all untreated patients after liver transplantation. While the course of hepatitis C in liver transplant recipients was believed to be rather benign in the late ‘80s and early ‘90s (Böker 1997), More recently HCV infection has been shown to lead to a more rapid progression of liver fibrosis posttransplant (Berenguer 2005, Neumann 2004) with cirrhosis within the first 5-10 years in 20-30% of patients. Because HCV infection takes a more rapid course posttransplant than in immunocompetent individuals, treatment needs are obvious.

Antiviral therapy may be started before transplant to prevent reinfection of the graft according to the consideration discussed above. If this approach is successful, reinfection can be prevented (Forns 2003, Curry 2015a). The approval of the new IFN-free regimens increased the safety and feasibility of therapy before and after liver transplantation. If available, treatment after liver transplantation should be initiated with IFN-free DAA regimens.

The efficacy of SOF/LDV + RBV has been examined in GT1 and GT4 infection after liver transplantation (Charlton 2015). Patients with prior treatment experience as well as patients with decompensated liver cirrhosis were included. Treatment duration was 12 or 24 weeks for SOF/LDV + RBV. SVR12 data were available in 111 patients without cirrhosis, 51 patients with Child A cirrhosis, 52 patients with Child B cirrhosis, 9 patients with Child C cirrhosis and 6 patients with fibrosing cholestatic hepatitis. In patients with compensated cirrhosis the SVR rates were similar to non-immunocompromised patients. In contrast, in Child C patients, the SVR rate declined to 60% for 12 weeks and 75% for 24 weeks of treatment (Table 25). Treatment-emergent death occurred in four patients due to progressive multifocal leukoencephalitis, thoracic aorta aneurysm dissection, internal bleeding and complications of cirrhosis. Some patients required erythropoietin treatment or blood transfusions due to RBV. Additional data are available from the SOLAR-2 study. In 168 patients with varying degrees of fibrosis including patients with compensated liver cirrhosis, the SVR rate for 12 or 24 weeks of SOF/LDV + RBV treatment was 95% and 98% (Table 25). In patients with decompensated liver disease SVR rates posttransplantation were 95% (19/20) for 12 weeks of treatment and 100% (16/16) for 24 weeks of treatment in CPT B patients. Only 6 patients with CTP C posttransplant were included and showed response rates of 50% (1/2) and 75% SVR (3/4) for 12 and 24 weeks of treatment, respectively (Manns 2016).

SOF/VEL given for 12 weeks has been evaluated in 79 patients with GT1-4 after liver transplantation. The SVR was 96% (Agarwal 2018) (Table 25).

As renal insufficiency is more frequent in transplanted patients, data with SOF free PI based therapies (GZR/EBR and GLE/PIB) are also important. GZR/EBR has been used in some patients after liver transplantation with comparable efficacy than in immunocompetent patients (Miuma 2018). Importantly, cyclosporine cannot be co-administered with GZR/EBR.

12 weeks GLE/PIB has been studies in 80 patients after liver transplantation. Most patients had mild fibrosis. SVR was 98% and only one patients had a virological failure (Reau 2018) (Table 25).

Overall, treatment in patients with compensated liver disease after transplantation is safe and effective with the new DAA and response rates are similar to patients without concomitant immunosuppressive regimens (Liao 2017).

Table 25. Pivotal phase 2 and 3 trials with DAA therapy in patients after liver transplantation. Studies are not head-to-head and SVR between studies are difficult to compare because there were significant differences in genetic and socioeconomic backgrounds. Dosage of the medications may vary depending on the immunosuppressive co-medication.
Study Treatment SVR
SOLAR-1
(Charlton et al., 2015)
n=214
a) 400/90 mg SOF/LDV + 600-1200 mg RBV 12 weeks <F3: 96%
CPT A: 96%
CPT B: 85%
CPT C; 60%
b) 400/90 mg SOF/LDV + 600-1200 mg RBV 24 weeks <F3: 98%
CPT A: 96%
CPT B: 88%
CPT C; 75%
SOLAR-2
(Manns et al., 2016)
n = 168
400/90 mg SOF/LDV + 600-1200 mg RBV 12 weeks GT1: 95%
GT2: 100%
GT3: 97%
GT4:100%
400/90 mg SOF/LDV + 600-1200 mg RBV 24 weeks
(F0 - compensated cirrhosis)
(Agarwal et al., 2018)
79 patients, 47% GT1 44% GT3, 18% cirrhosis
400/100 mg SOF/VEL 12 weeks 95%
98%
(Reau et al., 2018)
N=100, n=20 kidney-Tx, n=80 liver-Tx, naive GT1-6, exp. GT1,2,4-6, 80% F0-1
300/120 mg GLE/PIB 12 weeks 98%
RBV: ribavirin, SOF: sofosbuvir, LDV: ledipasvir, VEL: velpatasvir, GLE: glecaprevir,
PIB: pibrentasvir, CPT: Child-Pugh-Turcotte score

Patients with chronic kidney disease

Chronic hepatitis C is prevalent in patients with chronic kidney disease (CKD), including those with severe renal impairment (eGFR <30 ml/min/1.73 m2) and those who require hemodialysis or peritoneal dialysis. Treatment needs for HCV patients with CKD are obvious, especially if patients are considered for kidney transplantation. The outcome of HCV post-kidney transplantation is worse than for HCV negative patients after renal transplantation. In the past, patients after kidney transplantation could not be treated because IFN-based therapies were contraindicated posttransplantation since they may induce rejection. This has changed with the advent of DAA therapies (Reau 2018, Colombo 2017). However, SOF and its metabolites are mainly eliminated via renal clearance. In accordance with the FDA and EMA label, SOF is not recommended in patients with eGFR <30. Nevertheless, there are some reports about the use of SOF in patients with severe renal insufficiency or hemodialysis showing high efficacy and safety with the full dose of SOF (Manoj 2018). However, patients with CKD treated with SOF based therapies in the TARGET registry had higher rates of anaemia, worsening renal dysfunction and serious adverse events regardless of use of RBV (Saxena 2016). Thus, SOF free therapies including NS3/4A protease inhibitors and NS5A inhibitors should be used in patients with severe renal impairment (eGFR<30), if possible.

The C-SURFER study investigated 12 weeks GZR/EBR in patients with CKD stage 4-5 including 76% with hemodialysis and compared this to a placebo controlled deferred treatment group (Roth 2015). 12 weeks GZR/EBR showed 99% SVR in the per protocol analysis (Table 26). The treatment regimen was well tolerated with a low rate of adverse events.

12 weeks GL/PIB was investigated in the EXPEDITION-4 phase III trial in 104 patients with stage 4 or 5 CKD. Overall, 98% of patients achieved SVR but none of the patients had a virologic relapse. (Gane 2017a) (Table 26).

Table 26. Pivotal phase 2 and 3 trials with DAA therapy in patients with CKD including haemodialysis. Studies are not head-to-head and SVR between studies are difficult to compare because there were significant differences in genetic and socioeconomic backgrounds.
Study Treatment SVR
C-SURFER
(Roth 2015)
n=224
76% haemodialysis
a) 50/100 mg GZR/EBR 12 weeks
(n=111) plus 11 pharmakokinetic study
94% ITT, 99% mITT
GT1a: 100%
GT1b: 99%
b) placebo
(n=113)
(Gane et al., 2017a)
N=104
CKD 5 87%, GT1 52%, GT3 11%, cirrhosis 19%
300/120 mg GLE/PIB 12 weeks 98%, 100% mITT
RBV: ribavirin, EBR: elbasvir, GZR: grazoprevir, ITT: intention-to-treat, mITT: modified intention-to-treat excluding non-virological failures

Drug use and patients on stable maintenance substitution

Treatment of people who inject drugs (PWID) is an individual approach and should only be performed in an experienced multidisciplinary setting including hepatologists, psychiatrists and addiction specialists. Drug interactions with DAAs need to be considered.

In principle, treatment with DAA is possible and studies show excellent adherence in selected OST (opiate substitution) patients. One study with GZR/EBR showed that OST patients maintain abuse of concomitant drugs such as cocaine, amphetamines, benzodiazepines, but SVR rates were not impaired and adherence was excellent (Dore 2016). Even in patients with more recent active drug use (past 6 months), treatment is possible and effective. The SIMPLIFY study showed that 97 (94%) of 103 PWIDs achieved SVR after 12 weeks of SOF/VEL (Grebely 2018). Drug use before and during treatment did not affect SVR. However, reinfection appeared to be an issue even within the 24 weeks post treatment period (Dore 2016).

Patients with co-infections

Due to the similar routes of transmission, patients with chronic hepatitis C are frequently co-infected with hepatitis B virus, hepatitis D virus or human immunodeficiency virus. These important patient groups are discussed in chapters 10, 17 and 18. Importantly, HBV is usually suppressed in HBV/HCV co-infected patients (Wiegand 2015) and after successful DAA treatment of HCV, HBV reactivation can occur (Mücke 2018). Meanwhile, efficacy and adverse event rates with DAAs among patients with HCV/HIV coinfection are not different from those observed with HCV monoinfection. Meanwhile treatment recommendations are similar for HCV monoinfected and HCV/HIV co-infected patients. However, drug-drug interactions have to be considered (EASL 2018) (https://www.hcvguidelines.org/unique-populations/hiv-hcv).

Patients with hemophilia

Due to contaminated clotting factor concentrates, many patients with hemophilia were infected with HCV and/or HIV. Review of available data suggest that treatment success of HCV-infected hemophiliacs is similar to that achieved in the general HCV-infected population (Franchini 2008).

Patients with extrahepatic manifestations

More than 50% of HCV-infected patients suffer from extrahepatic manifestations ranging from fatigue to severe symptoms of mixed cryoglobulinaemia (Cacoub 1999) (see Chapter 15). The primary goal of treatment is HCV eradication, which is associated with improvement of clinical symptoms, especially in patients with mixed cryoglobulinaemia (Negro 2015, Cacoub 2018a). Insulin resistance can be improved, especially in HCV GT1 patients with SVR (Thompson 2012, Cacoub 2018a). Most of the data that elimination of HCV can reduce extrahepatic manifestations are derived from studies with IFN-based treatment.

Meanwhile IFN-free therapies are an option for patients with extrahepatic manifestations and first data are available. Data from a prospective international multi-centre cohort study of 148 patients with symptomatic HCV-associated cryoglobulinaemia vasculitis show high virological and clinical response after DAA therapy (SOF + DCV, n=53; SOF + RBV, n=51; SOF/LDV, n=23; or SOF + SMV, n=18). SVR was documented for 97.2% of patients and a complete clinical response was reported in 73%, a partial response in 23%, and no response in 4.8%. After a median follow-up time of 15.3 months, vasculitis manifestations cleared or significantly improved: purpura 97%, renal involvement 92%, arthralgia 86%, neuropathy 77.1%, and cryoglobulinaemia 52.2% (Cacoub 2018b). Case series have reported regression of non-Hodgkin's lymphoma following SVR with DAA therapies regimen with or without additional chemotherapy (Persico 2018b, Lim 2015, Arcaini 2016).

However, there may also be a point-of-no-return for extrahepatic manifestations. A retrospective analysis of HCV patients with asymptomatic and symptomatic extrahepatic manifestations who were treated with DAA ± PEG-IFN showed high SVR but among 7 patients with severe vasculitis (mostly renal impairment) only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. Three out four patients with life-threatening vasculitis received rituximab (Emery 2017).

Thus, in patients with severe symptoms of mixed cryoglobulinaemia, treatment with rituximab may be considered (EASL 2018).

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Hepatology 2018

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