Current Concepts and Challenges for the Direct-acting Antiviral Era in Hepatitis C Cirrhosis

A. Majumdar; M. T. Kitson; S. K. Roberts 

 Abstract

Background The burden of HCV cirrhosis is high and projected to increase significantly over the next decade. While interferon therapy is problematic in HCV cirrhosis, the era of direct-acting anti-viral (DAA) therapy provides effective treatment for patients with cirrhosis.

Aim To systematically review the results of DAA therapy to date in patients with HCV cirrhosis, and highlight the ongoing challenges for DAA therapy in this population.

Methods A structured Medline search was conducted to obtain phase II and III HCV trials in patients with cirrhosis. Citations from review articles were cross-referenced and conference abstracts from EASL and AASLD liver meetings for the preceding 3 years were reviewed manually. Keywords used included hepatitis C, cirrhosis and the DAA's: sofosbuvir, ledipasvir, velpatasvir, grazoprevir, elbasvir, daclatasvir, beclabuvir, asunaprevir, simeprevir, paritaprevir, ombitasvir and dasabuvir.

Results Successful direct-acting anti-viral treatment is now possible in patients with HCV-related cirrhosis including those with liver decompensation with several regimens now offering sustained virological response (SVR) of 90?95%. Overall success rates in GT1 cirrhosis are excellent while GT3-infected patients with cirrhosis remain hard to cure. The pangenotypic combination of sofosbuvir and velpatasvir holds promise for GT3 cirrhosis achieving SVR of ~90%.

Conclusions Potent DAA therapies provide much needed, safe and highly effective treatment options for persons with HCV cirrhosis including those previously deemed unsuitable for treatment. Combination therapy with two or more classes of drug is essential to achieve high efficacy and minimise viral resistance, with the role of ribavirin still under evaluation. However, several challenges remain including the hard-to-cure groups of GT3 cirrhosis and direct-acting anti-viral failures, and managing drug?drug interactions.

Introduction

Globally, chronic hepatitis C virus (HCV) infection affects over 180 million people. The resultant burden of liver disease is significant, with HCV remaining a major cause of cirrhosis and the leading indication for liver transplantation (LT).^[1?3] Across Europe, HCV seroprevalence rates are as high as 3.3% in some regions while chronic HCV infection currently affects an estimated 8.5 million persons.^[4] In the United States, around 2.7 million individuals have chronic HCV infection with HCV accounting for up to 13 000 deaths annually.^[5,6] Furthermore, the prevalence of HCV-related cirrhosis is estimated to be 25%, which is projected to increase to 37% by 2020.^[7,8]

Chronic HCV infection leads to cirrhosis in approximately 16% over 20 years of infection. Once cirrhosis is established, there is an estimated 3?5% annual risk of developing hepatocellular carcinoma (HCC) and a 3?6% annual risk of hepatic decompensation. Moreover, the risk of death within 1 year following hepatic decompensation is 15?20%.^[9?11] The successful endpoint of HCV treatment is sustained virological response (SVR). Achieving an SVR is associated with regression of hepatic fibrosis and in patients with cirrhosis, a reduction in portal hypertension, and attenuated risk of development of hepatic decompensation and HCC.^[12?16] These clinical outcomes have been shown to translate to a reduction in both liver and non-liver-related mortality and improvements in quality of life.^[17?21] Furthermore, it has been suggested that even those with advanced fibrosis or cirrhosis who achieve an SVR have an overall survival similar to the general population.^[22]

Peginterferon (PegIFN)-based therapy has been the mainstay of HCV treatment for over a decade. However, treatment in patients with cirrhosis has been difficult due to low SVR rates and higher risks of serious adverse events compared to those without cirrhosis.^[23?25] Additionally, those with advanced or decompensated liver disease, who arguably need treatment most, are unable to tolerate interferon-based therapy due to the significant risk of sepsis, liver failure and death.^[26?28] The direct-acting anti-viral (DAA) era of HCV therapy arrived in 2011 following the introduction of the protease inhibitors (PIs) boceprevir, telaprevir and subsequently simeprevir for HCV genotype 1 patients. Despite increasing SVR rates in combination with PegIFN and ribavirin (RBV), important real-world data from Europe reporting the use of these agents identified significant safety concerns in patients with advanced chronic liver disease.^[29]

Thus, the major focus in recent years has been the pursuit of safe and effective interferon-free drug regimens, particularly for those with advanced chronic liver disease and/or those who have failed interferon-based therapy. The rapid development of highly efficacious and well-tolerated, all-oral, interferon-free treatment for patients with cirrhosis is becoming a reality in many European countries as well as the USA. Currently, approved DAA regimens in Europe and/or the USA include the sofosbuvir/ledipasvir co-formulation, daclatasvir combined with sofosbuvir, simeprevir plus sofosbuvir, and the three DAA regimen of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir. However, the optimal duration of therapy, the ideal combination of drug classes and the role of RBV are some of the areas that are yet to be fully understood. Furthermore, many challenges remain, specifically regarding costs, reduced SVR rates for those with genotype 3 infection, the potential for viral resistance, drug?drug interactions and determining treatment algorithms for those who do not respond to DAA therapy. The aim of this review is to summarise the progress made in the treatment of patients with HCV-related cirrhosis to date, including results from conference abstracts awaiting peer-reviewed publication.

 Virology and Therapeutic Drug Classes

The HCV genome encodes a 3000 amino acid polyprotein, which is cleaved by host and viral proteases and translated into 10 mature viral proteins. The identification of the nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins of the HCV viral replication cycle and their recognition as therapeutic targets were particularly important breakthroughs that have resulted in the proliferation of the DAA landscape. Currently three broad drug classes exist (Figure 1); NS3/4A PIs, NS5A replication complex inhibitors and NS5B polymerase inhibitors, which are further divided into nucleos(t)ide inhibitors (NIs) or non-nucleoside inhibitors (NNIs).^[30?32]

(Enlarge Image)

Figure 1.

 

Characteristics of selected direct-acting anti-viral agents in relation to the HCV polyprotein.

 

NS3 and NS4A

The NS3 and NS4A viral proteins act in concert to perform a serine-type protease function, which is involved in the cleavage of the HCV viral polyprotein at four sites.^[33] First generation NS3/4A PIs (telaprevir, boceprevir) have an inherent low barrier to viral resistance and are largely HCV-1 specific. Newer-generation PIs such as grazoprevir have higher potency and an improved barrier to resistance, along with wider genotypic coverage and improved pharmacokinetics that allow for single daily dosing.^[34,35]

NS5a

The NS5A viral protein has no known enzymatic function, but is essential for RNA replication and the assembly of infectious virions via unclear mechanisms.^[36?39] As a result, the precise mode-of-action of NS5A inhibitors is not known, but may involve preventing the formation of the 'membranous web' that is host to HCV RNA replication.^[40] NS5A inhibitors (NS5AI) have a wider genotypic effect and are exceptionally potent, but generally possess a low barrier to viral resistance. The newer NS5A inhibitors [e.g. velpatasvir (GS-5816), elbasvir] provide more pan-genotypic activity than their predecessors (e.g. daclatasvir, ledipasvir).^[41?43]

NS5b

Amplification of the HCV genome is fundamentally dependent on the NS5B RNA-dependent RNA polymerase (RdRp), which can be inhibited by NIs or NNIs. NIs inhibit the RdRp by mimicking NS5B protein substrate, which leads to the termination of the newly synthesised viral RNA chain. NIs possess a high-resistance barrier, are highly effective and have pan-genotypic activity.^[42,44,45] Sofosbuvir, the most widely studied and only approved NI in both interferon-free and interferon-containing HCV regimens, has consistently shown excellent SVR rates, even in hard-to-cure populations, including those with cirrhosis. The many advantages of sofosbuvir make it an excellent backbone of any pan-genotypic DAA regimen. Alternatively, NNIs act as allosteric inhibitors by binding to the RdRp at a minimum of four possible sites and hinder polymerase function through conformational change. As a result, NNIs are chemically heterogenous with a low barrier to resistance and low to medium anti-viral activity in comparison with NIs. Additionally, NNIs do not appear as effective as sofosbuvir across multiple genotypes. However, due to structural heterogeneity and varied binding sites, multiple NNIs could potentially be used as part of a drug regimen and may thus overcome the inherent potential for resistance.^[42,43,46] Currently, the only approved and most widely used NNI is dasabuvir, which is used in combination with ritonavir-boosted paritaprevir (PI) and ombitasvir (NS5AI).

Treatment Endpoints

Combining multiple DAA classes with or without RBV has resulted in highly effective interferon-free drug regimens being developed.^[47,48] The primary goal of HCV therapy is to achieve an undetectable HCV RNA at 12 weeks (SVR12) or 24 weeks (SVR24) after the cessation of treatment. The concordance of SVR12 and SVR24 is 99% and therefore SVR12 is now deemed the more acceptable endpoint.^[49,50] Attaining SVR is associated with a definitive cure from chronic HCV infection in greater than 99%.^[51] 

 Interferon-based DAA Regimens

The NS3/4A PIs boceprevir and telaprevir were the first DAAs approved for use and when added to PegIFN plus RBV in patients with HCV genotype 1 infection (HCV-1), resulted in an increase in SVR rates by 30%. Furthermore, a shortening of therapy from 48 weeks to 24?28 weeks was possible in 50?60% of noncirrhotic patients. These first-generation PIs provided treatment options to those who had previously failed interferon-based therapy, with re-treatment particularly important in those with underlying advanced fibrosis and cirrhosis given their high risk of adverse outcomes. However, patients with more advanced liver disease were not well represented in phase II and III studies.^[52?57] The French real-world multicentre prospective cohort study (CUPIC) sought to evaluate the safety and efficacy of PI, PegIFN and RBV combination therapy in 674 patients with chronic HCV-1 and Child?Turcotte?Pugh (CTP) class A cirrhosis who were previous relapsers, partial responders or null responders to interferon-based anti-viral therapy. There was a 40% rate of serious adverse events, 6.4% rate of severe complications and 1.2% mortality rate. Those with a baseline albumin <35 g/L and platelet count of <100 × 10⁹/L had a 44.1% risk of death or severe complications.^[29] These data provided clarity as to which patients with compensated cirrhosis were not appropriate for interferon-based PI therapy.

Treatment with the second-generation PI simeprevir for 12 weeks in combination with 24 or 48 weeks of PegIFN and RBV, depending on response at weeks 4 and 12, was studied in treatment naïve HCV-1 infection yielding SVR rates of 58% and 65% in cirrhosis patients in the phase III QUEST-1 and QUEST-2 studies respectively.^[58,59] For treatment-experienced patients with compensated cirrhosis, the SVR12 rates were 82% in partial responders, 73% for relapsers and 46% for null responders after 48 weeks of treatment (12 weeks of simeprevir in addition to 48 weeks of PegIFN and RBV).^[60,61] Although likely to be eclipsed by more effective noninterferon DAA combinations, simeprevir with PegIFN plus RBV has been shown to be noninferior to telaprevir, but with better tolerability and once daily dosing, demonstrating that it has a role where access to other DAAs is limited.^[62,63] The Q80K NS3 viral polymorphism has been associated with PI resistance in genotype 1a infection treated with interferon-based drug regimens. However, the significance of the mutation is conflicting when using two classes of DAA.^{[58,59,64,65]}

The addition of sofosbuvir to PegIFN and RBV for 12 weeks appears to be the most potent interferon-based DAA regimen in patients with compensated cirrhosis. The phase III NEUTRINO study demonstrated an SVR12 could be attained in 80% of a subset of 54 predominantly HCV-1 patients with treatment-naïve compensated cirrhosis, compared to 92% in patients with genotype 1, 4, 5 or 6 infection without cirrhosis.^[66] The data regarding treatment-experienced patients with cirrhosis were previously limited to a cohort of 26 HCV-2- and HCV-3-infected patients who achieved SVR rates of 93% and 83% respectively.^[67] Real-world data for this regimen are similar; with treatment naïve HCV-1 patients attaining SVR12 in 81% compared to 62% in treatment experienced patients.^[68] Recently, results from the BOSON study have suggested that interferon-based therapy may still have an active role in the treatment of HCV-3 cirrhosis. An SVR of 91% (n = 23) was seen after 12 weeks therapy of sofosbuvir, PegIFN and RBV in treatment-naïve patients, compared with 86% (n = 35) in those who were treatment experienced. These results were superior to sofosbuvir and RBV for 24 weeks treatment, which achieved SVR12 rates of 82% (n = 22) and 77% (n = 34) in treatment naïve and experienced patients, respectively.^[69] Thus, the triple regimen of sofosbuvir and PegIFN plus RBV may have a role as a potential salvage therapy for HCV-3 cirrhosis nonresponders to DAA therapy. In addition, it is likely to be less expensive and by inference more cost-effective making it a potentially important regimen for health-resource poor countries.

Other interferon-containing DAA regimens have been less successful in the cirrhotic population. The NS5A inhibitor daclatasvir has also been investigated in interferon-based regimens for genotype 1 and 4 patients with an SVR24 rate of up to 63% in a small (n = 21) group of patients with cirrhosis after 24 weeks of therapy.^[70] The recent addition of asunaprevir, an NS3 PI, to this regimen increases SVR24 rates to over 90% in HCV-1 and HCV-4 patients with cirrhosis.^[71] 

Interferon-free DAA Regimens

The era of interferon-free DAA therapy promises a revolutionary change in the therapeutic options for those in most need of HCV eradication. Interferon-free DAA regimens are exceptionally well tolerated, with low rates of serious adverse events or discontinuation of therapy.^[47,48,72] Data regarding DAA therapy have predominantly described patients with genotype 1, 2 and 3 with limited data for genotypes 4 and 6. Table 1 and Table 2 summarise the significant trials of interferon-free DAA regimens according to genotype. Table 3 identifies key trials involving decompensated cirrhosis.

Genotype 1 and 4

Sofosbuvir/Ledipasvir. The phase III ION studies evaluating the fixed-dose combination (FDC) of sofosbuvir and the first generation NS5A inhibitor ledipasvir in treatment-naïve (ION-1), treatment-experienced (ION-2) HCV-1 patients and subsequent post hocpooled analysis of data from the phase IIb/III programme, demonstrated high efficacy and safety of this regimen in compensated HCV-1 cirrhosis. ION-1 included 136 treatment-naïve cirrhotic patients who received treatment for 12 or 24 weeks, with or without RBV. SVR12 was achieved in 97% treated for 12 weeks and 100% in those receiving 24 weeks of therapy.^[73] In ION-2, there were 88 treatment-experienced cirrhotic patients who achieved SVR12 rates of 82?86% and 100% in the 12 and 24-week arms respectively.^[74] In both studies the inclusion of RBV appeared to make no difference to the overall SVR rates in cirrhosis, nor was there a difference in results between genotype 1a and 1b patients. However, prior data from the ELECTRON trial suggested that RBV potentially improved outcomes in a treatment-experienced cirrhotic subset, with 100% (9/9) achieving SVR12 in the RBV plus FDC group compared to 70% (7/10) who received FDC alone.^[75] Subsequently, the SIRUS trial randomised 155 HCV-1 patients with compensated cirrhosis who had failed PI therapy to either sofosbuvir/ledipasvir FDC plus RBV for 12 weeks, or 24 weeks of the FDC alone and found similar SVR12 rates between the two regimens (96% vs. 97%).^[76] Concomitantly, a recent pooled analysis of all phase IIb and phase III trials that included cirrhotic patients with HCV-1 treated with this DAA combination (n = 513), including the SIRIUS population, demonstrated that RBV may improve SVR12 rates in treatment-experienced patients receiving 12 weeks of therapy (96% vs. 90%). Importantly, there was no difference seen in SVR12 rates between those receiving the sofosbuvir/ledipasvir FDC with RBV for 12 weeks and those receiving 24 weeks of FDC without RBV (96% vs. 98%).^[77] A small phase II trial has further demonstrated the potency of this combination with RBV in patients who had failed prior sofosbuvir therapy, with an overall SVR12 rate of 98% in a cohort comprising of 16/51 cirrhotics.^[78] Thus, in treatment-experienced patients with HCV-1 cirrhosis, the addition of RBV to the FDC of sofosbuvir/ledipasvir allows for shortening of treatment to 12 weeks vs. 24 weeks of treatment without RBV, without compromising SVR rates. This has significant cost-benefit implications. Based on the above data, sofosbuvir/ledipasvir FDC has been widely approved for the treatment of HCV-1 and HCV-4 infection including the Food and Drug Administration (FDA) in the USA, the European Medicines Agency and Commission, and the National Institute of Clinical Excellence (NICE) in the UK. More recently, Lawitz et al. found that in 19 HCV-1a cirrhotics that had previously failed 8?12 weeks of sofosbuvir/ledipasvir-based regiments, re-treatment with 24 weeks of the FDC resulted in SVR12 of 74%.^[79]

Paritaprevir/Ritonavir, Ombitasvir and Dasabuvir With/Without RBV. The three DAA regimen of ritonavir-boosted paritaprevir (PI), dasabuvir (NNI) and ombitasvir (NS5A inhibitor) plus RBV, one of the first in Europe to be licensed for HCV-1, also achieves excellent SVR12 rates in patients with HCV-1-compensated cirrhosis, regardless of prior treatment status. The phase III TURQUOISE-II trial was a large study dedicated to HCV-1-compensated cirrhosis, enrolling 380 treatment-naïve or treatment-experienced patients, and comparing 12 vs. 24 weeks treatment. In this study, SVR12 rates were 92% and 96% following 12 and 24 weeks therapy respectively. Results varied according to HCV-1 subtype, being higher in HCV-1b with SVR12 of 98.5% and 100%, compared with 89% and 94% in HCV-1a subtype following 12 and 24 weeks respectively. In the 12-week arm, consistently high SVR rates for prior partial responders (94%) and relapsers (97%) were achieved and did not vary according to HCV-1 subtype. However, among null responders to PegIFN and RBV results varied with subtype, being 100% in HCV-1b after 12 weeks treatment, while HCV-1a patients benefited from 24 weeks treatment with SVR12 of 93% vs. 80% for 12 weeks.^[80] Given the excellent results in HCV-1b cirrhosis, the phase IIIb TURQUOISE-III study evaluated the three DAA regimens without RBV in HCV-1b-compensated cirrhosis. All 60 enrolled patients achieved SVR12 including 33 with prior PegIFN/RBV treatment experience.^[81]Hence, for all HCV-1 cirrhosis patients, except prior HCV-1a null-responders who need 24 weeks, 12 weeks of ritonavir-boosted paritaprevir, dasabuvir and ombitasvir is sufficient sufficient, with RBV still needed in those with HCV-1a. Following approval of this regimen, post-marketing surveillance identified several patients with cirrhosis who developed hepatic decompensation and/or liver failure while receiving this therapy. This led to the US FDA issuing a warning that treatment with ritonavir-boosted paritaprevir, dasabuvir and ombitasvir can cause serious liver injury in patients with advanced liver disease.^[82]

Paritaprevir/Ritonavir/Ombitasvir. Modifying the above three DAA combination by omitting dasabuvir has shown promising results in one Japanese study of genotype 1b HCV patients. The reduced pill burden of this regimen has the added advantage of once-daily dosing. Of the 42 cirrhotic patients enrolled, 38 (91%) achieved an SVR12 after 12 weeks therapy.^[83]

Sofosbuvir and Simeprevir. Simeprevir and sofosbuvir were approved individually in the USA, but were subsequently shown to be effective in combination for HCV-1 in the phase IIb COSMOS trial, where an SVR12 was achieved in greater than 90% (n = 41) of compensated cirrhotic patients. This was regardless of duration of treatment (12 or 24 weeks), the use of RBV, prior treatment history or the presence of the Q80K mutation.^[64]Data from the HCV-TARGET real-world international cohort demonstrated SVR12 rates of 74% in 108 patients with HCV-1 cirrhosis, including a small proportion of patients with MELD scores >15, who received sofosbuvir and simeprevir. The addition of RBV did not improve SVR rates in 32 patients.^[84] The OPTIMIST-2 trial investigated a diverse cohort of 103 compensated HCV-1 cirrhosis patients and found an overall SVR of 83% (88% in treatment-naïve) after 12 weeks of treatment without RBV, with no significant difference between genotypes 1a and 1b. The presence of the Q80K mutation in genotype 1a patients resulted in a significantly lower SVR SVR12 of 74% in compared to 92% in those without.^[65,85] In contrast, Pearlman et al. achieved a 93% SVR12 rate with this regimen in 58 patients with HCV-1a-compensated cirrhosis, including an SVR of 92% in PegIFN/RBV null responders and 96% in those with the Q80K mutation.^[86] Hence, the importance of the Q80K mutation and role of baseline resistance testing in those treated with this regimen remains unclear.

Daclatasvir and Asunaprevir. The NS5A inhibitor daclatasvir combined with the PI asunaprevir, has been studied predominantly in genotype 1b due to limited efficacy in HCV-1a infection. In the large international HALLMARK-DUAL study that included 207 patients with HCV-1b cirrhosis, daclatasvir plus asunaprevir for 24 weeks achieved an overall SVR12 of 84% in cirrhosis. Subgroup analysis showed that SVR12 rates were higher in treatment-naïve (91%) and prior non-responders (87%) with cirrhosis than IFN ineligible or intolerant patientss (79%).^[87,88] Similar efficacy was achieved in the parallel phase III Japanese study in HCV-1b prior nonresponders and IFN-ineligible/intolerant patients, with 91% of cirrhotic patients achieving SVR24.^[89]

Grazoprevir/Elbasvir. The initial phase II C-WORTHY trial investigated grazoprevir (second generation PI) and elbasvir (NS5A inhibitor) with or without RBV for 12?18 weeks in previously untreated and null responders with HCV-1 cirrhosis achieving SVR12 rates of 90?97% and 92?100% respectively.^[90] Subsequently, a cohort of 70 treatment-naïve predominantly HCV-1 cirrhotic patients achieved an SVR12 of 97% in the phase III C-EDGE TN trial, after 12 weeks of grazoprevir/elbasvir alone.^[91] The equivalent PegIFN/RBV treatment-experienced trial found SVR rates ranging between 89% and 100%,^[92] while the C-SALVAGE study demonstrated that SVR24 rates of 94% could be achieved with the same regimen plus RBV in earlier generation PI nonresponders with HCV-1 cirrhosis.^[93,94] Subsequently, more robust data from a pooled analysis of 402 patients with HCV-1, -4 or -6 compensated cirrhosis from the phase II/III studies of grazoprevir?elbasvir confirmed the excellent efficacy and safety of this regimen in this population.^[95] SVR12 rates were 96?100% in treatment-naïve patients receiving 12 weeks therapy and were not influenced by RBV use or genotype subtype. However, among PegIFN/RBV nonresponders with HCV-1 and HCV-4 cirrhosis SVR12 rates were 100% in those treated for 16 or 18 weeks in combination with RBV compared to 89% in those treated for 12 weeks without RBV. Based on the above data this regimen has recently received FDA approval in the USA for the treatment of HCV-1 and HCV-4 infection including those with compensated cirrhosis.^[96]

Grazoprevir/Elbasvir and Sofosbuvir. Grazoprevir?elbasvir has been combined with sofosbuvir in the C-SWIFT trial, which investigated treatment durations of 6 weeks and 8 weeks in treatment-naïve HCV-1 cirrhotics, and 12 weeks in HCV-3 cirrhotics. SVR 12 rates of 80% (16/20) and 94% (17/18) were seen for the 6- and 8-week groups, respectively, in the HCV-1 group. Impressively in the HCV-3 subgroup, 91% (10/11) achieved an SVR12.^[97]

Sofosbuvir and Velpatasvir. A promising pangenotypic regimen in development is the co-formulation of sofosbuvir with the second generation NS5A inhibitor, velpatasvir (formerly GS-5816). At the higher dose of 100 mg of velpatasvir, phase II data demonstrated 100% SVR12 rates in cirrhotic HCV-1 patients with prior treatment failure with a PI after 12 weeks of therapy without RBV.^[98] Subsequently, the phase III ASTRAL-1 study evaluated the once daily FDC of sofosbuvir 400 mg and velpatasvir 100 mg in treatment-naïve and PI and PegIFN/RBV treatment-experienced patients with HCV-1, 2, 4, 5 and 6 infection. Of the 121 with compensated cirrhosis included in this study, 120 (99%) achieved an SVR12 after 12 weeks of treatment, comprising 72/73 (99%) with HCV-1 including all HCV-1a patients, and 27/27 (100%) with HCV-4.^[99]

Sofosbuvir, Velpatasvir and GS-9857. A shortened treatment duration of 6 weeks has also been investigated with the combination of sofosbuvir, velpatasvir and GS-9857 (second generation PI). SVR12 was seen in 87% (13/15) of treatment-naïve HCV-1 cirrhosis patients. For those who had prior DAA failure and cirrhosis, the SVR12 rate was lower at 60% (3/5).^[100]

Sofosbuvir Plus Ribavirin. In the phase II studies of sofosbuvir and RBV in patients with cirrhosis due to HCV-1, low SVR rates of around 50% were achieved in treatment-naïve patients after 24 weeks of therapy.^[101,102] In contrast, SVR12 rates appear higher in HCV-4 patients, being achieved in 78?100% after 24 weeks of treatment regardless of previous treatment status.^[103,104] However, both randomised controlled trials of 12 vs. 24 weeks treatment for HCV-4 infection involved small numbers of cirrhotic patients, with more robust SVR12 data expected to come from an ongoing large national Egyptian programme involving this regimen. Nevertheless, more effective combination DAA regimens have been developed for HCV-1 and HCV-4 cirrhosis as noted above, and the use of sofosbuvir plus RBV alone should only be considered if these are not available.

Genotype 2

Sofosbuvir. Limited numbers of patients with HCV-2 cirrhosis have been recruited into IFN-free trials, however, sofosbuvir and RBV remains the most studied regimen. For treatment-naïve patients, the FISSION, POSITRON and VALENCE trials found an SVR12 rate of 92%. In those who were PegIFN ineligible, unwilling or intolerant, SVR12 rates were reported as 94%.^[66,105,106] The FUSION and VALENCE trials included treatment-experienced cirrhotics who achieved lower SVR12 rates of 78%.^[105,106]

Sofosbuvir/velpatasvir. The phase III ASTRAL programme evaluating the FDC of sofosbuvir and velpatasvir for 12 weeks included a total of 29 patients with HCV-2 cirrhosis of whom 25 were treatment naïve.^[99,107] An SVR12 rate of 100% was demonstrated including a limited number of treatment experienced patients.

Genotype 3

Sofosbuvir. The FISSION (treatment naïve) and POSITRON (treatment experienced) trials were the first to identify lower SVR rates for patients with HCV-3 infection, particularly those with cirrhosis, when treated with sofosbuvir and RBV for 12 weeks. In cirrhotic patients, SVR12 was achieved at a rate of 34% for treatment naïve and 21% for treatment-experienced patients. By extending this regimen to 16 weeks, SVR12 rates could be increased to 61% in treatment-experienced patients with HCV-3 infection.^[66,105] The subsequent VALENCE trial confirmed that high SVR12 rates could be achieved in HCV-2 patients with cirrhosis after 12 weeks of therapy (100% for treatment naïve, 88% for treatment experienced). Extending treatment to 24 weeks for HCV-3 patients allowed for an improvement to 92% in treatment-naïve patients, but those who were treatment experienced remained at 62%.^[106]

Sofosbuvir and Daclatasvir. The ALLY-3 trial investigated sofosbuvir and daclatasvir for 12 weeks in both treatment-experienced and treatment-naïve HCV-3 patients. The overall SVR12 rate in the subset of 32 cirrhotic patients was low at 63%, with no significant difference when stratified by prior treatment status.^[108]Consequently, the phase IIIb ALLY-3+ study evaluated this regimen for 12 and 16 weeks in combination with RBV in 36 patients with compensated cirrhosis.^[109] The overall SVR12 following 12 weeks of treatment was 83% in untreated and 88% among previously treated patients, with no apparent benefit achieved from extending treatment to 16 weeks. Interim results from the French Compassionate Use Program supported the concept that the addition of RBV allowed for a shortened 12-week duration of this regimen, as opposed to a 24-week duration without RBV for HCV-3 cirrhosis, with SVR rates of 100% (n = 4) and 86% (n = 135) respectively.^[110] This regimen has recently been approved for the treatment of HCV-3 infection in the USA and is currently being investigated as a pan-genotypic therapy in combination with RBV in patients with advanced decompensated liver disease in the ALLY-1 trial, as described below.

Sofosbuvir/Velpatasvir. Pianko et al. evaluated the FDC of sofosbuvir and velpatasvir in treatment-experienced HCV-1 and HCV-3 patients, identifying this as a promising pangenotypic regimen. Among the treatment-experienced HCV-3 patients with cirrhosis that received sofosbuvir plus velpatasvir in the higher dose of 100 mg without and with RBV, SVR12 rates were 88% and 96% respectively.^[98] These results were confirmed in the recently published ASTRAL-3 phase III study that evaluated the 12-week regimen without RBV against 24 weeks of sofosbuvir plus RBV in patients with HCV-3 infection including 163 with compensated cirrhosis.^[107] Among the 80 with cirrhosis receiving sofosbuvir plus velpatasvir, SVR12 rates were 93% in treatment-naïve patients and 89% in those with prior treatment failure.

Pangenotypic Regimens

A small number of pangenotypic regimens have been studied exclusively in the cirrhotic population thus far, with the majority of data arising from the pre-LT setting, which is discussed below. Sofosbuvir/velpatasvir appears to have excellent pangenotypic activity including in decompensated cirrhosis as described below.^[99,107,111]Grazoprevir and elbasvir are currently being investigated with sofosbuvir as a pangenotypic regimen in patients with and without cirrhosis.^[47] Daclatsvir and sofosbuvir have been studied in a predominantly noncirrhotic population with HCV genotypes 1?3, however, studies are currently underway solely in patients with cirrhosis.^[112] Preliminary data from the ALLY-1 trial described the outcomes after 12 weeks of sofosbuvir, daclatasvir and RBV in patients with advanced cirrhosis including 80% with CTP B or C liver disease, or post-transplantation across multiple genotypes with encouraging results. In the cirrhotic cohort (n = 60) an overall SVR12 rate of 83% was observed. While CTP A and B patients attained SVR12 rates of 92% and 94%, respectively, the SVR rate was much lower in CTP C patients being achieved in only 56% of patients.^[113]

Decompensated Cirrhosis and pre-LT

In patients with HCV infection awaiting LT the primary aim of the therapy is to prevent recurrent HCV infection of the new liver, which is associated with reduced graft and patient survival.^[72] In patients with HCV genotypes 1?4 awaiting LT for HCC who were treated with sofosbuvir and RBV, 70% of those with an undetectable HCV RNA at the time of transplantation achieved a post-transplant virologic response, defined as a negative HCV RNA 12 weeks after LT. Those with an undetectable HCV RNA on treatment for >30 days prior to LT have a low risk of viral relapse and recurrent HCV infection in the graft.^[114] In patients with clinical decompensation who are not candidates for LT, the achievement of an SVR may improve liver synthetic function, clinical outcomes and survival. Sofosbuvir, ledipasvir, daclatasvir, ombitasvir and dasabuvir are safe to use in patients with CTP C cirrhosis, whereas the use of simeprevir, asunaprevir and paritaprevir/ritonavir is contraindicated.^[72]

Sofosbuvir/Ledipasvir. The SOLAR program evaluated sofosbuvir, ledipasvir and RBV for 12?24 weeks in patients with predominantly HCV genotype 1 infection and decompensated cirrhosis. In the SOLAR-1 trial, SVR rates of 87% were achieved after 12 weeks of treatment and 89% after 24 weeks. There was a resultant improvement in synthetic liver function in the majority of patients and subsequent increases in both MELD and CTP scores.^[115] The recent SOLAR-2 trial investigated the efficacy and tolerability of 12 vs. 24 weeks of the DAA regimen in a cohort of 164 pre- and post-transplant decompensated CTP B and C cirrhotic patients, of which up to 22% had MELD scores of >15 at baseline. Overall SVR12 rates for HCV-1 were 88% and 89% in the 12 and 24-week treatment arms respectively. A lower SVR12 of 72% (13/18) was observed in the subset of pre-transplant HCV-1 CTP C patients receiving 24 weeks therapy as compared to the 12 week arm (17/20).^[116]Foster et al. found similar results in an observational cohort of 467 decompensated patients with HCV-1 or HCV-3 who were treated with sofosbuvir plus either daclatasvir or ledipasvir, with or without RBV. SVR12 rates ranged from 59% to 70% in HCV-3, compared to 81%?86% in the HCV-1 patients. The baseline mean MELD score was 12, which at 4 weeks post end-of treatment, improved by greater than 2 points in 42%.^[117] Despite this, the long-term impact of achieving SVR in this patient group is still yet to be determined.

Sofosbuvir/Velpatasvir. The ASTRAL-4 phase III study evaluated the FDC of sofosbuvir and velpatasvir with and without RBV for 12?24 weeks in 267 previously treated and untreated patients with HCV genotypes 1?6 and decompensated cirrhosis.^[118] Overall rates of SVR12 were 83% in those receiving 12 weeks of the FDC, 94% in those receiving 12 weeks of FDC plus RBV, and 86% in those receiving 24 weeks of FDC without RBV. There were neither significant differences seen in response rates nor in rates of serious adverse events between the groups.

In the above studies, around 25?30% of patients clinically deteriorate with increasing MELD scores, despite the ongoing presence of a virological response. This raises questions regarding the appropriateness and safety of treatment in CTP C and/or high MELD score patients and as to whether a threshold MELD and/or CTP score exists beyond which DAA therapy is of no clinical benefit. Further prospective studies are urgently needed in this population to address these issues, including the identification of those patients in whom pre-transplant treatment is futile.

Post-LT

Interferon-free regimens have shown promise in the treatment of HCV in the post-transplant setting. Sofosbuvir and RBV for 24 weeks resulted in a 70% SVR rate in patients with recurrent HCV genotypes 1?4 and compensated liver disease.^[114] Sofosbuvir, ledipasvir and RBV for 12?24 weeks in those with recurrent HCV-1 and HCV-4 achieved SVR rates of 96?98% in noncirrhotic patients and also patients with CTP A cirrhosis. Moreover, SVR rates were 85?88% and 60?75% in those with CTP B and C cirrhosis respectively.^[115] The use of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir achieved an SVR rate of 97% in noncirrhotic patients with recurrent HCV-1 infection.^[119] Another promising regimen is the combination of daclatasvir and sofosbuvir for 24 weeks, which achieved SVR rates of between 91% and 100% in patients with genotypes 1, 3, 4 and 5. Of the 40 patients with F4 fibrosis, 39 achieved SVR.^[120] Similar results were seen in an interim analysis of a real-world observational cohort, with all 18 patients that had post-transplant cirrhosis achieving SVR12. The pre-transplant cirrhotic group in this study also achieved SVR12 rates of greater than 95% after 24 weeks of daclatasvir and sofosbuvir plus or minus RBV.^[121]

Drug/drug interactions (DDIs) with calcineurin inhibitors (CNI) are a significant issue in the post-transplant population. This is particularly true of paritaprevir/ritonavir, with an approximate 100-fold dose reduction required for tacrolimus and 70-fold for cyclosporin.^[122] The degree of CNI dose reduction required when using simeprevir or sofosbuvir/ledipasvir remains uncertain. Substantial CNI interactions are yet to be described for daclatasvir or sofosbuvir alone.^[50,72] However, data from the ANRS CULPIT trial reported that up-titration of immunosuppressant dosing for patients taking tacrolimus was required for 19% of study patients at week 4 of treatment with sofosbuvir plus daclatasvir, which then increased to 34% at the end of treatment. A similar increase was seen for the mTOR inhibitor, everolimus.^[120] This may be explained by an improvement in liver function and hence immunosuppressant clearance after virological response.

Drug/Drug Interactions

The emergence of real-world data regarding the use of DAAs has resulted in a broader understanding of complex DDIs. In the case of PIs such as simeprevir and ritonavir-boosted paritaprevir, such interactions were largely anticipated due to their extensive metabolism by the cytochrome p450 (CYP) 3A4 system. Co-administration of HIV anti-retroviral drugs, lipid-lowering therapy, anti-psychotics, anti-convulsants and anti-arrhythmic agents are potentially contraindicated in certain combinations and the appropriate guidelines should be consulted prior to treatment initiation.^[50] Sofosbuvir is known to have few significant drug interactions, although recently cases of symptomatic bradycardia have been reported when used in combination with ledipasvir, simeprevir or daclatasvir in patients who were taking amiodarone. The mechanism for this DDI is poorly understood and is reported to have caused one fatality due to cardiac arrest.^[123] Sofosbuvir, ledipasvir and daclatasvir all involve the p-glycoprotein pathway in their metabolism, with daclatasvir also being a CYP3A4 substrate. These pathways may be implicated in potential DDIs that could emerge with the widespread dissemination of DAA therapy.^[50]However, with the exception of PIs, drug?drug interactions are otherwise infrequent in the DAA era. 

 Effect of Drug Resistance on Treatment Efficacy

The impact of baseline NS5A-resistant-associated variants (RAVs), estimated to be 15?42% by population sequencing, on treatment response to NS5A inhibitor containing regimens has been of recent considerable interest. In those with HCV-1 cirrhosis treated with sofosbuvir/ledipasvir, baseline NS5A RAVs are associated with lower SVR rates in treatment-experienced patients with (and without) cirrhosis being 87% compared to 100% in those without following 24 weeks treatment. However, baseline NS5A RAV's do not significantly influence response rates in treatment-naïve cirrhotics with SVR rates unchanged at 96%.^[124] 

 Current Challenges

The significant advances made in the HCV therapeutic landscape have established the current era of interferon-free HCV treatment, yet several important challenges still exist. The issue of improving SVR in difficult-to-cure HCV-3 patients with cirrhosis requires particular attention. Interferon may still even have a role in this group until more effective DAA regimens are developed. Strategies that may improve the virological response in other genotypes may involve the inclusion of RBV, lengthening the duration of treatment, adding another class of DAA or developing more effective regimens with new agents. The question of how best to treat patients who have failed previous interferon-free therapy, particularly with failure of an NI and/or NS5A inhibitor, also requires more research. Furthermore, the significance of resistance associated variants and whether these should be tested for pre-treatment are areas of debate. The mechanisms of virological failure require better understanding, particularly in the case of sofosbuvir, where treatment failure occurs as relapse rather than virological breakthrough. Safety and tolerability of emerging and existing DAA regimens across genotypes and severity of liver disease also requires consensus. Data regarding the treatment of decompensated cirrhotics have now begun to emerge, but have yet to answer the question if there is a point where treatment should be deferred indefinitely, both in the transplant setting and in those who are not candidates for transplantation. Drug?drug interactions are another issue that can be anticipated to be of increasing significance as DAA therapy becomes widely disseminated. Finally, more data are required to guide the management of other difficult to treat groups with cirrhosis including HIV co-infection and those with chronic kidney disease.

Conclusions

The DAA era has resulted in the emergence of well-tolerated and highly effective HCV treatment options in patients with compensated and decompensated cirrhosis. While numerous regimens have been developed with considerable success, the increasing recognition of difficult to cure subgroups indicates that there is still some work to be done, particularly in cirrhotic treatment-experienced HCV-3 patients. The combination of a NS5B inhibitor (NI or NNI) with an NS5A inhibitor appears to be the most effective pangenotypic combinations. The role of RBV in interferon-free regimens is yet to be established, but may be of use in shortening the treatment duration in those with compensated cirrhosis. This is particularly relevant from a cost-effective viewpoint given the high costs associated with these agents. The rapid and revolutionary changes that have occurred thus far in the treatment of HCV as a result of the DAA era suggests that the future is optimistic for the treatment of patients with advanced liver disease and ultimately the global eradication of this virus.