Liver Transplantation

*Advances in Hepatology*

Abstract #9 93.

48, no 4:354-359.

4): A52,

(with HIV) cirrhotics with chronic hepatitis C: A randomized open label clinical pilot study: STOP C. Presented a t the American Association for the Study of Liver Diseases Liver Meeting, Boston MA, November 7-11, 2014.

[42] Dumea E, Cambrea CS, Petcu LC, Streinu Cercel A. Evaluation of liver diseases through transient elastography in patients with HIV infection. Archives of the Balkan Medical Union, 2013 vol

[43] Dumea E, Streinu-Cercel A., Rugină S, Petcu L.C., Halichidis S., Cambrea S.C. Noninvasive assessments (APRI, FIB-4, transient elastography) of fibrosis in patients with HIV and HIV/HBV infection. Proceedings of the 12th Edition of the Scientific Days of the National Institute for Infectious Diseases "Prof Dr Matei Bals", BMC Infectious Diseases 2016, 16(Suppl

[44] Dumea E, Cambrea S.C, Ilie M.M, Petcu L.C, Streinu Cercel A. Evolution of patients coinfected with HIV and hepatitis B: virologic, immunologic, hepatic, regimens. Romanian Journal of Infectious Diseases 2013, vol XVI, no. 4:

Alexandrescu L, Dumitru E. Increased rates of spontaneous clearance of hepatitis C virus in patients infected with HIV. J Gastrointestin Liver Dis., December 2014, vol.23, no.4:461-462

218-226. DOI: 10.37897/RJID

[45] Dumitru I., Rugina S.,

**80**

**83**

world [12, 13].

**Chapter 6**

**Abstract**

therapies.

liver transplantation

**1. Introduction**

Genotype 4

Liver Transplantation and HCV

End-stage liver disease secondary to hepatitis C virus (HCV) infection is a major indication for liver transplantation (LT) worldwide. Previous studies have shown a negative impact of HCV on patient and graft survival leading to an inferior transplant outcome when compared to other liver transplant indications. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East HCV-G4 infection is the most common genotype among transplant recipients. Direct antiviral agents (DAAs) have revolutionized the management of HCV infection in the pre- and post-transplant setting. Recent clinical trials have shown high sustained virologic response rates, shorter durations of treatment, and decreased adverse events when compared with the previous treatment of pegylated interferon (PEG-IFN)-based therapy. However, most of these studies were performed in HCV-G1-infected patients. Due to the low prevalence of HCV-G4 in Europe and the USA, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes. The aim of this chapter is to summarize the natural history and treatment outcome of HCV-G4 in the liver transplant setting, with particular attention to new HCV

**Keywords:** cirrhosis, direct antiviral agents, genotype 4, hepatitis C,

and improving the post-transplant outcome [5].

Hepatitis C virus (HCV) infection is one of the main indications for liver transplantation (LT) and is a major cause of liver related mortality [1, 2]. Patients transplanted for HCV-related cirrhosis have a worse 5-year survival than those with other indications [3, 4]. HCV eradication prior to LT will likely improve the outcome by eliminating the risk of post-transplant recurrence. Over the last decade, the development of highly effectively DAA agents has allowed for the safe and successful treatment of HCV, shrinking the number of recipients with chronic HCV

Hepatitis C genotype 4 (HCV-G4) is the most prevalent genotype in the Middle East, and Northern Africa [6–9]. Egypt is the most affected nation by HCV and HCV-G4 accounted for 94. 1% of infections. More than 90% of liver transplants in Egypt are for HCV –G4 [10]. Earlier studies from Saudi Arabia also demonstrated that HCV-G4 is the leading indication for liver transplantation [11]. On the other hand, HCV-G4 is a rare indication for liver transplantation in other parts of the

*Saad Alghamdi and Waleed Al-hamoudi*

#### **Chapter 6**

## Liver Transplantation and HCV Genotype 4

*Saad Alghamdi and Waleed Al-hamoudi*

#### **Abstract**

End-stage liver disease secondary to hepatitis C virus (HCV) infection is a major indication for liver transplantation (LT) worldwide. Previous studies have shown a negative impact of HCV on patient and graft survival leading to an inferior transplant outcome when compared to other liver transplant indications. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East HCV-G4 infection is the most common genotype among transplant recipients. Direct antiviral agents (DAAs) have revolutionized the management of HCV infection in the pre- and post-transplant setting. Recent clinical trials have shown high sustained virologic response rates, shorter durations of treatment, and decreased adverse events when compared with the previous treatment of pegylated interferon (PEG-IFN)-based therapy. However, most of these studies were performed in HCV-G1-infected patients. Due to the low prevalence of HCV-G4 in Europe and the USA, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes. The aim of this chapter is to summarize the natural history and treatment outcome of HCV-G4 in the liver transplant setting, with particular attention to new HCV therapies.

**Keywords:** cirrhosis, direct antiviral agents, genotype 4, hepatitis C, liver transplantation

#### **1. Introduction**

Hepatitis C virus (HCV) infection is one of the main indications for liver transplantation (LT) and is a major cause of liver related mortality [1, 2]. Patients transplanted for HCV-related cirrhosis have a worse 5-year survival than those with other indications [3, 4]. HCV eradication prior to LT will likely improve the outcome by eliminating the risk of post-transplant recurrence. Over the last decade, the development of highly effectively DAA agents has allowed for the safe and successful treatment of HCV, shrinking the number of recipients with chronic HCV and improving the post-transplant outcome [5].

Hepatitis C genotype 4 (HCV-G4) is the most prevalent genotype in the Middle East, and Northern Africa [6–9]. Egypt is the most affected nation by HCV and HCV-G4 accounted for 94. 1% of infections. More than 90% of liver transplants in Egypt are for HCV –G4 [10]. Earlier studies from Saudi Arabia also demonstrated that HCV-G4 is the leading indication for liver transplantation [11]. On the other hand, HCV-G4 is a rare indication for liver transplantation in other parts of the world [12, 13].

The frequency of infection with HCV-G4 is also increasing in European countries, particularly among intravenous drug users and immigrants [14–17]. HCV-G4 has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant. However, over the past five years' data on treatment outcomes of HCV-G4 in the DAA era has been accumulating.

The treatment outcome of HCV-G4 in the interferon era has been reported in multiple studies [18–23]. A higher rate of spontaneous resolution after acute HCV-G4 infection has been reported [24, 25]. Other studies associated HCV-G4 infection with hepatic steatosis [26, 27]. These observations may have an impact on the natural history and treatment outcomes of HCV-G4.

Direct antiviral agents (DAAs) represent a breakthrough in the management of HCV. First generation DAAs (telaprevir, boceprevir) in post-liver transplant patients resulted in sustained virological response of up to 60% with telaprevir in HCV-G1. However, significant side effects including severe anemia, skin complications and significant drug interactions resulted in major concerns [28]. These agents are currently contraindicated and are not used anymore. Second line direct-acting antiviral DAAs have emerged with better safety and efficacy profiles, leading to dramatic changes in the practice of HCV management [29–36]. An international, multicenter, long-term follow-up study of 530 patients with chronic HCV infection who received interferon based therapy demonstrated that among patients with advanced hepatic fibrosis, sustained virological response was associated with lower all-cause mortality [37]. The revolutionary discovery of DAAs makes chronic HCV infection a curable disease in patients with advanced liver disease. Liver function may improve after antiviral therapy in patients on the waiting list and could result in patient delisting. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be of benefit for certain patients. The, aim of this Chapter is to examine the natural history and treatment outcomes of HCV-G4 following liver transplantation. This review includes all published studies and abstracts involving HCV-G4 patients.

#### **2. Natural history of HCV-G4 after liver transplantation**

The introduction of DAAs is a significant therapeutic breakthrough in the management of HCV infection. With a very high cure rate, a large proportion of LT candidates and recipients can be cured of HCV infection by DAA therapies that are safe and well-tolerated. Due to the high efficacy of these drugs, a major decline was observed in the number of LT performed both in patients with decompensated cirrhosis with HCV and in those with hepatocellular carcinoma associated with HCV worldwide [38–40]. Furthermore, the survival of LT recipients with HCVrelated liver disease has clearly improved because of treatment for HCV recurrence. The advent of efficacious DAA therapy to treat HCV recurrence, resulted in an increasing trend to use HCV seropositive donors for both HCV seropositive and seronegative recipients with excellent outcome [41].

Re-infection of the graft is universal after liver transplantation regardless of genotype and has a negative impact on medium and long-term outcomes [42]. Western studies evaluating the natural history of HCV- G4 in the pre DAA era suggested a worse outcome compared to other genotypes. Zekry et al. analyzed factors that predicted outcome of HCV-liver transplant recipients in the Australian and New Zealand communities. Among 182 patient transplanted for HCV including 16 patients infected with HCV-G4 and a median follow-up of 4 years. HCV-G4 was associated with an increased risk of re-transplantation and death in univariate and multivariate analyses [43]. Whether this difference in outcomes was related to the

**85**

**Table 1.**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

fibrosis and cirrhosis [46–48].

Factors affecting transplant outcome

Viral load Genotype Coinfections

Compliance

Sarcopenia Steatosis Donor Age

Rejection

Alcohol consumption

Chronic kidney disease

Immunosuppression

*Factors affecting the outcome of HCV-related transplantation*

pathogenicity of HCV-G4 or to other factors not examined in this study, including donor age, immunosuppression, and compliance with medications, is not clear (**Table 1**). Furthermore, patients infected with HCV-G4 in this study were older and more likely to have coexisting hepatocellular carcinoma. In a larger study Gane *et al*. investigated the impact of persistent HCV infection after liver transplantation on patient and graft survival and the effects of the HCV genotype on the severity of recurrent hepatitis. 149 patients with HCV including 14 patients with HCV-G4 infection were followed for a median of 36 months; 623 patients without HCV infection who underwent liver transplantation for end-stage chronic liver disease were used as a control group. Approximately 50% of HCV-G4 had progressive liver disease (moderate hepatitis or cirrhosis) during the follow-up period [44]. In the same study, patients infected with G1b had the worst outcome, whereas patients infected with G2 and G3 had less severe disease recurrence. A more detailed single center study from the UK aimed at studying the impact of HCV-G4 on transplant outcome. The study group included 128 patients who underwent transplantation for HCV infection: 28 patients, genotype 1; 11 patients, genotype 2; 19 patients, genotype 3; and 32 Middle Eastern patients with genotype 4 [45]. A significantly higher fibrosis progression rate was observed in HCV-G4 patients compared with non-G4 patients, although their rates of survival were similar. The five-year cumulative rates for the development of cirrhosis or severe fibrosis were 84% in HCV-G4 infected patients and 24% in patients infected with other genotypes. In the United Kingdom, those Middle Eastern patients maybe the recipients of donated organs only when available organs are declined by all UK transplant centers for UK-born patients. Thus, genotype-4 patients are more likely to receive marginal livers or livers from an older donor. This policy may have led to the selection of inferior grafts for the HCV-G4 patients, who were predominantly non-UK citizens, leading to inferior results in these patients. It has been clearly shown that advanced donor age has a negative impact on the transplant outcome including rapid progression to

On the other hand, studies from the Middle East show a more favorable outcome. According to reports from Saudi Arabia and Egypt, overall graft and patient survival for HCV-G4 are comparable to rates reported in the international literature. Reports from Saudi Arabia reveal an overall three-year graft and patient survival rates of 90% and 80%, respectively [11, 49–53]. Similarly, in Egypt, where many

#### *Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

pathogenicity of HCV-G4 or to other factors not examined in this study, including donor age, immunosuppression, and compliance with medications, is not clear (**Table 1**). Furthermore, patients infected with HCV-G4 in this study were older and more likely to have coexisting hepatocellular carcinoma. In a larger study Gane *et al*. investigated the impact of persistent HCV infection after liver transplantation on patient and graft survival and the effects of the HCV genotype on the severity of recurrent hepatitis. 149 patients with HCV including 14 patients with HCV-G4 infection were followed for a median of 36 months; 623 patients without HCV infection who underwent liver transplantation for end-stage chronic liver disease were used as a control group. Approximately 50% of HCV-G4 had progressive liver disease (moderate hepatitis or cirrhosis) during the follow-up period [44]. In the same study, patients infected with G1b had the worst outcome, whereas patients infected with G2 and G3 had less severe disease recurrence. A more detailed single center study from the UK aimed at studying the impact of HCV-G4 on transplant outcome. The study group included 128 patients who underwent transplantation for HCV infection: 28 patients, genotype 1; 11 patients, genotype 2; 19 patients, genotype 3; and 32 Middle Eastern patients with genotype 4 [45]. A significantly higher fibrosis progression rate was observed in HCV-G4 patients compared with non-G4 patients, although their rates of survival were similar. The five-year cumulative rates for the development of cirrhosis or severe fibrosis were 84% in HCV-G4 infected patients and 24% in patients infected with other genotypes. In the United Kingdom, those Middle Eastern patients maybe the recipients of donated organs only when available organs are declined by all UK transplant centers for UK-born patients. Thus, genotype-4 patients are more likely to receive marginal livers or livers from an older donor. This policy may have led to the selection of inferior grafts for the HCV-G4 patients, who were predominantly non-UK citizens, leading to inferior results in these patients. It has been clearly shown that advanced donor age has a negative impact on the transplant outcome including rapid progression to fibrosis and cirrhosis [46–48].

On the other hand, studies from the Middle East show a more favorable outcome. According to reports from Saudi Arabia and Egypt, overall graft and patient survival for HCV-G4 are comparable to rates reported in the international literature. Reports from Saudi Arabia reveal an overall three-year graft and patient survival rates of 90% and 80%, respectively [11, 49–53]. Similarly, in Egypt, where many


#### **Table 1.** *Factors affecting the outcome of HCV-related transplantation*

active living–related liver transplant programs exist and HCV-G4 represents more than 90% of cases, graft and patient survival rates are approximately 86% [10].

Multiple recent studies from the Middle east evaluated the natural history of HCV-G4 following liver transplantation. A study from Saudi Arabia reported the results of patients who had biopsy-proven recurrent hepatitis C infection and made a comparison between patients with HCV-4 and non-HCV-4 genotype. They clearly demonstrated no significant differences between these two groups in terms of clinical, epidemiological, and histological factors and outcome. They found that in the initial liver biopsy, which was performed after a mean time from transplantation of more than 2 years, there were only four patients who had fibrosis scores greater than stage 3. Two of these patients progressed to cirrhosis on subsequent biopsies [54]. Among many factors included in that analysis, the only factor predictive of an advanced histological score was the HCV RNA level at the time of biopsy.

In studies published from Egypt reporting on living donor related liver (LDLT) transplantation of HCV-G4 patients, similar favorable outcomes were observed. Yosry et al. investigated the outcome of 74 Egyptian patients transplanted for HCV-G4. 31. 1% of patients developed HCV recurrence during a follow up period of 36 months. The majority of patients had mild recurrence, and 91% of the subjects had a fibrosis score of < or = F2. None of the transplanted patients developed cirrhosis or clinical decompensation. Recurrent hepatitis C virus infection was associated with a high pre and post-transplant viral load. The presence of antibodies to hepatitis B core antigen were also associated with disease recurrence [55]. In another study, recurrence was evaluated in 38 Egyptian patients infected with HCV-G4. Patient and graft survivals were 86.6% at the end of the 16 +/− 8.18 months (range, 4-35 months) follow-up period. Clinical HCV recurrence was observed in 10/38 patients (26. 3%). Similar to the previous study, none of the recipients developed cirrhosis or decompensation during the follow-up period [10]. Allam et al. compared the outcomes of Middle Eastern patients who received liver transplantation either in China or locally in Saudi Arabia, respective one- and three-year cumulative survival rates were 81% and 59% in patients transplanted in China compared with 90% and 84% for patients transplanted locally. The incidence of complications was significantly higher especially biliary complications, sepsis, metastasis and acquired HBV infection post-transplant in patients transplanted in China. Patients transplanted in Chine were more likely to undergo postoperative interventions and hospital admissions. This could be explained by the liberal recipient selection criteria, the use of donations after cardiac death, and to the limited post-transplant medical care [56].

HCV-G4 exhibits significant genetic diversity, and there are a number of viral subtypes. The impacts of the various subtypes have been demonstrated in recent studies; for example, HCV G1 subtype 1b patients were more likely to have a better post-transplant outcome compared with subtype 1a [57]. Studies performed in Egypt, where HCV-G4 subtypes 4a and 4b predominate, reveal a better antiviral treatment outcome compared with Saudi Arabia [58–60]. In a retrospective analysis of HCV-G4 patients, Roulot *et al*. reported better sustained virological response (SVR) in 4a subtype- compared with 4d subtype-infected individuals [61]. It is very important to point out the that the negative transplant outcome of HCV-G4 infected patients in the west is not accurate. The majority of recruited patients in these studies are older Egyptians, who have received marginal donor grafts. Co-morbidities, such as infection with schistosomiasis, and other unstudied variables may also have affected outcomes in these patients, leading to an impression that HCV-G4 is an aggressive virus. However, data originating from the Middle East, where HCV-G4 predominates, have revealed no significant difference in outcomes between G1 and G4.

**87**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

More importantly the recent introduction of DAAs have changed the outlook for HCV-infected patients. The use of DAA agents in the liver transplantation setting has eliminated post-transplant HCV recurrence and improved graft and patient

Viral eradication or suppression prior to liver transplantation reduces posttransplant recurrence rates [62]. Interferon-based therapy was the only treatment option for HCV prior to the DAA era, however, interferon was contraindicated in patients with advanced liver cirrhosis. This negatively impacted the HCV outcome

The limited treatment options lead multiple groups to carefully evaluate Interferon based therapy in the pre transplant setting. Everson *et al*. evaluated the effectiveness, tolerability, and outcome of a low accelerating dose regimen (LADR) of pegylated interferon (PEG-IFN) therapy in the treatment of patients with advanced HCV. This approach was poorly tolerated especially in patients with decompensated disease. One hundred twenty-four patients were treated with LADR, Sustained virological response was achieved in less than 25% and only 12/15 patients who became HCV-RNA negative prior to transplantation remained HCV-RNA negative 6 months after transplantation [64]. In a more recent study patient with various genotypes were randomized 2: 1 to treatment (n = 31) or untreated control (n = 16). Of the patients who were treated, 23 underwent liver transplantation, and 22% achieved a post-transplantation virological response. Although pre-transplant treatment prevented post-transplant recurrence in 25% of cases, including patients infected with HCV-G4, this approach was poorly tolerated and resulted in life-threatening complications [66]. With the introduction of DAA all trials and evaluating interferon based therapies were discontinued and interferon

Previously treatment options for patients with recurrent HCV after transplantation were limited. IFN based therapy for patients with post-transplant recurrence were the only available option in the past, these regimens are difficult to tolerate and have disappointing efficacy with hard-to-manage drug interactions. Reported SVR rates for PEG-IFN combination therapy following liver transplantation are lower than those in the nontransplant population. Treatment regimens have been hindered by a high incidence of adverse effects, leading to treatment withdrawal. Dabbous *et al*. evaluated 243 patients transplanted for HCV-G4-related cirrhosis. Patients with proven histological recurrence received PEG-IFN and ribavirin. Repeated liver biopsies were performed at 3, 6, and 12 months during treatment for the detection of immune-mediated rejection induced by interferon. Histopathological disease recurrence was high 56 (23%), and 42 patients completed the treatment. Five patients were excluded due to fibrosing cholestatic hepatitis; therefore, 37 patients were included in the study. Erythropoietin and granulocyte colony-stimulating factor were used in 70% of patients. SVR was achieved in 29 (78%) patients [67]. Ponziani *et al*. evaluated treatment responses in 17 Italian patients with HCV-G4 recurrence following liver transplantation. The observed overall survival after LT was 100% at 1 year and 83. 3% at 5 years. Thirty-five percent of patients achieved SVR. This study included patients treated with conventional interferon; the lack of aggressive management of hematological side effects and the inclusion of patients with advanced liver disease contributed to the low response rate [68].

survival irrespective of many other factors including viral genotype.

**3. Treatment of HCV in the peritransplant period**

**3.1 Pegylated interferon and ribavirin (RBV)**

in cirrhotic and organ transplant patients [63–65].

use in this setting is currently contraindicated.

More importantly the recent introduction of DAAs have changed the outlook for HCV-infected patients. The use of DAA agents in the liver transplantation setting has eliminated post-transplant HCV recurrence and improved graft and patient survival irrespective of many other factors including viral genotype.

#### **3. Treatment of HCV in the peritransplant period**

#### **3.1 Pegylated interferon and ribavirin (RBV)**

Viral eradication or suppression prior to liver transplantation reduces posttransplant recurrence rates [62]. Interferon-based therapy was the only treatment option for HCV prior to the DAA era, however, interferon was contraindicated in patients with advanced liver cirrhosis. This negatively impacted the HCV outcome in cirrhotic and organ transplant patients [63–65].

The limited treatment options lead multiple groups to carefully evaluate Interferon based therapy in the pre transplant setting. Everson *et al*. evaluated the effectiveness, tolerability, and outcome of a low accelerating dose regimen (LADR) of pegylated interferon (PEG-IFN) therapy in the treatment of patients with advanced HCV. This approach was poorly tolerated especially in patients with decompensated disease. One hundred twenty-four patients were treated with LADR, Sustained virological response was achieved in less than 25% and only 12/15 patients who became HCV-RNA negative prior to transplantation remained HCV-RNA negative 6 months after transplantation [64]. In a more recent study patient with various genotypes were randomized 2: 1 to treatment (n = 31) or untreated control (n = 16). Of the patients who were treated, 23 underwent liver transplantation, and 22% achieved a post-transplantation virological response. Although pre-transplant treatment prevented post-transplant recurrence in 25% of cases, including patients infected with HCV-G4, this approach was poorly tolerated and resulted in life-threatening complications [66]. With the introduction of DAA all trials and evaluating interferon based therapies were discontinued and interferon use in this setting is currently contraindicated.

Previously treatment options for patients with recurrent HCV after transplantation were limited. IFN based therapy for patients with post-transplant recurrence were the only available option in the past, these regimens are difficult to tolerate and have disappointing efficacy with hard-to-manage drug interactions. Reported SVR rates for PEG-IFN combination therapy following liver transplantation are lower than those in the nontransplant population. Treatment regimens have been hindered by a high incidence of adverse effects, leading to treatment withdrawal.

Dabbous *et al*. evaluated 243 patients transplanted for HCV-G4-related cirrhosis. Patients with proven histological recurrence received PEG-IFN and ribavirin. Repeated liver biopsies were performed at 3, 6, and 12 months during treatment for the detection of immune-mediated rejection induced by interferon. Histopathological disease recurrence was high 56 (23%), and 42 patients completed the treatment. Five patients were excluded due to fibrosing cholestatic hepatitis; therefore, 37 patients were included in the study. Erythropoietin and granulocyte colony-stimulating factor were used in 70% of patients. SVR was achieved in 29 (78%) patients [67]. Ponziani *et al*. evaluated treatment responses in 17 Italian patients with HCV-G4 recurrence following liver transplantation. The observed overall survival after LT was 100% at 1 year and 83. 3% at 5 years. Thirty-five percent of patients achieved SVR. This study included patients treated with conventional interferon; the lack of aggressive management of hematological side effects and the inclusion of patients with advanced liver disease contributed to the low response rate [68].

Al-hamoudi et al. assessed the safety and efficacy of PEG-IFN alpha-2a in combination with RBV in the treatment of recurrent HCV genotype 4 after LT. Pretreatment liver biopsies were obtained from all patients. Five patients had advanced pretreatment liver fibrosis. Only 14 (56%) patients achieved SVR. The most common adverse effects were flu-like symptoms and cytopenia. One patient developed severe rejection complicated by sepsis, renal failure, and death. Other adverse effects included depression, mild rejection, impotence, itching, and vitiligo [69].

#### **4. Treatment of advanced disease in the new era**

The treatment of chronic hepatitis C has been revolutionized with the introduction of DAAs. New oral DAAs have emerged with better safety and efficacy profiles, leading to dramatic changes in the practice of HCV management. The goal of HCV treatment is to reduce mortality and liver complications through virologic cure. The end point is sustained virological response (SVR), which is an undetectable viral load at least 12 weeks after completing treatment. The DAAs target various proteins throughout the HCV replication cycle [70]. These choices include sofosbuvir based therapy plus weight-adjusted RBV, ombitasvir/paritaprevir/ritonavir, elbasvir-grazoprevir and glecaprevir/pibrentasvir. The choice between them depends primarily on potential for drug interactions, availability, and cost. Data on the use of these new agents in cirrhotic G4 patients awaiting liver transplantation are limited. Up-to-date studies evaluating the safety and efficacy of these agents in HCV-G4 patients are summarized below.

#### **4.1 Sofosbuvir and ribavirin**

Sofosbuvir (SOF) is a novel pangenotypic nucleotide analog inhibitor that inhibits HCV RNA replication. SOF is administered orally and inhibits the HCV NS5B polymerase. SOF exerts potent antiviral activity against all HCV genotypes [71–75]**.**

Curry et al. conducted a trial to determine whether sofosbuvir and RBV treatment before liver transplantation could prevent HCV recurrence afterward. They included 61 patients with child A cirrhosis and HCV of any genotype. All involved patients were on waitlists for liver transplantation for hepatocellular carcinoma and received up to 48 weeks of sofosbuvir (400 mg) and RBV before liver transplantation. Of 46 patients who were transplanted, 43 had HCV-RNA levels of less than 25 IU/ml at the time of transplantation. Of these 43 patients, 30 (70%) exhibited a post-transplantation virological response at 12 weeks [76]. Another study evaluated the efficacy and safety of SOF in combination with RBV in HCV-G4 patients in patients of Egyptian ancestry. 60 patients were included and half of them were treatment-naïve. Patients were treated for 12 weeks (n = 31) or 24 weeks (n = 29). Overall, 23% of patients had cirrhosis. SVR was achieved by 68% of patients in the 12-week group, and by 93% of patients in the 24-week group. Treatment was well tolerated and none of the patients discontinued treatment due to an adverse event [77]. Doss et al. evaluated the efficacy and safety of SOF in combination with ribavirin in HCV-G4 patients in Egypt. 103 patients were included and received a combination of SOF and weight-adjusted RBV. 17% of the study population were cirrhotic. Patients with cirrhosis at baseline had lower rates of SVR (63% at 12 weeks, 78% at 24 weeks) than those without cirrhosis (80% at 12 weeks, 93% at 24 weeks). The most common adverse events were fatigue, headache, insomnia, and anemia. Two patients experienced serious adverse events. No adverse events resulted in treatment discontinuation [78]. In a more recent study, 2400 Egyptian patients with liver cirrhosis due to chronic HCV infection were treated with SOF

**89**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

considered the best treatment option (**Table 2**).

Colombo et al. evalaluated the safety and efficacy of LDV-SOF in kidney transplant recipients with chronic genotype 1 or 4 HCV infection and included patients with cirrhosis**.** Ten patients in this trial were infected with HCV-G4 and all included patients achieved SVR. Treatment with LDV-SOF for 12 or 24 weeks was well-tolerated and seemed to have an acceptable safety profile among kidney transplant recipients with HCV genotype 4 infection [85]. In a recently published study real-world effectiveness of LDV-SOF was evaluated. 135 patients infected with G4 were included, the overall SVR rate was 89.6% including treatment experienced and cirrhotic patients [86]. Charlton et al. (SOLAR-1) assessed treatment with LDV, SOF, and RBV in patients infected with HCV-G1 or HCV-G4. This study included a cohort of patients with cirrhosis who had not undergone liver transplantation. The SVR rate in the cirrhotic group was 86–89% [87]. Kohli et al. evaluated

**4.2 Sofosbuvir/ledipasvir (LDV)**

and RBV for 24 weeks. The majority of included patients were treatment-naive. The overall SVR rate was 71. 2%. The most common adverse events were fatigue, myalgia, headache, insomnia, and anemia. Only 5.6% of patients discontinued treatment due to the appearance of significant complications [79]. In another study 14 409 patients received either dual therapy, SOF/RBV for 6 months (group1) or triple therapy with SOF/peg-IFN-alfa-2a/RBV for 3 months (group 2), in a cohort of patients treated in National Treatment Programme affiliated centres in Egypt. In group 1, the SVR at week 12 was 94% and in group 2 the SVR was 78.7% [80]. The efficacy of this combination following LDLT was also evaluated in Saudi Arabia. Ajlan et al. reported the safety and efficacy data on 36 post liver transplant patients who received SOF and RBV ± peg-IFN. All patients were infected with HCV-G4, mean age was 56 years, and the cohort included 24 males and one patient had cirrhosis. The majority of patients had advanced fibrosis. 28 patients were treated with PEG-IFN and RBV in addition to SOF for 12 weeks and the remaining were treated with SOF and RBV only for 24 weeks. By week 4, only four (11. 1%) patients had detectable HCV RNA [81]. In another study 39 Egyptian liver transplant recipients were treated for recurrent HCV-G4 after transplantation with SOF and ribavirin for 6 months. SVR was achieved in 76% of recipients. SVR was significantly higher in treatment-naïve patients and in recipients with a low stage of fibrosis [82]. A prospective multicenter study enrolled 40 patients with compensated recurrent HCV infection of any genotype following liver transplantation. All patients received 24 weeks of SOF 400 mg daily and RBV. Of the 40 patients enrolled and treated, 40% had biopsy proven cirrhosis, and 88% received prior interferon treatment. SVR was achieved by 28 of 40 patients. Relapse accounted for all cases of virological failure, including the only patient with HCV-G4. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported [83]. Forns et al. conducted a post-transplantation study in which SOF and RBV were provided on a compassionate-use basis to patients with severe recurrent HCV, including those with fibrosing cholestatic hepatitis (FCH) and decompensated liver cirrhosis with a life expectancy of less than one year. Patients received SOF and RBV for 24–48 weeks, PEG-IFN was added in some patients. The study population included patients infected with HCV- G4. The overall SVR rate was 59% and was higher (73%) in those with early severe recurrence. 123 serious adverse events occurred in 49 patients (47%). Severe adverse events associated with hepatic decompensation were the most frequent, with 26 adverse events occurring in 19 patients (18%) [84]. However, with the emergence of other treatment options this combination is not

#### *Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

and RBV for 24 weeks. The majority of included patients were treatment-naive. The overall SVR rate was 71. 2%. The most common adverse events were fatigue, myalgia, headache, insomnia, and anemia. Only 5.6% of patients discontinued treatment due to the appearance of significant complications [79]. In another study 14 409 patients received either dual therapy, SOF/RBV for 6 months (group1) or triple therapy with SOF/peg-IFN-alfa-2a/RBV for 3 months (group 2), in a cohort of patients treated in National Treatment Programme affiliated centres in Egypt. In group 1, the SVR at week 12 was 94% and in group 2 the SVR was 78.7% [80].

The efficacy of this combination following LDLT was also evaluated in Saudi Arabia. Ajlan et al. reported the safety and efficacy data on 36 post liver transplant patients who received SOF and RBV ± peg-IFN. All patients were infected with HCV-G4, mean age was 56 years, and the cohort included 24 males and one patient had cirrhosis. The majority of patients had advanced fibrosis. 28 patients were treated with PEG-IFN and RBV in addition to SOF for 12 weeks and the remaining were treated with SOF and RBV only for 24 weeks. By week 4, only four (11. 1%) patients had detectable HCV RNA [81]. In another study 39 Egyptian liver transplant recipients were treated for recurrent HCV-G4 after transplantation with SOF and ribavirin for 6 months. SVR was achieved in 76% of recipients. SVR was significantly higher in treatment-naïve patients and in recipients with a low stage of fibrosis [82]. A prospective multicenter study enrolled 40 patients with compensated recurrent HCV infection of any genotype following liver transplantation. All patients received 24 weeks of SOF 400 mg daily and RBV. Of the 40 patients enrolled and treated, 40% had biopsy proven cirrhosis, and 88% received prior interferon treatment. SVR was achieved by 28 of 40 patients. Relapse accounted for all cases of virological failure, including the only patient with HCV-G4. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported [83]. Forns et al. conducted a post-transplantation study in which SOF and RBV were provided on a compassionate-use basis to patients with severe recurrent HCV, including those with fibrosing cholestatic hepatitis (FCH) and decompensated liver cirrhosis with a life expectancy of less than one year. Patients received SOF and RBV for 24–48 weeks, PEG-IFN was added in some patients. The study population included patients infected with HCV- G4. The overall SVR rate was 59% and was higher (73%) in those with early severe recurrence. 123 serious adverse events occurred in 49 patients (47%). Severe adverse events associated with hepatic decompensation were the most frequent, with 26 adverse events occurring in 19 patients (18%) [84]. However, with the emergence of other treatment options this combination is not considered the best treatment option (**Table 2**).

#### **4.2 Sofosbuvir/ledipasvir (LDV)**

Colombo et al. evalaluated the safety and efficacy of LDV-SOF in kidney transplant recipients with chronic genotype 1 or 4 HCV infection and included patients with cirrhosis**.** Ten patients in this trial were infected with HCV-G4 and all included patients achieved SVR. Treatment with LDV-SOF for 12 or 24 weeks was well-tolerated and seemed to have an acceptable safety profile among kidney transplant recipients with HCV genotype 4 infection [85]. In a recently published study real-world effectiveness of LDV-SOF was evaluated. 135 patients infected with G4 were included, the overall SVR rate was 89.6% including treatment experienced and cirrhotic patients [86]. Charlton et al. (SOLAR-1) assessed treatment with LDV, SOF, and RBV in patients infected with HCV-G1 or HCV-G4. This study included a cohort of patients with cirrhosis who had not undergone liver transplantation. The SVR rate in the cirrhotic group was 86–89% [87]. Kohli et al. evaluated


*SVR = sustained virological response, SOF = sofosbuvir, RBV = ribavirin, LDV = ledipsavir, DCV = daclatasvir, SIM = simeprevir, FCH = fibrosing cholestatic hepatitis, Peg-INF = pegylated interferon.*

#### **Table 2.**

*Prospective studies that included HCV-G4 patients following liver transplantation.*

12 weeks of combination therapy with LDV and SOV for patients with chronic HCV-G4 infections. 20 (95%) of 21 patients completed 12 weeks of treatment and achieved SVR (95% CI 76-100), including seven patients with cirrhosis. One patient was non-adherent to study drugs and withdrew from the study, but was included in the intention-to-treat analysis. No patients discontinued treatment because of adverse events [88]. Crespo et al. investigated the effectiveness and safety of DAAs in patients with HCV-G4 infection in routine practice. 130 patients with HCV-G4 were treated with LDV/SOV, SVR was achieved in 93. 2% of cirrhotic patients [89]. Abergel et al. also evaluated the efficacy and safety of therapy with LDV and SOF in patients with HCV-G4. Forty-four patients (22 treatments naïve and 22 treatment experienced) received a fixed-dose combination tablet of 90 mg LDV and 400 mg SOV orally once daily for 12 weeks. Ten patients (23%) had compensated cirrhosis. The SVR rate was 93% and was similar in treatment-naïve (95%, 21/22) and treatment-experienced (91%, 20/22) patients. Treatment was well tolerated with no serious adverse events [90]. Sanai et al. assessed real-world safety and efficacy of LDV/SOF with or without RBV in HCV-G4 infected patients with compensated and decompensated cirrhosis. This observational cohort (n = 213) included HCV-G4 treatment-naïve (59.6%) and -experienced (40.4%) patients with advanced fibrosis (F3, Metavir; n = 30), compensated (F4, n = 135) and decompensated cirrhosis (n = 48) treated for 12 (n = 202) or 24 weeks (n = 11) with LDV/SOF. RBV was dosed by physician discretion between 600 and 1200 mg daily. Patients with prior DAA failure were excluded from the analysis. Overall, 197 (92.5%) of the patients achieved SVR [91]. The SVR rate was as high as 98% for genotype 4 when using this combination to treat treatment-niave cirrhotic patients for 12 weeks [92]. Abaalkhail et al. evaluated prospectively the safety and efficacy of LDV-SOF for 12 to 24 weeks with or without RBV in treating HCV-4 infected patients with cirrhosis (cohort A) or post-liver transplantation (cohort B). A total of 111 patients (61 cirrhotic; 50 postliver transplants) with HCV genotype 4 were included. SVR was achieved in 91.8% and 86% of cohorts A and B, respectively. There were no treatment-related mortality or significant side effects [93].

**91**

patients [102–106].

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

reported drug-related adverse events [96].

**4.3 Sofosbuvir/daclatasvir (DCV)**

Cohort B of the SOLAR-1 study enrolled patients who had undergone liver transplantation and included patients with post-transplant liver cirrhosis. Patients were randomly assigned to receive a fixed-dose combination tablet containing LDV and SOF plus RBV for 12 or 24 weeks. The cohort included 108 post-transplant patients. SVR was achieved in 96–98% of patients without cirrhosis or with compensated cirrhosis, in 85%–88% of patients with moderate hepatic impairment, in 60%–75% of patients with severe hepatic impairment, and in all six patients with FCH [87]. Similarly, an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand evaluated treatment outcome in the pre and post-transplant settings. Cohort A included patient with cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned to receive 12 or 24 weeks of LDV (90 mg) and SOF (400 mg) once daily, plus RBV (600–1200 mg daily). The majority of patients were infected with HCV genotype 1 and only 37 were infected with genotype 4. Among all patients with genotype 4 HCV, SVR was achieved by 14 of 18 (78%) patients (12 weeks' treatment) and 16 of 17 (94%) patients (24 weeks' treatment) [94]. SOF/LDV combination was also evaluated in the post-transplant setting in a recently published German study that included both genotypes 1, 4. An overall SVR was achieved in 97% of patients [95]. The safety profile of LVD/SOF with RBV was evaluated in a pooled analysis of SOLAR-1 and -2 studies. These two studies included cirrhotic or post–liver transplantation patients infected with genotypes 1 and 4 and were randomized to 12 or 24 weeks of treatment. Treatment in the two trials was well tolerated and safe. RBVassociated anemia was the most common adverse effect, representing over 50% of

DCV is a pangenotypic NS5A inhibitor with a very low potential for drug interac-

tion and a favorable safety profile. EL-khayat et al. investigated the efficacy and safety of SOF/DCV for treatment of patients with HCV-G4 induced cirrhosis. This was a multicenter study involving 551 patients with HCV-G4 related cirrhosis; 432 naïve patients and 119 treatment-experienced patients. All patients received SOF/ DCV/RBV for 12 weeks and when RBV is contraindicated the treatment duration was extended to 24 weeks. SVR rate was 92% in naïve cirrhotic patients and 87% in previous treated patients [97]. In a French study, 176 HCV-G4 patients were treated with SOF and DCV. All the patients enrolled had advanced stages of liver fibrosis. The overall SVR rate was 90%, with the highest rate (97%) reached in cirrhotic patients treated with RBV, a the lowest (88%) in those treated without RBV [98]. In another recently published study involving only HCV-G4 patients, SVR was achieved in 100% of patients who received SOF/DCV with or without RBV. This study included patients with advanced fibrosis and cirrhosis. Adverse events occurred in 32% of patients, but none discontinued treatment [99]. The Phase II, open-label, nonrandomized IMPACT study assessed the efficacy of three DAAs (simeprevir, sofosbuvir, and daclatasvir) in HCV genotype 1/ 4-infected cirrhotic patients with portal hypertension or decompensated liver disease. All patients received simeprevir (SIM) 150 mg, DCV 60 mg, and SOF 400 mg once-daily for 12 weeks. All 40 patients included in the study achieved SVR and the combination was well tolerated [100]. The outcome of SOF/DCV/RBV in non-responders to prior sofosbuvir-based therapy was evaluated in a large Egyptian study that included 1014 patients in which 47%

were cirrhotic. Overall SVR was 90.6% with no major side effects [101].

Multiple other studies showed high SVR rates among genotype 4 infected

#### *Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

Cohort B of the SOLAR-1 study enrolled patients who had undergone liver transplantation and included patients with post-transplant liver cirrhosis. Patients were randomly assigned to receive a fixed-dose combination tablet containing LDV and SOF plus RBV for 12 or 24 weeks. The cohort included 108 post-transplant patients. SVR was achieved in 96–98% of patients without cirrhosis or with compensated cirrhosis, in 85%–88% of patients with moderate hepatic impairment, in 60%–75% of patients with severe hepatic impairment, and in all six patients with FCH [87]. Similarly, an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand evaluated treatment outcome in the pre and post-transplant settings. Cohort A included patient with cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned to receive 12 or 24 weeks of LDV (90 mg) and SOF (400 mg) once daily, plus RBV (600–1200 mg daily). The majority of patients were infected with HCV genotype 1 and only 37 were infected with genotype 4. Among all patients with genotype 4 HCV, SVR was achieved by 14 of 18 (78%) patients (12 weeks' treatment) and 16 of 17 (94%) patients (24 weeks' treatment) [94]. SOF/LDV combination was also evaluated in the post-transplant setting in a recently published German study that included both genotypes 1, 4. An overall SVR was achieved in 97% of patients [95].

The safety profile of LVD/SOF with RBV was evaluated in a pooled analysis of SOLAR-1 and -2 studies. These two studies included cirrhotic or post–liver transplantation patients infected with genotypes 1 and 4 and were randomized to 12 or 24 weeks of treatment. Treatment in the two trials was well tolerated and safe. RBVassociated anemia was the most common adverse effect, representing over 50% of reported drug-related adverse events [96].

#### **4.3 Sofosbuvir/daclatasvir (DCV)**

DCV is a pangenotypic NS5A inhibitor with a very low potential for drug interaction and a favorable safety profile. EL-khayat et al. investigated the efficacy and safety of SOF/DCV for treatment of patients with HCV-G4 induced cirrhosis. This was a multicenter study involving 551 patients with HCV-G4 related cirrhosis; 432 naïve patients and 119 treatment-experienced patients. All patients received SOF/ DCV/RBV for 12 weeks and when RBV is contraindicated the treatment duration was extended to 24 weeks. SVR rate was 92% in naïve cirrhotic patients and 87% in previous treated patients [97]. In a French study, 176 HCV-G4 patients were treated with SOF and DCV. All the patients enrolled had advanced stages of liver fibrosis. The overall SVR rate was 90%, with the highest rate (97%) reached in cirrhotic patients treated with RBV, a the lowest (88%) in those treated without RBV [98]. In another recently published study involving only HCV-G4 patients, SVR was achieved in 100% of patients who received SOF/DCV with or without RBV. This study included patients with advanced fibrosis and cirrhosis. Adverse events occurred in 32% of patients, but none discontinued treatment [99]. The Phase II, open-label, nonrandomized IMPACT study assessed the efficacy of three DAAs (simeprevir, sofosbuvir, and daclatasvir) in HCV genotype 1/ 4-infected cirrhotic patients with portal hypertension or decompensated liver disease. All patients received simeprevir (SIM) 150 mg, DCV 60 mg, and SOF 400 mg once-daily for 12 weeks. All 40 patients included in the study achieved SVR and the combination was well tolerated [100]. The outcome of SOF/DCV/RBV in non-responders to prior sofosbuvir-based therapy was evaluated in a large Egyptian study that included 1014 patients in which 47% were cirrhotic. Overall SVR was 90.6% with no major side effects [101].

Multiple other studies showed high SVR rates among genotype 4 infected patients [102–106].

Data on the use of DCV in the post-transplant setting for HCV-G4-infected patients are limited.

In a multicenter prospective study 137 patients with post-transplant HCV recurrence received SOF and DCV. This cohort included 12 patients infected with HCV-G4. The SVR rate after completing treatment was 96% under the intention-to treat analysis. No clinically relevant drug–drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs [107]. A recent prospective multicenter study evaluating SOF based therapy in the post liver transplant setting was conducted and included all genotpes. The main combination regimen was SOF/DCV (73.6%). SVR was 92.8% (on an intent-to-treat basis) [108]. Leroy *et al*. analyzed data from 23 patients with FCH who participated in a prospective cohort study in France and Belgium to assess the effects of antiviral agents in patients with recurrence of HCV infection after liver transplantation. Three patients with G4 infection were included in this study and all 3 achieved SVR [109].

#### **4.4 Sofosbuvir/Simeprevir (SIM)**

SIM is a NS3/4A protease inhibitor with antiviral activity against G1, G2, G4, G5, and G6.

An open-label, multicentre, phase IIa study evaluated the outcome of SIM plus SOF for eight or 12 weeks in HCV-G4 infected patients. This study included 23 cirrhotic patients who received a 12 week course of therapy. Treatment comprised SIM 150 mg and SOF 400 mg daily. All cirrhotic patients achieved SVR and the treatment was well tolerated [110]. In a phase III, open-label, single-arm study the efficacy and safety of 12 weeks of SIM plus SOF in treatment-naïve and experienced HCV-G4 infection, including cirrhotic patients was conducted. All patients achieved SVR including the cirrhotic patients. No serious adverse events were reported and no patients discontinued study treatment [111]. The combination of SIM/SOF in a recently published Egyptian study involving genotype 4 infected patients resulted in a SVR rate of 92% in 100 treated patients [112]. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed the combination of the three direct-acting antivirals SIM, DCV and SOF. All 40 patients achieved SVR [113]. Multiple other studies that included cirrhotic and treatment experienced patients treated with SIM and SOF revealed high SVR rates [114–116].

The efficacy and safety of SOF-based regimens in the real world among a cohort of Egyptian patients with recurrent HCV post LDLT was evaluated in HCV-G4 infected patients. 190 patients were included. Out of 190, 119 received SOF/RBV, 38 SOF/SIM, 22 SOF/DCV)/ ± RBV, and 11 received SOF/LDV/ ± RBV. SVR rates were as follow: 84.9% in SOF/RBV group, 94.7% in SOF/SIM, 100% in SOF/DCV, and 100% in SOF/LDV. Treatment was well tolerated with no significant drug–drug interactions [117]. The outcome of the combination SIM + SOF ± RBV in a group of liver transplant patients with HCV genotype 4 infection in Spain was evaluated in a real life study. This was a multicenter retrospective study, including 28 HCV genotype 4 patients from 11 liver transplant centers. The SVR was 95.23% including patients with advanced fibrosis and cirrhosis [118].

#### **4.5 Ombitasvir, ritonavir and paritaprevir**

The combination of ombitasvir, ritonavir and paritaprevir was evaluated in multiple studies involving compensated cirrhotic HCV-G4 patients and revealed high SVR rates reaching 100% in some studies [119–124]. In a recent meta-analyses, 20 cohorts across 12 countries were identified, totaling 5158 patients infected with

**93**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

use in the pre transplant setting is limited.

for patients infected with HCV-G4 [126].

HCV-G4 infected patients achieved SVR 12 [128].

**4.7 Sofosbuvir/Velpatasvir (VEL)**

with HCV-G4 achieved SVR [129].

during the study period [131].

the post-transplant setting [133].

of drug–drug interaction when used with protease inhibitors.

to evaluate SOV/VEL for decompensated cirrhotic patients [130].

**4.8 Sofosbuvir/Velpatasvir/Voxilaprevir (VOX)**

SVR rate was 100% for HCV-G4 infected patients [132].

**4.6 Glecaprevir/Pibrentasvir**

HCV-G4 was 100% [127].

G1 and 4. The overall SVR rates were 98.9% for HCV-G4 infected patients [125]. The regimen is contraindicated in Child Pugh classes B and C cirrhosis, therefor its

The EXPEDITION-1 trial enrolled 146 patients with compensated cirrhosis, 16 (11%) patients were infected with HCV-G4. Patients in this trial received a fixed dose of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks. SVR was 100%

EXPEDITION-8 is a randomized trial that enrolled 343 patients with HCV Genotypes 1–6 and compensated cirrhosis. All patients received an 8-week course of Glecaprevir/Pibrentasvir. Of 343 patients, 13 had HCV-G4. The SVR12 rate in

On the other hand, MAGELLAN-2 trial was a phase 3, open-label trial for patients at least 3 months post transplantation. The study enrolled 100 patients of HCV. Three patients with genotype 4 underwent LT. After a 12-week course, all

Immunosuppressive therapy should be monitored closely due to the possibility

In 2015, ASTRAL-1 evaluated the efficacy and safety of 12-week course of VEL and SOF. Of the 624 patients, 116 (19%) had genotype 4. One fourth of genotype 4 patients had cirrhosis. After a 12-week course of SOV/VEL, all patients (100%)

ASTRAL-4 trial enrolled 267 patients with decompensated cirrhosis, CPT B. The study was open label with 3 arms that included: SOF/VEL for 12 weeks, SOF/ VEL in addition to RBV for 12 weeks, or SOF/VEL for 24 weeks. In this trial, 8 (3%) patients had genotype 4. Regardless of the assigned arm, all genotype 4 patients (100%) achieved SVR. In this study, 81% of patients with MELD score above 15 had improvement after completion of treatment. This study was one of the earliest trials

In a recent trial 79 post liver transplant patients with HCV-G 1 and 4 received SOF/VEL daily for 12 weeks. In this trial, 4 patients were infected with HCV-G4. All patients with genotype 4 achieved SVR. There were no deaths or rejection episodes

POLARIS-1 trial assessed the safety and efficacy of SOF/VEL/VOX taken for 12 weeks vs. placebo. Patients with cirrhosis represented 46% of the study population. All patients with genotype 4 (22) were in the active treatment arm. By the end of the study period, 20 patients (91%) achieved SVR. One cirrhotic patient developed NS5A Y93H resistance-associated substitution and the other one did not receive treatment. In the POLARIS-4 trial, patients were assigned to either SOF/VEL/VOX or SOF/ VEL once daily for 12 weeks. All genotype 4 patients received SOF/VEL/VOX. The

The use of combined SOF/VEL/VOX is not recommended in patients with advanced liver disease CPT C. There are no currently strong data to support SOF/ VEL/VOX use post liver transplantation. Case reports showed favorable outcome in G1 and 4. The overall SVR rates were 98.9% for HCV-G4 infected patients [125]. The regimen is contraindicated in Child Pugh classes B and C cirrhosis, therefor its use in the pre transplant setting is limited.

#### **4.6 Glecaprevir/Pibrentasvir**

The EXPEDITION-1 trial enrolled 146 patients with compensated cirrhosis, 16 (11%) patients were infected with HCV-G4. Patients in this trial received a fixed dose of glecaprevir (300 mg)/pibrentasvir (120 mg) for 12 weeks. SVR was 100% for patients infected with HCV-G4 [126].

EXPEDITION-8 is a randomized trial that enrolled 343 patients with HCV Genotypes 1–6 and compensated cirrhosis. All patients received an 8-week course of Glecaprevir/Pibrentasvir. Of 343 patients, 13 had HCV-G4. The SVR12 rate in HCV-G4 was 100% [127].

On the other hand, MAGELLAN-2 trial was a phase 3, open-label trial for patients at least 3 months post transplantation. The study enrolled 100 patients of HCV. Three patients with genotype 4 underwent LT. After a 12-week course, all HCV-G4 infected patients achieved SVR 12 [128].

Immunosuppressive therapy should be monitored closely due to the possibility of drug–drug interaction when used with protease inhibitors.

#### **4.7 Sofosbuvir/Velpatasvir (VEL)**

In 2015, ASTRAL-1 evaluated the efficacy and safety of 12-week course of VEL and SOF. Of the 624 patients, 116 (19%) had genotype 4. One fourth of genotype 4 patients had cirrhosis. After a 12-week course of SOV/VEL, all patients (100%) with HCV-G4 achieved SVR [129].

ASTRAL-4 trial enrolled 267 patients with decompensated cirrhosis, CPT B. The study was open label with 3 arms that included: SOF/VEL for 12 weeks, SOF/ VEL in addition to RBV for 12 weeks, or SOF/VEL for 24 weeks. In this trial, 8 (3%) patients had genotype 4. Regardless of the assigned arm, all genotype 4 patients (100%) achieved SVR. In this study, 81% of patients with MELD score above 15 had improvement after completion of treatment. This study was one of the earliest trials to evaluate SOV/VEL for decompensated cirrhotic patients [130].

In a recent trial 79 post liver transplant patients with HCV-G 1 and 4 received SOF/VEL daily for 12 weeks. In this trial, 4 patients were infected with HCV-G4. All patients with genotype 4 achieved SVR. There were no deaths or rejection episodes during the study period [131].

#### **4.8 Sofosbuvir/Velpatasvir/Voxilaprevir (VOX)**

POLARIS-1 trial assessed the safety and efficacy of SOF/VEL/VOX taken for 12 weeks vs. placebo. Patients with cirrhosis represented 46% of the study population. All patients with genotype 4 (22) were in the active treatment arm. By the end of the study period, 20 patients (91%) achieved SVR. One cirrhotic patient developed NS5A Y93H resistance-associated substitution and the other one did not receive treatment.

In the POLARIS-4 trial, patients were assigned to either SOF/VEL/VOX or SOF/ VEL once daily for 12 weeks. All genotype 4 patients received SOF/VEL/VOX. The SVR rate was 100% for HCV-G4 infected patients [132].

The use of combined SOF/VEL/VOX is not recommended in patients with advanced liver disease CPT C. There are no currently strong data to support SOF/ VEL/VOX use post liver transplantation. Case reports showed favorable outcome in the post-transplant setting [133].

#### **4.9 Elbasvir/Grazoprevir (EBR/GZR)**

A randomized controlled open label trial assessed the effectiveness of EBR/GZR with or without RBV for 12 or 16 weeks. The study population was 420 patients out of whom 36 had HCV-G4. The SVR for HCV-G4 patients was 89% which improved with a longer duration of treatment [134].

Jacobson et al. published the integrated analysis of 6 clinical trials. The analysis included 402 patients who received EBR/GZR once daily +/− RBV, for 12-18 weeks. Twenty-three patients with HCV-G4 were included in the analysis. Six patients were treatment naïve and they all achieved SVR. In the treatment experienced group, 4 patients (100%) achieved SVR after 16-18 week of treatment. However, the success rate was lower in treatment experienced patients with a 12-week course without RBV (66.7%) or with RBV (80%) [135].

Data for this combination in the post-transplant setting is limited.

#### **4.10 DAA treatment failures**

Despite the high SVR rate associated with DAA in HCV-G4 infected patients, a small percentage of patients do not respond to treatment. In the early era of DAA the most common approach was to add RBV or in some studies PEG-IFN and extend the treatment duration. However, with the emergence of new DAA choices, changing to another DAA became the most common approach. Yousif et al. conducted a prospective cohort study to assess the safety and efficacy of 12 weeks' retreatment with either combination of SOF/DCV/SMV/RBV (45 patients) or SOF/OBV/PTV/r/RBV (163 patients) in patients who had previously failed NS5A inhibitors-based regimens. The overall SVR rates in the two groups were 98. 1% [136]. In another study, patients who failed SOF/DCV were retreated successfully with other DAAs [137]. In a recently published study quadruple regimen of (sofosbuvir, daclatasvir, and simeprevir with a weight-based ribavirin) in chronic HCV-G4 DAAs-experienced patients was successful in eradicating the virus [138]. Multiple other studies revealed similar results [139, 140].

#### **5. Timing of treatment for patients on the transplant list**

The management of hepatitis C virus (HCV) infection in patients with decompensated cirrhosis has evolved dramatically. DAAs have shown to be safe and effective in patients with decompensated cirrhosis with high SVR rates. However, it is still debatable on when to initiate treatment in patients with advanced liver disease. Krassenburg et al. evaluated the impact of SVR in a large international multicenter cohort study, including a large number of patients with HCV-related cirrhosis treated with DAAs. Achievement of SVR was independently associated with a 2. 5-fold lower risk of cirrhosis-related complications or death in patients with compensated cirrhosis. On the other hand, no clinical benefit was apparent with HCV eradication in patients with decompensated liver disease. Among patients with CP-B/C cirrhosis, the event-free survival and LT-free survival did not differ between those with SVR and those without SVR. Furthermore, MELD score improvement did not translate to a beneficial clinical outcome in these subset of patients. Thus, DAA therapy may lower prioritization for LT through MELD score reduction, which is likely to primarily affect those with a more urgent need liver transplantation [141]. Other recently published studies assessed the impact of DAAs on patients awaiting liver transplant. They evaluated whether patients can be first inactivated due to clinically improvement and subsequently delisted in a real

**95**

**Author details**

Saad Alghamdi1

walhamoudi@gmail.com

and Waleed Al-hamoudi1,2\*

\*Address all correspondence to: walhamoudi@ksu.edu.sa;

King Saud University, Riyadh, Saudi Arabia

provided the original work is properly cited.

1 Department of Liver Transplantation and Hepatobiliary Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

2 Gastroenterology Unit, Department of Medicine, College of Medicine,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

hypertensive complications.

life setting. Treated patient had a significant improvement in the median MELD and Child Pugh score. They concluded that all oral DAAs were able to reverse liver dysfunction and may result in delisting of about 20-30% of patients. Patients with lower MELD scores had higher chances to be delisted. However, the longer term benefits of therapy need to be ascertained [142, 143]. Similarly, Afdahl et al. evaluated the outcome of DAA in compensated and decompensated cirrhotic patients. They also measured the hepatic venous pressure gradient before and after treatment in fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension. They observed a clinically meaningful improvement in portal hypertension in addition to improvements in liver biochemistry, Child–Pugh score and Model for End-Stage Liver Disease scores [144]. The potential benefits of treating patients on the waiting list include potential improvements in overall clinical status that may salvage these patients from liver transplantation; reducing post-transplant recurrence; and avoiding possible post-transplant drug–drug interactions. One concern is that treating these patients may lower their MELD scores and drive them down the transplant list, thus delaying transplantation despite persistent portal

#### *Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

life setting. Treated patient had a significant improvement in the median MELD and Child Pugh score. They concluded that all oral DAAs were able to reverse liver dysfunction and may result in delisting of about 20-30% of patients. Patients with lower MELD scores had higher chances to be delisted. However, the longer term benefits of therapy need to be ascertained [142, 143]. Similarly, Afdahl et al. evaluated the outcome of DAA in compensated and decompensated cirrhotic patients. They also measured the hepatic venous pressure gradient before and after treatment in fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension. They observed a clinically meaningful improvement in portal hypertension in addition to improvements in liver biochemistry, Child–Pugh score and Model for End-Stage Liver Disease scores [144]. The potential benefits of treating patients on the waiting list include potential improvements in overall clinical status that may salvage these patients from liver transplantation; reducing post-transplant recurrence; and avoiding possible post-transplant drug–drug interactions. One concern is that treating these patients may lower their MELD scores and drive them down the transplant list, thus delaying transplantation despite persistent portal hypertensive complications.

### **Author details**

Saad Alghamdi1 and Waleed Al-hamoudi1,2\*

1 Department of Liver Transplantation and Hepatobiliary Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

2 Gastroenterology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

\*Address all correspondence to: walhamoudi@ksu.edu.sa; walhamoudi@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Kim WR. The burden of hepatitis C in the United States. Hepatology 2002; 36: S30-S34.

[2] Wiesner RH, Sorrell M, Villamil F. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003; 9: S1-S9.

[3] Garcia-Retortillo M, Forns X, Feliu A, Moitinho E, Costa J, Navasa M, et al. Hepatitis C virus kinetics during and immediately after liver transplantation. Hepatology 2002; 35: 680-687.

[4] Vinaixa C, Rubín A, Aguilera V, Berenguer M. Recurrence of hepatitis C after liver transplantation. Ann Gastroenterol 2013; 26:304-313.

[5] Fehily SR, Papaluca T, Thompson AJ. Long-Term Impact of Direct-Acting Antiviral Agent Therapy in HCV Cirrhosis: Critical Review. Semin Liver Dis. 2019 Jul;39(3):341-353.

[6] Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, Pybus OG, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015;61:77-87.

[7] Abdel-Aziz F, Habib M, Mohamed MK, Abdel-Hamid M, Gamil F, Madkour S, et al. Hepatitis C virus (HCV) infection in a community in the Nile Delta: Population description and HCV prevalence. Hepatology 2000;32:111-115.

[8] Al Traif I, Al Balwi MA, Abdulkarim I, Handoo FA, Alqhamdi HS, Alotaibi M, et al. HCV genotypes among 1013 Saudi nationals: A multicenter study. Ann Saudi Med 2013;33:10-12.

[9] Xu LZ, Larzul D, Delaporte E, Bréchot C, Kremsdorf D. Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon). J Gen Virol 1994;75:2393-2398.

[10] Yosry A, Esmat G, El-Serafy M, Omar A, Doss W, Said M, et al. Outcome of living donor liver transplantation for Egyptian patients with hepatitis c (genotype 4)-related cirrhosis. Transplant Proc 2008;40:1481-1484.

[11] Al-Sebayel M, Khalaf H, Al-Sofayan M, Al-Saghier M, Abdo A, Al-Bahili H, et al. Experience with 122 consecutive liver transplant procedures at King Faisal Specialist Hospital and Research Center. Ann Saudi Med 2007;27:333-338.

[12] Rustgi VK. The epidemiology of hepatitis C infection in the United States. J Gastroenterol 2007;42:513-21.

[13] Roche B, Samuel D. Risk factors for hepatitis C recurrence after liver transplantation. J Viral Hepat 2007;14(Suppl 1):89-96.

[14] Katsoulidou A, Sypsa V, Tassopoulos NC, Boletis J, Karafoulidou A, Ketikoglou I, et al. Molecular epidemiology of hepatitis C virus (HCV) in Greece: Temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates. J Viral Hepat 2006;13:19-27.

[15] Ansaldi F, Bruzzone B, Salamaso S, Rota MC, Durando P, Gasparini R, et al. Different seroprelavence and molecular epidemiology pattern of hepatitis C virus infection in Italy. J Med Virol 2005;76:327-332.

[16] Fernández-Arcás N, López-Siles J, Trapero S, Ferraro A, Ibá-ez A, Orihuela F, et al. High prevalence of hepatitis C virus subtypes 4c and 4d in Malaga (Spain): Phylogenetic and epidemiological analyses. J Med Virol 2006;78:1429-1435.

**97**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

Dubois M, Alric L, et al. Heterogeneity of hepatitis C virus genotype 4 strains circulating in south-western France. J

et al. Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-638.

[25] Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel Moneim A, Khalifa KE, et al. Duration of peginterferon therapy in acute hepatitis C: A randomized trial.

Hepatology 2006;43:923-931.

2008;47:1371-1383.

[26] Kamal S, Nasser I. Hepatitis C genotype 4: What we know and what we don't yet know. Hepatology

[27] AlQaraawi AM, Sanai FM, Al-Husseini H, Albenmousa A,

AIDS 2015 Jan 2;29(1):53-8.

Hindes RG, et al. Nucleotide

2013;368:34-44.

AlSheikh A, Ahmed LR, et al. Prevalence and impact of hepatic steatosis on the response to antiviral therapy in Saudi patients with genotypes 1 and 4 chronic hepatitis C. Dig Dis Sci 2011;56:1222-1228.

[28] Antonini TM, Furlan V, Teicher E, Haim-Boukobza S, Sebagh M, Coilly A, Bonhomme-Faivre L, et al. Therapy with boceprevir or telaprevir in HIV/ hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation.

[29] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT,

polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med

[30] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised,

multicentre phase 2 trial. Lancet

[31] Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir in combination with

2013;381:2100-2107.

[18] Dahlan Y, Ather HM, Al-ahmadi M, Batwa F, Al-hamoudi W. Sustained virological response in a predominantly hepatitis C virus genotype 4 infected population. World J Gastroenterol

[19] Al Ashgar H, Helmy A, Khan MQ, Al Kahtani K, Al Quaiz M, Rezeig M, et al. Predictors of sustained virological response to a 48-week course of pegylated interferon alfa-2a and ribavirin in patients infected with hepatitis C virus genotype 4. Ann Saudi

[20] Derbala MF, El Dweik NZ, Al Kaabi SR, Al-Marri AD, Pasic F, Bener AB, et al. Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: Ribavirin therapy. J Viral Hepat

[21] El Khayat HR, Fouad YM, El Amin H, Rizk A. A randomized trial of 24 versus 48 weeks of peginterferon alpha-2a plus ribavirin in Egyptian patients with hepatitis C virus genotype

4 and rapid viral response. Trop Gastroenterol 2012;33:112-7.

[22] Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Muhammadi M, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response. Hepatology 2007;46:1732-1740.

[23] Kamal SM. Hepatitis C genotype 4 therapy: Increasing options and improving outcomes. Liver Int 2009;29(Suppl 1):39-48.

[24] Kamal SM, Fouly AE, Kamel RR, Hockenjos B, Al Tawil A, Khalifa KE,

[17] Nicot F, Legrand-Abravanel F, Sandres-Saune K, Boulestin A,

Gen Virol 2005;86:107-114.

2009;15:4429-4433.

Med 2009;29:4-14.

2008;15:591-599.

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

[17] Nicot F, Legrand-Abravanel F, Sandres-Saune K, Boulestin A, Dubois M, Alric L, et al. Heterogeneity of hepatitis C virus genotype 4 strains circulating in south-western France. J Gen Virol 2005;86:107-114.

[18] Dahlan Y, Ather HM, Al-ahmadi M, Batwa F, Al-hamoudi W. Sustained virological response in a predominantly hepatitis C virus genotype 4 infected population. World J Gastroenterol 2009;15:4429-4433.

[19] Al Ashgar H, Helmy A, Khan MQ, Al Kahtani K, Al Quaiz M, Rezeig M, et al. Predictors of sustained virological response to a 48-week course of pegylated interferon alfa-2a and ribavirin in patients infected with hepatitis C virus genotype 4. Ann Saudi Med 2009;29:4-14.

[20] Derbala MF, El Dweik NZ, Al Kaabi SR, Al-Marri AD, Pasic F, Bener AB, et al. Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: Ribavirin therapy. J Viral Hepat 2008;15:591-599.

[21] El Khayat HR, Fouad YM, El Amin H, Rizk A. A randomized trial of 24 versus 48 weeks of peginterferon alpha-2a plus ribavirin in Egyptian patients with hepatitis C virus genotype 4 and rapid viral response. Trop Gastroenterol 2012;33:112-7.

[22] Kamal SM, El Kamary SS, Shardell MD, Hashem M, Ahmed IN, Muhammadi M, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: The role of rapid and early virologic response. Hepatology 2007;46:1732-1740.

[23] Kamal SM. Hepatitis C genotype 4 therapy: Increasing options and improving outcomes. Liver Int 2009;29(Suppl 1):39-48.

[24] Kamal SM, Fouly AE, Kamel RR, Hockenjos B, Al Tawil A, Khalifa KE, et al. Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy on sustained virologic response. Gastroenterology 2006;130:632-638.

[25] Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel Moneim A, Khalifa KE, et al. Duration of peginterferon therapy in acute hepatitis C: A randomized trial. Hepatology 2006;43:923-931.

[26] Kamal S, Nasser I. Hepatitis C genotype 4: What we know and what we don't yet know. Hepatology 2008;47:1371-1383.

[27] AlQaraawi AM, Sanai FM, Al-Husseini H, Albenmousa A, AlSheikh A, Ahmed LR, et al. Prevalence and impact of hepatic steatosis on the response to antiviral therapy in Saudi patients with genotypes 1 and 4 chronic hepatitis C. Dig Dis Sci 2011;56:1222-1228.

[28] Antonini TM, Furlan V, Teicher E, Haim-Boukobza S, Sebagh M, Coilly A, Bonhomme-Faivre L, et al. Therapy with boceprevir or telaprevir in HIV/ hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation. AIDS 2015 Jan 2;29(1):53-8.

[29] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34-44.

[30] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013;381:2100-2107.

[31] Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir in combination with

#### *Advances in Hepatology*

peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, doubleblind, phase 2 trial. Lancet Infect Dis 2013;13:401-408.

[32] Lalezari JP ND, Hyland RH. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naϊve patients with HCV infection: the QUANTUM study. J Hepatol 2013;58:S236.

[33] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-1887.

[34] Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867-1877.

[35] Osinusi A, Meissner EG, Lee YJ, Bon D, Heytens L, Nelson A, Sneller M, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. Jama 2013;310:804-811.

[36] AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015 Sep;62(3):932-954.

[37] van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, Duarte-Rojo A, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012 Dec 26;308(24):2584-2593.

[38] Flemming JA, Kim WR, Brosgart CL, Terrault NA. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017;65(3):804-812.

[39] Belli LS, Perricone G, Adam R, Cortesi PA, Strazzabosco M, Facchetti R, et al. Impact of DAAs on liver transplantation: major effects on the evolution of indications and results. An ELITA study based on the ELTR registry. J Hepatol. 2018;69(4):810-817.

[40] Crespo G, Trota N, Londoño M-C, Mauro E, Baliellas C, Castells L, et al. The efficacy of direct anti-HCV drugs improves early post-liver transplant survival and induces significant changes in waiting list composition. J Hepatol. 2018;69(1):11-17.

[41] Murag S, Dennis BB, Kim D, Ahmed A, Cholankeril G. Recent advances in liver transplantation with HCV seropositive donors. F1000Res. 2019 Dec 30;8:F1000 Faculty Rev-2151.

[42] Berenguer M, Prieto M, Rayón JM, Mora J, Pastor M, Ortiz V, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 2000;32:852-858.

[43] Zekry A, Whiting P, Crawford DH, Angus PW, Jeffrey GP, Padbury RT, et al.; Australian and New Zealand Liver Transplant Clinical Study Group. Liver transplantation for HCV-associated liver cirrhosis: Predictors of outcomes in a population with significant genotype 3 and 4 distribution. Liver Transpl 2003;9:339-347.

[44] Gane EJ, Portmann BC, Naoumov NV, Smith HM, Underhill JA, Donaldson PT, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996;334:815-820.

[45] Wali MH, Heydtmann M, Harrison RF, Gunson BK, Mutimer DJ. Outcome of liver transplantation

**99**

2001;33:2709.

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

for patients infected by hepatitis C, including those infected by genotype 4. [54] Mudawi H, Helmy A, Kamel Y, Al Saghier M, Al Sofayan M, Al Sebayel M, et al. Recurrence of hepatitis C virus genotype-4 infection following liver transplantation: Natural history and predictors of outcome. Ann Saudi Med

[55] Yosry A, Abdel-Rahman M,

Clin Transplant 2009;7:157-163.

Esmat G, El-Serafy M, Omar A, Doss W, et al. Recurrence of hepatitis c virus (genotype 4) infection after living-donor liver transplant in Egyptian patients. Exp

[56] Allam N, Al Saghier M, El Sheikh Y, Al Sofayan M, Khalaf H, Al Sebayel M, et al. Clinical outcomes for Saudi and Egyptian patients receiving deceased donor liver transplantation in China. Am J Transplant 2010;10:1834-1841.

[57] Zhou S, Terrault NA, Ferrell L, Hahn JA, Lau JY, Simmonds P, et al. Severity of liver disease in liver transplantation recipients with

hepatitis C virus infection: Relationship to genotype and level of viremia. Hepatology 1996;24:1041-1046.

[58] Alfaleh FZ, Hadad Q, Khuroo MS, Aljumah A, Algamedi A, Alashgar H, et al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int 2004;24:568-574.

[59] Khuroo MS, Khuroo MS, Dahab ST. Meta-analysis: A randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4. Aliment Pharmacol Ther

[60] Kamal SM, El Tawil AA, Nakano T, He Q, Rasenack J, Hakam SA, et al. Peginterferon {alpha}-2b and ribavirin therapy in chronic hepatitis C genotype 4: Impact of treatment duration and viral kinetics on sustained virological response. Gut 2005;54:858-866.

2004;20:931-8.

2009;29:91-7.

[46] Wali M, Harrison RF, Gow PJ, Mutimer D. Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C. Gut

[47] Burak KW, Kremers WK, Batts KP, Wiesner RH, Rosen CB, Razonable RR, et al. Impact of cytomegalovirus infection, year of transplantation, and donor age on outcomes after liver transplan-tation for hepatitis C. Liver

[48] Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, et al. Contribution of donor age to the recentdecrease in patient survival among HCV-infected liver transplant recipients. Hepatology

[49] Al-Sebayel M. Survival after liver transplantation: Experience with 89 cases. Ann Saudi Med

[50] Kizilisik TA, al-Sebayel M, Hammad A, al-Traif I, Ramirez CG, Abdulla A. Hepatitis C recurrence in liver transplant recipients. Transplant

[51] Al Sebayel M, Kizilisik AT, Ramirez C, Altraif I, Hammad AQ, Littlejohn W, et al. Liver transplantation: Experience at King Fahad National Guard Hospital, Riyadh, Saudi Arabia. Transplant Proc

Transplant Proc 1999;31:3157.

[52] al Sebayel M. Liver transplantation: Five-year experience in Saudi Arabia.

[53] Al Sebayel MS, Ramirez CB, Abou Ella K. The first 100 liver transplants in Saudi Arabia. Transplant Proc

Proc 1997;29:2875-2877.

1997;29:2870-2871.

Liver Transpl 2003;9:796-804.

2002;51:248-252.

Transpl 2002;8:362-369.

2002l;36:202-210.

1999;19:216-8.

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

for patients infected by hepatitis C, including those infected by genotype 4. Liver Transpl 2003;9:796-804.

[46] Wali M, Harrison RF, Gow PJ, Mutimer D. Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C. Gut 2002;51:248-252.

[47] Burak KW, Kremers WK, Batts KP, Wiesner RH, Rosen CB, Razonable RR, et al. Impact of cytomegalovirus infection, year of transplantation, and donor age on outcomes after liver transplan-tation for hepatitis C. Liver Transpl 2002;8:362-369.

[48] Berenguer M, Prieto M, San Juan F, Rayon JM, Martinez F, Carrasco D, et al. Contribution of donor age to the recentdecrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002l;36:202-210.

[49] Al-Sebayel M. Survival after liver transplantation: Experience with 89 cases. Ann Saudi Med 1999;19:216-8.

[50] Kizilisik TA, al-Sebayel M, Hammad A, al-Traif I, Ramirez CG, Abdulla A. Hepatitis C recurrence in liver transplant recipients. Transplant Proc 1997;29:2875-2877.

[51] Al Sebayel M, Kizilisik AT, Ramirez C, Altraif I, Hammad AQ, Littlejohn W, et al. Liver transplantation: Experience at King Fahad National Guard Hospital, Riyadh, Saudi Arabia. Transplant Proc 1997;29:2870-2871.

[52] al Sebayel M. Liver transplantation: Five-year experience in Saudi Arabia. Transplant Proc 1999;31:3157.

[53] Al Sebayel MS, Ramirez CB, Abou Ella K. The first 100 liver transplants in Saudi Arabia. Transplant Proc 2001;33:2709.

[54] Mudawi H, Helmy A, Kamel Y, Al Saghier M, Al Sofayan M, Al Sebayel M, et al. Recurrence of hepatitis C virus genotype-4 infection following liver transplantation: Natural history and predictors of outcome. Ann Saudi Med 2009;29:91-7.

[55] Yosry A, Abdel-Rahman M, Esmat G, El-Serafy M, Omar A, Doss W, et al. Recurrence of hepatitis c virus (genotype 4) infection after living-donor liver transplant in Egyptian patients. Exp Clin Transplant 2009;7:157-163.

[56] Allam N, Al Saghier M, El Sheikh Y, Al Sofayan M, Khalaf H, Al Sebayel M, et al. Clinical outcomes for Saudi and Egyptian patients receiving deceased donor liver transplantation in China. Am J Transplant 2010;10:1834-1841.

[57] Zhou S, Terrault NA, Ferrell L, Hahn JA, Lau JY, Simmonds P, et al. Severity of liver disease in liver transplantation recipients with hepatitis C virus infection: Relationship to genotype and level of viremia. Hepatology 1996;24:1041-1046.

[58] Alfaleh FZ, Hadad Q, Khuroo MS, Aljumah A, Algamedi A, Alashgar H, et al. Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int 2004;24:568-574.

[59] Khuroo MS, Khuroo MS, Dahab ST. Meta-analysis: A randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4. Aliment Pharmacol Ther 2004;20:931-8.

[60] Kamal SM, El Tawil AA, Nakano T, He Q, Rasenack J, Hakam SA, et al. Peginterferon {alpha}-2b and ribavirin therapy in chronic hepatitis C genotype 4: Impact of treatment duration and viral kinetics on sustained virological response. Gut 2005;54:858-866.

[61] Roulot D, Bourcier V, Grando V, Deny P, Baazia Y, Fontaine H, et al.; Observational VHC4 Study Group. Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection. J Viral Hepat 2007;14:460-467.

[62] Fortune BE, Martinez-Camacho A, Kreidler S, Gralla J, Everson GT. Posttransplant survival is improved for hepatitis C recipients who are RNA negative at time of liver transplantation. Transpl Int 2015;28:980-989.

[63] Everson GT. Treatment of hepatitis C in the patient with decompensated cirrhosis. Clin Gastroenterol Hepatol 2005;3(Suppl 2):S106-S112.

[64] Everson GT, Trotter J, Forman L, Kugelmas M, Halprin A, Fey B, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 2005;42:255-262.

[65] Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl 2002;8:350-355.

[66] Everson GT, Terrault NA, Lok AS, Rodrigo del R, Brown RS Jr, Saab S, et al.; Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology 2013;57:1752-1762.

[67] Dabbous HM, Elmeteini MS, Sakr MA, Montasser IF, Bahaa M, Abdelaal A, et al. Optimizing outcome of recurrent hepatitis C virus genotype 4 after living donor liver transplantation: Moving forward by looking back. Transplant Proc 2014;46:822-827.

[68] Ponziani FR, Milani A, Gasbarrini A, Zaccaria R, Viganò R, Donato MF, et al. Treatment of recurrent genotype 4 hepatitis C after liver transplantation: Early virological response is predictive of sustained virological response. An AISF RECOLT-C group study. Ann Hepatol 2012;11:338-342.

[69] Al-hamoudi W, Mohamed H, Abaalkhail F, Kamel Y, Al-Masri N, Allam N, et al. Treatment of genotype 4 hepatitis C recurring after liver transplantation using a combination of pegylated interferon alfa-2a and ribavirin. Dig Dis Sci 2011;56:1848-52.

[70] Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat. 2012 Jul;19(7):449-464.

[71] Pawlotsky JM. Treatment of chronic hepatitis C: Current and future. Curr Top Microbiol Immunol 2013;369:321-42. doi. org/10.1007/978-3-642-27340-7\_13

[72] Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34-44. doi. org/10.1056/NEJMoa1208953

[73] Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): An open-label, randomised, multicentre phase 2 trial. Lancet 2013;381:2100-2107. doi.org/10.1016/ S0140-6736(13)60247-0

[74] Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis

**101**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

C infection: A randomised, doubleblind, phase 2 trial. Lancet Infect Dis 2013;13:401-8. doi.org/10.1016/

et al, Clinical Study Sofosbuvir-Based Therapy for Genotype 4 HCV Recurrence

Experienced Patients. Can J Gastroenterol

Abdelmonem A, Sayed H, et al. Safety, Efficacy, and Tolerability of Sofosbuvir and Ribavirin in Management of Recurrent Hepatitis C Virus Genotype 4 After Living Donor Liver Transplant in Egypt: What Have We Learned so far? Hepat Mon. 2016 Apr 30;16(5):e35339.

[83] Charlton M, Gane E, Manns MP, Brown RS Jr, Curry MP, Kwo PY, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology

[84] Forns X, Charlton M, Denning J, McHutchison JG, Symonds WT, Brainard D, et al. Sofosbuvir

compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. Hepatology

[85] Colombo M, Aghemo A, Liu H, Zhang J, Dvory-Sobol H, Hyland R, et al. Treatment With Ledipasvir-Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial. Ann Intern Med. 2017 Jan 17;166(2):109-117.

[86] Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI, et al. Effectiveness of Sofosbuvir, Ledipasvir/ Sofosbuvir, or Paritaprevir/Ritonavir/ Ombitasvir and Dasabuvir Regimens for Treatment of Patients with Hepatitis C in the Veterans Affairs National Health Care System. Gastroenterology. 2016

2015;148:108-117.

2015;61:1485-1494.

Sep;151(3):457-471.e5.

[87] Charlton M, Everson GT,

Flamm SL, Kumar P, Landis C, Brown

Post-Liver Transplant Treatment-

[82] Dabbous HM, Montasser IF, Sakr MA, Refai R, Sayam M,

Hepatol. 2016;2016:2872371.

[75] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for

[76] Curry MP, Forns X, Chung RT, Terrault NA, Brown R Jr, Fenkel JM, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: An open-label study. Gastroenterology 2015;148:100-7.e1. doi.

org/10.1053/j.gastro.2014.09.023.

[77] Ruane PJ, Ain D, Stryker R, Meshrekey R, Soliman M, Wolfe PR, et al. Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry. J Hepatol. 2015;62(5):1040.

[78] 78Doss W, Shiha G, Hassany M, Soliman R, Fouad R, Khairy M, et al. Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis c genotype 4. J Hepatol 2015. doi. org/10.1016/j.jhep.2015.04.023.

[79] Abd-Elsalam S, Sharaf-Eldin M, Soliman S, Elfert A, Badawi R, Ahmad YK. Efficacy and safety of sofosbuvir plus ribavirin for treatment of cirrhotic patients with genotype 4 hepatitis C virus in reallife clinical practice. Arch Virol. 2018

[80] Elsharkawy A, Fouad R, El Akel W, El Raziky M, Hassany M, Shiha G, et al. Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt. Aliment Pharmacol Ther. 2017

[81] Ajlan A, Al-Jedai A, Elsiesy H, Alkortas D, Al-Hamoudi W, Alarieh R,

Jan;163(1):51-56.

Mar;45(5):681-687.

previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878- 87. doi.org/10.1056/NEJMoa1214853.

S1473-3099(13)70033-1

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

C infection: A randomised, doubleblind, phase 2 trial. Lancet Infect Dis 2013;13:401-8. doi.org/10.1016/ S1473-3099(13)70033-1

[75] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878- 87. doi.org/10.1056/NEJMoa1214853.

[76] Curry MP, Forns X, Chung RT, Terrault NA, Brown R Jr, Fenkel JM, et al. Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: An open-label study. Gastroenterology 2015;148:100-7.e1. doi. org/10.1053/j.gastro.2014.09.023.

[77] Ruane PJ, Ain D, Stryker R, Meshrekey R, Soliman M, Wolfe PR, et al. Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry. J Hepatol. 2015;62(5):1040.

[78] 78Doss W, Shiha G, Hassany M, Soliman R, Fouad R, Khairy M, et al. Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis c genotype 4. J Hepatol 2015. doi. org/10.1016/j.jhep.2015.04.023.

[79] Abd-Elsalam S, Sharaf-Eldin M, Soliman S, Elfert A, Badawi R, Ahmad YK. Efficacy and safety of sofosbuvir plus ribavirin for treatment of cirrhotic patients with genotype 4 hepatitis C virus in reallife clinical practice. Arch Virol. 2018 Jan;163(1):51-56.

[80] Elsharkawy A, Fouad R, El Akel W, El Raziky M, Hassany M, Shiha G, et al. Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt. Aliment Pharmacol Ther. 2017 Mar;45(5):681-687.

[81] Ajlan A, Al-Jedai A, Elsiesy H, Alkortas D, Al-Hamoudi W, Alarieh R, et al, Clinical Study Sofosbuvir-Based Therapy for Genotype 4 HCV Recurrence Post-Liver Transplant Treatment-Experienced Patients. Can J Gastroenterol Hepatol. 2016;2016:2872371.

[82] Dabbous HM, Montasser IF, Sakr MA, Refai R, Sayam M, Abdelmonem A, Sayed H, et al. Safety, Efficacy, and Tolerability of Sofosbuvir and Ribavirin in Management of Recurrent Hepatitis C Virus Genotype 4 After Living Donor Liver Transplant in Egypt: What Have We Learned so far? Hepat Mon. 2016 Apr 30;16(5):e35339.

[83] Charlton M, Gane E, Manns MP, Brown RS Jr, Curry MP, Kwo PY, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology 2015;148:108-117.

[84] Forns X, Charlton M, Denning J, McHutchison JG, Symonds WT, Brainard D, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. Hepatology 2015;61:1485-1494.

[85] Colombo M, Aghemo A, Liu H, Zhang J, Dvory-Sobol H, Hyland R, et al. Treatment With Ledipasvir-Sofosbuvir for 12 or 24 Weeks in Kidney Transplant Recipients With Chronic Hepatitis C Virus Genotype 1 or 4 Infection: A Randomized Trial. Ann Intern Med. 2017 Jan 17;166(2):109-117.

[86] Ioannou GN, Beste LA, Chang MF, Green PK, Lowy E, Tsui JI, et al. Effectiveness of Sofosbuvir, Ledipasvir/ Sofosbuvir, or Paritaprevir/Ritonavir/ Ombitasvir and Dasabuvir Regimens for Treatment of Patients with Hepatitis C in the Veterans Affairs National Health Care System. Gastroenterology. 2016 Sep;151(3):457-471.e5.

[87] Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, Brown RS Jr, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015 Sep; 149(3):649-659.

[88] Kohli A, Kapoor R, Sims Z, Nelson A, Sidharthan S, Lam B, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study. Lancet Infect Dis. 2015;15(9):1049.

[89] Crespo J, Calleja JL, Fernández I, Sacristan B, Ruiz-Antorán B, Ampuero J, et al; Spanish Group for the Study of the Use of Direct-acting Drugs Hepatitis C Collaborating Group. Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection. Clin Gastroenterol Hepatol. 2017 Jun;15(6):945-949.e1.

[90] Abergel A, Metivier S, Samuel D, Jiang D, Kersey K, Pang PS, et al. Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection. Hepatology. 2016 Oct;64(4):1049-1056.

[91] Sanai FM, Altraif IH, Alswat K, AlZanbagi A, Babatin MA, AlMousa A, et al. Real life efficacy of ledipasvir/ sofosbuvir in hepatitis C genotype 4-infected patients with advanced liver fibrosis and decompensated cirrhosis. J Infect. 2018 Jun;76(6):536-542.

[92] Shiha G, Esmat G, Hassany M, Soliman R, Elbasiony M, Fouad R, et al. Ledipasvir/sofosbuvir with or without ribavirin for 8 or 12 weeks for the treatment of HCV genotype 4 infection: results from a randomised phase III study in Egypt. Gut. 2019 Apr;68(4):721-728.

[93] Abaalkhail F, Elsiesy H, Elbeshbeshy H, Shawkat M, Yousif S, Ullah W, et al. Treatment of Patients With Hepatitis C Virus Infection With Ledipasvir-Sofosbuvir in the Liver Transplant Setting. Transplantation. 2017 Nov;101(11):2739-2745.

[94] Manns M, Forns X, Samuel D, Denning J, Arterburn S, Brandt-Sarif T, et al. Ledipasvir/sofosbuvir with ribavirin is safe and efficacious in decompensated and post-liver transplantation patients with HCV infection: Preliminary results of the SOLAR-2 trial. J Hepatol 2015;62:S187.

[95] Ciesek S, Proske V, Otto B, Pischke S, Costa R, Lüthgehetmann M, et al. Efficacy and safety of sofosbuvir/ ledipasvir for the treatment of patients with hepatitis C virus re-infection after liver transplantation. Transpl Infect Dis. 2016 Jun;18(3):326-332.

[96] Samuel D, Manns M, Forns X, Flamm SL, Reddy KR, Denning J, et al. Ledipasvir/sofosbuvir with ribavirin is safe in >600 decompensated and post-liver transplantation patients with HCV infection: An integrated safety analysis of the SOLAR-1 and SOLAR-2 trials. Lancet Infect Dis. 2016 Jun;16(6):685-697.

[97] El-Khayat H, Fouad Y, Mohamed HI, El-Amin H, Kamal EM, Maher M, et al. Sofosbuvir plus daclatasvir with or without ribavirin in 551 patients with hepatitis C-related cirrhosis, genotype 4. Aliment Pharmacol Ther. 2018 Mar;47(5):674-679.

[98] Hezode C, Abergel A, Chas J, et al. Sustanined virologic response to daclatasvir and sofosbuvir with or without ribavirin, among patients in the French daclatasvir ATU programme infected with HCV genotypes 4,5,6. J Hepatol. 2016;64:S133–S142.

[99] Babatin MA, Alghamdi AS, Albenmousa A, Alaseeri A, Aljarodi M, Albiladi H, et al. Efficacy and Safety of Simeprevir or Daclatasvir in Combination with Sofosbuvir for the

**103**

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

Treatment of Hepatitis C Genotype 4 Infection. J Clin Gastroenterol. 2018

predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Infect Drug Resist. 2018 Mar

[106] Omar H, El Akel W, Elbaz T, El Kassas M, Elsaeed K, El Shazly H, et al. Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt. Aliment Pharmacol Ther. 2018

[107] Coilly A, Fougerou-Leurent C, de Ledinghen V, Houssel-Debry P, Duvoux C, Di Martino V, et al.

Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence after liver transplantation - The CO23 ANRS CUPILT study. J Hepatol. 2016 Jun 1. pii: S0168-8278(16)30253-7.

[108] Dumortier J, Leroy V, Duvoux C, de Ledinghen V, Francoz C, Houssel-Debry P, et al. Sofosbuvir-based treatment of hepatitis C with severe fibrosis (METAVIR F3/F4) after liver transplantation. Liver Transpl. 2016

[109] Leroy V, Dumortier J, Coilly A, Sebagh M, Fougerou-Leurent C, Radenne S, et al. Efficacy of sofosbuvir

and daclatasvir in patients with fibrosing cholestatic hepatitis C after liver transplantation. Clin Gastroenterol Hepatol 2015 Nov; 13(11):1993-2001. doi: 10.1016/j.cgh.2015.05.030.

[110] El Raziky M, Gamil M, Ashour MK, Sameea EA, Doss W, Hamada Y, et al. Simeprevir plus sofosbuvir for eight or 12 weeks in treatment-naïve and treatment-

experienced hepatitis C virus genotype 4 patients with or without cirrhosis. J Viral Hepat. 2017 Feb;24(2):102-110.

[111] Buti M, Calleja JL, Lens S, Diago M, Ortega E, Crespo J, et al.

28;11:441-445.

Feb;47(3):421-431.

Oct;22(10):1367-1378.

[100] Lawitz E, Poordad F, Gutierrez JA, Beumont M, Beets G, Vandevoorde A, et al. Simeprevir, daclatasvir, and sofosbuvir for hepatitis C virus-infected patients: Long-term follow-up results from the open-label, Phase II IMPACT study. Health Sci Rep. 2020 Feb

[101] Darweesh SK, Elsaeed K, Omar H, El Raziky M, Elakel W, Elserafy M, et al. High SVR rate following retreatment of non-sustained virological responders to sofosbuvir based anti-HCV therapies regardless of RAS testing: A real-life multicenter study. Expert Rev Gastroenterol Hepatol. 2019

May/Jun;52(5):452-457.

22;3(2):e145.

Sep;13(9):907-914.

[102] Lashen SA, Shamseya MM, Madkour MA, Aboufarrag GA. Tolerability and effectiveness of generic direct-acting antiviral drugs in eradication of hepatitis C genotype 4 among Egyptian patients. Liver Int.

2019 May;39(5):835-843.

Oct;30(10):1194-1199.

Jul;12(4):348-355.

[104] Abdel-Moneim A, Aboud A, Abdel-Gabaar M, Zanaty MI, Ramadan M. Efficacy and safety of sofosbuvir plus daclatasvir with or without ribavirin: large real-life results of patients with chronic hepatitis C genotype 4. Hepatol Int. 2018

[105] Ahmed OA, Elsebaey MA, Fouad MHA, Elashry H, Elshafie AI, Elhadidy AA, et al. Outcomes and

[103] El-Nahaas SM, Fouad R,

Elsharkawy A, Khairy M, Elhossary W, Anwar I, et al. High sustained virologic response rate using generic directly acting antivirals in the treatment of chronic hepatitis C virus Egyptian patients: single-center experience. Eur J Gastroenterol Hepatol. 2018

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

Treatment of Hepatitis C Genotype 4 Infection. J Clin Gastroenterol. 2018 May/Jun;52(5):452-457.

[100] Lawitz E, Poordad F, Gutierrez JA, Beumont M, Beets G, Vandevoorde A, et al. Simeprevir, daclatasvir, and sofosbuvir for hepatitis C virus-infected patients: Long-term follow-up results from the open-label, Phase II IMPACT study. Health Sci Rep. 2020 Feb 22;3(2):e145.

[101] Darweesh SK, Elsaeed K, Omar H, El Raziky M, Elakel W, Elserafy M, et al. High SVR rate following retreatment of non-sustained virological responders to sofosbuvir based anti-HCV therapies regardless of RAS testing: A real-life multicenter study. Expert Rev Gastroenterol Hepatol. 2019 Sep;13(9):907-914.

[102] Lashen SA, Shamseya MM, Madkour MA, Aboufarrag GA. Tolerability and effectiveness of generic direct-acting antiviral drugs in eradication of hepatitis C genotype 4 among Egyptian patients. Liver Int. 2019 May;39(5):835-843.

[103] El-Nahaas SM, Fouad R, Elsharkawy A, Khairy M, Elhossary W, Anwar I, et al. High sustained virologic response rate using generic directly acting antivirals in the treatment of chronic hepatitis C virus Egyptian patients: single-center experience. Eur J Gastroenterol Hepatol. 2018 Oct;30(10):1194-1199.

[104] Abdel-Moneim A, Aboud A, Abdel-Gabaar M, Zanaty MI, Ramadan M. Efficacy and safety of sofosbuvir plus daclatasvir with or without ribavirin: large real-life results of patients with chronic hepatitis C genotype 4. Hepatol Int. 2018 Jul;12(4):348-355.

[105] Ahmed OA, Elsebaey MA, Fouad MHA, Elashry H, Elshafie AI, Elhadidy AA, et al. Outcomes and

predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Infect Drug Resist. 2018 Mar 28;11:441-445.

[106] Omar H, El Akel W, Elbaz T, El Kassas M, Elsaeed K, El Shazly H, et al. Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt. Aliment Pharmacol Ther. 2018 Feb;47(3):421-431.

[107] Coilly A, Fougerou-Leurent C, de Ledinghen V, Houssel-Debry P, Duvoux C, Di Martino V, et al. Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence after liver transplantation - The CO23 ANRS CUPILT study. J Hepatol. 2016 Jun 1. pii: S0168-8278(16)30253-7.

[108] Dumortier J, Leroy V, Duvoux C, de Ledinghen V, Francoz C, Houssel-Debry P, et al. Sofosbuvir-based treatment of hepatitis C with severe fibrosis (METAVIR F3/F4) after liver transplantation. Liver Transpl. 2016 Oct;22(10):1367-1378.

[109] Leroy V, Dumortier J, Coilly A, Sebagh M, Fougerou-Leurent C, Radenne S, et al. Efficacy of sofosbuvir and daclatasvir in patients with fibrosing cholestatic hepatitis C after liver transplantation. Clin Gastroenterol Hepatol 2015 Nov; 13(11):1993-2001. doi: 10.1016/j.cgh.2015.05.030.

[110] El Raziky M, Gamil M, Ashour MK, Sameea EA, Doss W, Hamada Y, et al. Simeprevir plus sofosbuvir for eight or 12 weeks in treatment-naïve and treatmentexperienced hepatitis C virus genotype 4 patients with or without cirrhosis. J Viral Hepat. 2017 Feb;24(2):102-110.

[111] Buti M, Calleja JL, Lens S, Diago M, Ortega E, Crespo J, et al. Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO). Aliment Pharmacol Ther. 2017 Feb;45(3):468-475.

[112] Abdel-Moneim A, Aboud A, Abdel-Gabbar M, Zanaty MI, Elbary AAA, Ramadan M. Sofosbuvir in combination with ribavirin or simeprevir: real-life study of patients with hepatitis C genotype 4. Ann Gastroenterol. 2019 Jan-Feb;32(1):93-98.

[113] Lawitz E, Poordad F, Gutierrez JA, Kakuda TN, Picchio G, Beets G, et al. Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease. J Viral Hepat. 2017 Apr;24(4):287-294.

[114] Ahmed OA, Elsebaey MA, Fouad MHA, Elkadeem M, Badawi R, Khayyal A, et al. Outcomes of Treatment and Predictors of Response to Sofosbuvir Plus Simeprevir in Hepatitis C Virus with Genotype-4 Infection. Infect Disord Drug Targets. 2020;20(3):389-395.

[115] Eletreby R, Elakel W, Said M, El Kassas M, Seif S, Elbaz T, et al. Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in 6211 chronic HCV genotype IV infected patients. Liver Int. 2017 Apr;37(4):534-541.

[116] Wang BQ, Wang YL, Shi KQ. Real life Egyptian experience of efficacy and safety of Simeprevir/Sofosbuvir therapy in HCV genotype IV infected patients. Liver Int. 2017 May;37(5):765.

[117] Yosry A, Gamal Eldeen H, Medhat E, Mehrez M, Zayed N, Elakel W, et al. Efficacy and safety of sofosbuvir-based therapy in hepatitis C virus recurrence post living donor liver transplant: A real life egyptian experience. J Med Virol. 2019 Apr;91(4):668-676.

[118] Sanchez Antolin G, Testillano M, Pascasio JM, Narvaez Rodriguez I, Prieto M, et al; Spanish Society of Liver Transplantation Study Group Collaborating Group. Efficacy and Safety of Therapy with Simeprevir and Sofosbuvir in Liver Transplant Recipients Infected by Hepatitis C Virus Genotype 4: Cohort Spanish Society of Liver Transplantation Cohort. Transplant Proc. 2016 Nov;48(9):3013-3016.

[119] Ferenci P, Bourgeois S, Buggisch P, Norris S, Curescu M, Larrey D, et al. Real-world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1- and 4-infected patients with diverse comorbidities and comedications: A pooled analysis of post-marketing observational studies from 13 countries. J Viral Hepat. 2019 Jun;26(6):685-696.

[120] Waked I, Shiha G, Qaqish RB, Esmat G, Yosry A, Hassany M, et al. Ombitasvir, paritaprevir, and ritonavir plus ribavirin for chronic hepatitis C virus genotype 4 infection in Egyptian patients with or without compensated cirrhosis (AGATE-II): a multicentre, phase 3, partly randomised open-label trial. Lancet Gastroenterol Hepatol. 2016 Sep;1(1):36-44.

[121] Asselah T, Hézode C, Qaqish RB, ElKhashab M, Hassanein T, Papatheodoridis G, et al. Ombitasvir, paritaprevir, and ritonavir plus ribavirin in adults with hepatitis C virus genotype 4 infection and cirrhosis (AGATE-I): a multicentre, phase 3, randomised open-label trial. Lancet Gastroenterol Hepatol. 2016 Sep;1(1):25-35.

[122] Aygen B, Demirtürk N, Yıldız O, Çelen MK, Çelik İ, Barut Ş, et al. Real-world efficacy, safety, and clinical outcomes of ombitasvir/paritaprevir/ ritonavir ± dasabuvir ± ribavirin combination therapy in patients with hepatitis C virus genotype 1 or

**105**

Mar;72(3):441-449.

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

4 infection: The Turkey experience experience. Turk J Gastroenterol. 2020 [128] Reau N, Kwo PY, Rhee S, Brown RS Jr, Agarwal K, Angus P, et al. Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients with Hepatitis C Virus Infection. Hepatology.

[129] Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015 Dec

[130] Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al; ASTRAL-4 Investigators. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015 Dec

[132] Bourlière M, Gordon SC, Flamm SL,

Cooper CL, Ramji A, Tong M, et al; POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017 Jun

[133] Cardona-Gonzalez MG,

Goldman JD, Narayan L, Brainard DM, Kowdley KV. Sofosbuvir, Velpatasvir, and Voxilaprevir for Treatment of Recurrent Hepatitis C Virus Infection After Liver Transplantation. Hepatol Commun. 2018 Nov 14;2(12):1446-1450.

[134] Asselah T, Reesink H, Gerstoft J,

Robertson M, et al. Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis. Liver Int. 2018

de Ledinghen V, Pockros PJ,

Sep;38(9):1583-1591.

2018 Oct;68(4):1298-1307.

31;373(27):2599-2607.

31;373(27):2618-2628.

Sep;69(3):603-607.

1;376(22):2134-2146.

[131] Agarwal K, Castells L, Müllhaupt B, Rosenberg WMC, McNabb B, Arterburn S, et al. Sofosbuvir/velpatasvir for 12 weeks in genotype 1-4 HCV-infected liver transplant recipients. J Hepatol. 2018

[123] Petta S, Marzioni M, Russo P, Aghemo A, Alberti A, Ascione A, et al; ABACUS study group; AIFA team. Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study. Lancet Gastroenterol Hepatol.

Apr;31(4):305-317.

2017 Jun;2(6):427-434.

[124] Perelló C, Carrión JA, Ruiz-Antorán B, Crespo J, Turnes J,

Viral Hepat. 2017;24:226-237.

[125] Wedemeyer H, Craxí A,

Roberts SK, et al. Real-world

Zuckerman E, Dieterich D, Flisiak R,

effectiveness of ombitasvir/paritaprevir/ ritonavir±dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 or 4 infection: A meta-analysis. J Viral Hepat. 2017 Nov;24(11):936-943.

[126] Forns X, Lee SS, Valdes J, Lens S, Ghalib R, Aguilar H, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, openlabel, multicentre phase 3 trial. Lancet Infect Dis. 2017 Oct;17(10):1062-1068.

[127] Brown RS Jr, Buti M, Rodrigues L, Chulanov V, Chuang WL, Aguilar H, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial. J Hepatol. 2020

Llaneras J, et al. Spanish Collaborative Group for the Study of the Use of Hepatitis C Direct-Acting Drugs. Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1-4 chronic hepatitis C virus infection. J

*Liver Transplantation and HCV Genotype 4 DOI: http://dx.doi.org/10.5772/intechopen.95831*

4 infection: The Turkey experience experience. Turk J Gastroenterol. 2020 Apr;31(4):305-317.

[123] Petta S, Marzioni M, Russo P, Aghemo A, Alberti A, Ascione A, et al; ABACUS study group; AIFA team. Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study. Lancet Gastroenterol Hepatol. 2017 Jun;2(6):427-434.

[124] Perelló C, Carrión JA, Ruiz-Antorán B, Crespo J, Turnes J, Llaneras J, et al. Spanish Collaborative Group for the Study of the Use of Hepatitis C Direct-Acting Drugs. Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1-4 chronic hepatitis C virus infection. J Viral Hepat. 2017;24:226-237.

[125] Wedemeyer H, Craxí A, Zuckerman E, Dieterich D, Flisiak R, Roberts SK, et al. Real-world effectiveness of ombitasvir/paritaprevir/ ritonavir±dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 or 4 infection: A meta-analysis. J Viral Hepat. 2017 Nov;24(11):936-943.

[126] Forns X, Lee SS, Valdes J, Lens S, Ghalib R, Aguilar H, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, openlabel, multicentre phase 3 trial. Lancet Infect Dis. 2017 Oct;17(10):1062-1068.

[127] Brown RS Jr, Buti M, Rodrigues L, Chulanov V, Chuang WL, Aguilar H, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial. J Hepatol. 2020 Mar;72(3):441-449.

[128] Reau N, Kwo PY, Rhee S, Brown RS Jr, Agarwal K, Angus P, et al. Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients with Hepatitis C Virus Infection. Hepatology. 2018 Oct;68(4):1298-1307.

[129] Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015 Dec 31;373(27):2599-2607.

[130] Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al; ASTRAL-4 Investigators. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015 Dec 31;373(27):2618-2628.

[131] Agarwal K, Castells L, Müllhaupt B, Rosenberg WMC, McNabb B, Arterburn S, et al. Sofosbuvir/velpatasvir for 12 weeks in genotype 1-4 HCV-infected liver transplant recipients. J Hepatol. 2018 Sep;69(3):603-607.

[132] Bourlière M, Gordon SC, Flamm SL, Cooper CL, Ramji A, Tong M, et al; POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017 Jun 1;376(22):2134-2146.

[133] Cardona-Gonzalez MG, Goldman JD, Narayan L, Brainard DM, Kowdley KV. Sofosbuvir, Velpatasvir, and Voxilaprevir for Treatment of Recurrent Hepatitis C Virus Infection After Liver Transplantation. Hepatol Commun. 2018 Nov 14;2(12):1446-1450.

[134] Asselah T, Reesink H, Gerstoft J, de Ledinghen V, Pockros PJ, Robertson M, et al. Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis. Liver Int. 2018 Sep;38(9):1583-1591.

[135] Jacobson IM, Lawitz E, Kwo PY, Hézode C, Peng CY, Howe AYM, et al Safety and Efficacy of Elbasvir/ Grazoprevir in Patients with Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis. Gastroenterology. 2017 May;152(6):1372-1382.e2.

[136] Yousif MM, Ahmed H, Elsadek HM, Shendi AM, Gouda TM, Elsayed IA, et al. Real-world safety and effectiveness of retreatment of Egyptian chronic hepatitis C patients not responding to NS5A inhibitorbased therapies. J Viral Hepat. 2020 Nov;27(11):1190-1201.

[137] Said EM, Abdulaziz BA, El Kassas M, El Attar IH, Emadeldeen M, Abd-Elsalam SM. High success rates for the use of sofosbuvir/ombitasvir/ paritaprevir/ritonavir+ribavirin and sofosbuvir/simeprevir/ daclatasvir+ribavirin in retreatment of chronic hepatitis C infection after unsuccessful sofosbuvir/daclatasvir therapy: a real-life experience. Arch Virol. 2020 Jul;165(7):1633-1639.

[138] Abo-Amer YE, Badawi R, El-Abgeegy M, Elsergany HF, Mohamed AA, Mostafa SM, et al. Quadruple Therapy Offers High SVR Rates in Patients with HCV Genotype 4 with Previous Treatment Failure. Adv Virol. 2020 Jul 24;2020:9075905.

[139] de Lédinghen V, Laforest C, Hézode C, Pol S, Renault A, Alric L, et al. Retreatment With Sofosbuvir Plus Grazoprevir/Elbasvir Plus Ribavirin of Patients With Hepatitis C Virus Genotype 1 or 4 Who Previously Failed an NS5A- or NS3-Containing Regimen: The ANRS HC34 REVENGE Study. Clin Infect Dis. 2018 Mar 19;66(7):1013-1018.

[140] Kondili LA, Gaeta GB, Brunetto MR, Di Leo A, Iannone A, Santantonio TA, et al. Incidence of DAA failure and the clinical impact of retreatment in real-life patients

treated in the advanced stage of liver disease: Interim evaluations from the PITER network. PLoS One. 2017 Oct 4;12(10):e0185728.

[141] Krassenburg LAP, Maan R, Ramji A, Manns MP, Cornberg M, Wedemeyer H, et al. Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity. J Hepatol. 2020 Nov 23:S0168-8278(20)33805-8.

[142] Belli LS, Berenguer M, Cortesi PA, Strazzabosco M, Rockenschaub SR, Martini S, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. J Hepatol. 2016 May 17. pii: S0168-8278(16)30196-9.

[143] Perricone G, Duvoux C, Berenguer M, Cortesi PA, Vinaixa C, Facchetti R, et al; European Liver and Intestine Transplant Association (ELITA). Delisting HCV-infected liver transplant candidates who improved after viral eradication: Outcome 2 years after delisting. Liver Int. 2018 Dec;38(12):2170-2177.

[144] Afdhal N, Everson GT, Calleja JL, McCaughan G, Bosch J, Denning J, et al. Effect of long term viral suppression with sofosbuvir + ribavirin on hepatic venous pressure gradient in HCV-infected patients with cirrhosis and portal hypertension. J Hepatol 2015;62(Suppl 2):S269–S270.

**107**

Section 6

Hepatocellular Carcinoma

and Antiviral Therapies

Section 6
