Hepatitis C treatment in liver transplant setting

Watch a video presentation of this article

Watch the interview with the author

Answer questions and earn CME

Abbreviations

AASLD

American Association for the Study of Liver Diseases

DAA

direct‐acting antiviral

FDA

US Food and Drug Administration

HCV

hepatitis C virus

LT

liver transplantation

PI

protease inhibitor

SVR

sustained virologic response.

Infection with hepatitis C virus (HCV) is currently the most common indication for liver transplantation (LT) in the United States. Compared to other etiologies, patient and graft survival rates are inferior due to progressive fibrosis driven by HCV recurrence.1 Recurrent hepatitis C infection of the allograft is universal and immediate following LT and associated with accelerated progression to cirrhosis (approximately 40% within 5 years of LT), graft loss, and death.2 Achievement of HCV sustained virologic response (SVR) is associated with improved graft and patient survival, but the timing of HCV treatment (pre‐LT versus post‐LT) is still debatable. The rapid evolution of HCV therapies over the past 3 years and approval of newer direct‐acting antivirals (DAAs) has mandated frequent changes to our approach to these patients. This review provides a concise update of American Association for the Study of Liver Diseases (AASLD) practice guidelines for HCV treatment and also includes the data presented at AASLD's The Liver Meeting, November 2014 in Boston, MA.

Timing of HCV Treatment

Historically, two principal strategies have existed to treat HCV: (1) pre–liver transplant for those who have well‐compensated cirrhosis and can tolerate 48 or 72 weeks of interferon‐based therapy, and (2) post–liver transplant, either pre‐emptive treatment or treatment following evidence of histological recurrence.3 Of all the host factors, cirrhosis has remained one of the important factors that negatively impacts SVR. Approval of DAAs and phasing out of interferon‐based therapies has resulted in simplified and shortened duration of therapies which are well tolerated by the majority of patients. As such, another approach that has emerged in many transplant hepatology practices is to offer abbreviated duration (4‐24 weeks) of oral DAA therapy to waitlisted patients, and have them undergo transplantation when they are aviremic. This strategy has prevented HCV recurrence in 64% of the transplant recipients.4

HCV Treatment in the Pre–Liver Transplant Setting

Interferon‐based therapy is ideally contraindicated in individuals with cirrhosis, because there is a potential risk of hepatic decompensation, infection/sepsis, and even death in this setting. Therefore, AASLD recommends HCV treatment with interferon‐free regimens (Table 1) that contain at least two DAAs for genotype 1 patients with compensated cirrhosis.5

Table 1.

Hepatitis C in Compensated Cirrhosis

Compensated Cirrhotics	DAA regimen	Duration	Preferred
Genotype 1
Treatment‐naive	a) Sofosbuvir 400 mg + ledipasvir 90 mg FDC daily	12 weeks	Y
	b) Paritaprevir 150 mg/ritonavir 100 mg daily + ombitasvir (25 mg) daily + dasabuvir 250 mg twice daily (add weight‐based ribavirin only in 1a) daily	12 weeks (1b) 24 weeks (1a)	Y Y
	c) Sofosbuvir 400 mg + simeprevir 150 mg daily	24 weeks	Y
Treatment experienced	a) Sofosbuvir 400 mg + ledipasvir 90 mg FDC daily	24 weeks	Y
Genotype 2
Treatment‐ naive/experienced (PR failure)	a) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily	16 weeks	Y
	b) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily + Peg‐IFN weekly	12 weeks	N
Genotype 3
Treatment‐ naive/experienced (PR failure)	a) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily	24 weeks	Y
	b) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily + Peg‐IFN weekly	12 weeks	N
Genotype 4
Treatment‐naive/ experienced (PR failure)	a) Sofosbuvir 400 mg + ledipasvir 90 mg FDC daily	12 weeks	Y
	b) Paritaprevir 150 mg/ritonavir 100 mg + ombitasvir (25 mg) + ribavirin (weight‐based) daily	12 weeks	Y
	c) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily	24 weeks	Y
	d) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily + Peg‐IFN weekly	12 weeks	N
Genotype 5
Treatment‐naive/experienced (PR failure)	a) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily + Peg‐IFN weekly	12 weeks	Y
	b) Ribavirin (weight‐based) daily + Peg‐IFN weekly	48 weeks	N
Genotype 6
Treatment‐ naive/experienced (PR failure)	a) Sofosbuvir 400 mg + ledipasvir 90 mg FDC daily	12 weeks	Y
	b) Sofosbuvir 400 mg daily + ribavirin (weight‐based) daily + Peg‐IFN weekly	12 weeks	N

Abbreviations: DAA, direct‐acting antiviral; FDC, fixed‐dose combination; Peg‐IFN, pegylated interferon.

In patients with decompensated cirrhosis with moderate or severe hepatic impairment, AASLD recommends management of such patients by a medical practitioner with expertise in HCV or ideally by a transplant physician. Given the paucity of data in newly approved DAAs, AASLD recommends the following treatment strategies (Table 2) in patients with decompensated cirrhosis.5 Preliminary results of a prospective multicenter study evaluating the efficacy of sofosbuvir and ledipasvir with ribavirin in patients with decompensated cirrhosis was presented at AASLD The Liver Meeting 2014.6 High rates of SVR were noted even in this difficult‐to‐treat population, with a trend for improvement in liver function.6, 7

Table 2.

Hepatitis C Treatment in Patients With Decompensated Cirrhosis

Decompensated Cirrhotics	DAA regimen	Duration	Preferred
Genotype 1, 4
Sofosbuvir‐naive	a) Sofosbuvir 400 mg + Ledipasvir 90 mg FDC daily + ribavirin (initial dose 600 mg daily, uptitrate as tolerated)	12 weeks	Y
	b) Sofosbuvir 400 mg + lesipasvir 90 mg FDC daily (ribavirin‐intolerant/ineligible)	24 weeks	Y
Sofosbuvir failure	Sofosbuvir 400 mg + ledipasvir 90 mg FDC daily + ribavirin (initial dose 600 mg daily, uptitrate as tolerated)	24 weeks	Y
Genotype 2, 3	Sofosbuvir 400mg daily + ribavirin (weight‐based) daily	48 weeks	Y

*Ribavirin (weight‐based): 1000 mg [<75 kg] to 1200 mg [≥75 kg]

Abbreviations: DAA, direct‐acting antiviral; FDC, fixed‐dose combination.

Newer Agents/Strategies

Daclatasvir and sofosbuvir with or without ribavirin for 12 weeks in those with HCV genotypes 1, 2, and 3 (phase 2 study) has showed 100% SVR in patients with advanced fibrosis (F3, F3‐4).8 A novel strategy of offering abbreviated duration (approximately 4‐16 weeks) of HCV therapy with DAA and LT of an aviremic patient has shown to prevent recurrent HCV in the allograft by 64%.4 Hepatitis C immunoglobulin (HCIG) is another agent under investigation which if administered in aviremic or low viremic (<100 IU/mL) in the peritransplant period could prevent recurrence in the allograft (Figure 1).9 An abstract in AASLD 2014 showed that HCV treatment with sofosbuvir‐ledipasvir combination did not improve quantitative hepatic function, hepatic filtration rate, or disease severity index in the short‐term follow‐up.10 Therefore, it can be argued that HCV treatment with newer DAAs could be potentially considered after LT in a subset of patients with decompensated cirrhosis who cannot tolerate or who failed therapy with the existing DAAs.

Figure 1.

HCV treatment options in a liver transplant candidate.

HCV treatment in the post&ndash;liver transplant setting

The severity of HCV recurrence post‐LT is quite variable and can range from more common mild elevation of serum aminotransferases to an infrequent occurrence of 2%‐5% of a severe, rapidly progressive, cholestatic hepatitis leading to graft failure within 1 year following LT. Many factors have been identified as predictors of more severe post‐LT recurrence including advanced donor age, higher HCV RNA levels at the time of LT, repeated bouts of rejection, and use of OKT3 or high‐dose intravenous steroid boluses for acute rejection.11, 12, 13 Other important recipient factors that predict advanced recurrent HCV include female sex, African American race, and coinfection with HIV.14, 15, 16

Pre‐emptive treatment of HCV recurrence after LT is commenced immediately post‐transplantation and is based on the hypothesis that virologic recurrence is universal in all patients. The potential advantages of this strategy are that HCV RNA levels will be at their lowest and liver fibrosis will be minimal.3 When pegylated interferon with ribavirin were standard‐of‐care for HCV treatment, many physicians preferred to wait for confirmed histologic recurrence in the allograft due to potential risks of rejection or de novo autoimmune hepatitis associated with interferon therapy. It seems feasible in the current interferon‐free era of HCV treatment, with better tolerability and fewer drug&ndash;drug interactions, that the former approach of pre‐emptive treatment will begin to gain favor and likely will become standard‐of‐care.

In recent years, achieving SVR has been shown to lead to increased graft survival, regression of graft fibrosis, and improvement in long‐term survival.17, 18 Previously, achieving SVR was quite challenging and fraught with complications. The use of pegylated interferon with ribavirin in the post‐LT setting has been associated with poor tolerability and, more importantly, poor SVR. A pooled analysis from 48 trials estimated SVR rates with pegylated interferon in combination with ribavirin were 27% with a pooled discontinuation rate of 26%.19

The first DAAs, telaprevir and boceprevir, both first‐generation protease inhibitors (PIs), were approved by the US Food and Drug Administration (FDA) in 2011 to be used in combination with pegylated interferon and ribavirin for treatment of genotype 1 HCV, but never received FDA approval for use in post‐LT patients. However, due to lack of better options and a dire need by some patients, these medications were used in the post‐LT setting. A recent multicenter retrospective study demonstrated an intent‐to‐treat SVR12 rate of 63%.20 Notoriously, the first‐generation PI had significant drug‐drug interactions requiring dose modifications of standard post‐LT immunosuppressive agents such as tacrolimus, cyclosporine, and mTOR inhibitors. Further complicating this treatment regimen, when these PIs were added to pegylated interferon and ribavirin, numerous adverse reactions were encountered, including severe anemia requiring blood transfusions, renal failure, and even death.

In late 2013 with the approval of simeprevir, a NS3/4A PI and sofosbuvir, a pan‐genotypic NS5B nucleotide analog, interferon‐free treatment of HCV has become an option with dramatically improved efficacy, and ease of HCV treatment after LT. In mid‐2014, based on the risks of interferon in LT patients, suboptimal SVR rates of 70% with sofosbuvir/ribavirin in post‐LT patients21 and impressive phase 2 data in non‐LT genotype 1 HCV patients from the COSMOS trial,22 the AASLD and Infectious Diseases Society of America issued guidance for the use of sofosbuvir plus simeprevir with or without ribavirin for 12 to 24 weeks.5 See Table 3 for current AASLD guidelines juxtaposed with our recommendations. Recently, data on the use of sofosbuvir plus simeprevir in post‐LT situations for genotype 1 HCV patients was presented at the AASLD 2014 annual meeting, demonstrating overall SVR12 rates of 91%‐92% with only 12 weeks of treatment and remarkably, independent of use of ribavirin.23, 24 Importantly, both studies noticed a significant decrease in SVR to approximately 65% in genotype 1a patients with Metavir F3‐F4 in allograft.23, 24

Table 3.

Hepatitis C Treatment Post–Liver Transplantation

Genotype	Per AASLD Guidelines
1a/1b	Daily fixed‐dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight‐based RBV for 12 weeks
	Or
	Daily fixed‐dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks is an alternative regimen for treatment‐naive patients with compensated liver disease who are RBV‐intolerant or ineligible
	Or
	Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight‐based RBV for 12 weeks for an alternative regimen for patients with HCV genotype 1 in the allograft, including compensated cirrhosis
2	Daily sofosbuvir (400 mg) and weight‐based RBV for 24 weeks
3	Daily sofosbuvir (400 mg) and weight‐based RBV for 24 weeks

Abbreviations: AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; RBV, ribavirin.

Also presented at the AASLD 2014 annual meeting was analysis from the SOLAR‐1 study, which evaluated 12 versus 24 weeks of sofosbuvir/ledipasvir plus weight‐based ribavirin among 223 genotype 1 and 4 patients who developed HCV recurrence following liver transplantation. Among noncirrhotic patients, SVR12 rates were 96% (n = 53/55) and 98% (n = 55/56) following 12 and 24 weeks of treatment, respectively. For patients with compensated cirrhosis, SVR12 rates were 96% for both 12 weeks (n = 25/26) and 24 weeks (n = 24/25) of therapy. SVR12 rates among patients with Child‐Pugh class B decompensated cirrhosis were 85% for 12 weeks (n = 22/26) and 83% for 24 weeks (n = 15/18) of therapy.7

Data were also presented at the 2014 AASLD annual meeting from an ongoing phase 2 trial known as the CORAL‐I study, which comprised treatment with ombitasvir (NS5A inhibitor), ABT‐450 (NS3/4A PI) boosted with ritonavir and dasabuvir (non‐nucleoside NS5B polymerase inhibitor) with ribavirin in adult noncirrhotic (Metavir score ≤ F2) genotype 1 HCV post‐LT patients. Results showed that noncirrhotic LT patients with recurrent genotype 1 HCV and who were new to treatment after transplantation achieved an SVR12 rate of 97.1% (n = 33/34) after 24 weeks of treatment (Figure 2).

Figure 2.

Hepatitis C treatment efficacy post&ndash;liver transplantation.

We are in a time of rapidly evolving treatment strategies for HCV and continue to make significant strides in the management of HCV, both pre‐ and post‐LT. Despite all the excitement and success in the treatment of HCV, none of the aforementioned regimens are FDA‐approved in the post‐LT setting and at this time are still considered off‐label. The expectation in the near term, with ever‐growing pressure, is that one or many regimens will be approved by the FDA. We should continue to push the boundaries and advocate aggressive HCV treatment in order to extend allograft and patient survival.