Managing HBV and HCV Infection Pre- and Post-liver Transplant

Abstract

Hepatitis B and C are common causes of end-stage liver disease and etiologies of liver transplantation. It is important to prevent recurrence in cases of hepatitis B. Nucleos(t)ide analogs are the mainstay of HBV treatment before (in patients with decompensated cirrhosis) and after liver transplantation. After the introduction of direct-acting antivirals, the treatment of HCV has become considerably easy. In patients with advanced HCV-related cirrhosis, it is better to do transplantation first and treat them after liver transplantation. The sustained virological response rates have improved from 8 to 50% in the interferon era to 90% in the direct-acting antivirals era. In the current review, we discuss the treatment of HBV and HCV before and after liver transplantation.

Chronic hepatitis B (CHB) is one of the major global health burdens. As per WHO estimates around 296 million people were living with chronic hepatitis B infection in 2019 and hepatitis B resulted in an estimated 820,000 deaths, mainly from cirrhosis and hepatocellular carcinoma.¹ A patient remains at risk of recurrent HBV infection after LT, and prevention of recurrence of hepatitis B in the graft is very important in ensuring graft and patient survival. The use of nucleos(t)ide analogs (NAs) is currently the mainstay of hepatitis B treatment before and after LT.² Interferon use is mostly not possible in the setting of decompensated cirrhosis or after LT (discussed in detail in the hepatitis C section of the manuscript).³ Currently 5 NAs have been approved for the treatment of CHB, these are either nucleoside analogs (lamivudine, telbivudine, and entecavir) or nucleotide analogs (adefovir and tenofovir). These NAs differ in the potential to select/have drug-resistant mutations after treatment (Table 1). Lamivudine was the first NA to be used, and is associated with a significant risk of drug resistance. Lamivudine, adefovir, telbivudine, and entecavir are associated with resistant mutations in 80%, 30%, 17%, and 1% after 5 years of treatment, respectively. Typical resistance to tenofovir has not been seen even after up to 7 years of treatment.⁴ The use of NAs with a high genetic barrier to resistance (entecavir and tenofovir) is associated with a very low risk of resistance and these agents are used as the first-line therapy.^2,5,6

Table 1.

Approved Oral Medications for Hepatitis B Treatment.

Name	Approved	Pro	Cons
Lamivudine	1998	Safe with minimal side effects Low cost	High incidence of resistance
Adefovir	2002	Low resistance	Long-term renal function decline Less potency
Entecavir	2005	Good potency for viral suppression Low resistance	High cost
Telbivudine	2006	Good potency for viral suppression Pregnancy category B	High incidence of resistance
Tenofovir	2008	Good potency for viral suppression Low resistance Pregnancy category B	Osteopenia Renal side effects (less with Tenofovir alafenamide)

MANAGEMENT OF HEPATITIS B BEFORE LIVER TRANSPLANTATION

Antiviral treatment is necessary for all patients diagnosed with hepatitis B-related cirrhosis, including those with decompensation.^2,7 Evidence shows that prolonged treatment leads to viral suppression with resultant histological improvement leading to regression of advanced fibrosis and even cirrhosis.^8,9 For patients waiting for LT, the rationale of treatment remains the same (prevention of worsening and stabilization). These patients are mostly treated with entecavir or tenofovir as the development of drug resistance is uncommon with these medications.² Entecavir is routinely used at a dose of 0.5 mg/day, but 1 mg/day dose may be used in patients with decompensation based on a study by Liaw et al. The authors found that entecavir 1 mg/day showed superior antiviral efficacy at 48 weeks compared to adefovir in patients with hepatic decompensation (Child-Turcotte-Pugh score >7).¹⁰ Tenofovir alafenamide (TAF) is a prodrug to tenofovir that has been approved recently. TAF results in higher intrahepatic concentrations of the active metabolite, and plasma levels remain low, thus toxicity profile (bone and renal) is favorable.¹¹ A large phase III trial demonstrated similar efficacy of TAF compared to TDF in terms of HBV DNA suppression along with improved safety profile.¹² The data on the use of TAF in decompensated cirrhosis patients is limited at the moment.

Treatment with NAs even at a decompensated stage is associated with survival benefits.¹³ A large prospective study showed that antiviral treatment was associated with an improved hepatic function [as improvement in Child-Pugh and Model for End-stage Liver Disease (MELD) scores] and transplant-free survival.¹⁴ An undetectable viral load at the time of transplantation is associated with less HBV recurrence, thus viral suppression to undetectable or low levels is an important part of efforts to prevent HBV recurrence. The direct correlation between HBV DNA levels at the time of LT and the rate of recurrence has been shown in studies.¹⁵ This, along with post-transplant prophylaxis, has resulted in HBV recurrence rates falling from levels reaching up to 100% to <10%.¹⁶

In the case of acute-on-chronic liver failure due to HBV, many times, dual antivirals have been tried. Lok et al. in 2012 published that the combination therapy of entecavir and tenofovir could provide more benefit in HBeAg-positive patients when baseline HBV DNA was ≥ 10⁸ IU/mL.¹⁷ Jindal et al. showed that the combination therapy of tenofovir and telbivudine (compared to tenofovir alone) improved survival in patients with ACLF despite comparable HBV DNA suppression.¹⁸ Recent study by Manik et al. also showed that combination of Telbivudine plus Tenofovir is safer with less nephrotoxicity and better outcomes.¹⁹ In a study of 40 patients with HBV-related ACLF by Juan Li et al. 60–85% of patients survived with the newer antivirals at 48 weeks.²⁰ In patients with high HBV DNA, we use dual antivirals (entecavir and tenofovir both) to rapidly decrease viral load (thus decreasing risk of recurrence). One of the antivirals (tenofovir) is stopped at 3 or 6 months after LT when HBsAg and HBV DNA are undetectable.

The supportive management of HBV-related acute liver failure (ALF) remains the same as other causes of ALF. The antiviral therapy should be started but it should not delay a liver transplant if a poor prognosis is anticipated. The recurrence of HBV in the liver graft can be prevented by the administration of HBIG (use depending on the risk of recurrence) and antiviral therapy.²¹

MECHANISMS OF HBV RECURRENCE AFTER LT

Hepatitis B in LT recipients can recur (pre-transplant hepatitis B positive status) or can happen de novo (from other persons, from anti-HBc positive donors). Use of organs from serum anti-HBc positive, HBsAg negative donors represent the major risk factor for the de novo of hepatitis B in LT recipients.²² HBV recurrence can present as acute or chronic hepatitis, fulminant hepatitis, and fibrosing cholestatic hepatitis.²³

When grafts are taken from donors with earlier HBV infection, the hepatocytes in the graft may contain cccDNA.²⁴ As no currently approved drugs can target and eliminate cccDNA, risk of HBV recurrence and graft injury remains after LT because of immunosuppression and lifelong prophylaxis is required.^25,26

The mechanism of HBV recurrence after LT includes saturation of HBIg by the high viral load and emergence of antibody-induced escape HBV mutants (mutations in the HBsAg). Mutations mostly occur at codon 145 of HBsAg by glycine-to-arginine substitution, which has been seen in transplant recipients receiving HBIg and in recipients of HBV vaccine.27, 28, 29

MANAGEMENT OF HBV AFTER LIVER TRANSPLANTATION

Recurrence of HBV after LT is defined as the reappearance of either HBsAg or detectable HBV DNA (or both). Contrary to normal immunocompetent population where HBsAg and HBV DNA both remain positive, post-LT population may have only reappearance of HBsAg without detectable HBV DNA and still require treatment to prevent occurrence of overt infection. Also, as HBsAg mutants are more common, it is important to check for HBV DNA besides HBsAg.^23,29 The recurrence happens in almost all if measures to prevent recurrence not used. In a study by O'Grady et al. HBV replication was seen in 17 out of 20 patients with HBV infection who were transplanted. There was graft loss in 12 patients over time.³⁰ There is considerable progress in prevention of recurrence and treatment of HBV, improving outcomes of HBV patients after LT. Patients with HBeAg positive status or HBeAg negative status with high HBV DNA or presence of antiviral drug-resistant strain remain at high risk of recurrence after LT.^15,16,27 In a study by Marzano et al. patients with HBV DNA higher than 100,000 copies/mL, 200–99,999 copies/mL, and DNA undetectable, hepatitis B recurred in 50%, 7.5%, and 0% of patients, respectively after transplant.¹⁵ In the study by Degertekin et al. involving 183 patients, the recurrence rate at 5 years was 15 percent in HbeAg positive status vs 5 percent in HBeAg negative status.³¹ The presence of HCC before LT or HCC recurrence after LT also affect HBV recurrence.³²

PREVENTION OF HEPATITIS B RECURRENCE AFTER LIVER TRANSPLANTATION

Various strategies used to prevent HBV recurrence after LT are the use of Hepatitis B immune globulin (HBIG), NAs or a combination of both.33, 34, 35, 36, 37, 38 The complete eradication of HBV is exceedingly rare from the host in CHB infection. In patients who achieve hepatitis B surface antigen (HBsAg) seroclearance, HBV may still persist within the host.^39,40 Despite removal of the liver, there is a persistence of HBV at several extrahepatic sites as the lymph nodes, spleen, and other organs.^41,42 This latent virus gets reactivated because of the immunosuppressive regimen after LT.⁴³ Before the availability of prophylaxis against HBV recurrence, graft and patient survival were very poor⁴⁴ and hepatitis leading to graft failure was almost universal.^30,33,45 After the development of oral NAs, the recurrence could be prevented or treated effectively.⁴⁶

HEPATITIS B IMMUNE GLOBULIN MONOTHERAPY

HBIG is a polyclonal antibody to HBsAg. It is derived from pooled human plasma. Although the exact mechanism for action of HBIG is unknown, it possibly acts by blocking receptors involved in the exportation of virions from extrahepatic sites along with the formation of immune complexes which result in neutralization of viral particles.⁴⁷ Samuel et al. published a breakthrough study in 1993. The authors showed a marked reduction in HBV recurrence (defined as HBsAg positive status) in patients who received HBIG. HBV recurrence decreased from 75 ± 6% in patients receiving no or short-term therapy with HBIG to 36 ± 4% in those receiving HBIG for 6 months or longer. The recurrence was almost similar to no-HBIG in patients who received HBIG for only 2 months. The survival was poor in the recurrence group as compared to no recurrence group.³³ Sawyer et al. used variable dosing of HBIG to maintain HBV surface antibody (HBsAb) levels >500 IU/L for the first 6 months, and reported recurrence rate of 22%.³⁴ Terrault et al. used a fixed dose of HBIG (10,000 IU monthly) and showed 19% recurrence at 2 years.³⁵

Viral mutants form secondary to random copying errors in the process of virus production. Among the various hepatitis B virus proteins, hepatitis B surface antigen (HBsAg) contains the dominant epitope which is crucial for binding to neutralizing antibodies. Researchers have identified approximately 30 immune-escape mutations in HBsAg. These mutants form more commonly in the setting of immunosuppression or with use of HBIG, as mutants are selected because of HBIG preventing wild-type virus from production. These escape mutants can evade neutralizing antibodies and may allow persistence of HBV infection.48, 49, 50 Immune-associated escape mutations can also impair HBsAg-recognition by antibodies induced by vaccine.⁴⁹ The use of HBIG provides good short-term results, but it's not a good long-term choice because of high cost, the need for indefinite therapy, and the development of HBIG-resistant mutants and a combination with NAs is associated with better outcomes.^50,51 The G145A mutation at the antigenic loop of the “a” determinant is the most common mutation associated with immune escape, and may diminish the efficacy of HBIG.^28,52,53 To decrease cost, HBIG was used at low dose or for a short duration with NAs (discussed later). Issues with the use of HBIG include high cost of HBIG and need for parenteral route of administration. Also, availability is an issue sometimes. Low-dose HBIG regimens decrease cost considerably (discussed later in combination therapy). These drawbacks and the arrival of antivirals (used alone or with short-term HBIG), abandoned its use as a monotherapy.

NA Monotherapy

Initial studies showed that lamivudine and adefovir were effective when used as monotherapy in reducing HBV recurrence after LT.^54,55 Lamivudine in various studies reduced the recurrence of HBV to 3.8%–40.4%.^54,56, 57, 58 However, use of medications with low genetic barrier to resistance for long-term is associated with significant rates of resistance. Fung J et al. used entecavir monotherapy in a cohort of 80 patients where 74% were HBV DNA positive at the time of LT.⁵⁹ The HBsAg seroclearance rate was 86% after 1 year and 91% after 2 years, although ten patients had reappearance of HBsAg. Out of 18 patients with HBsAg positive status at the last follow-up, only 1 was positive for detectable HBV DNA, which was also low level of HBV DNA (217 copies/ml).⁵⁹ The same author published a larger study (n = 362) with a long follow-up period of 8 years. The patients did not receive HBIG and were mainly on lamivudine or entecavir or a combination of NAs. Eighty-eight percent of patients had negative HBsAg and 98% had undetectable HBV DNA levels at 8 years. The recurrence happened in 16% of patients at 8 years. The recurrence happened mainly in the lamivudine group due to YMDD mutation, and no recurrence was seen in the entecavir group.³⁶ In a study by Wadhawan et al. after treatment with antiviral monotherapy, only 10% and 8% of patients were positive for HBsAg at 1- and 2-year follow-up respectively.⁶⁰

Combination Therapy

Combination therapy with HBIG and an NA is associated with very low recurrence rates after LT.³ Several large meta-analyses have shown that combination therapy is associated with reduced HBV-related mortality compared to HBIG alone.^37,38,55,61 Angus and colleagues studied lamivudine combined with a lower dose of HBIG (400 or 800 international units, administered intramuscularly daily for 1 week after transplantation followed by monthly dose).⁶² After a mean follow up of around 18 months, all patients were HBV DNA negative. Gane et al. performed a multicenter study (n = 147), and reported 1% and 4% HBV recurrence at 1 and 5 years respectively.⁶³ The low-dose HBIG regimens are significantly cheaper than high-dose HBIG regimens. The subcutaneous administration of HBIG is reported to decrease patient discomfort, and is associated with better patient satisfaction and compliance with maintenance of protective anti-HBs serum concentration.^64,65 Few studies have shown very low rates of recurrence using HBIG with a potent NA. Choudhary et al., in a large cohort of 176 patients showed that low-dose short-term HBIG with a high genetic barrier NA resulted in a substantially lower incidence of HBV recurrence (1%), even in high-risk patients.⁶⁶ An analysis including 11 trials (304 patients) of HBIG with either tenofovir or entecavir showed an overall 1% recurrence rate.⁶¹

Many institutions are now shifting towards HBIG-free regimens (oral NA therapy alone) following transplantation if they consider patients to be at low risk of recurrent infection or are discontinuing HBIG after a period of time. Table 2 summarizes various studies done for immunoprophylaxis of HBV infection in liver transplant recipients.^27,59,60,66, 67, 68, 69 With the availability of effective antiviral therapy (entecavir and tenofovir), most of patients are HBV DNA negative (undetectable levels) at the time of LT, and thus remain at low risk of HBV recurrence. However, achieving an undetectable HBV DNA is not possible in patients with recent diagnosis of CHB and HCC or in very sick patients. A suggested algorithm is shown in Figure 1. HBIG can be used in combination with NAs in patients with significant risk of HBV recurrence (drug resistance mutations, high HBV DNA levels at the time of LT), or in patients where HBV recurrence can lead to significant issues (risk of HCC, coinfection with hepatitis D or HIV). It is recommended that patients continue NA therapy indefinitely after LT and an agent with a high barrier to resistance should be used.⁷ Entecavir, TDF, and TAF are the preferred NAs because of low risk of resistance development against these agents. TAF or entecavir should be considered in patients who have renal dysfunction and/or bone disease.^2,7 Despite post-LT data being scarce, few studies have shown an improvement in the renal and bone profile in primary TAF use (versus TDF) or after switching TDF to TAF.^70,71 We at our center prefer use of entecavir as use of TDF (although less with TAF) is associated with slight renal risk.

Table 2.

Studies on the Use of Oral Antiviral Medications ± Finite Duration HBIG Use for the Prevention of Hepatitis B Recurrence After Liver Transplant.

Study	Number of patients	Median follow-up (months)	HBIG use	HBV recurrence (%)
Degertekin et al.31	23	53	12 months	13
Fung et al.59	80	26	No	23
Wadhawan et al.60	75	21	No	8
Choudhary et al.66	176	43	12 months	1
Teperman et al.67	16	18	6 months	0
Neff et al.68	10	31	7 months	0
Nath et al.69	14	14	7 days	0

HBIG: Hepatitis B immune globulin; HBV: hepatitis B virus.

Figure 1.

Suggested treatment algorithm for management of HBV before and after liver transplantation.

There have been attempts to withdraw NA therapy after LT but generally these patients were at low risk for HBV recurrence.^72,73 Lenci et al. attempted stepwise withdrawal of HBIG and NA in patients on minimal immunosuppression.⁷⁴ In a study of 30 patients, HBIG was withdrawn 6 months after the beginning of the screening phase and NA was also withdrawn 6 months later (after stopping HBIG). Recurrence of HBV was noted in 20% of patients, 60% developed anti-HBs titers >10 IU/L.⁷⁴ Currently NA withdrawal can't be recommended and studies with a larger sample size are required to assess the safety and efficacy of NAs’ withdrawal strategies.

The authors’ recommendation would be to give low-dose short-term HBIG for 1 year with lifelong antiviral (entecavir or tenofovir) in selected high-risk patients (Figure 1). We use HBIG as 10,000 international units (IU) intravenously in the anhepatic phase followed by 1000 IU IM daily for the first week, 1000 IU IM weekly for the next 3 weeks, and then 600–1000 IU IM monthly to keep anti-HBs levels at 100–250 IU/mL for a total duration of 1 year. The majority of patients are at low-risk of hepatitis B recurrence after transplantation and HBIG can be avoided, thus the current use of HBIG is rare.

RECIPIENTS OF HBCAB-POSITIVE GRAFTS

The covalently closed circular DNA (ccc DNA) of HBV can exist within the cell nucleus as a stable viral mini-chromosome that leads to persistence of HBV infection.⁷⁵ Thus, grafts from donors with previous HBV infection (i.e. anti-HBc positive, HBsAg and HBV DNA negative) with HBV cccDNA within the graft (hepatocytes) can lead to viral reactivation under the effect of post-LT immunosuppression. Even in non-LT immunosuppressed patients, HBV reactivation is well known in anti-HBc positive patients.⁷⁶ Cholongitas et al. analyzed 903 recipients of anti-HBc positive liver grafts from 39 studies. Recurrent HBV infection developed in 11% of HBsAg positive LT recipients of anti-HBc positive donors. In the absence of prophylaxis against HBV, de novo HBV infection developed in 47.8% of HBV naive recipients, 13.1% of anti-HBc +/anti-HBs negative recipients, 9.7% of only anti-HBs + recipients, and 1.4% of recipients with positive status for both anti-HBc and anti-HBs. HBV prophylaxis decreased de novo HBV infection rates considerably (3% for anti-HBc/anti-HBs positive and 12% for HBV naïve recipients). It is important to note that this systematic review did not include data on high genetic barrier antivirals (entecavir or tenofovir).²² The guidelines by the American Society of Transplantation Infectious Diseases recommend that HBV-naive recipients of anti-HBc positive donors should receive long-term antiviral prophylaxis.⁷⁷ We practice lifelong antivirals in these patients. We also use antivirals in recipients who are anti-HBc positive and getting anti-HBc negative grafts, although recommendation is weak. More recently, active immunization of transplant recipients before and after liver transplantation with monitoring of anti-HBs titers has been reported.^78,79 Wang et al. analyzed results of pre and post-LT vaccination in recipients of anti-HBc positive grafts. Patients with anti-HBs titer <1000 IU/L also received lamivudine. A total of 17.6% patients with titers <100 IU/L developed HBV recurrence.⁷⁸

The vaccination-based approach requires careful monitoring of vaccine response and requires further studies.

Future Directions

There are a lot of new drugs in clinical trial for hepatitis B. These new drugs target different sites of HBV replication cycle. New drugs targeting viral entry receptors, HBsAg release inhibitors, cccDNA disruption, nucleocapsid assembly modulation, and HBV transcription inhibition are in various stages of preclinical and early-stage trials.⁸⁰ Recently, Bepirovirsen has shown good response at 24 weeks with sustained HBsAg and HBV DNA loss in approximately 10% of patients.⁸¹ In the future, these drugs may be combined with NAs to potentially obtain a functional cure. There is no data on post-LT treatment regarding these newer drugs.

HEPATITIS C

HCV-related cirrhosis is the common cause of liver transplantation, in both the East and the West.^82,83 With the availability of highly efficacious newer direct-acting antivirals (DAAs), HCV has become a less common indication of LT.⁸⁴ An analysis of the etiology of LT in adult recipients from June 2010 to July 2018 showed that HCV as an indication of LT has declined from 28.4% during 2010–2014, to 16.3% during 2015–2018 (P = 0.000). Also, HCC was a more common indication than decompensated cirrhosis in the later era.⁸⁴ Similar findings (decreasing HCV in overall and HCC increasing as an indication for LT in HCV-cirrhosis) are described from another Indian center.⁸⁵

As HCV recurrence is easily treatable, LT can be done in sick patients and HCV can be treated after LT.

HCV TREATMENT BEFORE THE AVAILABILITY OF DIRECT-ACTING ANTIVIRALS

Studies in the interferon era showed that patients who achieved sustained viral response (SVR) had less all-cause or liver-related mortality.⁸⁶ HCV infection recurs in all patients with HCV RNA-positive status at the time of LT.^87,88 There are no effective agents unlike HBIG for hepatitis B that prevents HCV recurrence. HCV antibodies do not prevent HCV recurrence.⁸⁹ It is sometimes difficult to differentiate between acute cellular rejection and recurrent hepatitis C.⁹⁰

Some of the LT recipients have rapid fibrosis development after LT that progresses to recurrence of cirrhosis in the absence of HCV treatment.91, 92, 93 Thus, HCV recurrence led to poor outcomes after LT as compared to other etiologies.⁹⁴ The antiviral treatment before availability of DAAs was associated with significant treatment-related adverse events and poor SVR rates (very poor results genotype 1) in the interferon era.⁹⁵ The SVR rates were poorer as compared to non-LT populations due to immunosuppression and treatment-related AEs. In particular, steroid boluses were associated with worse outcomes in HCV patients.⁹⁶

Although pre-transplant HCV therapy and achievement of SVR were associated with less HCV recurrence, it was very difficult to achieve in patients with decompensated cirrhosis because of adverse events related to interferon therapy.^97,98 In a review of 3 pretransplant studies, the median SVR was only 19.6%.⁹⁹ As treatment with interferon and ribavirin was associated with significant adverse events, patients were treated after histological evidence of HCV recurrence and not immediately post-LT treatment because of poor tolerability.^95,100 A review of 19 studies (n = 611) showed only 30.2% mean SVR (range 8–50%). Dose reduction was seen in 73% and the treatment was discontinued in 27.6%.¹⁰⁰ Some patients also developed Immunologic graft complications (acute/chronic rejection and autoimmune-like hepatitis).101, 102, 103, 104

HCV TREATMENT AFTER THE AVAILABILITY OF DIRECT-ACTING ANTIVIRALS

The availability of DAAs led to remarkable improvement in SVR rates as compared to the interferon era.¹⁰⁵ The key studies regarding the efficacy of DAA in the treatment of decompensated cirrhosis are shown in Table 3.106, 107, 108, 109, 110, 111, 112, 113, 114, 115 As discussed in the comment's column of Table 3, negative predictors of SVR are the severity of liver disease (higher bilirubin, low albumin, CTP B or C versus A) and some specific genotypes (1A and 3). Also, some patients will face severe AEs and some patients will die waiting for improvement. It should also be noted that most of the available data is on the treatment of genotype 1, and most of the studies have not included patients with genotype 3 in significant numbers which is the most common genotype in India. Although it is shown that negative HCV RNA status was associated with no/less recurrence after LT, prevention of HCV recurrence is not a significant concern nowadays as post-transplant DAA-based therapy is highly efficacious.^116,117 There are several issues in treating decompensated HCV cirrhosis before LT despite relatively safe DAA-based treatment as discussed in Table 4.

Table 3.

Efficacy of DAA-based Therapy in Patients Suffering From Decompensated Cirrhosis.

Study or Author	Study population	SVR	Comments
Belperio PS106	243 with genotype 3 related decompensated cirrhosis	Daclatasvir or velpatasvir with sofosbuvir ± ribavirin 80–83% in various groups	88.6–92.5% in compensated cirrhosis
HCV-TARGET107	667 patients, Genotype 1, 231 non-transplant decompensated cirrhosis	87.5–100% in various arms	Compensated rather than decompensated (OR 2.41), albumin ≥3.5, total bilirubin ≤1.2 associated with higher SVR
Hepa-C registry108	843	SVR12 94% versus 78% in CTP A versus B or C respectively	Relapse rates 4% versus 14% in CTP-A versus B or C, 50% SAEs in patients with decompensated cirrhosis
Reddy KR109	240 patients with a MELD score of ≥10	Higher SVR in sofosbuvir + simeprevir ± ribavirin than sofosbuvir + ribavirin (66–74% versus 54%); Genotype 1b versus 1a (84% versus 64%), SVR for genotype 2 was 72% with sofosbuvir plus ribavirin, while genotype 3 patients had a substantially lower SVR (35%)	albumin level predicted SVR, elevated bilirubin level and GT1a were negative predictors
Welzel TM110	485, 42% Child-Pugh B/C Daclatasvir + Sofosbuvir ± Ribavirin	Genotype 3 in 21%, 91% SVR	28 treatment discontinuations because of adverse events (n = 18) or death (n = 10) 18 died during follow-up
SOLAR-2111	333 Decompensated cirrhosis Genotype 1 and 4 Treatment regimen- SOF + LDV + RBV	CTP-B: 87% (12 week)/96% (24 week); CTP-C: 85% (12 week), 78% (24 week)	Non-genotype 3 cohort, 17 patients died during the study period
ALLY-1112	N = 60 advanced cirrhosis Daclatasvir with sofosbuvir and ribavirin	SVR12 rates 93% in CTP- A or B versus 56% in CTP-C	Decompensated cirrhosis negative factor for SVR
ASTRAL 4113	267 12 weeks of sofosbuvir and velpatasvir 12 weeks of sofosbuvir and velpatasvir plus ribavirin 24 weeks of sofosbuvir and velpatasvir	SVR 83% in 12 weeks of sofosbuvir and velpatasvir, 94% in 12 weeks of sofosbuvir and velpatasvir plus ribavirin 86% in 24 weeks of sofosbuvir and velpatasvir	Serious adverse events in 16–19% 78% were genotype 1, 15% genotype 3
Saxena V114	160, 35% had CP-B/C SIM + SOF ± RBV for 12 weeks	genotype 1 and cirrhosis treated with	SVR12 in 73% of CTP-B or C versus 91% of CTP-A, more treatment discontinuations (11% versus 1%), AEs that required hospitalization (22% versus 2%), hepatic decompensating events (20% versus 3%)
SOLAR-1115	337 Decompensated cirrhosis SOF + LDV + RBV All but one genotype 1	CTP-B: 87% (12 week)/89% (24 week); CTP-C: 86% (12 week), 87% (24 week)	Non-genotype 3 cohort

OR: Odds ratio, CTP: Child-Turcotte-Pugh, MELD: model for end-stage liver disease, SOF: Sofosbuvir, LDV: Ledipasvir, RBV: Ribavirin, GT: genotype, SIM: simeprevir.

Table 4.

Issues in the Pretransplant Treatment of Decompensated HCV Related Cirrhosis.

Aspect	Pro	Cons	Comments
Improvement or stability of liver disease severity in patients listed for transplant patients	May reach LT as the disease is stabilized, some patients may get delisted Only option for patients not opting LT No data regarding outcomes of DAA-based therapies in patients with high MELD	Slight improvement of MELD score is not associated with significant clinical status improvement and patients are at disadvantage in getting organs due to low MELD	MELD improves by a few points only, not significantly in the majority of patients. Possibility of HCV resistant variants in case of relapse, may not HCV-positive cadaveric grafts More AEs in decompensated cirrhosis Risk of HCC remains
Prevention of post-LT HCV recurrence	Less recurrence	Lower SVR rates in pre-LT period, higher AEs, risk of mortality during treatment	MELD >18, discuss before treatment
Post-LT survival	Prevention of recurrent cirrhosis because of HCV	Post-LT treatment is easy, no significant AEs and better SVR rates (as compared to treatment in decompensated cirrhosis)	At our center, we start HCV treatment after LT in index admission only, well tolerated by patients

MELD: model for end-stage liver disease.

WHAT ARE THE CURRENT GUIDELINES?

Data modeling and cost studies suggest that treating HCV before LT could decrease life expectancy at MELD >27, and post-LT treatment is cost-effective at MELD >20 or in the presence of HCC.^118,119 The recommendations from EASL 2020 guidelines are shown in Table 5. The guidelines suggest that patients with decompensated cirrhosis with a MELD score equal to or more than 18–20 should be transplanted first and hepatitis C should be treated after LT.¹²⁰ As the major route of elimination for Glecaprevir and Pibrentasvir is biliary, this combination for 12 weeks can be used (recommendation B1) in patients with severe renal function impairment including dialysis; however, this combination should not be used in patients with coexistent decompensated cirrhosis.¹²⁰

Table 5.

Sofosbuvir-velpatasvir Combination-based Available Options in India (Based on EASL guidelines).¹²⁰

Group	Genotype, comments	Treatment
Compensated cirrhosis	Non-3 genotype Genotype 3	Sofosbuvir + velpatasvir for 12 weeks Weight-baseda ribavirin added for genotype 3
Decompensated cirrhosis	Any genotype, Treatment at experienced centers with option of LT (A1), close monitoring required MELD score <18-20- treat before LT (A1) Patints with a MELD score ≥18–20- LT first (B1), can treat if > 6 months (B1)	Sofosbuvir and velpatasvir with weight-based ribavirin for 12 weeks (A1). Combination of sofosbuvir and velpatasvir for 24 weeks without ribavirin if ribavirin cannot be used (A1).
After liver transplantation	No cirrhosis or compensated cirrhosis only: sofosbuvir and velpatasvir for 12 weeks Decompensated cirrhosis (CTP- B or C): sofosbuvir and velpatasvir with daily weight-based ribavirin for 12 weeks (B1) Combination of sofosbuvir and velpatasvir for 24 weeks without ribavirin if ribavirin cannot be used (B1)	Treat before the development of fibrosis

EASL: European Association for the Study of the Liver, MELD: model for end-stage liver disease, CTP: Child-Turcotte-Pugh.

^aWeight-based ribavirin (1000 mg dose for weight <75 kg and 1200 mg dose for ≥75 kg), respectively), ribavirin can be started at a lower dose (600 mg) in patients with CTP- B or C class and dose can be adjusted later as per tolerance (B1).

HOW MUCH IMPROVEMENT IS EXPECTED AFTER TREATMENT IN DECOMPENSATED CIRRHOSIS

A key question regarding improvement in decompensated cirrhosis is the extent of improvement and whether the treatment can delist a patient. One multicenter European study specifically looked at the delisting from transplant list. The authors included 103 patients from 11 European centers, 34 (33.3%) patients were inactivated (defined as a clinical and biochemical improvement) and 19.2% could be delisted (defined as a durable improvement) at 60 weeks. Although the baseline MELD ranged from 6 to 31, the median MELD was 16, and MELD score was >20 in 14 patients. The median MELD score improvement was 1.5 (15.5–14). Among patients with baseline MELD score >20, only two patients achieved inactivation. These 2 patients had acute-on-chronic liver failure associated with sepsis before starting DAA therapy.¹²¹

A further extension of this study is reported by Perricone et al. This study included 103 patients from a study by Belli et al. and an additional 39 patients. The cohort was followed up to 37.5 (34.6–41.7) months from the start of DAA treatment. The cumulative incidence of delisting was 7% at 48 weeks, 18% at 72 weeks, and 27% at 96 weeks. Patients with lower MELD scores (<16) had almost 50% chance of delisting. A total of 4 patients were relisted due to HCC (n = 1) or ascites (n = 3), and one patient died due to HCC. The median MELD of the study cohort was 16 (13–18 IQR). The median MELD was 14 (12–17.5) in delisted patients, versus 16 (14–19) in patients who could not be delisted. Among patients with MELD >20 at baseline, only 3/15 could be delisted.¹²² When we analyze these studies focusing on delisting, it should be kept in mind that the studies have not treated very sick patients (high MELD). It is also clear from these studies that patients with a high MELD have little chance of listing. A suggested algorithm is shown in Figure 2.

Figure 2.

Suggested treatment algorithm for management of HCV before and after liver transplantation.

ADVERSE EVENTS AND SAFETY ISSUES

The DAA-based treatment is generally tolerated by most of the patients. The common side effects are anemia, headache, nausea and fatigue.^105,120 Patients with decompensated cirrhosis experience more and severe adverse events (AEs). Severe AEs occurred in 16–19% of patients in the ASTRAL-4 cohort.¹¹³ In a review of the literature, Anand et al. found serious AEs and decompensation in approximately 20% of patients, therapy discontinuation in 10% of cases and deaths (while on treatment) in 0–4% cases.¹⁰⁵ It is important to note that some patients die while on treatment. Six and 5 patients in pre-LT cohorts in SOLAR 1 and 2 died while on therapy.^111,115 The study by Gray et al. noted 6% and 21% mortality in CTP B and C respectively.¹²³ An unexplained worsening also has been reported with treatment.¹²⁴ AEs are more common in patients with severe disease at baseline (higher MELD, low albumin) and older age. Fernández et al. reported SAEs in 50% patients with decompensated cirrhosis (versus 12% in CTP-A). An incident decompensation was noted in 7% and 6.4% of patients died. A baseline MELD predicted survival at a cut-off of 18.¹⁰⁸

TREATMENT AFTER LT

Post-LT patients without fibrosis have better SVR as compared to patients suffering from post-LT cirrhosis because of HCV recurrence. A meta-analysis of 22 studies including 1730 patients noted 90.1% SVR12. The SVR12 rate was higher in patients with mild fibrosis when compared to advanced fibrosis/cirrhosis (RR = 1.072). SAEs occurred in 8.3% and 3.3% discontinued treatment.¹¹⁷

Two Indian studies also have reported good results in treating LT recipients. A study from our center reported 89.4% SVR in a cohort of 76 patients. This cohort included 12 patients with earlier failed Peginterferon and Ribavirin-based treatment, 11 of these 12 achieved SVR12. Importantly, there were similar SVR rates in genotype 1 and 3.¹²⁵ In another study by Anand et al., SVR12 was achieved in 60 patients from a cohort of 63 patients (95.2%). The authors noted SVR24 was noted in 59 patients (93.7% of the cohort) with 24 weeks of sofosbuvir and ribavirin-based therapy.¹²⁶

Although pre-transplant HCV treatment is attractive for several reasons (Table 4), sick patients may be harmed more rather than benefited.¹²⁷

Timing of HCV Treatment After Liver Transplantation

The ideal timing to start HCV treatment is not clear from the available data, early treatment should decrease histological HCV recurrence and need of liver biopsy. The early HCV treatment should also decrease fibrosis.¹²⁸ At our center, we start HCV treatment after LT in the index admission only which is well tolerated by the patients.

Management of Relapse After Liver Transplantation

There is little data on how to treat patients post-LT with a history of DAA failure. There is a successful treatment report by using sofosbuvir/velpatasvir/voxilaprevir combination for 16 weeks (ribavirin also added in last 8 weeks) in patients with acute hepatitis secondary to genotype 3 HCV.¹²⁹ Higley et al. used this combination (sofosbuvir/velpatasvir/voxilaprevir) for 12 weeks in 6 LT recipients with history of previous DAA-based treatment failure. The authors noted that minor reductions in calcineurin inhibitor dosing were needed, there were no adverse events or rejection episodes and all patients achieved SVR.¹³⁰

ROLE OF BIOPSY AND LIVER STIFFNESS MEASUREMENT AFTER LIVER TRANSPLANTATION

The recurrence of hepatitis B and C is detected by blood tests (HBsAg, HBV DNA, and HCV RNA) done for surveillance or done for evaluation of graft dysfunction. A liver biopsy is not needed unless graft dysfunction is present. In contrast to HBV where recurrence after LT is uncommon, recurrence was universal in recipients with HCV RNA positive status at the time of LT. Historically protocol liver biopsies were commonly performed in patients undergoing LT for HCV-related liver disease as interferon was poorly tolerated and recipients were treated only in the presence of histological HCV recurrence. Now with availability of newer anti-viral agents, a liver biopsy is rarely performed to look for histological recurrence as patients can be treated early after LT.¹³¹ Several studies have shown the utility of transient elastography(TE)/FibroScan after LT in diagnosing patients with significant and advanced fibrosis, although the data is available mostly in HCV-positive recipients. Accurate assessment is confounded by many factors which can influence the liver stiffness after LT (inflammation secondary to recurrence of viral hepatitis or due to immunologic injury, biliary issues, cardiac disease). A study from our center in patients with post-LT non-alcoholic steatohepatitis patients showed that FibroScan cut-offs may be higher than normal population (likely due to inflammation). In a study of post-transplant non-alcoholic fatty liver disease from our center, the liver stiffness values were 18.1 (9.7–22.5) kPa in patients with stage 1 or 2 fibrosis and were 9.7 (4.0–12.7 in patients without fibrosis¹³² Transient elastography is a promising non-invasive tool to assess graft fibrosis progression after LT in patients with HCV recurrence, as well as for screening of late graft fibrosis of other etiologies.^133,134 In one study, increase in liver stiffness over time was related to signs of liver disease like alanine transaminase, replicating HCV, and biliopathy but was also related to other factors such as cyclosporine treatment.¹³⁴ A rising liver stiffness value may also suggest rapid fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation.¹³⁵ In the era of newer DAA where treatment for HCV recurrence can be done early after LT (before histological recurrence), fresh data is needed to assess the role of transient elastography. There are no recommendations on frequency and timing of monitoring HBsAg and HBV DNA after LT, we do these tests 6 monthly or in the presence of graft dysfunction. We do HCV RNA every 6 months (in initial years) in patients with HCV.

LT is the gold standard treatment for HBV and HCV-related end-stage liver disease with or without HCC, with comparable outcomes to the other indications in the current era. The success of LT for HBV or HCV depends on the appropriate management and prevention of recurrence of these viruses. The prophylaxis and treatment of recurrent HBV varies according to region or center protocol. The treatment approach should be individualized based on each patient's characteristics. Patients with a high HBV viral load at the time of LT may be considered for the use of HBIG in addition to use of NAs. Most importantly, the more potent antivirals (ETV, TDF, and TAF) should be the first-line agents and are continued lifelong either as a combination or monotherapy. HCV treatment is now very simplified with the introduction of newer DAA with very high SVR rates. The treatment of HCV can be done pre- or post-transplant depending on the MELD score and availability of liver transplantation.

Credit authorship contribution statement

NK, NSC: draft writing.

NSC: critical revision.

Funding

None.

Conflicts of interest

None for any author.