Single-Center Experience in Pre-transplant Hepatitis C Virus (HCV) Treatment Among Living Donor Liver Transplant Candidates: Bridging the Direct-Acting Antivirals (DAA)

Abstract

Background

Treatment with DAAs before deceased donor liver transplantation has been shown to be an effective strategy to prevent post-transplant HCV recurrence, with a 95% cure-rate among individuals who achieve undetectable HCV VL for ≥30 days pre-transplant. This strategy has not been evaluated in LDLT.

Material/Methods

We evaluated outcomes in LDLT recipients treated with DAAs pre-transplant and bridged with 4 weeks of post-transplant SOF. All cases of LDLT at Johns Hopkins (1/1/2014-3/1/15) were retrospectively reviewed.

Results

There were 4 HCV+ LDLT cases treated with DAAs pre- and post-transplant. Pre-transplant DAA regimens included SOF plus SIM in 2 cases of HCC and SOF plus RBV in 2 cases of ESLD. All patients achieved negative VL by week 7 of treatment and all patients had at least 30 days of HCV RNA negativity at the time of LDLT. Patient 4 had a delay in LDLT due to uncontrolled pulmonary hypertension, and experienced viral breakthrough because of treatment interruption. Due to concerns for SOF resistance, a salvage regimen of LDV-SOF and SIM was used. Post-LDLT patients 1–3 received 4 weeks of SOF monotherapy and patient 4 received 14 weeks of LDV-SOF. Three patients achieved SVR12. One died from non-HCV related complications at 4 months post-LDLT.

Conclusions

Our preliminary experience suggests that bridging DAAs pre- and post-LDLT is an effective strategy to prevent HCV recurrence. With delays in transplant and prolonged use of SOF/RBV, there is a risk of viral breakthrough, but a salvage strategy of triple DAA therapy can be effective.

Background

Hepatitis C virus (HCV) infection is one of the most common causes of end-stage liver disease (ESLD) and, along with hepatocellular carcinoma (HCC), is one of the major causes of liver transplantation (LT) in developed countries [1,2]. In patients with detectable HCV viral load (VL) at time of LT, post-transplant recurrence is nearly universal and can lead to accelerated progression to cirrhosis, loss of graft function, and even death [3–5]. Without treatment, more than 95% of recipients have persistent viremia at the post-LT period [6]. Under post-LT immunosuppression, chronic hepatitis C is accelerated, with progression to cirrhosis in 10–30% of LT recipients at 5 years and more than 40% at 10 years. Of those patients who progress to cirrhosis, more than 40% develop decompensated disease within 1 year and over 70% within 3 years. Those that develop decompensated disease have a 3-year survival rate of <10% compared to >60% in immunocompetent patients who develop decompensation [4).

Given the large waiting list and long waiting times for organs from deceased LT donors, a growing number of living donor liver transplantations (LDLTs) are performed [7]. HCV-infected (HCV+) recipients represents 24.5% of all LTs per year, making treatment of HCV and prevention of recurrence imperative for long-term survival benefits [2].

Treatment of HCV with interferon-based regimens are poorly tolerated and relatively ineffective [8,9]. Up to one-third of patients discontinue treatment due to adverse events [10]. Sofosbuvir (SOF) is a direct-acting antiviral (DAA) that is highly effective against HCV [11,12]. SOF in combination with Simeprevir (SIM), Ledipasvir (LDV), Daclatasvir (DAC), or Velpatasvir (VEL), with or without ribavirin (RBV), is effective and safe in pre-transplant ESLD and also in post-LT settings [13–19]. The sustained virological response (SVR) rate of treatment reaches up to 100% in these settings.

Timing of treatment is an important issue among liver transplant waitlisted candidates in the era of an effective cure for HCV infection. Treatment with DAAs before deceased donor LT has been shown to be an effective strategy to prevent post-LT HCV recurrence. The recurrence rate is inversely proportional to number of days without detectable VL in serum of recipients before the surgery, with 95% of patients achieving cure if an undetectable HCV viral load is maintained for ≥30 days prior to LT [20]. On the other hand, given our ability to schedule the date of surgery for living donor liver transplantations (LDLTs), we have a unique opportunity to evaluate the optimal timing to maximize DAA efficacy and protect the graft from reinfection in LDLTs.

There is no previous study in the literature addressing the particular issue of HCV treatment timing for LDLT. We explored the bridging strategy of pre- and post-transplant DAA treatment to protect the graft, among live donor recipients [21].

Material and Methods

After obtaining IRB approval, a retrospective study was performed among all cases of LDLT performed for HCV at Johns Hopkins Hospital in Baltimore, MD, USA from January 1, 2014 through March 1, 2015. Demographic characteristics (age, sex, race), genotype, previous HCV treatment history, MELD score, underlying liver disease (ESLD, HCC), and DAA regimen was recorded. All patients were treated with DAAs pre-LT at least for 1 month and bridged with at least 4 weeks of post-LT SOF. Genotype-specific DAA regimens were selected according to AASLD guidelines at the time of the study period.

Design of treatment and follow-up is illustrated in Figure 1. Viral load was documented weekly until the end of treatment. Time to reaching the first negative HCV RNA result was recorded. LT surgery was planned after the patient had negative VL with at least 4 weeks of DAA treatment. Bridging through and pursuing after the LDLT, 1 month of SOF maintenance treatment was given to the recipient. During the peri-operative period, the daily DAA treatment was given through the NG tube. After the end of the maintenance period, HCV RNA levels were followed monthly for 3 months. SVR12 was defined as HCV RNA negativity 12 weeks after completion of the antiviral treatment.

Figure 1.

Bridging DAA strategy for HCV+LDLT.

Results

A total of 6 cases of HCV LDLT were treated for HCV-related decompensated liver cirrhosis or HCC. Two patients previously treated with interferon-based regimens and who had already cleared the HCV prior to LDLT were excluded from the study. Four cases were treated with DAAs starting from the pre-LDLT period and bridged with at least 1 month of post-transplant SOF. Demographic characteristics and the findings related to treatment are shown in Table 1. Pre-LDLT DAA regimens included SOF plus Simeprevir (SIM) 400 mg daily and 150 mg daily, respectively, in 2 cases of hepatocellular carcinoma (HCC), and SOF plus ribavirin (RBV) 400 mg daily and 600 mg twice daily, respectively, in 2 cases of end-stage liver disease (ESLD).

Table 1.

Characteristics of the LDLT recipients with bridging DAA treatment for HCV.

Patient #	1	2	3	4
Age/Sex	67/M	64/M	58/M	55/M
Race	Middle Eastern	Middle Eastern	Caucasian	Caucasian
Indication for LDLT	HCC	HCC	ESLD	ESLD/Hepato Pulmonary Syndrome
HCV Genotype	4	1b	2b	1a
Treatment history	PEG/RBV	Naive	PEG/RBV	Naive
HCV Regimen	SOF/SIM	SOF/SIM	SOF/RBV	SOF/RBV LDV/SOF + SIM (Salvage treatment)
Time to first undetectable HCV RNA	3 weeks	3 weeks	7 weeks	13 weeks 3 weeks (Salvage)
Timing of LDLT	Week 10 of HCV treatment	Week 18 of HCV treatment	Week 16 of HCV treatment	Week 7 of HCV salvage treatment
Timing of LDLT from first negative HCV RNA	7 weeks	15 weeks	9 weeks	4 weeks
Biological MELD	13	10	7	14
LDLT year	2014	2014	2014	2015
Post-LDLT treatment	SOF 4 weeks	SOF 4 weeks	SOF 4 weeks	LDV/SOF 14 weeks
Outcome	SVR 12	Death from multi-organ failure	SVR 12	SVR 12

Viral load negativity was achieved in all cases with various genotypes (i.e., 4, 1b, 2b, 1a) by 3 weeks of treatment in the first 2 patients and by week 7 in the third patient (Table 1). The first 2 patients (GT 4 and 1b, respectively) were treated with SOF/SIM and the third one (GT 2b) was treated with SOF/RBV. Patient 4 had a problematic course due to uncontrolled pulmonary hypertension. Initially, VL negativity was achieved by the 13^th week the SOF/RIBA treatment regimen. Due to uncontrolled pulmonary hypertension, LDLT was delayed while the DAA treatment continued. By week 29 of treatment, the HCV RNA level was 59 000 IU/ml. It was noted that in the month prior to this viral breakthrough, he had missed 5 doses of SOF while hospitalized and received low doses of RBV (200 mg 3 times daily instead of 600 mg twice daily) due to anemia. Due to theoretical concerns for SOF resistance (commercial testing was not available at this time), a regimen of SOF/LDV and SIM was initiated and VL negativity was achieved by week 3 of this treatment. LDLT surgery was performed at week 7 of this salvage regimen, whereas LDLT was performed at 10, 18, and 16 weeks after DAA initiation in patients 1–3, respectively.

In the post-LDLT phase, patients 1–3 received 4 weeks of SOF monotherapy 400 mg daily and patient 4 received 14 weeks of LDV-SOF 90–400 mg, respectively, for maintenance. Three patients achieved SVR12. One patient died at 4 months post-LT due to non-HCV-related complications (sepsis due to multi-organ failure). No SVR12 serum sample was obtained.

Discussion

It is well known that HCV infection can lead to accelerated liver fibrosis in the post-LT setting, with development of cirrhosis in 15–30% of cases within 5 years [5,22]. The most feared clinical complication is severe fibrosing cholestatic hepatitis, which is seen in less than 10% of LT recipients in the early post-LT period, leading to graft loss and, in some cases, death.

Recently, there have been substantial developments in HCV treatment. DAA treatment either during the pre- or post-LT period demonstrates high SVR rates with good tolerability [13–19].

There are few ways to protect the graft from recurrent HCV infection. One is to eradicate the virus in the pre-LT period. This is ideal because the risk of graft infection is essentially zero in the graft. Studies have shown that achieving SVR prior to LT reduces liver-related morbidity and mortality and risk for re-transplantation [23], but this can take 3–6 months. In this period, the patient is still at risk of developing HCC as well as being at risk of adverse effects (e.g., anemia) or other co-morbidities (e.g., hepatorenal syndrome) that may complicate the treatment or require interruption [24,25]. This was the case in patient 4 in our report, who required a long duration of SOF/RBV before achieving RNA negativity (at week 13) followed with viral breakthrough under treatment at week 29. Furthermore, intra-hepatic persistence of HCV-RNA can be responsible for early relapses after the LT, despite the negative VL determination before the surgery [26]. Therefore, waiting for at least 24 weeks after the completion of the DAA treatment is suggested for maximal therapeutic efficacy [27]. This approach always has a risk of further decompensation episodes.

The second common way to protect the graft is early post-transplant treatment with DAAs. The primary evidence for this approach comes from studies performed among deceased donor liver transplant recipients. Obviously, the timing of the surgery and the type of the donor (HCV-positive versus -negative) cannot be predicted.

We present an alternative approach of bridging DAA treatment pre- and post-LT in live-donor LT when the timing of surgery is predictable and the donor is HCV-negative. DAA treatment chosen according to particular genotype of the patient is initiated in the pre-LT period, and LDLT surgery is scheduled after assuring VL negativity for at least 4 weeks. With this approach, 2 main sources of reinfection, the serum and liver, are cleared from the HCV virus and, with a short-term post-transplant course, SVR12 is obtained.

This may be a cost-effective treatment with shorter duration compared to the 6-month treatment proposed for cirrhotic patients. Early in the study period, DAAs other than SOF and SIM were not clinically available. Later, we were able to incorporate LDV in the salvage treatment of patient 4. Newer regimens with high efficacy and pan-genotypic activity, such as Sofosbuvir/Velpatasvir, may also be ideal regimens for this strategy.

Conclusions

Our preliminary experience suggests that bridging DAAs before and after live donor liver transplantation is an effective strategy to prevent HCV recurrence. With delays in transplantation and prolonged use of SOF/RBV, there is a risk of viral breakthrough, but a salvage strategy of triple DAA therapy can be effective.

Abbreviations

DAAs

direct-acting antivirals

ESLD

end-stage liver disease

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

LDLT

living donor liver transplantation

LDV

Ledipasvir

MELD

model for end-stage liver disease

PEG+RIBA

Pegylated interferon plus Ribavirin

SIM

Simeprevir

SOF

Sofosbuvir

SVR12

sustained virologic response at 12 weeks

RBV

Ribavirin

VL

viral load

LLOD

lower level of detection