
==== Front
Liver Transpl
Liver Transpl
LVT
Liver Transplantation
1527-6465
1527-6473
Lippincott Williams & Wilkins Hagerstown, MD

38771635
LT-23-715
10.1097/LVT.0000000000000399
00007
3
Original Articles: Peritransplant and Posttransplant Management and Outcomes
Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population
https://orcid.org/0000-0002-4898-7778
Reddy K. Rajender 1ReddyR@PennMedicine.upenn.edu

https://orcid.org/0000-0002-5605-8995
Weinberg Ethan M. 1ethan.weinberg@pennmedicine.upenn.edu

https://orcid.org/0000-0003-1322-5332
Gonzalez Stevan A. 2Stevan.Gonzalez@BSWHealth.org

https://orcid.org/0000-0002-6402-5333
Izzy Manhal J. 3manhal.izzy@vumc.org

https://orcid.org/0000-0003-4095-8144
Simonetto Douglas A. 4simonetto.douglas@mayo.edu

https://orcid.org/0000-0002-2153-3194
Frederick R. Todd 5Todd.Frederick@sutterhealth.org

https://orcid.org/0000-0002-0536-7253
Rubin Raymond A. 6raymond.rubin@piedmont.org

https://orcid.org/0000-0001-5596-864X
Fricker Zachary zfricker@bidmc.harvard.edu
7
https://orcid.org/0009-0009-7853-1542
Ikahihifo-Bender Jade 1jade.ikahihifo-bender@pennmedicine.upenn.edu

https://orcid.org/0009-0006-8821-387X
Harte Maggie 1maggie.harte@pennmedicine.upenn.edu

Garcia Sandra 2Sandra.Garcia@bswhealth.org

Campbell Kathryn 3kathryn.e.campbell@vumc.org

https://orcid.org/0000-0001-7212-8132
Olofson Amy 4olofson.amy@mayo.edu

Razavi Ryan F. 5Ryan.Razavi@sutterhealth.org

James Janelle M. 6Janelle.James1@piedmont.org

Patel Het 7hetpatel2006@gmail.com

https://orcid.org/0009-0007-8801-9775
Kim-Lee Grace 1GraceKim.Lee@pennmedicine.upenn.edu

https://orcid.org/0009-0002-8988-8837
Witkiewicz Sherry 8sherryw@ihcresearch.com

Tobin William 8billt@ihcresearch.com

https://orcid.org/0000-0001-9155-3513
Jamil Khurram 9khurramjamil@yahoo.com

1 Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
2 Division of Hepatology, Department of Medicine, Simmons Transplant Institute, Baylor Scott & White All Saints Medical Center, Fort Worth, Texas, USA
3 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
4 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
5 Division of Hepatology, Department of Advanced Organ Therapies and Transplantation, California Pacific Medical Center, San Francisco, California, USA
6 Department of Transplantation, Piedmont Transplant Institute, Piedmont Healthcare, Atlanta, Georgia, USA
7 Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
8 International HealthCare, LLC, Norwalk, Connecticut, USA
9 Formerly at Department of Research & Development, Mallinckrodt Pharmaceuticals, Scientific Affairs, Bridgewater, New Jersey, USA
Correspondence K. Rajender Reddy, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. Email: reddyr@pennmedicine.upenn.edu
10 2024
22 5 2024
30 10 10261038
2 12 2023
6 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

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==== Body
pmcINTRODUCTION

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a serious complication of decompensated cirrhosis with limited therapeutic options and is associated with significant morbidity and mortality.1–4 The previously accepted HRS-1 subtype has been updated by the International Club of Ascites to HRS-AKI, which encompasses smaller increases in serum creatinine (SCr) over short-term periods and allows for earlier intervention.5–8

Liver transplantation (LT) remains the definitive therapy for patients with HRS-AKI yet accessibility is limited by common contraindications in this patient population and organ availability. Additionally, kidney dysfunction and the need for renal replacement therapy (RRT) are associated with poor pre-LT and post-LT outcomes.9–12 Sustained renal failure requiring simultaneous liver and kidney transplantation (SLKT) places greater demand on the already inadequate supply of renal allografts. A thorough study of pharmacologic therapy has been necessary to address this unmet medical need of patients with HRS-AKI facing barriers to LT as well as recipients facing poor post-LT outcomes.

Vasoconstrictors, namely terlipressin, norepinephrine (NorEpi), and midodrine and octreotide (M&O), in combination with albumin, act on splanchnic circulation to improve renal function in patients with HRS-AKI.1,2,4,13–15 At the conception of the present Continuous INfusion oF Terlipressin for SUbjects with HRS-AKI on the LivEr Transplant Waiting List study (INFUSE; NCT04460560), there were no therapies approved by the Food and Drug Administration (FDA) for HRS-AKI in the United States. The then prevailing standard in the United States, off-label M&O use, has been challenged by comparative efficacy data from emerging meta-analyses.15–20 In many areas outside the United States, terlipressin has been the standard of care in the treatment of patients with cirrhosis and esophageal variceal hemorrhage for decades and those with HRS-AKI more recently.21–25

The CONFIRM study (NCT02770716) verified the safety and efficacy of bolus-injection terlipressin in patients with HRS-AKI who were enrolled at North American centers between 2016 and 2019.26 Moreover, the 2021 American Association for the Study of Liver Diseases (AASLD) Guidelines indicate terlipressin as the superior treatment for HRS-AKI due to greater efficacy than M&O and more robust data than NorEpi.1,2 Treatment with terlipressin may also provide protective renal benefits, including decreased need for RRT, decreased rate of SLKT, and overall improved transplant outcomes.9,10,27–31 Although bolus-injection terlipressin was approved by the US FDA as a therapy for HRS-AKI in September 2022, concerns remain regarding adverse events (AEs), mortality impact, and effect on transplant priority.25 Real-world implementation hinges on robust local data after decades of discussion within the medical community.

The safety profile of bolus-dose terlipressin for HRS-AKI is well established with known safety concerns in patients with acute-on-chronic liver failure (ACLF) grade 3, SCr > 5 mg/dL, and Model for End-Stage Liver Disease (MELD) score ≥ 35.26,29,32–36 The cardiopulmonary and ischemic AEs associated with terlipressin are predictable and can be readily managed by dose reduction or interruption in hospital-care settings.26,34–39 Both terlipressin bolus and continuous infusion have been shown to be effective in the treatment of HRS-AKI, with fewer AEs occurring among those receiving continuous infusion.40 The INFUSE study aimed to confirm the safety and efficacy of a single bolus-loading dose injection followed by continuous terlipressin infusion in a patient population made up of candidates of LT.

METHODS

The study protocol conforms to the ethical guidelines of the Declarations of Helsinki and Istanbul, as reflected in a priori approval by the research ethics committees at the sponsoring institution (University of Pennsylvania) and each participating institution, was registered in ClinicalTrials.gov (NCT04460560) and has an Investigational New Drug application (146962). Written informed consent was obtained from patients or legally authorized representatives prior to enrollment.

The INFUSE study was completed in 50 adult patients with cirrhosis, ascites, and HRS-AKI based on the 2015 revised International Club of Ascites diagnostic criteria. The enrollment period was from December 15, 2020, to August 22, 2022, and entailed 196 screen failures (Supplemental Figure S1, http://links.lww.com/LVT/A593). Due to initial slow enrollment, 10 patients ineligible for transplant at the time of enrollment (20%) were treated with terlipressin as well after discussion among the investigators; while not eligible for transplant at presentation, they could not be ruled out as candidates later on. Candidates of LT were defined as those on the waitlist, those in evaluation, and those who were eligible but had not officially begun the evaluation process at the time of enrollment. The qualifying SCr value was measured prior to administration of the study drug and after diuretic withdrawal and at least 48 hours of albumin administration for circulatory volume expansion. The absence of sustained improvement in renal function, defined as <20% decrease in SCr above 1.5 mg/dL or ≥20% decrease in SCr with plateau above 1.5 mg/dL for another 48 hours, was also an inclusion criterion. Continuous pulse oximetry monitoring was not a requirement in the study protocol. Patients receiving M&O or NorEpi as standard of care were eligible for inclusion, providing these medications were discontinued at the time of enrollment.

Patients with European Association for the Study of the Liver-Chronic Liver Failure Consortium ACLF grade 3, SCr > 5.0 mg/dL, or MELD score ≥ 35 were excluded. Additional exclusions were uncontrolled sepsis or uncontrolled bacterial infection; shock; current or recent (within 4 wk) exposure to nephrotoxic agents; estimated life expectancy<7 days; advanced HCC with life expectancy <6 months; superimposed acute liver injury due to drugs, supplements, viral hepatitis, or toxins; evidence of obstructive uropathy or parenchymal renal disease; evidence of acute tubular necrosis or intrinsic renal disease (including the presence of casts on urinary sediment and hematuria on urinalysis); pregnancy; severe cardiovascular disease; current or recent (within 4 weeks) RRT or anticipation of RRT within 3 days of enrollment; TIPS within 30 days; known allergy or sensitivity to terlipressin; and participation (within 30 d) in other clinical research with investigational products that would adversely affect participation.

Terlipressin patients were given an initial bolus prior to continuous infusion in order to achieve therapeutic levels earlier than continuous infusion alone. The bolus was prepared by reconstituting 1 vial of 1 mg terlipressin acetate with 5 mL of sterile 0.9% sodium chloride solution. Terlipressin acetate was diluted with sterile 0.9% sodium chloride to prepare various continuous infusion doses. Following the initial 0.5 mg bolus, terlipressin was administered as a continuous infusion starting at 2 mg per day and increasing up to 8 mg per day based on SCr response and tolerability as follows: increase to 4 mg per day if SCr did not decrease at least 30% from baseline by day 3; increase to 6–8 mg per day, per principal investigator discretion, if SCr did not decrease at least 50% from baseline by day 5. If the infusion was paused for more than 4 hours, a 0.5 mg bolus was administered prior to restarting the infusion. Patients could be treated for a maximum of 14 days. If reversal of HRS-AKI or maximum anticipated effect (no decrease in SCr 72 hours following maximum dose) was achieved prior to day 14 of treatment, terlipressin could be stopped per principal investigator discretion. Patients were retreated if they returned by day 90 of follow-up with similar symptoms and again met eligibility criteria. The dosing of albumin was recorded and infused at the discretion of the treating clinician; guidance was provided to decrease the respiratory risks seen with albumin administration (Supplemental Figure S2, http://links.lww.com/LVT/A593).

A historical cohort included 50 patients who, after diuretic withdrawal and albumin replacement therapy, received at least 48 hours of M&O or NorEpi for HRS-AKI and would have otherwise met the same eligibility criteria as the patients in the terlipressin cohort; 46 of 50 (92%) received M&O and 4 of 50 (8%) received NorEpi (Supplemental Figure S3, http://links.lww.com/LVT/A593). Historical cases included critical clinical data points to enable comparison of the cohorts. The historical cases were hospitalized during the period from January 2015 up to site Institutional Review Board approval for this study. Patients enrolled in a blinded clinical trial during this period were excluded.

A complete response to treatment for both the terlipressin and historical cohorts was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr ≤ 1.5 mg/dL. Partial response to treatment was defined as a ≥ 30% decrease in SCr with EOT SCr > 1.5 mg/dL. Nonresponse was defined as a <30% decrease in SCr.

Outcomes/analysis

The primary efficacy assessment was the rate of response in the terlipressin cohort. Comparison was made to the response rate observed in the historical cohort. The 30-day and 90-day follow-up SCr measures were also compared across cohorts. Comparison of continuous variables was made via non-parametric tests (eg, Wilcoxon Rank Sum, Kruskal-Wallis). Comparisons of frequency for categorical variables were made via the Fisher exact test. Competing risk analyses were used to assess the incidence of RRT (with death and transplantation as competing risks) and LT (with death as a competing risk) as well as death (with LT and RRT as competing risks).

Safety review for the terlipressin cohort included serious adverse events (SAEs) of interest (namely ischemia and respiratory failure), unanticipated AEs, and mortality up to 90 days post-EOT. Outcomes were adjudicated by a panel of investigators. SAEs or AEs were not captured in the historical M&O/NorEpi cohort.

RESULTS

Demographic and clinical characteristics, namely age, sex, race, ethnicity, SCr, and MELD, at baseline were comparable between cohorts (Table 1). Days on treatment were comparable, while median SCr, MELD, and concurrent albumin dose at EOT were significantly lower for the terlipressin cohort compared to the historical cohort (Table 2). The complete, partial, and nonresponse rates were 64%, 16%, and 20% for the terlipressin cohort and 16%, 12%, and 72% for the historical cohort, respectively (Figure 1). Complete response rates were significantly higher in the terlipressin cohort (p<0.001).

TABLE 1 Demographics and clinical characteristics of each cohort at baseline

	Historical	Prospective		
Parametera	M&O/NorEpi (N=50), n (%)	Terlipressin (N=50), n (%)	p	
Age (y)	61 (30–83)	59 (28–78)	NS (0.25)	
Male sex	26 (52)	27 (54)	NS (>0.99)	
Race	—	—	NS (0.17)	
 White	41 (82)	42 (84)	—	
 Black/African American	4 (8)	7 (14)	—	
 Native Hawaiian/Other Pacific Islander	1 (2)	1 (2)	—	
 Not reported	4 (8)	0 (0)	—	
Ethnicity	—	—	NS (> 0.99)	
 Not Hispanic or Latino	44 (88)	43 (86)	—	
 Hispanic or Latino	5 (10)	6 (12)	—	
 Not Reported	1 (2)	1 (2)	—	
Etiology of liver disease	—	—	NS (0.90)	
 Alcohol-associate	24 (48)	26 (52)	—	
 NASH	15 (30)	15 (30)	—	
 Other or cryptogenic	11 (22)	9 (18)	—	
AKI stage	—	—	NS (0.71)	
 1B	15 (30)	14 (28)	—	
 2	23 (46)	20 (40)	—	
 3	12 (24)	16 (32)	—	
Transplant candidates	
 Overall	34 (68)	40 (80)	NS (0.25)	
  Waitlist	−16/34 (47)	−5/40 (12.5)	0.003	
  Evaluation	−15/34 (44)	−23/40 (57.5)	—	
  Eligible	−3/34 (9)	−12/40 (30)	—	
SCr (mg/dL)	2.6 (1.6–4.9)	2.6 (1.5–4.9)	NS (0.70)	
MELD score	28 (20–34)	24 (16–34)	NS (0.33)	
MELD-Na score	30 (21–34)	28 (18–35)	NS (0.24)	
MELD 3.0 scorec	30 (21–37)	29 (21–37)	NS (0.18)	
Total prior albumin dose (g)b	188 (1–425)	250 (42–624)	<0.001	
a Values presented are frequency (%) for categorical parameters and median (minimum–maximum) for continuous parameters unless otherwise noted.

b One retrospective patient censored due to outside albumin challenge.

c MELD 3.0 was calculated retrospectively as MELD-Na was used for LT allocation at the time of enrollment.

Abbreviations: AKI, acute kidney injury; M&O, midodrine and octreotide; MELD, Model for End-Stage Liver Disease; NorEpi, norepinephrine; SCr, serum creatinine.

TABLE 2 Laboratory and treatment parameters of each cohort at the end of treatment

	Historical	Prospective		Prospective Terlipressin		
Parametera	M&O/NorEpi(N=50)	Terlipressin (N=50)	p	CR (N=32)	PR (N=8)	NR (N=10)	p	
SCr (mg/dL)	2.1 (1.0–7.8)	1.4 (0.8–3.1)	p<0.001	1.2 (0.8–1.5)	1.9 (1.7–2.4)	2.5 (1.5–3.1)	—	
MELD score	25 (16–32)	19 (11–33)	p<0.001	18 (11–31)	22 (14–29)	23 (16–33)	—	
MELD-Na score	25 (16–35)	24 (11–33)	p=0.02	22 (11–31)	25 (16–29)	26 (18–33)	—	
MELD 3.0 scoreb	26 (17–38)	23 (12–36)	p=0.01	—	—	—	—	
Days of treatment	7 (3–14)	8 (2–14)	NS (0.65)	8 (3–14)	10 (3–14)	5 (2–14)	NS (0.12)	
Terlipressin dose (mg)	
 Daily, mean	NA	3.4 (1.3–6.2)	—	3.0 (1.6–5.6)	4.5 (1.5–6.2)	3.6 (1.3–5.6)	NS (0.06)	
 Total	NA	21.0 (2.5–86.5)	—	20.5 (6.5–72.5)	46.5 (4.5–86.5)	16.5 (2.5–78.5)	NS (0.13)	
Concurrent albumin dose (g)	
 Daily, mean	32 (0–100)	14 (0–41)	p<0.001	16 (0–41)	14 (0–33)	8 (0–29)	NS (0.06)	
 Total	206 (0–725)	75 (0–450)	p<0.001	81 (0–412.5)	88 (0–450)	25 (0–400)	NS (0.10)	
a Values presented are median (minimum–maximum) unless otherwise noted.

b MELD 3.0 was calculated retrospectively as MELD-Na was used for LT allocation at the time of enrollment.

Abbreviations: CR, complete response group; EOT, end of treatment; M&O, midodrine and octreotide; MELD, Model for End-Stage Liver Disease; NorEpi, norepinephrine; NR, nonresponse group; PR, partial response group; SCr, serum creatinine.

FIGURE 1 Response rates, etiology of liver disease, and AKI stage among terlipressin cohort. (A) Overall response rates to terlipressin in the prospective cohort and M&O/NorEpi in the historical cohort. (p<0.001, Fisher exact test). (B) Etiology of liver disease and response to treatment among terlipressin cohort (p=0.51, Fisher exact test). (C) AKI stage and response to treatment among terlipressin cohort (p=0.40, Fisher exact test). Abbreviations: AKI, acute kidney injury; CR, complete response; M&O, midodrine and octreotide; NorEpi, norepinephrine; NR, nonresponse; PR, partial response.

Safety and mortality

SAEs of interest, such as ischemia and respiratory failure or unanticipated AEs were collected in the terlipressin cohort only. There were no drug-related ischemic or cardiac events. One patient had hypoxic respiratory failure due to fluid overload and responded to diuretics while terlipressin was held. This was during retreatment for recurrence of HRS-AKI a few weeks after initial treatment with terlipressin. During the second episode, the patient received 450 g albumin over 11 days while investigator had asked the medical team to hold albumin at certain periods; the patient also developed pneumonia in the interim, which was treated with antibiotics. This event may be described as “pulmonary edema with hypoxia,” aggravated by excess albumin infusion, and resolved following interruption of albumin dosing and cautious diuresis. One patient had an AE of interest (possibly drug-related rash).

In the terlipressin cohort, there were 3 deaths by day 30 of follow-up (2 progressive liver failure and 1 progressive renal failure) and 8 additional deaths by day 90 (4 progressive liver failure, 1 progressive renal failure, 1 spontaneous bacterial peritonitis, 1 unspecific cirrhosis/diabetes complications, and 1 unknown). Survival at days 30 and 90 of follow-up were 94% and 78% for the terlipressin cohort and 82% and 68% for the historical cohort, respectively (Table 3). By competing risk analysis, there was no difference in cumulative incidence of death at 90 days in the terlipressin patients by response group (Figure 2).

TABLE 3 Need for RRT and survival status at day 30 and day 90 of follow-up (A) by historical and prospective cohorts and (B) by response within each cohort

(A)	
	Historical		Prospective		
Parametera	M&O/NorEpi (N=50), n (%)		Terlipressin (N=50), n (%)	p	
RRT started byb	
 Day 30	13 (26)		9 (18)	NS (0.47)	
 Day 90	14 (28)		9 (18)	NS (0.34)	
Alive at	
 Day 30	41 (82)		47 (94)	NS (0.12)	
 Day 90	34 (68)		39 (78)	NS (0.37)	
(B)	
	Historical M&O/NorEpi		Prospective Terlipressin		
Parameter a	CR (N=8)	PR (N=6)	NR (N=36)	p	CR (N=32)	PR (N=8)	NR (N=10)	p	
RRT started byb	
 Day 30	0	2 (33)	13 (36)	NS (0.13)	1 (3)	1 (13)	7 (70)	<0.001	
 Day 90	1 (13)	2 (33)	13 (36)	NS (0.50)	1 (3)	1 (13)	7 (70)	<0.001	
Alive at	
 Day 30	7 (88)	6 (100)	28 (78)	NS (0.71)	31 (97)	7 (88)	9 (90)	NS (0.29)	
 Day 90	6 (75)	5 (83)	23 (64)	NS (0.71)	25 (78)	7 (88)	7 (70)	NS (0.79)	
a Values presented are frequency (%).

b Intraoperative RRT censored (1 prospective case and 1 retrospective case). RRT started for 1 sepsis case by day 30 and for 1 delayed graft failure case by day 90, included in retrospective totals.

Abbreviations: CR, complete response group; M&O, midodrine and octreotide; NorEpi, norepinephrine; NR, nonresponse group; PR, partial response group; RRT, renal replacement therapy.

FIGURE 2 Survival, renal replacement therapy (RRT), and liver transplant (LT) by day 90 of follow-up. (A) Cumulative incidence of death with LT and use of RRT as competing risks by terlipressin response group (p=0.13). (B) Need for RRT by terlipressin response group (p<0.001, RRT-free survival with death and LT as competing risks). (C) Rate of transplantation (LT-alone or simultaneous liver and kidney transplant) by terlipressin response group (p=0.20, transplant-free survival with death as competing risk). Abbreviation: NO, nonresponse group.

RRT and transplantation

When analyzed with death and LT as competing risks, incident use of RRT by day 90 of follow-up was also statistically similar but numerically lower in the terlipressin cohort (18% vs. 28%, Table 3). In a similar analysis within the terlipressin response groups, however, the incident use of RRT was significantly greater in nonresponders compared to partial or complete responders (70% vs. 13% and 3%, p<0.001, Figure 2). Landmarked analysis beginning on day 14 to account for different exposure times also indicates that cumulative incidence of RRT was greater for nonresponders to terlipressin compared to partial or complete responders (p<0.001, Supplemental Figure S4, http://links.lww.com/LVT/A593).

Cumulative incidence of death with LT and use of RRT as competing risks by cohort (p=0.13) was similar between cohorts, and cumulative incidence of death with LT and use of RRT as competing risks by terlipressin response group (p=0.13) was similar (Figure 2). However, the need for RRT by terlipressin response group (p<0.001, RRT-free survival with death and LT as competing risks) was statistically significantly greater among subjects with no response to terlipressin. Finally, the rate of transplantation (LT-alone or SLKT) by terlipressin response group (p=0.20, transplant-free survival with death as competing risk) was similar.

At enrollment of the terlipressin cohort, 40 of 50 patients (80%) were considered candidates for transplant, with 12.5% on the waitlist, 57.5% in evaluation, and 30% eligible (Table 1). This proportion is similar to 34 of 50 (68%) candidates of transplant in the historical cohort, but the breakdown by status differed with 47% on the waitlist, 44% in evaluation, and 9% eligible. Median time to transplant was statistically similar yet numerically higher in the prospective terlipressin cohort at 22 days (ranging from 0 to 89 d) compared to 5.5 days (ranging from 0 to 80 d) in the historical M&O/NorEpi cohort.

Nineteen of the 40 candidates for transplant (48%) in the terlipressin cohort underwent LT or SLKT by day 90 of follow-up (Table 4). This 90-day transplant rate in the terlipressin cohort is similar to the historical cohort (48% vs. 53%). Sixteen of 40 candidates of LT in the terlipressin cohort underwent LT-alone during this period, which is similar to 16 of 34 historical candidates of LT (40% vs. 47%). Of the 16 terlipressin patients who underwent LT-alone, a numerically higher proportion were complete responders to terlipressin compared to partial and nonresponders (63% vs. 6% and 31%). Three of 40 candidates of LT in terlipressin cohort underwent SLKT by day 90 of follow-up, which is comparable to 2 of 34 historical candidates of LT (8% vs. 6%). None of the complete responders to terlipressin underwent SLKT, while 2 partial and 1 nonresponder underwent SLKT.

TABLE 4 Transplant rates at day 90 of follow-up

	Historical	Prospective		Prospective Terlipressin		
Parametera	M&O/NorEpi (N=50), n (%)	Terlipressin (N=50), n (%)	p	CR (N=32)	PR (N=8)	NR (N=10)	p	
Candidatesb	34 (68)	40 (80)	NS (0.25)	24 (75)	8 (100)	8 (80)	NS (0.35)	
LT or SLKT total	18/34 (53)	19/40 (48)	NS (>0.99)	10/24 (42)	3/8 (38)	6/8 (75)	NS (0.31)	
LT-alonec	16/34 (47)	16/40 (40)	—	10/16 (63)	1/16 (6)	5/16 (31)	—	
SLKTc	2/34 (6)	3/40 (8)	—	0/3 (0)	2/3 (67)	1/3 (33)	—	
a Values presented are frequency (%) unless otherwise noted.

b Candidates defined as waitlisted for LT, in evaluation, or eligible with anticipation of being listed.

c For LT alone and SLKT parameters by prospective response, values presented are proportion of CR, PR, or NR among those who underwent transplants (%).

Abbreviations: CR, complete response group; LT, liver transplant; M&O, midodrine and octreotide; NorEpi, norepinephrine; NR, nonresponse group; PR, partial response group; SLKT, simultaneous liver and kidney transplant.

MELD scores

Baseline MELD and MELD-Na, presented here as median (IQR), were statistically similar between terlipressin and historical cohorts (MELD: 24 [9.5] vs. 28 [5.5]; MELD-Na: 28 [9.5] vs. 30 [5.0], Figure 3), while EOT MELD and MELD-Na significantly differed between cohorts (MELD: 19 [7.0] vs. 25 [5.0], p<0.001; MELD-Na: 24 [7.0] vs. 25 [8.0], p=0.02). A limitation of this comparison is that EOT MELD was not available for 5 terlipressin and 13 historical patients. Within the terlipressin cohort, the response groups had statistically similar baseline MELD and MELD-Na scores: 24 (9.0) and 28 (10) for complete response, 27 (9.0) and 29 (8.0) for partial response, and 25 (7.5) and 29 (8.0) for nonresponse.

FIGURE 3 Median MELD and MELD-Na at baseline* and EOT.^a (A) Median MELD scores. Levels of significance: *p=0.33, ^p<0.001 (Wilcoxon rank sum test). (B) Median MELD-Na scores. Levels of significance: *p=0.24, ^p=0.02 (Wilcoxon rank sum test). aBaseline MELD/MELD-Na missing for 3 terlipressin and 7 historical patients. EOT MELD/MELD-Na missing for 5 terlipressinn and 13 historic patients. EOT scores not significantly compared for response groups as groups were defined by EOT creatinine. Abbreviations: CR, complete response; EOT, end of treatment; MELD, Model for End-Stage Liver Disease; M&O, midodrine and octreotide; NorEpi, norepinephrine; NR, nonresponse; PR, partial response.

SCr levels

Median SCr levels at baseline of the terlipressin and historical cohorts were statistically similar at 2.6 (1.3) and 2.6 (1.5) mg/dL, respectively (Table 1). The terlipressin cohort had lower median SCr levels than the historical cohort at EOT (1.4 [0.8] vs. 2.1 [1.7] mg/dL, p<0.001) and day 30 of follow-up (1.5 [0.9] vs. 2.1 [1.5] mg/dL, p=0.05). By day 90 of follow-up, while the terlipressin cohort SCr remained lower (1.2 [0.5] vs. 1.7 [1.2] mg/dL, p=0.60), this difference was no longer statistically significant. Median EOT SCr was lower than median baseline SCr for patients treated with terlipressin, and day 30 and day 90 median SCr values remained lower for the complete and partial response groups. Patients who received transplants were deceased or had missing values were censored from follow-up calculations. D30 and D90 SCr were available for 26 and 16 terlipressin patients, respectively. D30 and D90 SCr were available for 21 and 11 historical patients, respectively. For the terlipressin nonresponse group, D90 SCr was available for only 1 patient.

Treatment with continuous terlipressin infusion following a bolus effectively lowered SCr levels throughout treatment. Patients who responded to treatment tended to sustain this improvement throughout the follow-up periods. Three of 32 patients with complete response returned by day 90 of follow-up with recurrence of HRS-AKI and were retreated. Two completely responded to retreatment; one was taken off treatment after 1 day in preparation for transplant.

DISCUSSION

HRS-AKI poses a significant burden on the US health care system. In 2019, 27,180 HRS hospitalizations cost an estimated 4.2 billion USD for care and led to an in-hospital mortality rate of 23.7%.3 As LT is not a viable option for all patients, continuous terlipressin infusion has the potential to close the gap in treatment for HRS-AKI. Widespread implementation of this treatment is impeded by concerns relating to the safety and efficacy of terlipressin, uncertainty regarding the optimal patient population to receive terlipressin, and concerns that successful treatment of HRS-AKI thus improving MELD scores might delay patients getting organ offers.

In our study, a high complete response rate of 64% with a favorable safety profile was observed with continuous terlipressin infusion in a population of candidates who received LT. This complete response rate was significantly higher than that of the historical cohort (64% vs. 16%). These results are similar to what has been seen in other continuous terlipressin infusion studies outside of the United States.35,40,41

In the CONFIRM study, Wong and colleagues noted that patients with highly advanced liver disease, as noted by MELD score above 35 and multiorgan failure of ACLF grade 3, had higher rates of SAEs when treated with terlipressin bolus compared to placebo.25 Terlipressin-treated patients in CONFIRM had a higher rate of mortality than the placebo group (11% vs. 2%), primarily due to respiratory failure.25 Continuous infusion of terlipressin may address this safety concern, as this strategy has been more effective at lower total doses with fewer adverse events than bolus administration in several studies.28,40,42–45 Post hoc analyses of data pooled from CONFIRM and 2 other North American placebo-controlled studies of terlipressin for HRS-AKI found a significant association between lower baseline SCr and higher HRS reversal and survival rates.26,29 The present INFUSE study sought to evaluate the safety and efficacy of continuous infusion terlipressin with guidance from these parameters.

In the INFUSE study, no drug-related cardiac or respiratory failure SAEs were encountered, while numerically higher survival rates at days 30 and 90 of follow-up among the terlipressin cohort compared to the historical cohort were observed (94% vs. 82% at day 30 and 78% vs. 68% at day 90). Administration via continuous infusion and exclusion of ACLF grade 3, SCr > 5.0 mg/dL, or MELD ≥ 35 may have mitigated SAEs of consequence in the INFUSE study. Safety issues that may persist after consideration of these variables are likely predictable and manageable.26,34–39 A notable finding from the 2020 Arora et al35 study, which did not select for a transplant-eligible population, was that the AEs experienced were mild and reversible with reduction or stoppage of continuous terlipressin infusion.

Median baseline SCr was similar between cohorts, but the terlipressin cohort had statistically lower median SCr levels than the historical cohort at EOT and day 30 of follow-up and numerically lower median SCr at day 90 of follow-up. Within the terlipressin cohort, responders had improvement in median SCr levels at all subsequent time points compared to baseline. Continuous terlipressin infusion following a bolus effectively lowered median SCr levels throughout treatment; among complete responders, this improvement was sustained in follow-up. Of the 3 complete responders who were treated for recurrence of HRS-AKI within 90 days, 2 completely responded to retreatment, and 1 was taken off treatment prior to transplant.

Another concern associated with terlipressin for HRS-AKI is the effect of treatment on rates of RRT and LT. RRT may serve as a bridge to transplantation for the candidates of LT with HRS-AKI, but RRT is associated with poor pre-LT and post-LT outcomes and also increases the cost of peritransplant care substantially.9–12 An alternative bridge to transplantation, which preserves renal function without compromising survival outcomes, is desirable for patients with HRS-AKI. Through retrospective analysis of patients who received terlipressin and albumin for HRS-AKI prior to LT, Piano et al27 showed that responders had lower rates of RRT before and after LT and also lower incidence of CKD within the year after LT. In addition, a retrospective analysis of those in CONFIRM who had LT noted that the rate of RRT after LT was lower in the terlipressin cohort compared to those who received placebo.31 The present INFUSE study also found that the need for RRT by day 90 of follow-up was significantly lower in terlipressin complete responders compared to partial and nonresponders (3% vs. 13% and 70%). Overall, the need for RRT was statistically similar yet numerically lower in the terlipressin cohort compared to the historical cohort (18% vs. 28%). A larger sample may be required to confirm this difference, as many factors influence the decision to initiate RRT.

Of the candidates for transplant treated with terlipressin, 48% underwent LT-alone or SLKT by day 90 of follow-up, comparable to the observed proportion of historical transplant candidates treated with M&O/NorEpi who underwent transplant (53%). This is also comparable to the proportions of US candidates listed in 2018 and 2019 who received a deceased donor LT of any type within 1 year—49% and 50%, respectively.46,47 A high proportion of terlipressin-treated recipients of LT were complete responders (63%), and none of the complete responders needed SLKT within 90 days.

While the terlipressin cohort had a lower EOT MELD, LT frequency remained high in conjunction with a decreased need for RRT compared to both the historical cohort and the national candidate rate, mitigating concern for impacted organ access due to favorable response to terlipressin.

Of those who had a complete response to terlipressin, 59% were patients with alcohol-associated liver disease. A numerically higher complete response rate was seen among patients with alcohol-associated liver disease (73%) compared to other etiologies (54%). A similar phenomenon was observed among the alcoholic hepatitis subgroup of the CONFIRM and REVERSE trials; presumably, some of the patients in INFUSE with alcohol-associated liver disease had a reversible component to their liver disease and thus a favorable outcome.48 In the CONFIRM/REVERSE alcoholic hepatitis subgroup, 38.0% of patients who received terlipressin achieved HRS reversal, defined as at least one SCr value on treatment ≤ 1.5 mg/dL, compared to 13.1% of patients who received placebo.48 At day 30 of CONFIRM/REVERSE follow-up, 33.9% of the terlipressin group compared to 10.7% of the placebo group were alive, not on RRT, and maintained reversal.48 It is known that with abstinence, patients with alcohol-associated liver disease have the potential for spontaneous liver function recovery and a decreased need for transplant with continued abstinence. For this patient population, terlipressin offers a potential bridge to continued recovery with abstinence.

The INFUSE study was limited by a small sample size and the lack of a contemporaneous, control cohort. However, real-world implementation of terlipressin following FDA approval is likely to provide more robust data in this cohort of patients. We did not define response rates by International Club of Ascites criteria but agreed-upon criteria. Additionally, comparison of transplant rates and outcomes between noncontemporaneous cohorts may not be ideal because of the changing dynamics in organ allocation policies over time. Yet, the comparison may provide some insights on treatment responses and transplant outcomes over time.

The INFUSE trial is the first US-based study of early HRS-AKI intervention with continuous terlipressin infusion in a candidate population for LT. In patients with HRS-AKI, treatment with continuous terlipressin infusion facilitated high response rates with a favorable safety profile, while LT-alone was accomplished in a high proportion of complete responders.

Supplementary Material

ACKNOWLEDGMENTS

The authors thank the patients for their participation, research assistants and nurses for their help, and Mallinckrodt Pharmaceuticals for supporting the study with an external collaboration grant. The authors thank Daniel Kurtz for his assistance in manuscript editing and formatting. The authors also thank the presentation of INFUSE data at AASLD 2022, EASL 2023, and AASLD 2023.

AUTHOR CONTRIBUTIONS

K. Rajender Reddy and Ethan M. Weinberg conceptualized and designed the study with critical input from Khurram Jamil. K. Rajender Reddy drafted the manuscript with support from Zachary Fricker and for all authors to critically review. K. Rajender Reddy supervised the study as Grace Kim-Lee, Sherry Witkiewicz, and William Tobin provided administrative and technical support. Jade Ikahihifo-Bender, Maggie Harte, Sandra Garcia, Kathryn Campbell, Amy Olofson, Ryan F. Razavi, Janelle M. James, Het Patel, Grace Kim-Lee, Sherry Witkiewicz, and William Tobin were involved in acquisition of data. K. Rajender Reddy, Ethan M. Weinberg, Stevan A. Gonzalez, Manhal J. Izzy, Douglas A. Simonetto, R. Todd Frederick, Raymond A. Rubin, and Zachary Fricker supervised data acquisition and subsequently analyzed and interpreted the data. Zachary Fricker performed the statistical analysis.

FUNDING INFORMATION

Funding was provided by Mallinckrodt Pharmaceuticals through an external collaboration research grant.

CONFLICTS OF INTEREST

K. Rajender Reddy consults for, advises, and received grants from Mallinckrodt. He consults for and received grants from Biovie. He consults for Spark, Novo Nordisk, and Genfit. He advises Novartis and Astra Zeneca. He received grants from BMS, Intercept, Sequana, Grifols, Exact Sciences, TARGET, and Merck. He receives royalties from UpToDate and is an associate editor for Gastroenterology. Ethan M. Weinberg consults for, advises, and received grants from Mallinckrodt. He consults for Biovie, Sequana, PharmaIN, and Novo Nordisk. He lectures for the Institute for Medical and Nursing Education. Stevan A. Gonzalez is on the speakers’ bureau for and advises Mallinckrodt. He is on the speakers’ bureau for AbbVie. Douglas A. Simonetto consults for Mallinckrodt, BioVie, Evive, and Resolution Therapeutics. R. Todd Frederick consults for Mallinckrodt and Tennor. He received grants from Astra Zeneca, River2Renal, and Salix. He is on the DSMB for Miromatrix. Raymond A. Rubin received grants from and is on the speakers’ bureau for Mallinckrodt. He is on the speakers’ bureau for Cook. He received grants from Novo Nordisk, Moderna, and Intercept. Zachary Fricker consults for Pick Research and Back Bay Life Sciences. He received grants from Mallinckrodt, Lipocine Inc., and Bausch. Sherry Witkiewicz is employed by International HealthCare, LLC. William Tobin discloses a services contract with UPenn. Khurram Jamil is employed by, owns patents with, and owns stock in Mallinckrodt. The remaining authors have no conflicts to report.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; ACLF, acute-on-chronic liver failure; AEs, adverse events; EOT, end-of-treatment; FDA, Food and Drug Administration; HRS-AKI, hepatorenal syndrome-acute kidney injury; INFUSE, INfusion oF Terlipressin for SUbjects with HRS-AKI on the LivEr Transplant Waiting List; LT, liver transplant(ation); M&O, midodrine and octreotide; MELD, Model for End-Stage Liver Disease; NorEpi, norepinephrine; RRT, renal replacement therapy; SAEs, serious adverse events; SCr, serum creatinine; SLKT, simultaneous liver and kidney transplant.

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