From Child-Pugh to MELD score and beyond: Taking a walk down memory lane.

The Child-Turcotte-Pugh (CTP) and the MELD (Model for End-Stage Liver Disease) scores were designed to predict the outcome of decompressive therapy for portal hypertension. They were prospectively validated to predict mortality risk in patients with a wide spectrum of liver disease etiology and severity. Unlike the CTP score, the MELD score was derived from prospectively gathered data. Its calculation was based on serum bilirubin, serum creatinine, international normalized ratio (INR) and etiology of liver disease. Instituting a continuous disease severity score that de-emphasizes waiting time resulted in better categorization of waiting patients and enhanced transparency. The US instituted the MELD system in 2002 and soon thereafter, MELD-based liver allocation was adopted throughout the world including Latin America. The most significant impact of MELD-based policies has been the reduction of waiting-list mortality. In the years after implementation of the MELD system, several options have been proposed to improve the MELD score's accuracy. Adding serum sodium (MELD-Na) increased the accuracy of the score in predicting waiting list mortality, thus completing the original MELD score as a prognostic model in liver allocation. On the 20th anniversary of the creation of MELD score we present a brief account of its development, its use to stratify patients on the waiting list for liver transplantation as well as its adoption as liver allocation system .

Failure in all steps of hepatocellular carcinoma surveillance process is frequent in daily practice.

INTRODUCTION AND OBJECTIVES: Failures at any step in the hepatocellular carcinoma (HCC) surveillance process can result in HCC diagnostic delays and associated worse prognosis. We aimed to estimate the prevalence of surveillance failure and its associated risk factors in patients with HCC in Argentina, considering three steps: 1) recognition of at-risk patients, 2) implementation of HCC surveillance, 3) success of HCC surveillance. METHODS: We performed a multi-center cross-sectional study of patients at-risk for HCC in Argentina seen between10.01.2018 and 10.30.2019. Multivariable logistic regression analysis was used to identify correlates of surveillance failure. RESULTS: Of 301 included patients, the majority were male (74.8%) with a mean age of 64 years old. At the time of HCC diagnosis, 75 (25%) patients were unaware of their diagnosis of chronic liver disease, and only 130 (43%) patients were under HCC surveillance. Receipt of HCC surveillance was significantly associated with follow-up by a hepatologist. Of 119 patients with complete surveillance, surveillance failure occurred in 30 (25%) patients. Surveillance failure was significantly associated with alpha fetoprotein ≥20 ng/mL (OR 4.0, CI 95% 1.43-11.55). CONCLUSIONS: HCC surveillance failure was frequent in all the evaluated steps. These data should help guide strategies to improve the implementation and results of HCC surveillance in our country.

Outbreak of hepatitis A in a post-vaccination era: High rate of co-infection with sexually transmitted diseases.

INTRODUCTION AND OBJECTIVES: After hepatitis A (HAV) mandatory immunization in 2005 in Argentina, the incidence of HAV declined drastically. However, several new autochthonous cases of HAV have been reported since 2017. We aimed to evaluate the clinical and epidemiological characteristics and possible transmission routes of affected patients. PATIENTS OR MATERIALS AND METHODS: We performed a cross-sectional study of patients residing in Argentina with acute hepatitis A between 30.06.2017 and 31.12.2018. RESULTS: 66 cases of HAV were registered. Fifty-six patients (86%) were males, with a mean age of 34 ±â€¯12 years old. The most likely routes of transmission were sexual intercourse of men with men, reported by 31 patients. Additionally, 23% and 26% of patients tested positive for HIV and syphilis, respectively. In total, 35% of patients required hospitalization. When assessing outcomes, 79% had a mild presentation and 21% had a severe/fulminant presentation: one patient underwent liver transplantation, and one patient died. CONCLUSIONS: Our study describes that during the study period, HAV infection affected predominantly young adults, particularly men who have sex with men. An elevated proportion of them was diagnosed with a concomitant sexually transmitted disease, and several patients had a severe presentation of the disease.

Argentinian clinical practice guideline for surveillance, diagnosis, staging and treatment of hepatocellular carcinoma.

The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.

Latin American Association for the study of the liver (ALEH) practice guidance for the diagnosis and treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently represents an epidemic worldwide. NAFLD is the most frequently diagnosed chronic liver disease, affecting 20-30% of the general population. Furthermore, its prevalence is predicted to increase exponentially in the next decades, concomitantly with the global epidemic of obesity, type 2 diabetes mellitus (T2DM), and sedentary lifestyle. NAFLD is a clinical syndrome that encompasses a wide spectrum of associated diseases and hepatic complications such as hepatocellular carcinoma (HCC). Moreover, this disease is believed to become the main indication for liver transplantation in the near future. Since NAFLD management represents a growing challenge for primary care physicians, the Asociación Latinoamericana para el Estudio del Hígado (ALEH) has decided to organize this Practice Guidance for the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease, written by Latin-American specialists in different clinical areas, and destined to general practitioners, internal medicine specialists, endocrinologists, diabetologists, gastroenterologists, and hepatologists. The main purpose of this document is to improve patient care and awareness of NAFLD. The information provided in this guidance may also be useful in assisting stakeholders in the decision-making process related to NAFLD. Since new evidence is constantly emerging on different aspects of the disease, updates to this guideline will be required in future.

A Latin American survey on demographic aspects of hospitalized, decompensated cirrhotic patients and the resources for their management.

INTRODUCTION & OBJECTIVES: Liver cirrhosis is a major cause of mortality worldwide. Adequate diagnosis and treatment of decompensating events requires of both medical skills and updated technical resources. The objectives of this study were to search the demographic profile of hospitalized cirrhotic patients in a group of Latin American hospitals and the availability of expertise/facilities for the diagnosis and therapy of decompensation episodes. METHODS: A cross sectional, multicenter survey of hospitalized cirrhotic patients. RESULTS: 377 patients, (62% males; 58±11 years) (BMI>25, 57%; diabetes 32%) were hospitalized at 65 centers (63 urbans; 57 academically affiliated) in 13 countries on the survey date. Main admission causes were ascites, gastrointestinal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis/other infections. Most prevalent etiologies were alcohol-related (AR) (40%); non-alcoholic-steatohepatitis (NASH) (23%), hepatitis C virus infection (HCV) (7%) and autoimmune hepatitis (AIH) (6%). The most frequent concurrent etiologies were AR+NASH. Expertise and resources in every analyzed issue were highly available among participating centers, mostly accomplishing valid guidelines. However, availability of these facilities was significantly higher at institutions located in areas with population>500,000 (n=45) and in those having a higher complexity level (Gastrointestinal, Liver and Internal Medicine Departments at the same hospital (n=22). CONCLUSIONS: The epidemiological etiologic profile in hospitalized, decompensated cirrhotic patients in Latin America is similar to main contemporary emergent agents worldwide. Medical and technical resources are highly available, mostly at great population urban areas and high complexity medical centers. Main diagnostic and therapeutic approaches accomplish current guidelines recommendations.

Trends in liver transplantation for hepatitis C in a country with reduced access to direct-acting antiviral agents.

BACKGROUND: Hepatitis C virus (HCV)-related cirrhosis is a leading indication for liver transplantation (LT) worldwide. Access to effective HCV treatment is inequitable globally. We aimed to analyze whether the introduction of effective HCV treatment caused an impact in LT trends in a middle-income country. METHODS: Cross-sectional analysis of all adult patients who were listed/received a LT in Argentina for HCV, alcohol-related liver disease (ALD), or autoimmune hepatitis/primary biliary cirrhosis (AIH/PBC) from 2007 to 2017. Joinpoint regression analysis was used to identify changes in the cumulative incidence rates in waiting list (WL) registration, WL mortality, and LT. RESULTS: Liver transplantation WL for HCV increased significantly between 2007 and 2014, with an annual percentage change (APC) +7.8%, P = .01, followed by a downward slope from 2014 to 2017 with an APC -9.8%, P = .1. There were no significant changes in WL mortality. LT trends remained stable. LT for HCV without MELD exception points for HCC decreased (APC -6.6%, P = .01), whereas LT for HCV with HCC exception points increased (APC +11.1, P = .01) during the study period. CONCLUSION: Waiting list and LT for HCV without HCC decreased, whereas LT for HCV and HCC increased; this may be related to selective antiviral treatment access for patients with advanced fibrosis.

Clinical epidemiology of acute hepatitis C in South America.

There is scarce data pertaining to acute hepatitis C (aHC) infection in South America. We aimed to describe clinical characteristics and evolution of aHC in a South American cohort. A retrospective survey was conducted at 13 hepatology units. All patients ≥16 years old with aHC diagnosis were included. Demographic, clinical and outcome information were registered in a standardized ad hoc questionnaire. Sixty-four patients were included. The majority were middle-aged (median age: 46 years) and female (65.6%); most of them were symptomatic at diagnosis (79.6%). HCV-1 was the most prevalent genotype (69.2%). Five patients had liver failure: three cases of severe acute hepatitis, one case of fulminant hepatitis and one case of acute-on-chronic liver failure. Nosocomial exposure was the most prevalent risk factor. Evolution was assessed in 46 patients. In the untreated cohort, spontaneous resolution occurred in 45.8% and was associated with higher values of AST/ALT and with the absence of intermittent HCV RNA viremia (P = 0.01, 0.05, and 0.01, respectively). In the treated cohort, sustained virological response was associated with nosocomial transmission and early treatment initiation (P = 0.04 each). The prevalence of nosocomial transmission in this South-American cohort of aHC stresses the importance of following universal precautions to prevent HCV infection. J. Med. Virol. 89:276-283, 2017. © 2016 Wiley Periodicals, Inc.

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America.

Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real-clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real-world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child-Pugh B at baseline and one patient died due to multi-organ failure. Follow up HCV-RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child-Pugh A cirrhosis in non-European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child-Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.

Donor selection criteria for liver transplantation in Argentina: are current standards too rigorous?

Organ shortage is the major limitation for the growth of deceased donor liver transplant worldwide. One strategy to ameliorate this problem is to maximize the liver utilization rate. To assess predictors of liver utilization in Argentina. The national database was used to analyze transplant activity in 2010. Donor, recipient, and transplant variables were evaluated as predictors of graft utilization of number of rejected donor offers before grafting and with the occurrence of primary nonfunction (PNF) or early post-transplant mortality (EM). Of the 582 deceased donors, 293 (50.3%) were recovered for liver transplant. Variables associated with the nonrecovery of the liver were age ≥46 years, umbilical perimeter ≥92 cm, organ procurement outside Gran Buenos Aires, AST ≥42 U/l and ALT ≥29 U/l. The median number of rejected offers before grafting was 4, and in 71 patients (25%), there were ≥13. The only independent predictor for the occurrence of PNF (3.4%) or EM (5.2%) was the recipient's emergency status. During 2010 in Argentina, the liver was recovered in only half of donors. The low incidence of PNF and EM and the characteristics of the nonrecovered liver donors suggest that organ acceptance criteria should be less rigorous.

[Impact of COVID-19 pandemic in liver transplantation in Argentina. Other collateral damage]. / Impacto de la pandemia por COVID-19 sobre el trasplante hepático en la Argentina. Otro daño colateral.

The COVID-19 pandemic declared in March 2020, has generated worldwide concern due to its effect on the health of the population and the potential health collapse. The strategy of "flattening the curve" through social distancing made it possible to adapt the resources of the health system to patients with COVID-19, but results in other areas of health could not be predicted. The objective of this work was to analyze the consequences of the pandemic on liver transplantation in general and for hepatocarcinoma (HCC). The following studies were carried out: a) a retrospective analysis using data from the CRESI / INCUCAI to compare admission to the waiting list, mortality on the list, donation and liver transplantation from 03/20 to 08/15, 2019 and the same period in 2020, and b) a survey of the transplant centers with the highest transplant activity to assess the effect of the measures taken in different institutional and regional situations. The first analysis showed a 55% decrease in liver transplants, with a similar reduction in donation and admission to the liver waiting list; while HCC transplantation rose from 10% in 2019 to 22% in 2020. The second analysis showed that the occupancy rate of beds by COVID-19 patients / week was variable: from 0.4% to 42.0%. The number of surgeries, hepato-bilio-pancreatic, resection of HCC and liver transplantation, were reduced by 47%, 49%, 31% and 36% respectively. The reduction in transplant activity mainly affected centers with high occupancy due to COVID-19. The final long-term outcome will need to be assessed.

La pandemia COVID-19 declarada en marzo del 2020, ha generado preocupación mundial por su efecto en la salud de la población y el potencial colapso sanitario. La estrategia de "aplanar la curva" mediante el distanciamiento social permitió adaptar los recursos del sistema de salud a pacientes con COVID-19, pero no se pudo prever su repercusión en otras áreas de la salud. El objetivo de este trabajo fue analizar las consecuencias de la pandemia sobre el trasplante hepático en general y por hepatocarcinoma (HCC). Fueron realizados los siguientes estudios: a) un análisis retrospectivo utilizando datos del CRESI/INCUCAI para comparar ingreso en lista de espera, mortalidad en lista, donación y trasplante hepático desde 20/03 a 15/08, 2019 e igual periodo de 2020, y b) una encuesta a los centros de trasplante de mayor actividad trasplantológica para valorar el efecto de las medidas tomadas en diferentes situaciones institucionales y regionales. El primer análisis evidenció una disminución del 55% de los trasplantes hepáticos, con una reducción similar en la donación y en el ingreso a lista de espera hepática; mientras que el trasplante por HCC ascendió de 10% en 2019 a 22% en 2020. El segundo análisis, mostró que la tasa de ocupación de camas por pacientes COVID-19/semana fue variable: de 0.4% al 42.0%. El número de cirugías, hepato-bilio-pancreática, resección de HCC y trasplante hepático, se redujeron en 47%, 49%, 31% y 36% respectivamente. La reducción de la actividad trasplantológica afectó mayormente los centros con alta ocupación por COVID-19. El impacto final a largo plazo deberá evaluarse.

[Intestinal transplant. Review and description of its evolution in Latin America]. / Trasplante intestinal. Revisión y descripción de su evolución en Latinoamérica.

Intestinal failure remains a cause of morbidity and mortality in children and adults. Currently intestinal failure patients must be evaluated by a multidisciplinary team in order to optimize parenteral support, to determine the chances for rehabilitation or the need for transplantation. Intestinal transplant has been the last abdominal organ to evolve. Indications and procedures have been refined and standardized; new immunosuppressive drugs and the experience of treating these patients in a limited number of centres have reduced complications and improved survival. Forty years after the first attempt, intestinal transplant can now be successfully performed in Latin-America. The aims of this review are to update the current status of intestinal transplant, to highlight new developments and the evolution in our continent and to provide the basic knowledge in the management of intestinal failure patients for nutritionists, gastroenterologists and surgeons.

[Indications and timing of liver transplantation]. / Indicaciones y oportunidad del trasplante hepático.

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

Unresolved issues in the prophylaxis of bacterial infections in patients with cirrhosis.

Bacterial infections are highly prevalent and a frequent cause of hospitalization and short-term mortality in patients with cirrhosis. Due to their negative impact on survival, antibiotic prophylaxis for bacterial infections in high-risk subgroups of patients with cirrhosis has been the standard of care for decades. Patients with prophylaxis indications include those at risk for a first episode of spontaneous bacterial peritonitis (SBP) due to a low ascitic fluid protein count and impaired liver and kidney function, patients with a prior episode of SBP and those with an episode of gastrointestinal bleeding. Only prophylaxis due to gastrointestinal bleeding has a known and short-time duration. All other indications imply long-lasting exposure to antibiotics - once the threshold requirement for initiating prophylaxis is met - without standardized criteria for re-assessing antibiotic interruption. Despite the fact that the benefit of antibiotic prophylaxis in reducing bacterial infections episodes and mortality has been thoroughly reported, the extended use of antibiotics in patients with cirrhosis has also had negative consequences, including the emergence of multi-drug resistant bacteria. Currently, it is not clear whether restricting the use of broad and fixed antibiotic regimens, tailoring the choice of antibiotics to local bacterial epidemiology or selecting non-antibiotic strategies will be the preferred antibiotic prophylaxis strategy for patients with cirrhosis in the future.

Consensus, Dilemmas, and Challenges in Living Donor Liver Transplantation in Latin America.

We reviewed the history, volume, outcomes, uniqueness, and challenges of living donor liver transplantation (LDLT) in Latin America. We used the data from the Latin American and Caribbean Transplant Society, local transplant societies, and opinions from local transplant experts. There are more than 160 active liver transplant teams in Latin America, but only 30 centers have used LDLT in the past 2 years. In 2014, 226 LDLTs were done in the region (8.5% of liver transplant activities). Living donor liver transplantation is mainly restricted to pediatric patients. Adult-to-adult LDLT activities decreased after the implementation of the model for end-stage liver disease score and a concomitant increase on the rate of deceased donors per million population. Posttransplant outcome analysis is not mandatory, transparent or regulated in most countries. More experienced teams have outcomes comparable to international expert centers, but donor and recipient morbidity might be underreported. Latin America lags behind in terms of the number of adult LDLT and the rate of living donor utilization in comparison with other continents with similar donation rates. Local alliances and collaborations with major transplant centers in the developed world will contribute to the development of LDLT in Latin America.

Early and frequent histological recurrence of Crohn's disease in small intestinal allografts.

BACKGROUND: Recurrence of Crohn's disease in small intestinal allografts, although rarely described, can cause serious morbidity and jeopardize graft survival among transplant recipients with Crohn's disease. However, systematic studies to determine the frequency, predictors, and clinical implications of recurrent Crohn's disease have not been reported METHODS: We analyzed our transplant program's experience with small intestinal allografts in patients with Crohn's disease based on retrospective review of clinical and pathological records and corresponding pathology slides. RESULTS: Of 67 patients undergoing 70 transplantations between 1998 and 2004, six adults (three males, three females; mean age 48.1 years) had Crohn's disease complicated by short gut syndrome and total parenteral nutrition failure. Four survivors surveyed endoscopically for a mean 29 (range, 20-40) months and underwent a mean 37 endoscopic examinations with biopsies (range, 31-44) while on maintenance immunosuppression. Despite absence of any endoscopic or clinical manifestations of Crohn's disease throughout this period, two patients had granulomatous enteritis characteristic of Crohn's disease in multiple biopsies, one patient in 8/44 examinations (18%) ranging from 34 days to 20 months postoperatively and the other in 6/32 examinations (19%) ranging from 20 days to 22 months postoperatively. No comparable changes occurred in 57 other patients without Crohn's disease followed endoscopically under the same protocol CONCLUSIONS: Histological recurrence of Crohn's disease may occur in small intestinal allografts despite the absence of endoscopic and clinical disease manifestations. Such recurrences are probably not rare, may occur as early as 3 weeks after transplantation, and do not necessarily portend early clinical recurrence or mandate aggressive therapy to prevent allograft loss.

Role of systemic inflammation in cirrhosis: From pathogenesis to prognosis.

The natural history of cirrhosis can be divided into an initial stage, known as compensated cirrhosis, and an advanced stage which encompasses both decompensated cirrhosis and acute-on-chronic liver failure (ACLF). The latter syndrome has been recently described as an acute deterioration of liver function in patients with cirrhosis, which is usually triggered by a precipitating event and results in the failure of one or more organs and high short-term mortality rates. Each stage is characterized by distinctive clinical manifestations and prognoses. One of the key elements involved in cirrhosis physiopathology is systemic inflammation, recently described as one of the components in the cirrhosis-associated immune dysfunction syndrome. This syndrome refers to the combination of immune deficiency and exacerbated inflammation that coexist during the course of cirrhosis and relates to the appearance of clinical complications. Since systemic inflammation is often difficult to assess in cirrhosis patients, new objective, reproducible and readily-available markers are needed in order to optimize prognosis and lengthen survival. Thus, surrogate serum markers and clinical parameters of systemic inflammation have been sought to improve disease follow-up and management, especially in decompensated cirrhosis and ACLF. Leukocyte counts (evaluated as total leukocytes, total eosinophils or neutrophil:lymphocyte ratio) and plasma levels of procalcitonin or C-reactive protein have been proposed as prognostic markers, each with advantages and shortcomings. Research and prospective randomized studies that validate these and other markers are clearly warranted.

Combinational Effect of CYP3A5 and MDR-1 Polymorphisms on Tacrolimus Pharmacokinetics in Liver Transplant Patients.

OBJECTIVES: Previous studies have reported reduced tacrolimus dose-adjusted exposure in individuals expressing the CYP3A5*1 allele (reference single nucleotide polymorphism identification number 776746). However, results on patients from South America are scarce. The objective of this study was to investigate the influence of CYP3A5 and MDR1 allelic variants and their correlation on the pharmacokinetics of tacrolimus and a modified release formulation of tacrolimus in stable patients with liver transplant. MATERIALS AND METHODS: This was a prospective, single center, open-label study. Included patients were ≥ 18 years old and receiving a stable dose of tacrolimus for at least 6 months. Patients receiving stable treatment of twice daily tacrolimus were switched to a once-daily dose of modified release tacrolimus, on a milligram-to-milligram basis, with the modified release formulation administered for at least 4 weeks. Blood levels of tacrolimus were obtained before and 1 month after treatment was switched to the modified release formulation. RESULTS: The frequency of the intron 3 allelic variant of the CYP3A5 isoform (G-to-A substitution at nucleotide 6986) in recipients was 16.6% and 25% in donors. Dose levels of tacrolimus and the modified formulation were significantly higher in donors and recipients who expressed CYP3A5 versus donors and recipients who did not express this allele. In addition, patients who received a liver from a donor expressing CYP3A5 had significantly lower trough concentrations of tacrolimus and the modified formulation. CYP3A5 expression in the donor liver affected tacrolimus (40.46%, P = .001) and modified formulation (37.56%, P = .001) variability. No association was found between the ABCB1 genotype and levels of tacrolimus or its modified formulation. CONCLUSIONS: Our data suggest that CYP3A5*1 in either the donor or recipient resulted in higher mean daily doses of tacrolimus or its modified formulation to achieve target drug exposure in liver transplant patients.