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1.  Excellent Outcome Following Down-Staging of Hepatocellular Carcinoma Prior to Liver Transplantation: An Intention-to-Treat Analysis 
Hepatology (Baltimore, Md.)  2008;48(3):819-827.
We previously reported encouraging results of down-staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2–5 cm or two to three lesions <3 cm) for orthotopic liver transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer-term outcome data on HCC down-staging in a larger cohort of 61 patients with tumor stage exceedingT2criteriawhowere enrolled between June 2002 and January 2007. Eligibility criteria for down-staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down-staging was required before OLT. Tumor down-staging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) had received OLT, including two who had undergone live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after down-staging were 87.5% and 69.3%, respectively. The 1-year and 4-year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alpha-fetoprotein > 1,000 ng/mL.
Conclusion
Successful down-staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome.
doi:10.1002/hep.22412
PMCID: PMC4142499  PMID: 18688876
2.  Alcohol Use and Hepatitis C 
Hepatology (Baltimore, Md.)  2002;36(5 0 1):S220-S225.
Excess alcohol consumption can worsen the course and outcome of chronic hepatitis C. It is important to distinguish between alcohol abuse, which must be treated on its own merits, and the effect of alcohol use on progression, severity, and treatment of hepatitis C. Most studies on the effects of alcohol on hepatitis C have focused on patients, with high levels of daily alcohol intake. Indeed, the adverse effects of light and moderate amounts of alcohol intake on hepatitis C virus (HCV) infection have not been clearly shown, and only limited studies have been performed. Sex differences exist in the effect of alcohol on fibrosis as well as on the severity of hepatitis C. Alcohol use has been reported to be associated with lower responses to therapy and, in some studies, higher HCV RNA levels and increased HCV quasi-species. Few studies address the treatment of hepatitis C in the alcoholic individual or determine the effect of continued light or moderate alcohol use on the outcome of treatment response. In summary, many critical questions remain regarding the interactions between alcohol and hepatitis C. Currently, the evidence from the literature shows that heavy alcohol intake worsens the outcome of HCV infection. The literature is inadequate to provide definitive recommendations regarding the effect of light to moderate alcohol use in patients with hepatitis C.
doi:10.1053/jhep.2002.36811
PMCID: PMC4123319  PMID: 12407597
3.  Computerized Assessment of Competence-Related Abilities in Living Liver Donors: The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) 
Clinical transplantation  2013;27(4):633-645.
Background
Despite its importance, determination of competence to consent to organ donation varies widely based on local standards. We piloted a new tool to aid transplant centers in donor assessment.
Methods
We assessed competence-related abilities among potential living liver donors (LDs) in the 9-center A2ALL study. Prospective LDs viewed an educational video, and were queried to assess Understanding, Appreciation, Reasoning, and ability to express a Final Choice using the MacArthur Competence Assessment Tool for Clinical Research, adapted for computerized administration in LDs (“MacLiver”). Videotaped responses were scored by a clinical neuropsychologist (JF).
Results
Ninety-three LDs were assessed. Mean (standard deviation; domain maximum) scores were: Understanding: 18.1 (2.6; max=22), Appreciation: 5.1 (1.0; max=6), Reasoning: 3.1 (0.8; max=4), and Final Choice: 3.8 (0.5; max=4). Scores did not differ by demographics, relationship to the recipient, eligibility to donate, or eventual donation (p>0.4). Higher education was associated with greater Understanding (p=0.004) and Reasoning (p=0.03).
Conclusion
Standardized, computerized education with independent ratings of responses may (1) alert the clinical staff to potential donors who may not be competent to donate, and (2) highlight areas needing further assessment and education, leading to better informed decision-making.
doi:10.1111/ctr.12184
PMCID: PMC4096778  PMID: 23859354
Living Donation; Comprehension; MacArthur Competence Assessment Tool for Clinical Research; Informed Consent; Ethics; Transplantation
4.  De novo malignancies following liver transplantation: a case–control study with long-term follow-up 
Clinical transplantation  2006;20(5):617-623.
Background
Long-term survival data on de novo malignancy are limited following orthotopic liver transplantation (OLT) when compared with controls without malignancies.
Methods
Over a 12 yr period at our institution, 50 of 1043 patients (4.8%) who underwent OLT were identified to have 53 de novo malignancies. The clinical characteristics and survival of these patients were retrospectively reviewed and compared with a control cohort of 50 OLT recipients without malignancy matched with the incidence cases by age, year of OLT, sex, and type of liver disease.
Results
Chronic hepatitis C, alcohol and primary sclerosing cholangitis were the three leading causes of liver disease. Skin cancer was the most common malignancy (32%), followed by gastrointestinal (21%), including five small bowel tumors, and hematologic malignancies (17%). The cases and controls were not significantly different in the immunosuppressive regimen (p = 0.42) or the number of rejection episodes (p = 0.92). The five- and 10-year Kaplan–Meier survival rates for the cases were 77% and 34%, respectively, vs. 84% and 70%, respectively, for the controls (p = 0.02 by log-rank test). Patients with skin cancers had survival similar to the controls, but significantly better than non-skin cancers (p = 0.0001). The prognosis for patients with gastrointestinal tumors was poor, with a median survival of 8.5 months after the diagnosis.
Conclusion
In this single institutional study, de novo malignancies after OLT were uncommon. Patients with non-skin cancer after OLT had diminished long-term survival compared with the controls. Our results differ from other reports in the high incidence of gastrointestinal malignancies with attendant poor prognosis.
doi:10.1111/j.1399-0012.2006.00527.x
PMCID: PMC4050657  PMID: 16968488
de novo malignancies; orthotopic liver transplantation
5.  A Randomized Controlled Trial of Pretransplant Antiviral Therapy to Prevent Recurrence of Hepatitis C after Liver Transplantation 
Hepatology (Baltimore, Md.)  2013;57(5):1752-1762.
Hepatitis C virus (HCV) infection recurs in liver recipients who are viremic at transplantation. We conducted a randomized controlled trial to test the efficacy and safety of pre-transplant pegylated interferon alpha-2b plus ribavirin (Peg-IFN-a2b/RBV) for prevention of post-transplant HCV recurrence. Enrollees had HCV and were listed for liver transplantation, with either potential living donors or MELD upgrade for hepatocellular carcinoma. Patients with HCV genotypes (G) 1/4/6 (n=44/2/1) were randomized 2:1 to treatment (n=31) or untreated control (n=16); HCV G2/3 (n=32) were assigned to treatment. Overall, 59 were treated and 20 were not. PEGIFN alfa-2b, starting at 0.75 μg/kg/wk, and ribavirin (RBV), starting at 600 mg/d, were escalated as tolerated. Patients assigned to treatment versus control had similar baseline characteristics. Combined virologic response (CVR) included pre-transplant sustained VR (SVR12) and post-transplant VR (pTVR), defined as undetectable HCV RNA 12 weeks after end of treatment or transplant, respectively. In intent-to-treat analyses, 12 (19%) assigned to treatment and 1 (6%) assigned to control achieved CVR (p=0.29); per-protocol values were 13 (22%) and 0 (0%) (p=0.03). Among treated G1/4/6 patients, 23/30 received transplant of whom 22% had pTVR; among treated G2/3 patients 21/29 received transplant, of whom 29% had pTVR. pTVR was 0%, 18%, and 50% in patients treated for <8, 8–16, and >16 weeks, respectively (p=0.01). Serious adverse events (SAEs) occurred with similar frequency in treated versus untreated patients (68% vs. 55%, p=0.30) but the number of SAEs per patient was higher in the treated group (2.7 vs. 1.3, p=0.003).
Conclusion
Pretransplant treatment with PEGIFN/RBV prevents post-transplant recurrence of HCV in selected patients. Efficacy is higher with >16 weeks of treatment, but treatment is associated with increased risk of potentially serious complications.
doi:10.1002/hep.25976
PMCID: PMC3510348  PMID: 22821361
Peginterferon alfa-2b; Ribavirin; Cirrhosis; Waiting List; post-transplant virologic response
6.  Acute Hepatitis C in an HIV-Infected patient: A Case Report and Review of Literature 
ABSTRACT
With the decrease in transmission via transfusions and injection drug use, acute symptomatic hepatitis C is infrequently seen in developed countries. We report a case of a human immunodeficiency virus (HIV)–infected adult who presented with abdominal pain. His alanine aminotransferase was greater than sixty times the upper limit of normal without any evidence on examination of fulminant hepatic failure. His workup revealed an elevated hepatitis C viral level with a negative hepatitis C antibody. He was discharged once his liver function tests improved. As an outpatient, he had a recurrent bout of symptoms with an elevation of his alanine aminotransferase and hepatitis C viral levels that promoted anti-hepatitis C virus treatment. This case illustrates the importance of considering acute hepatitis C as a cause of acute hepatitis in HIV-infected men who have sex with men. While patients with acute symptomatic hepatitis C generally have a higher rate of spontaneous viral clearance compared to those with an insidious acute infection, most still progress to chronic hepatitis C infection, and patients with HIV coinfection carry a higher risk of progression to chronic disease.
doi:10.1007/s11606-012-2258-3
PMCID: PMC3631075  PMID: 23151989
acute hepatitis C virus; human immunodeficiency virus; hepatitis C virus treatment
7.  Projected Future Increase in Aging HCV-Infected Liver Transplant Candidates: A Potential Effect of HCC 
Background
In the US, the peak hepatitis C (HCV) antibody prevalence of 4% occurred in persons born in calendar years 1940 to 1965.
Aim
To examine observed and projected age-specific trends in the demand for liver transplantation (LTx) among patients with HCV-associated liver disease stratified by concurrent hepatocellular carcinoma (HCC).
Methods
All new adult LTx candidates registered with the Organ Procurement and Transplantation Network for LTx between 1995 and 2010 were identified. Patients who had primary, secondary, or text field diagnoses of HCV with or without HCC, were identified.
Results
There were 126,862 new, primary registrants for LTx, 52,540 (41%) with HCV. The number of new registrants with HCV was dramatically different by age at calendar year, suggesting a birth cohort effect. When stratified by birth year in 5-year intervals, the birth cohorts with the highest frequency of HCV in decreasing order were those born 1951-1955, 1956-1960, 1946-1950, and 1941-1945. These four birth cohorts, spanning 1941 to 1960 accounted for 81% of all new registrants with HCV. A 4-fold increase in new registrants with HCV and HCC occurred between calendar years 2000 to 2010 in the 1941-1960 birth cohorts. By 2015, we anticipate an increasing proportion of new registrants with HCV will have HCC and be over the age of 60 (born on or before 1955).
Conclusions
The greatest demand for LTx due to HCV-associated liver disease is occurring among individuals born between 1941 and 1960. This demand appears to be driven by the development of HCC in patients with HCV. Over the coming decade, the projected increase in demand for LTx from an aging HCV infected population will challenge the transplant community to reconsider current treatment paradigms.
doi:10.1002/lt.23551
PMCID: PMC3518670  PMID: 23008049
Hepatitis C; Hepatocellular carcinoma; liver transplantation
8.  PHOENIX: A Randomized Controlled Trial of Peginterferon Alfa-2a Plus Ribavirin as a Prophylactic Treatment After Liver Transplantation for Hepatitis C Virus 
The efficacy, tolerability, and safety of the prophylactic treatment of hepatitis C virus (HCV) after liver transplantation (LT) with peginterferon alfa-2a and ribavirin are not known. LT recipients with HCV were randomized to peginterferon alfa-2a/ribavirin treatment or observation 10 to 26 weeks post-LT. Prophylaxis patients received peginterferon alfa-2a (135 μg/week for 4 weeks and then 180 μg/week for 44 weeks) plus ribavirin (the initial dose of 400 mg/day was escalated to 1200 mg/day). Observation patients received the same regimen only upon significant HCV recurrence (histological activity index ≥ 3 and/or fibrosis score ≥ 2). The primary endpoint was the proportion of patients with histological evidence of significant HCV recurrence 120 weeks after randomization. In all, 115 patients were randomized (prophylaxis arm, n = 55; observation arm, n = 60). Sustained virological response was achieved by 12 of 54 prophylaxis patients (22.2%) and by 3 of 14 observation patients who switched to treatment (21.4%). On an intent-to-treat basis, significant HCV recurrence at 120 weeks was similar in the prophylaxis (61.8%) and observation arms (65.0%, P = 0.725). The patient and graft survival rates and the rates of biopsy-proven acute cellular rejection were similar in the 2 study arms. Approximately 70% of the treated patients in both arms had at least one dose reduction for safety reasons. The most common adverse event leading to treatment withdrawal was anemia. Because of the safety profile of peginterferon alfa-2a/ribavirin and the lack of a clear benefit in terms of HCV recurrence and patient or graft survival, this study does not support the routine use of prophylactic antiviral therapy.
doi:10.1002/lt.22271
PMCID: PMC3736350  PMID: 21506241
9.  Outcomes of Donor Evaluation in Adult-to-Adult Living Donor Liver Transplantation 
Hepatology (Baltimore, Md.)  2007;46(5):1476-1484.
The purpose of donor evaluation for adult-to-adult living donor liver transplantation (LDLT) is to discover medical conditions that could increase the donor postoperative risk of complications and to determine whether the donor can yield a suitable graft for the recipient. We report the outcomes of LDLT donor candidates evaluated in a large multicenter study of LDLT. The records of all donor candidates and their respective recipients between 1998 and 2003 were reviewed as part of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). The outcomes of the evaluation were recorded along with demographic data on the donors and recipients. Of the 1011 donor candidates evaluated, 405 (40%) were accepted for donation. The donor characteristics associated with acceptance (P < 0.05) were younger age, lower body mass index, and biological or spousal relationship to the recipient. Recipient characteristics associated with donor acceptance were younger age, lower Model for End-stage Liver Disease score, and shorter time from listing to first donor evaluation. Other predictors of donor acceptance included earlier year of evaluation and transplant center.
Conclusion
Both donor and recipient features appear to affect acceptance for LDLT. These findings may aid the donor evaluation process and allow an objective assessment of the likelihood of donor candidate acceptance.
doi:10.1002/hep.21845
PMCID: PMC3732162  PMID: 17668879
10.  Incidence and Severity of Acute Cellular Rejection in Recipients Undergoing Adult Living Donor or Deceased Donor Liver Transplantation123 
Living donor liver transplantation (LDLT) may have better immunological outcomes compared to deceased donor liver transplantation (DDLT). The aim of this study was to analyze the incidence of acute cellular rejection (ACR) after LDLT and DDLT.
Data from the Adult-to-Adult Living Donor Liver Transplantation (A2ALL) Retrospective Cohort Study on 593 liver transplants done between May 1998 and March 2004 were studied (380 LDLT; 213 DDLT). Median LDLT and DDLT follow-up was 778 and 713 days, respectively. Rates of clinically treated and biopsy-proven ACR were compared.
There were 174 (46%) LDLT and 80 (38%) DDLT recipients with ≥1 clinically treated episodes of ACR, whereas 103 (27%) LDLT and 58 (27%) DDLT recipients had ≥1 biopsy-proven ACR episode. A higher proportion of LDLT recipients had clinically treated ACR (P=0.052), but this difference was largely attributable to one center. There were similar proportions of biopsy-proven rejection (P=0.97) and graft loss due to rejection (P=0.16). Longer cold ischemia time was associated with a higher rate of ACR in both groups despite much shorter median cold ischemia time in LDLT.
These data do not show an immunological advantage for LDLT, and therefore do not support the application of unique post-transplant immunosuppression protocols for LDLT recipients.
doi:10.1111/j.1600-6143.2008.02487.x
PMCID: PMC3732169  PMID: 19120082
11.  Complementary and Alternative Medicine Use in Chronic Liver Disease Patients 
Goals
To examine a wide range of sociodemographic and clinical characteristics as potential predictors of complementary and alternative medicine (CAM) use among chronic liver disease (CLD) patients, with a focus on CAM therapies with the greatest potential for hepatotoxicity and interactions with conventional treatments.
Background
There is some evidence that patients with CLD commonly use CAM to address general and CLD-specific health concerns.
Study
Patients enrolled in a population-based surveillance study of persons newly diagnosed with CLD between 1999 and 2001 were asked about current use of CAM specifically for CLD. Socio-demographic and clinical information was obtained from interviews and medical records. Predictors of CAM use were examined using univariate and multivariate logistic regression analysis.
Results
Of the 1040 participants, 284 (27.3%) reported current use of at least 1 of 3 CAM therapies of interest. Vitamins or other dietary supplements were the most commonly used therapy, reported by 188 (18.1%) patients. This was followed by herbal medicine (175 patients, 16.8%) and homeopathy (16 patients, 1.5%). Several characteristics were found to be independent correlates of CAM use: higher education and family income, certain CLD etiologies (alcohol, hepatitis C, hepatitis C and alcohol, and hepatitis B), and prior hospitalization for CLD.
Conclusions
Use of CAM therapies that have the potential to interact with conventional treatments for CLD was quite common among this population-based sample of patients with CLD. There is a need for patient and practitioner education and communication regarding CAM use in the context of CLD.
doi:10.1097/MCG.0b013e3181b766ed
PMCID: PMC3730290  PMID: 19779363
complementary and alternative medicine; chronic liver disease; epidemiology
12.  Effects of Ethnicity and Socioeconomic Status on Survival and Severity of Fibrosis in Liver Transplant Recipients With Hepatitis C Virus 
The ethnicity and socioeconomic status of the host may affect the progression of hepatitis C virus (HCV). We aimed to compare survival and fibrosis progression in Hispanic white (HW) and non-Hispanic white (NHW) recipients of liver transplantation (LT) with HCV. All HW and NHW patients with HCV who underwent transplantation between January 2000 and December 2007 at 2 centers were retrospectively assessed. The primary outcomes were the time to death, death or graft loss due to HCV, and significant fibrosis [at least stage 2 of 4]. Five hundred eleven patients were studied (159 HW patients and 352 NHW patients), and the baseline demographics were similar for the 2 groups. NHW patients were more likely to be male, to have attended college, and to have private insurance, and they had a higher median household income (MHI). The unadjusted rates of survival (log-rank P = 0.93), death or graft loss due to HCV (P = 0.89), and significant fibrosis (P = 0.95) were similar between groups. In a multivariate analysis controlling for center, age [hazard ratio (HR) per 10 years = 1.43, P = 0.01], donor age (HR per 10 years = 1.25, P = 0.001), and rejection (HR = 1.47, P = 0.048) predicted death, whereas HW ethnicity (HR = 1.06, P = 0.77) was significant. Independent not predictors of significant fibrosis were HW ethnicity (HR = 2.42, P = 0.046), MHI (HR per $10,000 = 1.11, P = 0.01), donor age (HR per 10 years = 1.13, P = 0.02), cold ischemia time (HR = 1.06, P = 0.03), and the interaction between ethnicity and MHI (HR = 0.82, P = 0.03). In conclusion, there is no difference in post-LT survival or graft loss due to HCV between HW patients and NHW patients. Socioeconomic factors may influence disease severity; this is suggested by our findings of more significant fibrosis in HW patients with a low MHI.
doi:10.1002/lt.23376
PMCID: PMC3674870  PMID: 22467547
13.  Outcomes of Liver Transplantation in HCV-HIV Coinfected Recipients 
Liver Transplantation  2012;18(6):716-726.
BACKGROUND
Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in HIV-infected patients due to reportedly poor outcomes.
METHODS
This prospective U.S. multicenter cohort study compared patient and graft survival in 89 HCV-HIV coinfected versus 2 different controls groups: 235 HCV monoinfected LT controls and all U.S. transplant recipients ≥65 years.
RESULTS
The 3-year patient and graft survival rates (95% CI) were 60% (47–71%) and 53% (40–64%) in HCV-HIV versus 79% (72–84%) and 74% (66–79%) in HCV recipients (both p<0.001) and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among HCV-HIV patients, older donor age (HR=1.3 per decade), combined kidney-LT (HR=3.8), HCV-positive donor (HR=2.5), and body mass index (BMI) less than 21 kg/m2 (HR=3.2) were independent predictors of graft loss. In patients without these latter 3 factors, patient and graft survival were similar to those in U.S. LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher in HCV-HIV versus HCV (log rank p=0.02) but cumulative incidence of severe HCV disease (29% versus 23% at 3 years, respectively) were not significantly different (p=0.21).
CONCLUSIONS
Patient and graft survival are lower in HCV-HIV compared to HCV alone LT patients. Importantly, rates of treated acute rejection but not HCV disease severity are significantly higher in HCV-HIV compared to HCV recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients but recipient and donor selection as well as management of acute rejection strongly influence outcomes.
doi:10.1002/lt.23411
PMCID: PMC3358510  PMID: 22328294
cirrhosis; acute rejection; body mass index; donor age; recurrent hepatitis
14.  Donor-Recipient Race Mismatch in African-American Liver Transplant Patients with Chronic Hepatitis C 
Liver Transplantation  2012;18(5):524-531.
African-American (AA) donor-recipient race mismatch has been associated with graft loss and mortality, but studies of the association between race mismatch and HCV disease severity are lacking. HCV-infected first adult liver transplant recipients from 4 U.S. centers (N=1,093, 11% AA) were followed for a median of 3.05 years to determine rates of advanced HCV disease (bridging fibrosis or cirrhosis) and graft failure. The cumulative 4-year unadjusted rate of advanced disease was 40% for Non-AAs and 56% for AAs (p<0.01); 59% and 54% for AA recipient-donor race matched and mismatched patients, respectively (p=0.89). In adjusted models, both recipient AA race (vs. nonAA) (HR=1.47, 95% CI: 1.06-2.03, p=0.02) and AA recipient-donor mismatch (vs. matched) (HR=1.48, 95% CI: 1.03-2.12, p=0.03) were significant predictors of advanced fibrosis; other independent predictors were donor age (HR=1.21; p<0.01) and cytomegalovirus infection (HR=1.59, p<0.01). The 4-year unadjusted cumulative rate of HCV-associated graft loss was 10% for Non-AAs and 17% for AAs (p<0.01), with 0% for matched and 21% for mismatched AA recipient-donor patients (p<0.01). In adjusted models, AA recipient-donor mismatched patients had a 62% higher rate of graft loss (HR=1.62, 95% CI: 1.14-2.29, p<0.01) and AA recipient-donor matched patients a 76% lower rate (HR=0.24, 95% CI: 0.06-0.97, p=0.05) of graft loss/mortality than non-AA recipients. We conclude that HCV-infected AA recipient-donor mismatched patients are at high risk for advanced HCV disease and HCV-related graft loss and are a patient group that will benefit from new therapeutic strategies to prevent graft loss.
doi:10.1002/lt.22461
PMCID: PMC3314141  PMID: 22140019
15.  Risk of Advanced Fibrosis with Grafts from Hepatitis C Antibody Positive Donors: A Multicenter Cohort Study (CRUSH-C) 
Liver Transplantation  2012;18(5):532-538.
Over the last decade, use of liver grafts from hepatitis C (HCV) antibody positive donors [HCV(+)D] has tripled in the U.S. Although prior studies demonstrated no association between HCV(+)D status and graft loss, the effects of HCV(+)D on histologic outcomes are not well known. HCV-infected recipients at 5 U.S. centers from 2002–2007 surviving >30 days with ≥1 post-transplant biopsy were included. Cox regression was used to examine the association between HCV(+)D status and advanced fibrosis (≥stage 3/4). Of 1,206 patients, 99 (8%) received a HCV(+)D graft. Recipients of HCV(+)D versus HCV(−)D grafts were older (p=0.03), but otherwise similar. HCV(+)D were of significantly lower quality as measured by the donor risk index (p<0.001). Advanced fibrosis occurred in 32% of HCV(+)D versus 28% of HCV(−)D graft recipients (p=0.39). Unadjusted 1- and 3-year rates of advanced fibrosis were significantly higher for HCV(+)D (14 and 48%) compared to HCV(−)D (7 and 33%) graft recipients (p=0.01). Transplantation with HCV(+)D grafts was associated with a 58% increased risk of advanced fibrosis (95% CI:1.05–2.36; p=0.03). However, in an analysis stratified at the mean donor age of 45 years, HCV(+)D status was only associated with advanced fibrosis with donors ≥45 years (HR, 1.76; 95%CI, 1.06–2.93; p=0.03) and not with donors <45 years (HR, 0.94; 95%CI:0.47–1.87; p=0.85). In conclusion, careful consideration of risk-benefit is needed with use of HCV(+)D grafts. Recipients of HCV(+)D grafts, especially from older donors, should undergo close monitoring for more rapidly progressive fibrosis. Studies are needed to determine whether early HCV therapy modifies this risk.
doi:10.1002/lt.23396
PMCID: PMC3334393  PMID: 22271671
16.  Liver transplant recipient survival benefit with living donation in the MELD allocation era1,2,3 
Hepatology (Baltimore, Md.)  2011;54(4):1313-1321.
Receipt of a living donor liver transplant (LDLT) has been associated with improved survival compared with waiting for a deceased donor liver transplant (DDLT). However, the survival benefit of liver transplant has been questioned for candidates with model for end-stage liver disease (MELD) scores< 15, and the survival advantage of LDLT has not been demonstrated during the MELD allocation era, especially for low MELD patients. Transplant candidates enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study after 02/28/02 were followed for a median of 4.6 years. Starting at the time of presentation of the first potential living donor, mortality for LDLT recipients was compared to mortality for patients who remained on the waiting list or received DDLT (no LDLT group) according to categories of MELD score (<15 or 15+) and diagnosis of hepatocellular carcinoma (HCC). Of 868 potential LDLT recipients (453 with MELD<15; 415 with MELD 15+ at entry), 712 underwent transplantation (406 LDLT; 306 DDLT), 83 died without transplant, and 73 were alive without transplant at last follow-up. Overall, LDLT recipients had 56% lower mortality (hazard ratio (HR)=0.44, 95% confidence interval [CI] 0.32–0.60; p<0.0001). Among candidates without HCC, mortality benefit was seen both with MELD<15 (HR=0.39;p=0.0003) and MELD 15+ (HR=0.42;p=0.0006). Among candidates with HCC, a benefit of LDLT was not seen for MELD<15 (HR=0.82, p =0.65) but was seen for MELD 15+ (HR=0.29, p=0.043).
Conclusions
Across the range of MELD scores, patients without HCC derived a significant survival benefit when undergoing LDLT rather than waiting for DDLT in the MELD liver allocation era. Low MELD candidates with HCC may not benefit from LDLT.
doi:10.1002/hep.24494
PMCID: PMC3184197  PMID: 21688284
Living donor liver transplantation; cirrhosis; end stage liver disease; mortality; outcomes
17.  Hepatitis C Virus Infected Females Have a Higher Risk of Advanced Fibrosis and Graft Loss after Liver Transplantation than Males 
Hepatology (Baltimore, Md.)  2011;54(2):418-424.
In natural history studies of hepatitis C virus (HCV) infection, women have a lower risk of disease progression to cirrhosis. Whether gender influences outcomes of HCV in the post-transplant setting is unknown. All patients transplanted for HCV-related liver disease from 2002–2007 at 5 U.S. transplant centers were included. The primary outcome was development of advanced disease, defined as biopsy-proven bridging fibrosis or cirrhosis. Secondary outcomes included death, graft loss, and graft loss with advanced recurrent disease. 1,264 patients were followed for a median of 3.0 years (IQR 1.8–4.7) −304 (24%) were female. The cumulative rate of advanced disease at 3-years was 38% for females and 33% for males (p=0.31) but after adjustment for recipient age, donor age, donor anti-HCV positivity, post-transplant HCV treatment, cytomegalovirus infection and center, female gender was an independent predictor of advanced recurrent disease (HR, 1.31; 95%CI, 1.02–1.70; p=0.04). Among women, older donor age and treated acute rejection were the primary predictors of advanced disease. The unadjusted cumulative 3–year rates of patient and graft survival were numerically lower in females than males, 75% vs. 80% and 74% vs. 78%, and in multivariable analyses, female gender was an independent predictor for death (HR, 1.30; 95%CI, 1.01–1.67; p=0.04) and graft loss (HR, 1.31; 95%CI, 1.02–1.67; p=0.03).
Conclusion
Female gender represents an under-recognized risk factor for advanced recurrent HCV disease and graft loss. Further studies are needed to determine whether modification of donor factors, immunosuppression, and post-transplant therapeutics can equalize HCV-specific outcomes in women and men.
doi:10.1002/hep.24390
PMCID: PMC3144983  PMID: 21538434
HCV outcomes; fibrosis; HCV treatment
18.  Laboratory test results after living liver donation in the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL) 
Liver Transplantation  2011;17(4):409-417.
Introduction
Information on long-term health among living liver donors is incomplete. Because changes in standard laboratory tests may reflect underlying health among donors, pre- and post- donation results were examined in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL).
Methods
A2ALL followed 487 living liver donors who donated at nine U.S. transplant centers between 1998 and 2009. Aminotransferase and alkaline phosphatase activities (AST, ALT, AP), bilirubin, INR, albumin, white blood cell count (WBC), hemoglobin, platelet count, ferritin, serum creatinine and BUN were measured at evaluation and post-donation: 1 week, 1 month, 3 months, 1 year and yearly thereafter. Repeated measures models were used to estimate median lab values at each time point and test for differences between values at evaluation (baseline) and post-donation time points.
Results
Platelet counts were significantly decreased at every time point compared to baseline, and at three years were 19% lower. Approximately 10% of donors had a platelet count ≤150 (×1000/mm3) at 2–3 years post-donation. Donors with a platelet count ≤150 (×1000/mm3) at one year had had significantly lower mean platelet counts (189±32) vs. the remainder of the cohort (267±56, p<0.0001) at evaluation. Statistically significant differences from evaluation were noted for AST, AP, INR and albumin through the first year, although most measurements were in the normal range. Median values for WBC, hemoglobin, ferritin, albumin, serum creatinine, BUN, and INR were not substantially outside the normal range at any time point.
Conclusions
After three months, most laboratory values return to normal among right hepatic lobe liver donors, with slower return to baseline levels for AST, AP, INR and albumin. Persistently decreased platelet counts warrant further investigation.
doi:10.1002/lt.22246
PMCID: PMC3295864  PMID: 21445924
living donor liver transplantation; complications; liver transplantation; liver function tests; hepatectomy
19.  Gender Differences in Liver Donor Quality Are Predictive of Graft Loss 
Some studies have found that donor-recipient gender mismatch predicts post-transplant outcomes but whether this is independent of donor quality is unknown. To evaluate the association between gender mismatch and graft loss, 11,508 females(F) and 16,714 males(M) who underwent liver transplant from 3/1/2002-12/31/2007 were studied. Of 11 donor characteristics, clinically relevant differences between F and M donors were median age (47 vs. 39yrs), height (165 vs. 178cm), and proportion dying of stroke (59 vs. 35%) [p<0.001 for all]. The donor risk index was significantly lower for F than M donors (1.3 vs. 1.6, p<0.001). Recipients of gender mismatched grafts had an 11% higher risk of graft loss (p<0.001). Compared to M→M donor-recipient matched transplants in univariable analysis, F→M mismatch was associated with a 17% increased risk of graft loss (95%CI=1.11-1.24, p<0.001), whereas M→F mismatch was not (HR=1.02; 95% CI=0.96-1.09; p=0.46). However, adjustment for significant recipient and donor factors eliminated the association between F→M mismatch and graft loss (HR=0.95; 95%CI=0.89-1.02; p=0.18). In conclusion, donor quality differs significantly between female and male donors – female donors are older, shorter, and die more frequently of stroke – and gender differences in donor quality, rather than gender mismatch are predictive of graft loss.
doi:10.1111/j.1600-6143.2010.03385.x
PMCID: PMC3076602  PMID: 21219572
Donor risk index; donor age; gender-mismatch
20.  Height Contributes to the Gender Difference in Wait-list Mortality Under the MELD-Based Liver Allocation System 
This study examined factors associated with the gender disparity in wait-list mortality in the MELD era. Adult patients listed for liver transplantation from 2002-2008 were included. Females [12,585(36%)] and males [22,126(64%)] differed clinically by age (54 vs. 52 years), height (1.6 vs. 1.8 meters), listing estimated glomerular filtration rate [eGFR; 70 vs. 83 ml/min], and cirrhosis etiology. Holding MELD constant, females were at 19% (95%CI, 1.13-1.25, p<0.001) higher risk of wait-list mortality than males under the current allocation system. The relative hazard increased with worsening renal function, whether measured by serum creatinine or eGFR. Adjustment for MELD, age, African-American race, cirrhosis etiology, region, and ABO group attenuated this relative hazard (HR 1.16; 95%CI, 1.10-1.22; p<0.001) but additional adjustment for height completely explained this gender disparity in wait-list mortality (HR 1.05; 95%CI, 0.98-1.12; p=0.2). Transplantation rates, however, remained lower among females, even after adjustment for height (HR 0.88; 95%CI, 0.82-0.92; p<0.001). In conclusion, under the current liver allocation system, women have a 19% increased risk of wait-list mortality compared to men with the same MELD scores. Height contributes to this gender disparity, possibly reflecting differences in transplantation rates for shorter individuals.
doi:10.1111/j.1600-6143.2010.03326.x
PMCID: PMC3059496  PMID: 21087414
21.  Influence of Cannabis Use on Severity of Hepatitis C Disease 
Background
Complications of hepatitis C virus (HCV) infection are primarily related to the development of advanced fibrosis.
Methods
Baseline data from a prospective community-based cohort study of 204 persons with chronic hepatitis C virus (HCV) infection were used for analysis. The outcome was fibrosis score on biopsy and the primary predictor evaluated was daily cannabis use.
Results
The median age of the cohort was 46.8 years, 69.1% were male, 49.0% were Caucasian, and the presumed route of infection was injection drug use in 70.1%. The median lifetime duration and average daily use of alcohol were 29.1 years and 1.94 drink equivalents per day. Cannabis use frequency (within prior 12 months) was daily in 13.7%, occasional in 45.1%, and never in 41.2%. Fibrosis stage, assessed by Ishak method, was F0, F1–2 and F3–6 in 27.5%, 55.4% and 17.2% of subjects, respectively. Daily compared to non-daily cannabis use was significantly associated with moderate to severe fibrosis (F3–6 versus F1–2) in univariate [OR = 3.21 (95% CI, 1.20–8.56), p = 0.020] and multivariate analyses (OR = 6.78, (1.89–24.31), p=0.003). Other independent predictors of F3–6 were ≥11 portal tracts (compared to <5, OR = 6.92 (1.34–35.7), p=0.021] and lifetime duration of moderate and heavy alcohol use [OR per decade = 1.72 (1.02–2.90), p=0.044].
Conclusion
We conclude that daily cannabis use is strongly associated with moderate to severe fibrosis and that HCV-infected individuals should be counseled to reduce or abstain from cannabis use.
doi:10.1016/j.cgh.2007.10.021
PMCID: PMC3184401  PMID: 18166478
fibrosis; alcohol; viral load; marijuana; cirrhosis
22.  Outcomes in Hepatitis C Virus–Infected Recipients of Living Donor vs. Deceased Donor Liver Transplantation 
In this retrospective study of hepatitis C virus (HCV)–infected transplant recipients in the 9-center Adult to Adult Living Donor Liver Transplantation Cohort Study, graft and patient survival and the development of advanced fibrosis were compared among 181 living donor liver transplant (LDLT) recipients and 94 deceased donor liver transplant (DDLT) recipients. Overall 3-year graft and patient survival were 68% and 74% in LDLT, and 80% and 82% in DDLT, respectively. Graft survival, but not patient survival, was significantly lower for LDLT compared to DDLT (P = 0.04 and P = 0.20, respectively). Further analyses demonstrated lower graft and patient survival among the first 20 LDLT cases at each center (LDLT ≤20) compared to later cases (LDLT > 20; P = 0.002 and P = 0.002, respectively) and DDLT recipients (P < 0.001 and P = 0.008, respectively). Graft and patient survival in LDLT >20 and DDLT were not significantly different (P = 0.66 and P = 0.74, respectively). Overall, 3-year graft survival for DDLT, LDLT >20, and LDLT ≤20 were 80%, 79% and 55%, with similar results conditional on survival to 90 days (84%, 87% and 68%, respectively). Predictors of graft loss beyond 90 days included LDLT ≤20 vs. DDLT (hazard ratio [HR] = 2.1, P = 0.04), pretransplant hepatocellular carcinoma (HCC) (HR = 2.21, P = 0.03) and model for end-stage liver disease (MELD) at transplantation (HR = 1.24, P = 0.04). In conclusion, 3-year graft and patient survival in HCV-infected recipients of DDLT and LDLT >20 were not significantly different. Important predictors of graft loss in HCV-infected patients were limited LDLT experience, pretransplant HCC, and higher MELD at transplantation.
doi:10.1002/lt.20995
PMCID: PMC3155862  PMID: 17192908
23.  Progression of Biopsy-Measured Liver Fibrosis in Untreated Patients with Hepatitis C Infection: Non-Markov Multistate Model Analysis 
PLoS ONE  2011;6(5):e20104.
Background
Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times.
Methods
We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR) quantified the estimated effects of covariates on progression risk at any given time.
Results
Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018), and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002). When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80). There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059). Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection.
Discussion
The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating active disease and high risk, while longer time already spent in a stage indicates quiescent disease and low risk.
doi:10.1371/journal.pone.0020104
PMCID: PMC3103523  PMID: 21637766
24.  Hospitalization Rates Before and After Adult-to-Adult Living Donor or Deceased Donor Liver Transplantation1,2,3 
Annals of surgery  2010;251(3):542-549.
Objective
To compare rates of hospitalization before and after adult-to-adult living donor liver transplant (LDLT) and deceased donor liver transplant (DDLT).
Summary background data
LDLT recipients have been reported to have lower mortality but a higher complication rate than DDLT recipients. The higher complication rate may be associated with greater consumption of inpatient hospital resources and a higher burden of disease for LDLT recipients.
Methods
Data from the 9-center Adult-to-Adult Living Donor Liver Transplantation (A2ALL) retrospective cohort study were analyzed to determine pre-transplant, transplant, and post-transplant hospitalizations among LDLT candidates (potential living donor was evaluated) who received LDLT or DDLT. Hospital days and admission rates for LDLT and DDLT patients were calculated per patient-year at risk, starting from the date of initial potential donor history and physical examination. Rates were compared using overdispersed Poisson regression models.
Results
Among 806 candidates, 384 received LDLT and 215 received DDLT. In addition to the 599 transplants, there were 1913 recipient hospitalizations (485 pre-transplant; 1428 post-transplant). Mean DDLT recipient pre-transplant, transplant, and post-transplant lengths of stay were 5.8±6.3, 27.0±32.6, and 9.0±14.1 days, respectively, and for LDLT were 4.1±3.7, 21.4±24.3, and 7.8±11.4 days, respectively. Compared to DDLT, LDLT recipients had significantly lower adjusted pre-transplant hospital day and admission rates, but significantly higher post-transplant rates. Significantly higher LDLT admission rates were observed for biliary tract morbidity throughout the second post-transplant year. Overall hospitalization rates starting from the point of potential donor evaluation were significantly higher for eventual recipients of LDLT.
Conclusions
LDLT recipients, despite lower acuity of disease, have higher hospitalization requirements when compared to DDLT recipients. Continuing efforts are warranted to reduce the incidence of complications requiring post-LDLT inpatient admission, with particular emphasis on biliary tract issues.
doi:10.1097/SLA.0b013e3181ccb370
PMCID: PMC3088992  PMID: 20130466
25.  Specific HLA Class I and II Alleles Associated with Hepatitis C Virus Viremia 
Hepatology (Baltimore, Md.)  2010;51(5):1514-1522.
Studies of human leukocyte antigen (HLA) alleles and their relation with hepatitis C virus (HCV) viremia have had conflicting results. However, these studies have varied in size and methods, and few large studies assessed HLA class I alleles. Only one study conducted high resolution class I genotyping. The current investigation therefore involved high-resolution HLA class I and II genotyping of a large multi-racial cohort of US women with high prevalence of HCV and HIV. Our primary analyses evaluated associations between twelve HLA alleles identified through a critical review of the literature and HCV viremia in 758 HCV-seropositive women. Other alleles with >5% prevalence were also assessed; previously unreported associations were corrected for multiple comparisons. DRB1*0101 (prevalence ratio [PR] = 1.7; 95% confidence interval [CI] = 1.1–2.6), B*5701 (PR=2.0; 95% CI = 1.0–3.1), B*5703 (PR = 1.7; 95% CI = 1.0–2.5), and Cw*0102 (PR = 1.9; 95% CI = 1.0–3.0) were associated with the absence of HCV RNA (i.e., HCV clearance), while DRB1*0301 (PR = 0.4; 95% CI = 0.2–0.7) was associated with HCV RNA positivity. DQB1*0301 was also associated with the absence of HCV RNA but only among HIV-seronegative women (PR = 3.4; 95% CI = 1.2–11.8). Each of these associations was among those predicted. We additionally studied the relation of HLA alleles with HCV infection (serostatus) in women at high risk of HCV from injection drug use (IDU; N=838), but no significant relationships were observed.
Conclusion
HLA genotype influences host capacity to clear HCV viremia. The specific HLA associations observed in the current study are unlikely to be due to chance since they were a priori hypothesized.
doi:10.1002/hep.23515
PMCID: PMC2946382  PMID: 20169624
human leukocyte antigen; HIV; injection drug user; multiple comparisons; killer immunoglobulin-like receptor

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