In the US, the peak hepatitis C (HCV) antibody prevalence of 4% occurred in persons born in calendar years 1940 to 1965.
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).
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.
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).
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.
Hepatitis C; Hepatocellular carcinoma; liver transplantation
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.
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.
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.
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.
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.
There is some evidence that patients with CLD commonly use CAM to address general and CLD-specific health concerns.
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.
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.
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.
complementary and alternative medicine; chronic liver disease; epidemiology
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.
Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in HIV-infected patients due to reportedly poor outcomes.
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.
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).
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.
cirrhosis; acute rejection; body mass index; donor age; recurrent hepatitis
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.
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.
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).
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.
Living donor liver transplantation; cirrhosis; end stage liver disease; mortality; outcomes
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).
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.
HCV outcomes; fibrosis; HCV treatment
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).
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.
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.
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.
living donor liver transplantation; complications; liver transplantation; liver function tests; hepatectomy
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.
Donor risk index; donor age; gender-mismatch
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.
Complications of hepatitis C virus (HCV) infection are primarily related to the development of advanced fibrosis.
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.
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].
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.
fibrosis; alcohol; viral load; marijuana; cirrhosis
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
human leukocyte antigen; HIV; injection drug user; multiple comparisons; killer immunoglobulin-like receptor
Multistate modeling methods are well-suited for analysis of some chronic diseases that move through distinct stages. The memoryless or Markov assumptions typically made, however, may be suspect for some diseases, such as hepatitis C, where there is interest in whether prognosis depends on history. This paper describes methods for multistate modeling where transition risk can depend on any property of past progression history, including time spent in the current stage and the time taken to reach the current stage. Analysis of 901 measurements of fibrosis in 401 patients following liver transplantation found decreasing risk of progression as time in the current stage increased, even when controlled for several fixed covariates. Longer time to reach the current stage did not appear associated with lower progression risk. Analysis of simulation scenarios based on the transplant study showed that greater misclassification of fibrosis produced more technical difficulties in fitting the models and poorer estimation of covariate effects than did less misclassification or error-free fibrosis measurement. The higher risk of progression when less time has been spent in the current stage could be due to varying disease activity over time, with recent progression indicating an “active” period and consequent higher risk of further progression.
fibrosis; hepatitis C; liver transplant; memoryless assumptions; multistate modeling
Although the primary mode of hepatitis C virus (HCV) transmission is exposure to blood products or injection drug use (IDU), studies have found varying independent risk factors for HCV infection among persons with no history of IDU or exposure to blood products. For HIV-infected women, sexual transmission may be another potential source of HCV infection. HIV-infected and HIV-negative women at risk for HIV enrolled in the Women's Interagency HIV Study (WIHS) during October 1994 to November 1995 and again between October 2001 and November 2002 were studied. Clinical and demographic factors associated with HCV seroprevalence were assessed in multivariate logistic regression models controlling for history of blood transfusion and IDU. Among 3636 women with HCV results, 31.5% were HCV antibody positive (HCV+) including 13.5% with no reported history of IDU or blood transfusions. Multivariate logistic regression analyses stratified on IDU showed that among women with no history of IDU, sex with an IDU male was independently associated with HCV positivity (odds ratio [OR] = 2.8, 95% confidence [CI] = 2.1, 3.8, p < 0.0001) after controlling for blood transfusion, age, HIV infection, unemployment, birth in the United States, history of hepatitis B infection, and current smoking status. Further stratification on HIV status showed that the association was significant only for the HIV+ (OR = 1.9, 95% CI = 1.3, 2.7, p = 0.0007) compared to the HIV− women (OR = 1.1, 95% CI = 0.4, 2.7) although these odds ratios were not significantly different (p = 0.25). For HIV-positive women with no reported history of IDU, sex with an IDU male was independently associated with HCV suggesting that sexual transmission may be an important mode of HCV transmission for these high-risk women.
BACKGROUND & AIMS
In the last decade, significant progress has been made in the treatment of liver disease associated with chronic hepatitis, especially in patients infected with the hepatitis B virus (HBV). To investigate whether the population-wide application of antiviral therapies has impacted liver transplant waiting list registration, we analyzed longitudinal trends in waiting list registration for patients with hepatitis B and C and those with nonviral liver disease.
This study represented a retrospective analysis of registry data containing all US liver transplant centers. All adult, primary liver transplantation candidates registered to the Organ Procurement and Transplantation Network between 1985 and 2006 were included in the analysis. Standardized incidence rates were calculated for waiting list registration for liver transplantation by underlying disease (HBV and HCV infection and other) and by indication for transplantation (fulminant liver disease, hepatocellular carcinoma [HCC], and end-stage liver disease [ESLD]).
Of 113,927 unique waiting list registrants, 4793 (4.2%) had HBV, and 40,923 (35.9%) had HCV infections; the remaining 68,211 (59.9%) had neither. The incidence of waiting list registration for ESLD and fulminant liver disease decreased, whereas that for HCC increased. The decrease in ESLD registration was most pronounced, and the increase in HCC was least dramatic among registrants with hepatitis B. The decrease in registration for ESLD secondary to HCV infection was also significantly larger than that for ESLD patients with non-viral etiologies.
The pattern of liver transplantation waiting list registration among patients with hepatitis B suggests that the widespread application of oral antiviral therapy for HBV contributed to the decreased incidence of decompensated liver disease.
Organ procurement in China has been criticized because of its reliance on executed prisoners as donors. We aimed to assess the influence of perceptions about organ procurement practices in China on domestic patient care decisions.
An anonymous Internet administered case-based questionnaire was used to survey an sample of healthcare professionals with affiliations to hepatology and transplantation professional societies.
Of 674 completed surveys, the vast majority (93%) of the respondents were physicians, surgeons or allied transplant professionals actively caring for liver transplant patients and 81% practiced in the United States (US). A strong majority believed procurement practices were ethically sound in the US and Europe (87% and 73%) but fare fewer believed that procurement practices were ethically sound in China (4%, p<0.001). In case-based questions, lack of confidence in the ethical standards of organ procurement in China predicted patient-care decisions. The majority would provide post-transplantation care for patients who underwent liver transplantation at another domestic center, in a foreign country and in China (90%,78%,63%, respectively, p<0.001) yet respondents who suspected unethical procurement practices in China were more reluctant to do so (p<0.001).
Transplant professionals expressed concern about organ procurement practices in China which influenced their patient care decision-making.
Transplant tourism; medical ethics; liver transplantation; health policy; medical decision-making; Internet survey
Although the primary mode of hepatitis C virus (HCV) transmission is exposure to blood products or injection drug use (IDU), studies have found varying independent risk factors for HCV infection among persons with no history of IDU or exposure to blood products. For HIV-infected women, sexual transmission may be another potential source of HCV infection. HIV-infected and HIV-negative women at risk for HIV enrolled in the Women’s Interagency HIV Study (WIHS) during October 1994 to November 1995 and again between October 2001 and November 2002 were studied. Clinical and demographic factors associated with HCV seroprevalence were assessed in multivariate logistic regression models controlling for history of blood transfusion and IDU. Among 3636 women with HCV results, 31.5% were HCV antibody positive (HCV+) including 13.5% with no reported history of IDU or blood transfusions. Multivariate logistic regression analyses stratified on IDU showed that among women with no history of IDU, sex with an IDU male was independently associated with HCV positivity (odds ratio [OR] = 2.8, 95% confidence [CI] = 2.1, 3.8, p < 0.0001) after controlling for blood transfusion, age, HIV infection, unemployment, birth in the United States, history of hepatitis B infection, and current smoking status. Further stratification on HIV status showed that the association was significant only for the HIV+ (OR = 1.9, 95% CI = 1.3, 2.7, p = 0.0007) compared to the HIV− women (OR = 1.1, 95% CI = 0.4, 2.7) although these odds ratios were not significantly different ( p = 0.25). For HIV-positive women with no reported history of IDU, sex with an IDU male was independently associated with HCV suggesting that sexual transmission may be an important mode of HCV transmission for these high-risk women.
Pure red cell aplasia due to anti-epoetin antibodies is a known complication of epoetin therapy for anemia due to chronic kidney disease. This disease has not previously been well described in the setting of therapy for chronic hepatitis C virus infection. While treatment for pure red cell aplasia due to anti-epoetin antibodies is usually with immunosuppressive therapy such as calcineurin inhibition, the safety of this treatment in chronic hepatitis C virus infection is unknown. To date, little has been published on the efficacy of rituximab on pure red cell aplasia due to anti-epoetin antibodies.
This report describes a 65-year-old Asian-American woman who developed pure red cell aplasia from high titer neutralizing anti-epoetin antibodies after epoetin-alfa therapy during ribavirin and peg-interferon treatment for chronic hepatitis C virus infection. We describe the outcome of her treatment with rituximab. The reticulocyte count increased, and anti-epoetin antibody titer decreased with a loss of neutralizing activity in vitro, leading to a reduction in blood transfusions, and eventual resolution of anemia, without reactivation of hepatitis C virus.
The diagnosis of pure red cell aplasia from anti-epoetin antibodies should be considered in patients undergoing therapy for chronic hepatitis C virus infection who develop severe anemia after administration of erythropoietin or darbepoetin. Though it is currently an off-label indication, rituximab is a therapeutic option for patients with pure red cell aplasia due to anti-epoetin antibodies.