Jennifer L. Dodge

Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV partners study.

The efficiency of hepatitis C virus (HCV) transmission by sexual activity remains controversial. We conducted a cross‐sectional study of HCV‐positive subjects and their partners to estimate the risk for HCV infection among monogamous heterosexual couples. A total of 500 anti–HCV‐positive, human immunodeficiency virus–negative index subjects and their long‐term heterosexual partners were studied. Couples were interviewed separately for lifetime risk factors for HCV infection, within‐couple sexual practices, and sharing of personal grooming items. Blood samples were tested for anti‐HCV, HCV RNA, and HCV genotype and serotype. Sequencing and phylogenetic analysis determined the relatedness of virus isolates among genotype‐concordant couples. The majority of HCV‐positive index subjects were non‐Hispanic white, with a median age of 49 years (range, 26‐79 years) and median of 15 years (range, 2‐52 years) of sexual activity with their partners. Overall, HCV prevalence among partners was 4% (n = 20), and nine couples had concordant genotype/serotype. Viral isolates in three couples (0.6%) were highly related, consistent with transmission of virus within the couple. Based on 8,377 person‐years of follow‐up, the maximum incidence rate of HCV transmission by sex was 0.07% per year (95% confidence interval, 0.01‐0.13) or approximately one per 190,000 sexual contacts. No specific sexual practices were related to HCV positivity among couples. Conclusion: The results of this study provide quantifiable risk information for counseling long‐term monogamous heterosexual couples in which one partner has chronic HCV infection. In addition to the extremely low estimated risk for HCV infection in sexual partners, the lack of association with specific sexual practices provides unambiguous and reassuring counseling messages. (HEPATOLOGY 2013)

Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria.

We report on the long‐term intention‐to‐treat (ITT) outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing downstaging to within Milan/United Network for Organ Sharing T2 criteria before liver transplantation (LT) since 2002 and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The downstaging subgroups include 1 lesion >5 and ≤8 cm (n = 43), 2 or 3 lesions at least one >3 and ≤5 cm with total tumor diameter ≤8 cm (n = 61), or 4‐5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n = 14). In the downstaging group, 64 patients (54.2%) had received LT and 5 (7.5%) developed HCC recurrence. Two of the five patients with HCC recurrence had 4‐5 tumors at presentation. The 1‐ and 2‐year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the downstaging group versus 20.3% and 25.6% in the T2 group (P = 0.04). Kaplan‐Meiers 5‐year post‐transplant survival and recurrence‐free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). The 5‐year ITT survival was 56.1% in the downstaging group versus 63.3% in the T2 group (P = 0.29). Factors predicting dropout in the downstaging group included pretreatment alpha‐fetoprotein ≥1,000 ng/mL (multivariate hazard ratio [HR]: 2.42; P = 0.02) and Childs B versus Childs A cirrhosis (multivariate HR: 2.19; P = 0.04). Conclusion: Successful downstaging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post‐transplant survival, comparable to those meeting T2 criteria without downstaging. Owing to the small number of patients with 4‐5 tumors, further investigations are needed to confirm the efficacy of downstaging in this subgroup. (Hepatology 2015;61:1968–1977)

Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: Implications for the current organ allocation policy

It has been shown that patients with hepatocellular carcinoma (HCC) meeting the United Network for Organ Sharing T2 (Milan) criteria have an advantage in comparison with patients without HCC under the current organ allocation system for liver transplantation (LT). We hypothesized that within the T2 HCC group, there is a subgroup with a low risk of wait‐list dropout that should not receive the same listing priority. This study evaluated 398 consecutive patients with T2 HCC listed for LT with a Model for End‐Stage Liver Disease exception from March 2005 to January 2011 at our center. Competing risk (CR) regression was used to determine predictors of dropout. The probabilities of dropout due to tumor progression or death without LT according to the CR analysis were 9.4% at 6 months and 19.6% at 12 months. The median time from listing to LT was 8.8 months, and the median time from listing to dropout or death without LT was 7.2 months. Significant predictors of dropout or death without LT according to a multivariate CR regression included 1 tumor of 3.1 to 5 cm (versus 1 tumor of 3 cm or less), 2 or 3 tumors, a lack of a complete response to the first locoregional therapy (LRT), and a high alpha‐fetoprotein (AFP) level after the first LRT. A subgroup (19.9%) that met certain criteria (1 tumor of 2 to 3 cm, a complete response after the first LRT, and an AFP level ≤ 20 ng/mL after the first LRT) had 1‐ and 2‐year probabilities of dropout of 1.3% and 1.6%, respectively, whereas the probabilities were 21.6% and 26.5% for all other patients (P = 0.004). In conclusion, a combination of tumor characteristics and a complete response to the first LRT define a subgroup of patients with a very low risk of wait‐list dropout who do not require the same listing priority. Our results may have important implications for the organ allocation policy for HCC. Liver Transpl 19:1343‐1353, 2013.

A US multicenter study of hepatitis C treatment of liver transplant recipients with protease-inhibitor triple therapy

BACKGROUND & AIMS NS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited. METHODS This was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12). RESULTS The intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p<0.001). Adverse effects were common; 21% of patients experienced hemoglobin <8g/dl and 57% required blood transfusions during the first 16 weeks. Twenty seven percent were hospitalized and 9% died; all were liver-related. CONCLUSIONS The addition of boceprevir or telaprevir to peginterferon and ribavirin yields SVR12 of 63% in liver transplant recipients with genotype 1 recurrent HCV, despite a high prevalence of advanced fibrosis and prior non-response to peginterferon and ribavirin. Rapid virologic response predicted a high likelihood of SVR. Despite a doubling of SVR rates, poor tolerability and high rates of adverse events were frequent and pose barriers to its widespread application.

Functional decline in patients with cirrhosis awaiting liver transplantation: Results from the functional assessment in liver transplantation (FrAILT) study.

Cirrhosis is characterized by sarcopenia and malnutrition, leading to progressive functional decline. We aimed to objectively measure functional decline in patients with cirrhosis awaiting liver transplantation and its association with waiting list mortality. Consecutive adults listed for liver transplantation with laboratory Model for End‐Stage Liver Disease (MELD) ≥12 at a single center underwent functional status assessments at every outpatient visit using the Short Physical Performance Battery (0 = impaired to 12 = robust), consisting of gait, chair stands, and balance tests. Joint linear time‐to‐event analyses modeled the simultaneous impact of the longitudinal trajectory of physical function on waiting list mortality (=death or delisted for being too sick for liver transplantation). Included were 309 liver transplantation candidates. Median laboratory MELD was 15, serum albumin was 3.0 g/dL, 28% had ascites, 18% had hepatic encephalopathy, and 83% were Child class B or C. At a median follow‐up of 14 months, 15% died or were delisted and 28% underwent liver transplantation. Average physical function worsened per 3 months on the waiting list: −0.38 kg in grip strength, −0.05 meters/second in gait, 0.03 seconds in chair stands, and −0.16 Short Physical Performance Battery points. In joint models of longitudinal trajectories of physical function and waiting list mortality adjusted for MELD‐Na, albumin, hepatocellular carcinoma, and baseline physical function, the longitudinal trajectories of each physical function measure were significantly associated with waiting list mortality: grip (hazard ratio = 0.89, 95% confidence interval 0.83‐0.95), gait (hazard ratio = 0.72, 95% confidence interval 0.62‐0.84), chair stands (hazard ratio = 1.17, 95% confidence interval 1.09‐1.25), and Short Physical Performance Battery <10 (hazard ratio = 1.45, 95% confidence interval 1.15‐2.20). Conclusion: Liver transplantation candidates experience significant functional decline on the waiting list, despite modest wait time and low baseline MELD; decline in physical function is associated with an increased risk of death or delisting, independent of liver disease severity. (Hepatology 2016;63:574–580)

Center competition and outcomes following liver transplantation

In the United States, livers for transplantation are distributed within donation service areas (DSAs). In DSAs with multiple transplant centers, competition among centers for organs and recipients may affect recipient selection and outcomes in comparison with DSAs with only 1 center. The objective of this study was to determine whether competition within a DSA is associated with posttransplant outcomes and variations in patients wait‐listed within the DSA. United Network for Organ Sharing data for 38,385 adult cadaveric liver transplant recipients undergoing transplantation between January 1, 2003 and December 31, 2009 were analyzed to assess differences in liver recipients and donors and in posttransplant survival by competition among centers. The main outcome measures that were studied were patient characteristics, actual and risk‐adjusted graft and patient survival rates after transplantation, organ quality as quantified by the donor risk index (DRI), wait‐listed patients per million population by DSA, and competition as quantified by the Hirschman‐Herfindahl index (HHI). Centers were stratified by HHI levels as no competition or as low, medium (or mid), or high competition. In comparison with DSAs without competition, the low‐, mid‐, and high‐competition DSAs (1) performed transplantation for patients with a higher risk of graft failure [hazard ratio (HR) = 1.24, HR = 1.26, and HR = 1.34 (P < 0.001 for each)] and a higher risk of death [HR = 1.21, HR = 1.23, and HR = 1.34 (P < 0.001 for each)] and for a higher proportion of sicker patients as quantified by the Model for End‐Stage Liver Disease (MELD) score [10.0% versus 14.8%, 20.1%, and 28.2% with a match MELD score of 31‐40 (P < 0.001 for each comparison)], (2) were more likely to use organs in the highest risk quartile as quantified by the DRI [18.3% versus 27.6%, 20.4%, and 31.7% (P ≤ 0.001 for each)], and (3) listed more patients per million population [18 (median) versus 34 (P = not significant), 37 (P = 0.005), and 45 (P = 0.0075)]. Significant variability in patient selection for transplantation is associated with market variables characterizing competition among centers. These findings suggest both positive and negative effects of competition among health care providers. Liver Transpl 19:96–104, 2013.

Projected future increase in aging hepatitis C virus–infected liver transplant candidates: A potential effect of hepatocellular carcinoma

In the United States, the peak hepatitis C virus (HCV) antibody prevalence of 4% occurred in persons born in the calendar years 1940‐1965. The goal of this study was to examine observed and projected age‐specific trends in the demand for liver transplantation (LT) among patients with HCV‐associated liver disease stratified by concurrent hepatocellular carcinoma (HCC). All new adult LT candidates registered with the Organ Procurement and Transplantation Network for LT 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 LT, and 52,540 (41%) had HCV. The number of new registrants with HCV dramatically differed by the age at calendar year, and this suggested a birth cohort effect. When the candidates were stratified by birth year in 5‐year intervals, the birth cohorts with the highest frequency of HCV were as follows (in decreasing order): 1951‐1955, 1956‐1960, 1946‐1950, and 1941‐1945. These 4 birth cohorts, spanning from 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 the calendar years 2000 and 2010 in the 1941‐1960 birth cohorts. By 2015, we anticipate that an increasing proportion of new registrants with HCV will have HCC and be ≥60 years old (born in or before 1955). In conclusion, the greatest demand for LT 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. During the coming decade, the projected increase in the demand for LT from an aging HCV‐infected population will challenge the transplant community to reconsider current treatment paradigms. Liver Transpl, 2012.

Time to transplantation as a predictor of hepatocellular carcinoma recurrence after liver transplantation

In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC); it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non–HCC‐related death, or last follow‐up. The cumulative incidence of HCC recurrence was compared for patients waiting ≤120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%‐3.8%] and 5.6% (95% CI = 5.0%‐6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting ≤120 days (2.2% versus 3.9%, P = 0.002); however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the institution of a mandatory waiting time after an exception is granted. Liver Transpl 20:937–944, 2014.

Development of a novel frailty index to predict mortality in patients with end-stage liver disease

Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the Model for End‐Stage Liver Disease (MELD) Sodium (MELDNa) score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in patients with cirrhosis. Consecutive outpatients listed for liver transplantation at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting because of sickness). We selected the frailty index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the frailty index to MELDNa. Included were 536 patients with cirrhosis with median MELDNa of 18. One hundred seven (20%) died/were delisted. The final frailty index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the frailty index to correctly rank patients according to their 3‐month waitlist mortality risk (i.e., concordance‐statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa+frailty index together. Compared with MELDNa alone, MELDNa+frailty index correctly reclassified 16% of deaths/delistings (P = 0.005) and 3% of nondeaths/delistings (P = 0.17) with a total NRI of 19% (P < 0.001). Compared to those with robust frailty index scores (<20th percentile), cirrhotics with poor frailty index scores (>80th percentile) were more impaired by gait speed, difficulty with Instrumental Activities of Daily Living, exhaustion, and low physical activity (P < 0.001 for each). Conclusion: Our frailty index for patients with cirrhosis, comprised of three performance‐based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. (Hepatology 2017;66:564–574).

Cancer in Migrant and Seasonal Hired Farm Workers

ABSTRACT Studies of cancer among farm workers are difficult to conduct and interpret given the unique nature of this occupational group. The transitory nature of the work, high levels of poverty, and lack of legal documentation make epidemiologic studies difficult to accomplish. Nevertheless, this workforce in the United States, which numbers as much as 3 million persons, is a high isk population due to exposures to numerous toxic substances, including excessive sunlight, heat, dangerous machinery, fumes, fertizers, dust, and pesticides. We summarize characteristics of farm workers (i.e., demographics, health care) from the National Agricultural Workers Survey (NAWS) and the California Agricultural Workers Survey (CAWS) and present findings from a series of studies conducted among farm workers in California. The epidemiology literature was reviewed and methods for a unique farm worker union-based epidemiologic study are presented. Farm workers in California and the rest of the United States, many of whom are seasonal and migrant workers are at elevated risk for numerous forms of cancer compared to the general population and specific pesticides may be associated with this altered risk. Elevated risks have been found for lymphomas and prostate, brain, leukemia, cervix, and stomach cancers.