Mandana Khalili

Applicability, Tolerability and Efficacy of Preemptive Antiviral Therapy in Hepatitis C‐Infected Patients Undergoing Liver Transplantation

Preliminary studies suggest preemptive anti‐HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg‐IFN) interferon alfa‐2b (3 MU thrice weekly or 1.5 μg/kg weekly), or IFN/peg‐IFN plus ribavirin (600 mg increased to 1.0–1.2 g daily) was initiated 2–6 weeks post‐transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end‐stage liver disease (MELD) and Childs‐Pugh scores pre‐transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full‐dose treatment during treatment. End‐of‐treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with ‘sicker’ patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.

New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection.

Epidemiological studies suggest diabetes mellitus (DM) may be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Since diabetes and HCV are common in liver transplant recipients, we sought to examine the unique contribution of HCV infection to risk of de novo diabetes posttransplantation. Using a cohort of 555 liver transplant recipients (median age 49 years, 54% males, 82% Caucasian) without preexisting diabetes from 3 U.S. centers enrolled between 1990 and 1994 and followed for a median duration of 5 years, we determined the incidence of de novo diabetes and the independent predictors of the development of diabetes. De novo diabetes was defined by the use of antidiabetic medications. De novo diabetes developed in 209/555 (37.7%) patients of whom 157 (28.3%) had transient‐DM (T‐DM) and 52 (9.4%) had persistent‐DM (P‐DM). Among HCV‐infected transplant recipients, de novo T‐DM and P‐DM developed in 26% and 14%, respectively. HCV was predictive of P‐DM (P = .02) but not T‐DM. Older age (P = .03) and tacrolimus use (P = .02) were also independent predictors of P‐DM. In conclusion, de novo diabetes is common in transplant recipients, but is typically transient in nature. However, among those developing de novo persistent diabetes, HCV is one of the most important risk factors. This adds further support to the epidemiological data linking HCV and diabetes. (Liver Transpl 2004;10:349–355.)

A Randomized Trial of a Hepatitis Care Coordination Model in Methadone Maintenance Treatment

OBJECTIVES We evaluated the efficacy of a hepatitis care coordination intervention to improve linkage to hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination and clinical evaluation of hepatitis C virus (HCV) infection among methadone maintenance patients. METHODS We conducted a randomized controlled trial of 489 participants from methadone maintenance treatment programs in San Francisco, California, and New York City from February 2008 through June 2011. We randomized participants to a control arm (n = 245) and an intervention arm (n = 244), which included on-site screening, motivational-enhanced education and counseling, on-site vaccination, and case management services. RESULTS Compared with the control group, intervention group participants were significantly more likely (odds ratio [OR] = 41.8; 95% confidence interval [CI] = 19.4, 90.0) to receive their first vaccine dose within 30 days and to receive an HCV evaluation within 6 months (OR = 4.10; 95% CI = 2.35, 7.17). A combined intervention adherence outcome that measured adherence to HAV-HBV vaccination, HCV evaluation, or both strongly favored the intervention group (OR = 8.70; 95% CI = 5.56, 13.61). CONCLUSIONS Hepatitis care coordination was efficacious in increasing adherence to HAV-HBV vaccination and HCV clinical evaluation among methadone patients.

Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C.

OBJECTIVE:The aim of this study was to compare the potential efficacy and safety of a combination of interferon and ribavirin with that of interferon and amantadine in patients who had previously failed to respond to interferon monotherapy.METHODS:A total of 29 patients were randomized to 3 million units of α-interferon three times weekly with 1000 mg of ribavirin daily (group A, n = 14) or an identical dose of α-interferon and amantadine hydrochloride given in a dose of 200 mg daily (group B, n = 15). Patients were treated for 24 wk and observed for 24 wk posttreatment.RESULTS:The treatment groups were evenly matched with respect to gender, frequency of genotype 1, presence of fibrosis, as well as baseline alanine aminotransferase (ALT) and HCV RNA levels. At the end of therapy, five of 14 or 36% of patients in group A versus 0 of 15 in group B had both normal serum ALT and nondetectable HCV RNA by polymerase chain reaction (p = 0.017). A complete response was sustained, however, in only two of 13 patients (15%) in group A who completed 24 wk of observation posttreatment.CONCLUSIONS:A substantial proportion of interferon nonresponders have an end-of-treatment biochemical and virological response to a combination of interferon and ribavirin, and sustained responses are possible. The addition of amantadine to interferon, in contrast, does not seem to enhance the antiviral effectiveness of interferon in patients who have previously failed to respond.

Hepatitis B Virus–Specific and Global T-Cell Dysfunction in Chronic Hepatitis B

BACKGROUND & AIMS T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

Comparison of surrogate and direct measurement of insulin resistance in chronic hepatitis C virus infection: Impact of obesity and ethnicity

Studies using surrogate estimates show high prevalence of insulin resistance in hepatitis C infection. This study prospectively evaluated the correlation between surrogate and directly measured estimates of insulin resistance and the impact of obesity and ethnicity on this relationship. Eighty‐six nondiabetic, noncirrhotic patients with hepatitis C virus (age = 48 ± 7 years, 74% male, 44% white, 22% African American, 26% Latino, 70% genotype 1) were categorized into normal‐weight (body mass index [BMI] < 25, n = 30), overweight (BMI = 25‐29.9, n = 38), and obese (BMI ≥ 30, n = 18). Insulin‐mediated glucose uptake was measured by steady‐state plasma glucose (SSPG) concentration during a 240‐minute insulin suppression test. Surrogate estimates included: fasting glucose and insulin, glucose/insulin, homeostasis model assessment (HOMA‐IR), quantitative insulin sensitivity check index (QUICKI), insulin (I‐AUC) and glucose (G‐AUC) area under the curve during oral glucose tolerance test, and the Belfiore and Stumvoll indexes. All surrogate estimates correlated with SSPG, but the magnitude of correlation varied (r = 0.30‐0.64). The correlation coefficients were highest in the obese. I‐AUC had the highest correlation among all ethnic and weight groups (r = 0.57‐0.77). HOMA‐IR accounted for only 15% of variability in SSPG in the normal weight group. The common HOMA‐IR cutoff of ≤3 to define insulin resistance had high misclassification rates especially in the overweight group independent of ethnicity. HOMA‐IR > 4 had the lowest misclassification rate (75% sensitivity, 88% specificity). Repeat HOMA‐IR measurements had higher within‐person variation in the obese (standard deviation = 0.77 higher than normal‐weight, 95% confidence interval = 0.25‐1.30, P = 0.005). Conclusion: Because of limitations of surrogate estimates, caution should be used in interpreting data evaluating insulin resistance especially in nonobese, nondiabetic patients with HCV. HEPATOLOGY 2010

Long-Term Histological Effects of Preemptive Antiviral Therapy in Liver Transplant Recipients with Hepatitis C Virus Infection

The long‐term effects of preemptive antiviral therapy on fibrosis progression in liver transplant recipients with hepatitis C virus (HCV) were examined in a cohort of consecutive liver transplant recipients who received preemptive antiviral therapy for 48 weeks (95% were virologic nonresponders). Control patients were transplanted during this same period but did not receive preemptive therapy. Patients were followed to the date of last biopsy and censored at the time of subsequent HCV treatment. Eighty‐six patients surviving ≥90 days were included. Treated and control patients were similar, except that treated patients had longer histological follow‐up (60 versus 50 months), a lower median Model for End‐Stage Liver Disease score at liver transplant (17 versus 23), and a shorter median length of hospital stay (6 versus 9.5 days). In the uncensored analysis, the cumulative probability of a Batts‐Ludwig fibrosis score ≥ 2 at 48 months post–liver transplant was 22% in the preemptive therapy group and 49% in the nonpreemptive therapy group (P = 0.08). In multivariate analysis, preemptive therapy was associated with a 48% reduced risk of a fibrosis score ≥ 2 (hazard ratio = 0.52, 95% confidence interval = 0.24‐1.12, P = 0.09), but this failed to achieve statistical significance. Receipt of preemptive therapy was associated with a delay in subsequent HCV therapy for moderate to severe disease (fibrosis score ≥ 2 or moderate necroinflammatory activity) with a median time of 36.3 months versus 20.3 months in the preemptive and nonpreemptive groups (P = 0.004). We conclude that preemptive antiviral therapy in virologic nonresponders delays the time to subsequent HCV treatment and may confer a reduced risk of fibrosis progression. Further study of preemptive antiviral therapy is warranted. Liver Transpl 14:1491–1497, 2008.

A mentor development program for clinical translational science faculty leads to sustained, improved confidence in mentoring skills.

Mentorship is crucial for academic productivity and advancement for clinical and translational (CT) science faculty. However, little is known about the long‐term effects of mentor training programs. The University of California, San Francisco (UCSF), Clinical and Translational Science Institute launched a Mentor Development Program (MDP) in 2007 for CT faculty. We report on an evaluation of the first three cohorts of graduates from the MDP. In 2010, all Mentors in Training (MITs) who completed the MDP from 2007 to 2009 (n= 38) were asked to complete an evaluation of their mentoring skills and knowledge; all MITs (100%) completed the evaluation. Two‐thirds of MDP graduates reported that they often apply knowledge, attitudes, or skills obtained in the MDP to their mentoring. Nearly all graduates (97%) considered being a mentor important to their career satisfaction. Graduates were also asked about the MDPs impact on specific mentoring skills; 95% agreed that the MDP helped them to become a better mentor and to focus their mentoring goals. We also describe a number of new initiatives to support mentoring at UCSF that have evolved from the MDP. To our knowledge, this is the first evaluation of the long‐term impact of a mentor training program for CT researchers. Clin Trans Sci 2012; Volume 5: 362–367

Hepatocellular carcinoma screening practices and impact on survival among hepatitis B-infected Asian Americans.

Summary.  Asians Americans have a high burden of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC). HCC screening practices in this population are unknown. We aimed to investigate predictors and patterns of HCC screening and its impact on survival in HBV‐infected Asian Americans. Clinical data were obtained from a retrospective cohort of 1870 HBsAg‐positive Asians in San Francisco’s safety net clinics. In 824 patients at‐risk for HCC, screening (≥1 imaging and/or AFP per year) decreased from 67% to 47% to 24% from the 1st to 2nd to 10th year after HBV diagnosis, respectively. AFP, imaging, and imaging plus AFP were used in 37%, 14%, and 49% during the first year after diagnosis, and imaging plus AFP increased to 64% by the 10th year. Among 1431 patients followed in 2007, age 40–64 years, female gender, cirrhosis, hepatologist evaluation, HBV diagnosis after 2003, and testing for HBeAg were associated with HCC screening. Of the 51 patients with HCC, more cirrhotics received screening and were diagnosed with early stage disease. Median survival following HCC diagnosis was higher in screened patients (1624 days vs. 111 days, P = 0.02). MELD score at HCC diagnosis (HR 1.2, 95% CI 1.1–1.3) and receipt of curative therapy (HR 0.3, 95% CI 0.08–0.94) were associated with survival. Screening rates in at‐risk Asian Americans, particularly among noncirrhotics, were suboptimal and decreased over time. Among patients with HCC, receipt of prior screening improved survival, and this survival benefit was related to better liver function at HCC diagnosis and receipt of curative therapy.

Impact of Insulin Resistance on HCV Treatment Response and Impact of HCV Treatment on Insulin Sensitivity Using Direct Measurements of Insulin Action

OBJECTIVE Insulin resistance, as measured by surrogate markers, is associated with lower response to hepatitis C virus (HCV) therapy and may improve with HCV eradication. We prospectively evaluated the impact of directly measured insulin resistance and abnormal glucose metabolism on achieving sustained virologic response (SVR) with HCV therapy and assessed whether SVR results in improved insulin sensitivity and fasting glucose. RESEARCH DESIGN AND METHODS A total of 50 noncirrhotic, nondiabetic, HCV-infected patients (27 untreated, 23 treated with pegylated interferon/ribavirin, nonrandomized) underwent clinical and histologic evaluation and 75-g oral glucose tolerance test. Insulin sensitivity was assessed directly with insulin suppression test by measuring steady-state plasma glucose (SSPG) concentration during a 240-min infusion of octreotide, glucose, and insulin. Of the subjects, 43 had at least one follow-up evaluation. RESULTS Patient characteristics were median age 48, 57% male, and 52% white. SVR was achieved in 61% (14 of 23) of treated subjects. SVR was independently associated with HCV genotypes 2 and 3 (odds ratio 8.8 [95% CI 1.2–61.7]) but was not strongly associated with insulin sensitivity. When controlling for elapsed time between measurements, being on interferon, and BMI, SSPG decreased by 36 mg/dL (−88 to 16) in those with SVR and decreased by 28 mg/dL (−93 to 38) in those without SVR, compared with the untreated group. BMI (coefficient 9.1 per 5 units; 95% CI 5.3–12.9) and interferon use (coefficient 56; 95% CI 6.8–105) were associated with SSPG. CONCLUSIONS Insulin resistance does not appear to be strongly associated with SVR. HCV therapy may improve insulin resistance regardless of virologic response; however, BMI and interferon use were clearly associated with insulin resistance.