Khanh K. Nguyen

Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil

Renal dysfunction has been reported in patients treated with adefovir dipivoxil (ADV); however, its incidence and clinical importance may be underappreciated given the lack of long‐term follow‐up and data outside of a clinical trial setting. Our goal was to examine the severity and incidence of renal dysfunction in a real‐life setting for patients treated with ADV and whose baseline estimated glomerular filtration rate (eGFR) was >50 mL/minute. We performed a cohort study of 290 chronic hepatitis B patients: 145 patients treated with 10 mg ADV and 145 patients unexposed to ADV at two community clinics, who were matched for age (±10 years), sex, and baseline eGFR. The exposed and unexposed populations were well‐matched with a similar mean age (46–47 years), proportion of male patients (76.5%), baseline serum creatinine (0.97–0.99 mg/dL), and baseline creatinine clearance (85.0–85.4 mL/minute). The incidence density for renal dysfunction defined by treatment termination and/or development of eGFR ≤50 mL/minute was five cases per 100 patient‐years in the exposed group compared with 1.36 cases per 100 patient‐years in the unexposed group (P = 0.02). The relative risk of exposed to unexposed was 3.68 (95% confidence interval 1.1–19.3). On Cox proportional hazard analysis also inclusive of sex, ADV was a significant predictor of significant renal dysfunction (hazard ratio [HR] 3.94, P = 0.03). There were also significant trends for age >50 years (HR 3.49, P = 0.087), mild renal impairment at baseline (HR 4.49, P = 0.073), and hypertension and/or diabetes mellitus (HR 2.36, P = 0.074). Conclusion: ADV is an independent predictor for significant deterioration of renal function. Patients on ADV should be monitored, especially patients who are older, have baseline renal insufficiency, or have hypertension and/or diabetes mellitus. (HEPATOLOGY 2009.)

Significant Prevalence of Histologic Disease in Patients With Chronic Hepatitis B and Mildly Elevated Serum Alanine Aminotransferase Levels

BACKGROUND & AIMSnSerum ALT remains the most accessible test available to clinicians for monitoring chronic hepatitis B virus infection, but appropriate action when ALT levels are only mildly elevated is ambiguous in standard guidelines.nnnMETHODSnA retrospective study was conducted to investigate the prevalence of significant histology in a patient population with mildly elevated serum ALT levels. A total of 193 consecutive patients were selected and divided into 2 groups according to HBeAg status. Patients were further divided into cohorts on the basis of their highest ALT elevation during follow-up and whether it was 1-1.5 times the upper limit of normal (ULN), 1.5-2 times the ULN, or greater than twice the ULN. The ULN that was used is 30 U/L for men and 19 U/L for women.nnnRESULTSnIn all cohorts there was a substantial fraction of patients with histologic disease as evaluated by liver biopsy. HBeAg-negative patients were older, had lower viral load, and had a higher prevalence of disease. After adjustments for age, HBeAg status and HBV DNA viral load were not predictors of significant histology. Age >35 years, male gender, and increasing ALT levels were predictors for significant histology on multivariate analysis.nnnCONCLUSIONSnA substantial proportion of patients with mildly elevated ALT levels have significant histologic disease. The prevalence increased with the higher ALT levels and age.

High frequency of recurrent viremia after hepatitis B e antigen seroconversion and consolidation therapy.

Background: The primary treatment endpoint for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is HBeAg seroconversion; however, data on the durability of response are inconsistent. Goals: Our goal was to investigate the rate of recurrent viremia after HBeAg seroconversion and subsequent discontinuation of therapy. Methods: We retrospectively studied 88 consecutive Asian American patients who achieved HBeAg seroconversion [loss of HBeAg and development of antibody to HBeAg (anti-HBe)] among 458 HBeAg-positive patients who received oral antiviral therapy at 3 US clinics between March 1998 and November 2010. Recurrent viremia was defined as reappearance of detectable serum hepatitis B virus DNA (>100 IU/mL) on 2 consecutive laboratory tests from previously undetectable levels. Results: Antiviral medications used at the time of HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), and combination therapy (3%). Antiviral therapy was continued after HBeAg seroconversion in 49 patients (group I) and discontinued in the other 39 patients after consolidation therapy [median=12 months (range, 1 to 55 mo)] (group II). No patients in group I experienced recurrent viremia, whereas 90% in group II did. Elevated alanine aminotransferase also occurred in 38% of group II patients [median peak alanine aminotransferase 249 IU/mL (range, 93 to 1070 IU/mL)]. Conclusions: Despite consolidation therapy, almost all patients who discontinued therapy after achieving HBeAg seroconversion and complete viral suppression experienced recurrent viremia, and close to half also experienced biochemical flares. HBeAg seroconversion does not seem to be a durable treatment endpoint for many patients, and they should be monitored carefully for virologic relapse and biochemical flares if antiviral therapy is withdrawn.

Histological disease in Asian-Americans with chronic hepatitis B, high hepatitis B virus DNA, and normal alanine aminotransferase levels.

OBJECTIVES:At present there is no clear consensus on how patients with chronic hepatitis B (CHB), high serum hepatitis B virus (HBV) DNA, and normal alanine aminotransferase (NLALT) levels should be managed. This study hypothesizes that a significant proportion of such patients may have histological disease.METHODS:We carried out a retrospective study of 101 consecutive treatment-naive patients with CHB who underwent liver biopsies at a community gastroenterology clinic and had high HBV DNA and NLALT (≤40u2009U/l) levels at the time of biopsy. All patients were Asians. ALT levels were observed for a period of time before liver biopsy and were used to classify patients into two groups, namely those with only NLALT levels and those with fluctuating ALT (FLALT) levels. All patients had at least two ALT measurements during this period of time. Significant histology was defined as stage ≥2 fibrosis or stage 1 fibrosis plus grade ≥2 inflammation using the Batts–Ludwig scoring system.RESULTS:In patients with NLALT levels, the proportions of those with significant histology were 0, 22, and 45% for age ≤35, 36–50, and >50 years, respectively (n=11, n=27, n=19; P=0.033). In patients who had FLALT levels, the corresponding proportions were 22, 42, and 69% (n=9, n=22, n=13; P=0.091). After adjustments for gender, hepatitis B e antigen (HBeAg) status, and mean pre-biopsy HBV DNA levels, significant predictors of histological disease were older age (odds ratio (OR)=6.2 for age 36–50 years and OR=17.6 for age >50 years compared with age ≤35 years, P=0.041 and P=0.003, respectively) and FLALT levels (OR=3.6, P=0.008). Sub-analysis of patients with NLALT levels using lower cutoffs (30u2009U/l for men and 19u2009U/l for women) showed similar trends.CONCLUSIONS:Patients with CHB, high HBV DNA, and NLALT levels and aged more than 35 years or those with FLALT levels may have significant histological disease (22–70%).

Medication Nonadherence with Long-Term Management of Patients with Hepatitis B e antigen-Negative Chronic Hepatitis B

Background and AimsAntiviral treatment responses for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are well-defined by data from registration trials but may differ from patients seen in community settings where medical adherence is usually not as strictly monitored. The goal of this study was to examine the long-term outcomes of HBeAg-negative patients in a community clinical setting.MethodsWe performed a cohort study of 189 consecutive treatment-naïve patients with CHB who were treated with either entecavir (ETV) 0.5xa0mg daily (nxa0=xa0107) or adefovir dipivoxil (ADV) 10xa0mg daily (nxa0=xa082) from 2002 to 2009 at two community clinics.ResultsAll patients were Asians. Both ETV and ADV cohorts had similar median baseline ALT and HBV DNA levels. By year 4, a similar proportion of ETV and ADV patients who remained on monotherapy achieved complete viral suppression (91–96%); however, more patients in the ADV cohort required alternative therapy (27 vs. 5%). No patients in the ETV cohort developed resistance while 18% of the ADV cohort did. Cumulative nonadherence rates were 10 and 12% in ADV and ETV cohorts, respectively.ConclusionsFailure to monotherapy in a community clinical setting is due to both antiviral resistance and patient nonadherence. Medication nonadherence is likely to be a more important contributor to treatment failure than antiviral resistance, especially with new anti-HBV agents such as ETV and tenofovir.

Response to pegylated interferon and ribavirin in Asian American patients with Chronic hepatitis C genotypes 1 vs 2/3 vs 6.

Summary.u2002 Chronic hepatitis C is generally underappreciated in Asian Americans, and most pivotal studies were conducted in western countries and only included a small numbers of Asian patients. Our goal was to examine and compare treatment outcomes in these patients with genotypes 1 vs 2/3 vs 6. We performed a retrospective cohort study of 167 consecutive treatment‐naïve Asian American patients treated with pegylated interferon (PEG IFN) plus ribavirin (RBV) at two community clinics in Northern California from 12/00 to 1/08. Primary outcome was sustained virological response rate by intention‐to‐treat analysis. The overall completion rate was 76%, and treatment adherence (completion of ≥75–80% PEG IFNu2003+u2003RBV dose for ≥75–80% of intended duration) was 74%. Significant depression was noted in only 4% of patients. Sustained virologic response in patients with genotype 6 treated for 48u2003weeks was similar to that seen in those with genotype 2/3 (74%vs 75%, Pu2003=u20030.89) and significantly higher than those with genotype 1 (74%vs 49%, Pu2003=u20030.016). On multivariate analysis inclusive of sex, age, body mass index (≤25 vs >25) and viral load, only treatment adherence and genotype (2/3 and 6 treated for 48u2003weeks) were found to be significant predictors of sustained virologic response. We conclude that significant depression is rare in Asian American patients (4%). Patients with genotype 6 treated for 48u2003weeks appear to have a similar treatment response rate as patients with genotype 2/3 and a significantly higher response rate than those with genotype 1.

Randomized controlled trial of pegylated interferon‐alfa 2a and ribavirin in treatment‐naive chronic hepatitis C genotype 6

Hepatitis C virus (HCV) genotype is an important criteria in determining duration of therapy and predictor of sustained virologic response (SVR) to pegylated interferon (PEG IFN) and ribavirin (RBV) therapy. Optimal duration of therapy for patients with HCV genotype 6 is not known. We conducted a multicenter, open‐label randomized controlled trial of patients with HCV genotype 6 at five gastroenterology clinics in the western U.S. Patients were stratified by viral load and histologic stage and assigned to receive PEG IFN‐α2a 180 μg subcutaneously weekly and weight‐based oral RBV 800 to 1,200 mg daily for 24 or 48 weeks. Primary outcome measurement was SVR rate by intention‐to‐treat analysis. From February 2005 to October 2007 a total of 60 patients (age 51 ± 10 years, 47% male, log HCVRNA 6.3 ± 1.1 IU/mL) were enrolled: 27 patients to 24 weeks and 33 patients to 48 weeks of therapy. In the 24‐week and 48‐week groups, 96% and 97% achieved early virologic response (P = 0.90); 89% versus 94% achieved end of therapy virologic response (P = 0.48). SVR was achieved in 70% versus 79% of patients assigned to 24 weeks versus 48 weeks (P = 0.45). Rapid virologic response (RVR) was a significant predictor of SVR in the 48‐week group and trending towards significance in the 24‐week group: 82% and 83% of those with RVR achieved SVR versus 33% and 29% for the 24‐week and 48‐week groups, respectively (P = 0.07 and P = 0.02). Conclusion: There was no significant difference in SVR rates in patients with HCV genotype 6 treated with PEG IFN‐α2a and RBV for 24 versus 48 weeks. (HEPATOLOGY 2010;52:1573‐1580)

Adherence to Screening for Hepatocellular Carcinoma Among Patients with Cirrhosis or Chronic Hepatitis B in a Community Setting

BackgroundScreening for hepatocellular carcinoma (HCC) has been shown to improve survival via earlier cancer detection. Although HCC screening is considered standard of care in the USA, little is known of the adherence to this practice, especially in a community setting.AimsOur primary goal was to evaluate adherence to HCC screening and to find predictors of screening adherence in a community setting. Our secondary objective was to determine the impact of screening on survival.MethodsWe studied a cohort of 557 consecutive patients at high risk for HCC: patients with cirrhosis and older chronic hepatitisxa0B (CHB) patients without cirrhosis (≥45xa0years old). Patients initiated screening 1/2001–1/2005 and were monitored ≥12xa0months to 12/2008 in two community gastroenterology clinics in Northern California. HCC screening was categorized into four groups based on combined frequency of serum alpha-fetoprotein and imaging: optimal, suboptimal, poor, and no screening.ResultsAbout 40.6% of our cohort received poor or no screening. Noncirrhotic CHB patients had worse screening than cirrhotic patients. Multivariate analysis revealed that patients with a greater number of clinical visits per year were 3.4 times more likely to have regular screening than patients with fewer clinical visits per year (Pxa0<xa00.001). There was a trend for association between HCC screening and greater access to curative treatment.ConclusionSince more frequent clinic visits is a strong independent predictor of improved screening adherence, regular routine clinic visits may help improve adherence to HCC screening, which may also lead to improved clinical outcomes.

Risk factors, genotype 6 prevalence, and clinical characteristics of chronic hepatitis C in Southeast Asian Americans.

PurposeAlthough infection with hepatitis C virus (HCV) affects 32 million individuals from Southeast Asia, little is known about the mode of HCV acquisition and the epidemiology of chronic hepatitis C (CHC) in these individuals. Our goal was to examine risk factors for HCV acquisition, prevalence, and clinical characteristics of HCV genotype 6 compared with genotypes 1 and 2/3 in Southeast Asian (SEA) patients.MethodsWe performed a cross-sectional study of 308 consecutive SEA Americans with CHC evaluated by five gastroenterologists from January 2000 to December 2008 at two community clinics in northern California via medical record review, using a case report form.ResultsA significant proportion of patients (41%) could not recall any specific risk factors for HCV acquisition. The most commonly reported risk factor in patients who reported at least one risk factor was history of surgeries (34%), followed by blood transfusion (25%) and acupuncture (13%). Among patients with core sequence testing for HCV genotype (nxa0=xa0181), the most common HCV genotypes were genotype 1 (42%) and genotype 6 (41%), followed by genotype 2/3 (17%). There were no major differences in the clinical and virological characteristics between the different genotype groups (1 vs. 2/3 vs. 6).ConclusionHCV genotype 6 is as common as genotype 1 in SEAs. Commonly known risk factors for HCV acquisition were not readily identifiable in a large proportion of SEA Americans (41%) and may not be useful in identifying at-risk individuals for HCV screening in this population.

Similar treatment response to peginterferon and ribavirin in Asian and Caucasian patients with chronic hepatitis C.

OBJECTIVES:Previous studies have found ethnicity to be an important predictor of outcomes of treatment with peginterferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C. Although the expected sustained virological response (SVR) rates of Hispanics and African Americans are lower than those of Caucasians, SVR rates in Asians appear to be more favorable. However, in some of these studies, hepatitis C virus (HCV) genotype was identified by INNO-LiPA assay, which can mistype the easier-to-treat HCV genotype 6 as genotype 1. Our goal was to compare SVR rates among Caucasian and Asian-American patients with genotype 1 and 2/3 infection whose HCV genotypes were accurately classified by core sequencing testing.METHODS:A cohort of 269 consecutive treatment-naive HCV-infected patients with genotype 1 or 2/3 (157 Caucasians and 112 Asians) treated with PEG-IFN+RBV from January 2001 to November 2007 at four community-based gastroenterology clinics in Northern California were studied. The analysis of data was by intention-to-treat.RESULTS:The SVR rates for patients with genotype 1 were 45% for Caucasians and 52% for Asians (P=0.37). The SVR rates for patients with genotype 2/3 infection was 77% for Asians and 74% for Caucasians (P=0.7). On multivariate logistic regression analyses adjusting for age, alanine aminotransferase (ALT), baseline viral load, HCV genotype, and treatment adherence, we did not find Asian ethnicity to predict SVR. On a separate analysis, we found that Asians who had HCV genotype 1 or 1b by the less accurate INNO-LiPA assay had significantly higher SVR rates than Caucasians with genotype 1 (64% vs. 45%, respectively, P=0.03).CONCLUSIONS:SVR rates were similar in Asian Americans and Caucasians infected with HCV genotype 1 or 2/3 when HCV genotype classification was accurately determined.