Huy A. 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.)

Influence of psychiatric diagnoses on interferon-α treatment for chronic hepatitis C in a veteran population

OBJECTIVE:The prevalence of psychiatric problems and substance abuse is high in the veteran population with hepatitis C. The purpose of this study was to retrospectively analyze the effect of preexisting psychiatric conditions in veteran patients undergoing treatment with interferon α-2b (IFN-α) with respect to adverse events, compliance, and treatment response.METHODS:Thirty-three veterans with chronic hepatitis C were treated with IFN-α (5 million units three times weekly) for 6 months, followed by a tapering dose for an additional 6 months. All patients fulfilled standard criteria for treatment eligibility. Psychiatric diagnoses, adverse events, and virological and biochemical responses to therapy were determined.RESULTS:Nineteen of 33 (58%) patients with hepatitis C had documented psychiatric conditions before starting IFN-α therapy. Of the patients with preexisting psychiatric diagnoses, 13/19 (68%) developed major adverse events requiring intervention or discontinuation of therapy. In contrast, 4/14 (29%) patients without psychiatric diagnoses developed major adverse events (p = 0.024) In the psychiatric group, 6/19 (32%) developed major neuropsychiatric side effects compared with 2/14 patients (14%) in the nonpsychiatric group (p = 0.25). Patients with and without psychiatric diagnoses had equivalent biochemical and virological responses to therapy. Overall, only 2/33 (6%) patients had a sustained virological response.CONCLUSIONS:Veterans with chronic hepatitis C and psychiatric diagnoses experienced a significantly greater number of major adverse events during treatment with IFN-α. Veteran patients with hepatitis C should be carefully screened for psychiatric conditions and may require more intensive monitoring during IFN-α therapy.

Spectrum of disease in U.S. veteran patients with hepatitis C

OBJECTIVE:Hepatitis C virus (HCV) infection is more prevalent in U.S. veterans attending Veterans Affairs Medical Centers than in the general population. The purpose of this study was to examine the risk factors, psychiatric and substance abuse conditions, and severity of liver disease in veterans with HCV.METHODS:The medical records and liver biopsies of 206 consecutive patients with HCV attending a multidisciplinary medical/psychiatric chronic hepatitis clinic and who met eligibility criteria for interferon α-2b therapy were reviewed.RESULTS:The mean age was 46.5 ± 6.8 yr and 77% were Vietnam-era veterans. Risk factors included i.v. drug use (64%), blood transfusion (15%), and cocaine use (9%), and were unknown in 12%. The average estimated duration of disease was 24 ± 7.6 yr. A history of alcohol abuse or dependence was identified in 80% of patients. Psychiatric illnesses were present in 60%, the most common being depression and posttraumatic stress disorder. Overall, 89% of patients had documented psychiatric and/or substance abuse diagnoses. Severe fibrosis (stages 3–4) was present in 32% and severe inflammation (grades 2–3) was present in 71% of biopsies. Psychiatric and substance abuse diagnoses did not correlate with severity of liver disease. A total of 145 patients (71%) were prescribed interferon-based treatment. The overall virological sustained response rates were 16% after interferon monotherapy and 28% after interferon/ribavirin therapy. Reasons for not receiving interferon therapy included minimal fibrosis on liver biopsy (37 patients [18%]), worsening medical conditions (nine [4%]), and worsening psychiatric and substance abuse problems (14 [7%]).CONCLUSIONS:Advanced fibrosis is common in this cohort of veteran patients with chronic hepatitis C, and the overwhelming majority of these patients have psychiatric and/or substance abuse diagnoses. Despite these comorbidities, the majority received interferon therapies in the context of a multidisciplinary clinic. These data emphasize the importance of hepatitis C care that includes linkage of medical care and psychiatric services.

Application of Data Mining to Network Intrusion Detection: Classifier Selection Model

As network attacks have increased in number and severity over the past few years, intrusion detection system (IDS) is increasingly becoming a critical component to secure the network. Due to large volumes of security audit data as well as complex and dynamic properties of intrusion behaviors, optimizing performance of IDS becomes an important open problem that is receiving more and more attention from the research community. The uncertainty to explore if certain algorithms perform better for certain attack classes constitutes the motivation for the reported herein. In this paper, we evaluate performance of a comprehensive set of classifier algorithms using KDD99 dataset. Based on evaluation results, best algorithms for each attack category is chosen and two classifier algorithm selection models are proposed. The simulation result comparison indicates that noticeable performance improvement and real-time intrusion detection can be achieved as we apply the proposed models to detect different kinds of network attacks.

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

BACKGROUND & AIMS Serum 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. METHODS A 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. RESULTS In 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. CONCLUSIONS A 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 (≤40 U/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 (30 U/l for men and 19 U/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%).

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

Summary.  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 IFN + RBV 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 48 weeks was similar to that seen in those with genotype 2/3 (74%vs 75%, P = 0.89) and significantly higher than those with genotype 1 (74%vs 49%, P = 0.016). 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 48 weeks) 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 48 weeks 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)

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.