936. Predictors Of Significant Histological Findings In Chronic Hepatitis B Patients With Persistently Normal ALT Levels

H. Gu; Q. Xie; H. Wang; Z. Lin; W. Cai; X. Zhou; H. Yu; Q. Guo

 

Background and Aim

Current guidelines recommend antiviral therapy for chronic hepatitis B (CHB) patients with elevated ALT and high viral load. Little histological data exists for CHB patients with persistently normal ALT levels (PNAL) and low viral load since disease progression is thought to be rare. The aim of the study is to find the predictors of significant histological findings (significant necroinflammation with a score of HAI 4 or greater and/or significant fibrosis Ishak's staged at 3 or greater) in such patients.

 

Methods

The study of all patients with CHB who underwent percutaneous liver biopsy and who had detectable viral load (Taqman Real Time PCR, lower limit of detection is 103copies/ml) was performed. 139 patients who had PNAL (defined as normal ALT measured on at least 3 occasions in the intervals of more than two months over a period of 12 or more months apart prior to biopsy) were identified (group A). These patients were compared with 135 patients with abnormal ALT during the same period and who had no prior antiviral treatment. The comparisons included age, ALT, viral load, HBeAg status, and histological finding.

 

Results

The ALT values of all 139 patients with PNAL had been normal from one year to thirty years, and the median was six years. Even though 66 (47.5%) patients with PNAL had normal liver histology, 33 (23.7%) patients were found to have significant histological findings, even 13 (9.4%) had established cirrhosis. When compared to patients within 0-0.75 × ULN ALT, patients within 0.75-1 × ULN ALT had higher rate of significant histological findings (43.5% vs. 19.8%, p=0.029). In the subgroup of patients with PNAL, significant histological findings increased sharply after the age of 40 yrs as seen in other cohorts (p=0.005). However, the subgroup of patients with PNAL and significant histological findings was not identified by viral load or HBeAg status.

 

Conclusions

We found 23.7% of CHB patients with PNAL regardless of HBeAg status or viral load levels had significant histological findings including inflammation and fibrosis. Liver biopsy should be considered in CHB patients with PNAL and detectable viral load, even LVL, especially in those older than age 40 years and higher ALT within 0.75-1 × ULN.

 


937. Treatment-induced HBeAg Seroconversion Is a Poor Therapeutic Endpoint

A. Myat Oo; S. Lim; S. Wasser

 

HBeAg seroconversion is considered a key therapeutic endpoint of chronic hepatitis B treatment, but its effectiveness as an endpoint is compromised by HBeAg negative reactivation and its durability, consequently we sought to examine these events in patients with well documented spontaneous or treatment induced HBeAg seroconversion.

 

Methods

All patients with documented HBeAg seroconversion were followed prospectively at 3-6monthly intervals. Persistent reactivation was defined as ALT> ULN, for >2 time points, with detectable HBV DNA. Seroreversion was defined as return of HBeAg with or without loss of anti-HBe, after loss of HBeAg and development of anti-HBe. The outcome events of reactivation and seroreversion were compared in spontaneous and treatment induced seroconversion using Kaplan-Meier survival analysis and Cox Regression. Data is presented as median (range).

 

Results

There were 298 patients with documented seroconversion, of which 116 patients were treatment-induced and 182 were spontaneous. The patients were mainly male (71.81%), with age of 34.81 (68.7) years, with follow up duration of 39.29 (188.03) months post-seroconversion. Persistent reactivation occurred in 71 patients (Cumulative proportion=39.27%), with older age (P=0.001), male gender (P=0.002), higher ALT at seroconversion (P=0.006) being more likely to develop reactivation. No significant difference rate of reactivation was observed among different treatment groups (IFN, lamivudine and adefovir) (P=0.598).

 

Treatment-induced seroconversion was less robust and remission of ALT was of shorter duration than spontaneous seroconverters (median 14.13 months versus 22.44 months, P=0.037). They were also more likely to develop HBeAg negative reactivation at 48 months (37.76% versus 24.96%, P= 0.0482). Treatment responders are more likely to develop reactivation after adjusting for age, gender and ALT with Cox regression (Adjusted cumulative proportion 48.5% versus 34.0% at 96 months, P=0.045). HBeAg reversion occurred in 39 patients (19.64%). Again, treatment induced seroconverters are more likely to get HBeAg reversion than spontaneous seroconverters: 24.09% versus 11.29% at 48 months (P=0.0094). After adjusting for age, gender, and ALT at seroconversion by Cox regression, the difference is consistent (P=0.010).

 

Conclusion

The effectiveness of treatment induced seroconversion is significantly worse than that of spontaneous seroconverters with significantly higher and faster HBeAg negative reactivation rate with less durable seroconversion over time. Treatment induced seroconversion may not be a good therapeutic endpoint in the treatment of chronic hepatitis B.

 


942. A High Prevalence of Significant Liver Disease in Asymptomatic Hepatitis B Patients with High Viral Load; Candidates for Antiviral Therapy

J. Park; Y. Park; D. Kim; Y. Paik; K. Lee; B. Moon; K. Han; C. Chon; Y. Moon; S. Ahn

 

Background and Aim

Current treatment guidelines recommend that antiviral therapy should be considered in chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite ALT levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels.

 

Methods

Between January 2003 and June 2006, all consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, expressed HBsAg for at least 6 months, and had detectable serum HBV DNA on a direct hybridization assay, and normal or slightly elevated serum ALT levels (≤ 2×ULN) for 12 months were included in this study. One hundred and five patients were enrolled. Serum ALT levels were tested in at least three consecutive samples within a 12-month period, and all values were less than two times normal. Histological assessment was based on the METAVIR classification (significant histology was defined as ≥ grade A2 or ≥ stage F2).

 

Results

All 105 patients had HBV DNA titers above 105 copies/mL. The mean (± SD) ALT level at biopsy was 42 ± 19 (range, 8-75) and the mean age was 37 ± 14 years (range, 18-68). 36 patients had persistently normal ALT levels. Significant fibrosis was observed in 63 patients (60.0%) and significant histology was found in 69 patients (65.7%). On multivariate analysis, the serum ALT levels and age at study entry were independent meaningful factors associated with significant histology. Compared to the lowest ALT levels (< 0.5× ULN), 0.5-1× ULN, 1-1.5× ULN and 1.5-2× ULN had odds ratios (95% CI) for significant histology of 1.1 (0.2-5.1), 3.9 (0.7-21.6) and 8.0 (1.1-60.5), respectively. Compared to patients younger than 20 years, the odds ratios for patients in their 20s, 30s, 40s, and over 50 years old were 7.1 (1.4–36.9), 14.2 (2.1–94.2), 24.4 (4.2–141.3), and 38.8 (4.0–309.8), respectively.

 

Conclusion

A large proportion of CHB patients with high viral load and ALT two times or less than the ULN had significant liver disease on liver biopsy. Our findings warrant a more accurate evaluation in a practical setting and, if confirmed, would have a great impact on future treatment approaches for patients awaiting potential antiviral therapy.

 


944. Oncologists and Hepatitis B: Results of a Questionnaire Survey to Determine Their Current Level of Awareness and Clinical Practice of Antiviral Prophylaxis to Prevent Reactivation

J. H. Lewis; A. Farhadi; O. S. Khokhar; L. H. McGrail

 

The risk of chronic hepatitis B virus (CHBV) reactivation under the influence of chemotherapy or other immuno-suppression is being increasingly recognized. However, many oncologists either have not observed this complication, and/or are not aware of current recommendations for Hep B prophylaxis.

 

Methods

In an effort to determine the degree of awareness of the potential reactivation risk and to understand the current practice of screening and prevention among oncologists, we prepared a questionaire that was administered to 131 Hematology-Oncology physicians in the Washington, DC area during March and April 2007. Questions related to their awareness of the risk of hepatitis B reactivation, screening patients for HBV, awareness of preventative treatment for HBV and how they would administer prophylaxis and follow their patients.

 

Results

Responses to 10 questions are as follows:

1) Are you aware that reactivation of HBV can occur: Yes 78%; No 22%.

2) Are you aware that prophylactic antiviral therapy is available: Yes 56%; No 44%.

3) Have you ever seen reactivation of HBV in your practice: Yes 30%; No 70%.

4) Do you screen for HBV prior to chemotherapy: Yes 38% (86% use selective criteria vs. 14% use universal screening); No 62%.

5) Which patients would you prophylax: chronic carrier 46%; active HBV 76%; resolved HBV infection 52%.

6) Which antiviral would you give: lamivudine 46%; adefovir 14%; not sure 48%.

7) How often would you monitor: q2wk 4%; q4wk 18%; q6wk 14%; q8wk 16%; q12wk 12%; not sure 36%.

8) How long would you continue prophylaxis after completing chemotherapy: 1 mo. 8%; 2 mo. 15%; 3 mo. 71%; 4 mo. 8%.

9) Would you monitor for reactivation even if you did not give prophylaxis: Yes 66%; No 6%; Not sure 28%.

10) Would you want a gastroenterologist or hepatologist to follow the patient with you: Yes 88%; No 12%.

 

Discussion

While most oncologists are aware of the potential risk of HBV reactivation, only 30% have ever seen a reactivation and most are not screening pts for HBV prior to chemotherapy. Fewer than half of our respondents were aware that prophylactic antiviral agents are available , and even fewer were aware that prophylaxis has been shown to reduce HBV flares, and most were not sure what agent to select. A majority would , however, seek the recommendations of a gastroenterologist or hepatologist and most felt that prophylactic treatment should continue for at least 3 months after chemotherapy was completed.

 

Conclusion

Improving awareness of HBV reactivation and antiviral prophylaxis in the Oncology community appears warranted.

 


945. Pre-emptive Lamivudine Reduces the Risk of Chemotherapy-Induced HBV-Related Morbidity and Mortality in HBsAg-Positive Cancer Patients: Meta-analysis

R. Loomba; A. Rowley; R. Wesley; T. Liang; J. H. Hoofnagle; F. Pucino; G. Csako

 

Background

Lamivudine (LAM) has been used for preventing HBV-reactivation in hepatitis B surface antigen (HBsAg)-positive cancer patients undergoing chemotherapy but its beneficial effects have not been assessed quantitatively.

 

Purpose

To estimate the degree of beneficial effect of pre-emptive LAM in reducing chemotherapy-induced HBV-related morbidity and mortality in HBsAg-positive cancer patients.

 

Methods

Databases searched (until February 2007) included Medline, Ovid, Toxnet, Scopus, and Web of Science. Studies with data suitable for risk estimation of cancer chemotherapy-induced HBV reactivation in HBsAg-positive patients receiving pre-emptive LAM vs. controls that met the pre-specified criteria on outcomes and sample size. 2 investigators independently performed the literature search and data extraction, and 2 different investigators independently reviewed whether the studies met pre-specified criteria. A two-tailed p-value <0.05 was considered statistically significant. Comprehensive Meta-Analysis Software was used for the analysis.

 

Results

Twelve studies met predefined criteria (2 RCT, 6 prospective, and 4 retrospective cohort studies). Of 12 trials in the meta-analysis, 10 were conducted in East Asia, and one each in Turkey and Israel. All studies were in English except for one in Chinese. 214 patients received pre-emptive LAM, and 399 patients served as controls receiving either no (3 studies) or deferred LAM (9 studies). The log odds ratios demonstrating risk reduction with pre-emptive LAM vs. no pre-emptive LAM in HBsAg- positive individuals undergoing cancer chemotherapy was 0.06 (95% confidence interval [CI], 0.03-0.13) for HBV reactivation, 0.07 (95% CI, 0.04-0.14) for HBV-related hepatitis, 0.20 (95% CI, 0.06-0.64) for liver failure, and 0.21 (95% CI, 0.08-0.58) for mortality. Combining results from all the studies indicated that HBV reactivation was decreased from 35.6% to 2.8% (p<0.0001) with pre-emptive LAM therapy, while HBV-related hepatitis was decreased from 32.3% to 2.8% (p < 0.0001), HBV-related liver failure from 5.7% to 0.5 % (p = 0.0002) and HBV-related mortality from 7.0% to 0.5 % (p < 0.0001). Based upon this analysis, 1 death can be prevented by treating 15 patients with pre-emptive LAM in this clinical setting.

 

Limitations: Small studies; only two involved a randomized-controlled design.

 

Discussion

This meta-analysis demonstrated that pre-emptive LAM reduces the risk of HBV-reactivation, HBV-related hepatitis, HBV-related acute liver failure, and HBV-related mortality by 16, 14, 5, and 5-fold, respectively.

 

Conclusions

HBsAg-positive patients undergoing cancer-chemotherapy warrant pre-emptive therapy with LAM.

 


968.Estimating the Impact of Chronic Hepatitis B on Future Liver-related Morbility, Mortality and Cost in Spain

M. Buti; M. Brosa; M. A. Casado; M. Rueda; R. Esteban

 

Background and Aims

Chronic hepatitis B (CHB) is a common infection often producing progressive disease. Some studies suggest that HBV-related complications will increase in the future, impacting future disease costs. Our aim was to estimate future morbidity, mortality and costs associated with CHB infection in a cohort of patients in Spain.

 

Methods

A Markov model was used to project HBV-related complications and costs over the next 20 years in a cohort of 132,028 patients representing the HBV-infected population in Spain. This cohort was stratified according to age (25-34, 35-44, 45-54, 55-64, 65-74 years), HBeAg status (13% HBeAg-positive and 87% HBeAg-negative), and the degree of liver disease. The probabilities of disease progression in the model were obtained from data published in the literature, and the cost of the disease and its complications were based on actual variable costs from the Spanish Health Care System. An annual 3.5% discount rate was applied to the costs.

 

Results

A greater disease progression and morbidity will be observed in HBeAg-negative patients compared with HBeAg-positive patients, with a higher proportion of HBeAg-negative patients requiring liver transplant (9% vs. 5%) and a higher proportion of deaths (59% vs. 45%). The total cost of the HBV-infected cohort during the next 20 years will be US$5,007 million. The disease progression in HBeAg-negative patients requires an additional cost of 65% in relation to HBeAg-positive patients. The mean estimated cost in US$ per patient and the different stage of the disease distribution over the next 20 years are shown in the table below.

 

Conclusions

In the future, HBV mortality, morbidity, and associated cost will increase. Treatment of the CHB-infected population potentially may control the infection, reduce progression, increase patient survival and reduce the need for liver transplantation.

 

 

HBeAg+

HBeAg-

Total

 

Cost per patient (%)

Patients (%)

Cost per patient (%)

Patients (%)

Cost per patient (%)

Patients (%)

CHB

$1,485 (5)

20,224 (45)

$1,664 (4)

19,606 (22)

$1,604 (4)

39,830 (30)

Cirrhosis

$636 (2)

1,457 (3)

$1,195 (3)

6,203 (7)

$1,006 (3)

7,661 (6)

Decompensated Cirrhosis

$341 (1)

323 (1)

$674 (2)

1,290 (1)

$561 (1)

1,613 (1)

Hepatocellular Carcinoma

$1,395 (5)

180 (1)

$1,917 (4)

699 (1)

$1,740 (5)

879 (1)

Liver Transplant

$22,430 (81)

2,416 (5)

$35,882 (83)

7,993 (9)

$31,336 (83)

10,409 (8)

Death

$1,236 (4)

20,012 (45)

$1,900 (4)

51,624 (59)

$1,676 (4)

71,636 (54)

Total

$27,523 (100)

44,613 (100)

$43,231 (100)

87,415 (100)

$37,923 (100)

132,028 (100)

 


971. Predictors of Liver Decompensation in HBeAg–negative Patients with Chronic Hepatitis B

Y. Benhamo1; Y. Ngo; R. Morra; V. Ratziu; V. Thibault; T. Poynard

 

Objective

To determine factors affecting liver decompensation in patients with chronic hepatitis B.

 

Methods

Predictors of liver decompensation (ascitis, liver insufficiency, encephalopathy, gastro-intestinal bleeding) were retrospectively evaluated in a cohort of 336 HBeAg- patients referred to the Hepatology Departement of Pitié Salpêtrière Hospital (Paris France) since 1980. Patients co-infected with HIV, HDV and HCV were excluded. Age, race, oral anti-HBV therapy (lamivudine, adefovir, tenofovir, entecavir), IFN based therapy, baseline ALT and serum HBV DNA were analyzed using Kaplan Meyer (KM) survival curves. A Cox regression analysis was performed to assess independent predictors of liver decompensation.

 

Results

Main baseline characteristics of included patients are summarized in the table. Age, sex, race, oral anti HBV therapy, serum ALT, serum HBV DNA were significantly associated with liver decompensation in univariate analysis. Age (>35 years, RR 25.72 (3.08-214.80), p= 0.003) and high baseline serum HBVDNA (>6 log copies/mL, RR 11.97 (2.75-52.13), p<0.001) remained independently associated with the risk of liver decompensation in the Cox analysis (n=252).

 

Conclusion

High HBV DNA (> 6 log copies/mL) and age older than 35 years strongly predict the risk of liver decompensation in HBeAg- patients. These patients should be actively considered for anti-HBV therapy independently of serum ALT level.

This study was supported by IDENIX PHARMACEUTICAL

 

Main baseline characteristics in HBeAg- (n=336)

Median (95 CI) follow up (months)

68.37 (61.42-72.52)

Mean (95% CI) Age (years)

38.12 (36.74-38.49)

Male (%)

237 (70.54)

Race

- African n (%)

- Asian n (%)

- Cocasian n (%)

180 (53.57)

87 (25.89)

69 (20.54)

Alcool consumption ≥50 g/day n (%)

16 (4.88)

Median (95% CI) ALT (UI/L)

ALT ≥2 x ULN*

34 (31-38)

90 (26.79)

HBV DNA n (%)

- ≥6 log copies/mL

- 4≤ <6 log copies/mL

- <4 log copies/mL

- Undetermined

25 (7.44)

99 (29.46)

128 (38.10)

80 (23.81)

Anti HBV therapy

- IFN based n (%)

- Oral n (%)

- Untreated

20 (5.95)

214 (63.69)

118 (35.12)

HBsAg seroconversion n (%)

4 (1.83)

Liver decompensation n (%)

41 (12.20)

ULN time the upper limit of normal

 


1474. Barriers to Viral Hepatitis Treatment for At-Risk Groups: Impacts of Policies and Processes

A. B. Jessop; M. Burke

 

Background

Hepatitis B and C viruses infect an estimated 4-5 million Americans. We know that much morbidity and mortality can be prevented through awareness, preventive behaviors, and treatment. Unfortunately, population groups most impacted by hepatitis C (racial and ethnic minorities, people with drug, alcohol, and incarceration histories) are typically least able to negotiate the policy and healthcare systems in order to receive optimum care. This project examined barriers to hepatitis C prevention, diagnosis, and especially treatment for at-risk population groups in the Philadelphia, PA region.

 

Methods

Methods of data collection included key informant interviews, extensive literature review, and focus group and individual interviews. Target groups included current or former substance users, currently or formerly incarcerated individuals, MSM, HIV infected adults, and African American, Hispanic, and Asian men and women ages 18-40. Analysis was iterative and inductive. We generated general themes or categories of barriers, identified consensus in the three sources, examined the context of the barriers for our target populations, and identified potential means to overcome barriers.

 

Results

Three barrier categories were identified: Structural Barriers, Social/ Community Barriers, and Individual Barriers. Barriers from one category frequently overlapped, exacerbated or created barriers within other categories. We present actions or changes that could be implemented within medical communities, government agencies, insurance providers, and community agencies to remove or alleviate barriers to hepatitis care.

 

Conclusions

Most barriers can be addressed through policy and procedure changes. Others can be addressed through carefully designed awareness and education programs for medical providers, social service agency personnel, hepatitis patients and the general public.