Cost of Treatment

 

#1003. Modeling for the Most Cost-Effective Treatment Strategy for HBeAg Positive Chronic Hepatitis B

Y. Dan; C. Wai; S. Lim

 

Pegylated interferon and entecavir are two of the newest drugs to be licensed for treatment of chronic hepatitis B (CHB), joining an array of treatment options available. However, choosing the optimal strategy for treatment of CHB is complicated by many factors including cost, resistance in nucleose/nucleote analogs and age of the patient. We performed a cost effectiveness analysis using a Markov model based on population perspective to determine the most ideal treatment strategy.

 

Methodology:

The following treatment strategies were compared over a 5-year perspective: 1) No treatment; 2)Lamivudine with salvage therapy by adefovir/ entecavir; 3) Adefovir with salvage therapy by entecavir; 4) entecavir first line monotherapy; 5) interferon with lamivdudine for non-responders; 6)Pegylated interferon with lamivudine/ adefovir/ entecavir for non-responders; 7) Pegylated interferon monotherapy. Additional cost incurred for progression to cirrhosis and death, seroconversion, resistance and disease progression rates were obtained from published literature and projection performed using computer algorithm where 5-year data was not available. End point indicis were cost per seroconversion and incremental cost per Quality adjusted life years (ICER) saved.

 

Results:

Over 5 years, entecavir was the cheapest most cost-efficient strategy with incremental $898 for every additional seroconversion, incremental USD11 500 for every HCC prevented and USD2200 for every decompensated cirrhosis prevented. Pegylated interferon regimens, though highly effective (56% seroconversion at 5 years) was offset by their high cost (USD26K per patient). If pegylated interferon cost can be halved (24 weeks treatment) while maintaining similar efficacy, it becomes cost-effective over 10 years with ICER < USD50 000. Using incremental cost per QALY, entecavir was the most cost-effective with ICER of USD5842/QALY saved. Lamivudine with adefovir/ entecavir salvage had an ICER of USD9268 compared to no treatment. Cost-effectiveness was most sensitive to incidence of cirrhosis and liver cancer.

 

Discussion:

Entecavir is the most cost effective strategy for HBeAg positive patients over a 5-year perspective with its higher cost being offset by decreased progression of disease although long term efficacy and low resistance rate remains unproven. Projection over longer time spans improves the cost-effectiveness of pegylated interferon regimen suggesting possible role in younger population.

 

Who Is Infected and Needs Treatment?

 

#1006. Chronic Hepatitis B Virus Infection: Disease Characteristics in a Managed Care Population, 1995-2004

S. R. Bialek; H. Wang; B. P. Bell; N. A. Terrault; M. M. Manos

 

Management of chronic hepatitis B virus (HBV) infection continues to evolve, as new antivirals are developed and benefits of long-term control of viral replication are documented. The magnitude of the patient population with chronic infection appropriate for therapy is unknown, as population-based studies are lacking. We examined characteristics of chronic HBV infections in an ethnically diverse, managed care patient population in northern California.

 

Methods:

Electronic medical records of all enrollees >18 years of age were reviewed to identify those with chronic HBV infection (positive hepatitis B surface antigen (HBsAg) test or diagnosis of chronic hepatitis B) as of December 2002. Data were abstracted from electronic medical records during 1995-2004. Analysis of diagnostic work-up and treatment was limited to the patients diagnosed prior to 2002 and enrolled in the health plan through 2004 (follow-up subgroup).

 

Results:

Of 2,315,526 adult enrollees, 9,362 (0.4%) had chronic HBV infection. Of these, 4,723 (50.5%) were male and 4,926 (52.6%) were aged 18-44 years. Based on preferred language, 2,249 (24.5%) were Asian. 220 (2.4%) were co-infected with HIV and 268 (2.9%) with hepatitis C virus. A total of 52 (0.6%) had hepatocellular carcinoma (HCC) and 262 (2.8%) had decompensated cirrhosis. A total of 510 (5.5%) underwent liver biopsy. AFP screening was conducted at least once in 4,309 (47.6%) of the 9,507 with >12 months follow-up, including 1582 (57.3%) patients > 50 years old. Of the 5,952 adults in the follow-up subgroup, 2,832 (49.9%) of 5,713 tested had elevated liver enzymes (1 or more times). Compared to those with normal enzymes, patients with elevated liver tests more frequently had HCC (0.8% vs 0.07%, p<0.0001) and decompensated cirrhosis (6.0% vs. 0.4%, p<0.0001). Evaluation of those with elevated liver enzymes included HBV DNA testing in 46.5%, HBeAg in 71.9% and liver biopsy in 11.8%. Of 741 patients with elevated liver enzymes and detectable HBV DNA, of whom 42.1% were HBeAg-positive and 52.5% were HBeAg-negative, 339 (45.6%) were treated (61% of those HBeAg-positive and 37% of those HBeAg-negative).

 

Conclusions:

In this diverse population, a wide spectrum of clinical manifestations of chronic HBV infection were identified through routine clinical care. Serious sequelae were apparent in only 3%. Approximately half of those with chronic infection had elevated liver enzymes. Among those with elevated liver enzymes and HBV DNA, HBeAg-positive and HBeAg-negative chronic HBV were nearly equally prevalent. These results highlight the large number of patients with chronic HBV who may be potential candidates for future therapy.

 

#1018. Clinical Characteristics of Asian-Americans Infected with Hepatitis B Diagnosed by Community-Based Screenings in New York City

H. Pollack; A. Sherman; T. Tsang; K. Wan; H. Lupatkin; G. Villaneuva; A. Tso; T. Angela; P. Michael; K. Pearl; R. Ruchel; M. Rey; H. Tobias

 

Relatively little has been reported on the characteristics of persons identified as HBsAg+ at community-based screening events, a group that probably better reflects the burden of disease within the community at large than patients followed in hepatology clinical practices. We reported in 2005 on the results of screening more than 1800 Asian Americans in NYC for hepatitis B infection at no cost or low cost for HBV by the Asian American Hepatitis B Program (AAHBP). In this study, we describe the clinical characteristics of the 255 HBsAg+ persons who had complete clinical and laboratory data at the time of this analysis: 72.5% were male. Ages ranged between 19 and 74 years, with a mean of 37.7 years. Approximately 80% were Chinese and 16% Korean, one-third had lived in the U.S. <5 yrs and 75% were uninsured. A total of 26.7% were HBeAg+ and 70% were HBeAb+. ALT levels ranged from 7 to 647, with a mean of 45.3. The mean VL was 2.1 X 108 copies/ml. Viral loads were undetectable in 28.6%, < 104 in 25.9%, between 104 and 105 in 12.2%, and greater than 105 in one third. Of those with viral loads > 105, 9.4% had ALT >2X ULN. Genotypes, of those tested, were evenly dived between B and C.

 

Conclusion:

In conclusion, among HBsAg+ persons diagnosed at large community-based screenings almost 75% had active infection (HBV viremic), of whom almost half are at a high risk for developing hepatocellular carcinoma. Approximately 10% met treatment criteria as per current AASLD

guidelines. This information should be valuable in estimating the burden of HBV-related disease and projecting the long-term morbidity and cost of care among those infected within this population.

 

Pegylated Interferon

 

#970. Significant Reduction of HBsAg in the Sera of HBeAg-Negative Chronic Hepatitis B Patients Treated with Peginterferon Alfa-2a Alone or in Combination with Lamivudine

M. Brunetto; F. Bonino; F. Moriconi; M. Patrick; L. K. George; F. Patrizia; C. Yurdaydin; T. Piratvisuth; K. Luo; Y. Wang; S. Hadziyannis; E. Wolf; P. Matei

 

Background:

The ultimate goal of therapy in chronic HBV infection is the achievement of hepatitis B surface antigen (HBsAg) seroconversion, an entical state to that achieved effectively after self-limited acute infection and leading to prolonged survival. In a recent multinational trial, loss of HBsAg was reported in patients treated with peginterferon alfa-2a (40KD) alone or in combination with lamivudine (LAM), but not with LAM monotherapy.

 

Objectives:

To quantify the reduction of HBsAg upon treatment with peginterferon alfa-2a alone, ± LAM or LAM alone.

 

Methods:

We measured serum HBsAg pre-treatment, at the end of treatment (week 48) and 24 weeks post-treatment (week 72), using the Architect HBsAg assay (Abbott Lab) in a subset (386 of 537) of HBeAg-negative patients treated with 180mcg peginterferon alfa-2a once-weekly (qw) plus placebo daily (n=127), 180mcg peginterferon alfa-2a + 100mg LAM qd (n=137), or 100mg LAM qd (n=122).

 

Results:

In peginterferon alfa-2a groups 10 (4%) patients lost HBsAg at 72 weeks – 6 monotherapy and 4 combination therapy. Mean baseline HBsAg level was 3.4 log IU/ml without difference among treatment groups (table). In peginterferon alfa-2a patients ± LAM HBsAg reductions were significant during treatment and follow-up (p < 0.001) whereas no significant reductions were observed in LAM patients (table). HBsAg reductions were most profound in genotype A patients, intermediate in genotype B and C and least in genotype D patients. Among peginterferon alfa-2a monotherapy patients mean HBsAg reductions at the end of treatment were 1.16, 0.75 and 0.38 log IU/mL for genotype A (n=8), B/C (n=97) and D (n=17), respectively. The corresponding reductions 24 weeks post-treatment were 1.05, 0.60 and 0.36 log IU/mL.

 

Conclusions:

Peginterferon alfa-2a ± LAM proves a significant HBsAg reduction in the sera of HBeAg-negative chronic hepatitis B patients. In contrast, no significant HBsAg reduction was observed during LAM monotherapy. The degree of HBsAg reduction seems to be HBV genotype-dependent.

 

HBsAntigen (log IU/ml

PEG-IFN

 

(n=127)

PEG-IFN+

LAM

(n=137)

LAM

 

(n=122)

Pre-trmt†

3.32±0.61

3.46±0.58

3.43±0.57

Reduction vs pre-trmt†

Week 48

Week 72

0.71±1.28*

0.59±1.20*

0.67±1.17*

0.51±1.03*

0.02±0.42

0.06±0.46

Pts with reduced HBsAg (week 72 vs. pre-trmt)

>= 2.0 log

>= 1.0 log

>= 0.5 log

10/127(8%) §

19/127(15%)#

50/127(39%)§

11/137(8%) §

24/137(18%)§

39/137(28%)§

0

6/122(5%)

12/122 (10%)

†mean ± SD *p<0.01 (vs. baseline); §p<0.01 (vs. lamivudine); #p=0.01 (vs. lamivudine)

 

# 972. Suppression of HBV DNA in Patients with HBeAg-negative CHB Treated with Peginterferon Alfa-2a (40KD) ± Lamivudine: 2-Year Follow-up Results

P. Marcellin; F. Bonino; G. K. Lau; P. Farci; C. Yurdaydin; T. Piratvisuth; K. Luo; S. Gurel; S. Hadziyannis; Y. Wang; M. Popescu

 

Background:

HBeAg-negative chronic hepatitis B (CHB) is associated with poor prognosis, low rates of treatment response and high rates of relapse, especially following treatment with nucleos(t)e analogues. Significantly higher response rates 24 weeks post-treatment have been demonstrated in patients receiving peginterferon alfa-2a +/- lamivudine, versus lamivudine alone, in a large multinational trial.

 

Objective:

To evaluate the durability of virological and biochemical response to peginterferon alfa-2a +/- lamivudine for up to 2 years post-treatment.

 

Methods:

In the initial study, HBeAg-negative CHB patients received 180μg peginterferon alfa-2a (40KD) once-weekly (qw) plus either placebo daily (qd) or 100 mg lamivudine (qd) for 48 weeks, and were assessed 6 months post-treatment. In a roll-over long-term observational study, 116/177 (66%) of those receiving peginterferon alfa-2a plus placebo, and 114/179 (64%) receiving the combination with lamivudine, were assessed for HBV DNA suppression to <20,000 cp/mL, <10,000 cp/mL and <400 cp/mL and ALT normalization <1 X ULN, (30 or >30–≤ 50 IU/L) at 6, 9, 12 and 24 months post-treatment.

Results:

HBV DNA suppression at 1 and 2 years post-treatment is shown in the table below. HBV DNA levels were stable from 9 months to 24 months post-treatment and there was no significant difference in the virological response between patients treated with peginterferon alfa-2a monotherapy and peginterferon alfa-2a plus lamivudine. ALT normalisation at 1 and 2 years post-treatment was 50% versus 45% and 32% versus 28% for patients treated with peginterferon alfa-2a monotherapy versus the combination with lamivudine, respectively. A total of 11/116 patients receiving peginterferon alfa-2a monotherapy lost HBsAg during the study, of whom six developed anti-HBs antibody, maintained over 2 years of follow-up. Of those receiving the combination with lamivudine, 14/114 lost HBsAg, and six developed anti-HBs antibody at some time during the study, which was maintained in two patients up to 2 years post-treatment.

 

Conclusions:

Peginterferon alfa-2a proves durable ALT normalization and HBV DNA suppression to less than 10,000 cp/mL, a level that has recently been associated with a considerably reduced risk of disease complications and hepatocellular cancer, for up to 2 years post-treatment. Patients who relapsed, did so in the early months of follow-up. 

 

 

HBV DNA response 1 year post-treatment (%)

HBV DNA response 2 years post-treatment (%)

HBV DNA cp/mL

<20,000

<10,000

<400

<20,000

<10,000

<400

Peginterferon alfa-2a

(n=116)*

35

30

15

29

28

16

Peginterferon alfa-2a + Lamivudine

(n=114)*

35

31

12

25

21

11

*missing data was considered as non-response

 

#974. Peginterferon Alpha-2B Is Well Tolerated and Leads to High Virological and Histological Response Rates in Chronic Hepatitis B Patients with Advanced Fibrosis

E. H. Buster; M. van Zonneveld; P. E. Zondervan; B. E. Hansen; E. Verhey; S. W. Schalm; H. L. Janssen

 

HBeAg-seroconversion and serum HBV DNA below 10,000 copies/ml are associated with decreased risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma. Since peginterferon (PEG-IFN) therapy may precipitate dangerous immunological flares, patients with advanced fibrosis are often refrained from this therapy.

 

Aim:

To investigate the efficacy and safety of PEG-IFN α-2b in patients with advanced fibrosis.

 

Methods:

A total of 266 patients participating in a global randomized controlled study were assigned to 52 weeks of PEG-IFN α-2b alone (100µg weekly, n=136) or in combination with lamivudine (100mg daily, n=130), and were followed for 26 weeks after therapy. Treatment groups were comparable regarding baseline characteristics and all outcome parameters. 239 patients who had a liver biopsy taken at baseline were included in this analysis. Advanced fibrosis was defined as Ishak fibrosis score 4-6.

 

Results:

A total of 70 of the 239 patients had advanced fibrosis (29%). Rates of HBeAg seroconversion, HBsAg seroconversion, improvement of necroinflammation and HBV DNA <400 copies/ml were higher in patients with advanced fibrosis compared to those without (table). Improvement of fibrosis and HBV DNA <10,000 copies/ml were observed significantly more frequent in patients with advanced fibrosis compared to those without (table, p<0.001 and p=0.04). Most adverse events occurred equally in those with or without advanced fibrosis. Fatigue, anorexia and thrombocytopenia were more prevalent among those with advanced fibrosis (p<0.01). Necessity for dose reduction or discontinuation was comparable for both patient groups. Serious adverse events occurred in 4% of patients with advanced fibrosis and 5% of those without. One patient with advanced fibrosis had temporarily elevated bilirubin, which resolved after scheduled discontinuation of therapy. No other signs of liver failure were encountered.

 

Conclusion:

PEG-IFN is safe and leads to high rates of virological and histological response in HBeAg-positive patients with advanced fibrosis. Since PEG-IFN therapy results in sustained off-therapy response, patients with advanced fibrosis and fully compensated liver disease should not be excluded from PEG-IFN treatment.

 

 

Advanced Fibrosis(n=70)

No Advanced

Fibrosis (n=169)

p

HBeAg seroconversion

35.8%

28.7%

0.29

HBsAg seroconversion

8.6%

4.1%

0.21

HBV DNA <10,000 copies/ml

29.5%

16.8%

0.04

HBV DNA <400 copies/ml

13.1%

7.4%

0.19

Mean reduction viral load

2.58log10

2.27log10

0.45

Improvement fibrosis (1 point)*

66.0%

25.6%

<0.001

Improvement necroinflammation (2 points)*

52.4%

50.0%

0.84

*Second biopsy taken at week 52

 

#975. Early Peginterferon Alpha-2B Induced HBeAg Loss Results in Increased Rates of HBsAg Loss and Undetectable HBV DNA

E. H. Buster; M. van Zonneveld; B. E. Hansen; E. Verhey; H. L. Janssen

 

Long-term follow-up studies of interferon-alpha in chronic HBV have shown improved outcome in patients with HBeAg loss compared to those without. Recently, serum HBV DNA below 10,000 copies/ml was found to be independently associated with decreased risk of developing cirrhosis, hepatic decompensation and hepatocellular carcinoma.

 

Aim:

To investigate the relation between timing of peginterferon alpha-2b (PEG-IFN α-2b) induced HBeAg loss, and decline in serum HBV DNA and HBsAg loss.

 

Methods:

A total of 266 patients participating in a global randomized controlled study were assigned to 52 weeks of PEG-IFN α-2b alone (100µg weekly, n=136) or in combination with lamivudine (100mg daily, n=130), and were followed for 26 weeks after therapy. Treatment groups were comparable regarding baseline characteristics.

 

Results:

Rates of HBeAg loss we comparable in patients treated with PEG-IFN α-2b alone or in combination with lamivudine at week 78 (36% and 35%, p=0.91), as well as HBV DNA <400 copies/ml (7% and 9%, p=0.43). Patients with HBeAg loss were more likely to have HBV DNA below 10,000 copies/ml at week 78 than patients without (49% vs 2%, p<0.001), as well as HBV DNA < 400 copies/ml (22% vs 0%, p<0.001). Among patients with loss of HBeAg at week 78, 56% lost HBeAg before week 32, 24% between week 32 and 52, and 20% during post-treatment follow-up (week 52-78). HBsAg loss at week 78 occurred in 17% of patients with HBeAg loss. HBsAg loss occurred significantly more often in patients with HBeAg loss before week 32 (see table, p<0.03). Off treatment sustainability of HBeAg loss also tended to be higher among those with an early HBeAg loss (75% vs 64%, p=0.25). HBeAg loss before week 32 was found to significantly increase rates of HBV DNA <10,000 and 400 copies/ml at week 78 (see table). Baseline HBV DNA was lower in patients with HBeAg loss than those without, but comparable in the subgroups with HBeAg loss.

 

Conclusion:

PEG-IFN α-2b induced HBeAg loss before week 32 results in significantly higher rates of HBsAg loss and greater viral decline at week 78 compared to late HBeAg loss.

 

Timing of PEG-IFN α-2b (and lamivudine) induced HBeAg loss and response at week 78:

 

 

HBeAg loss

 

 

 

≤wk 32(n=53)

wk >32-≤52(n=23)

wk >52-78(n=19)

p

No BeAg loss(n=171)

Mean HBV DNA (log10)

3.87

4.62

5.27

0.03*

8.36

HBV DNA <10,000 copies/ml

62%

46%

16%

<0.001*

2%

HBV DNA <400 copies/ml

32%

9%

11%

0.04Ą

0%

HBsAg loss

30%

4%

5%

<0.03§

0%

HBsAg seroconversion

28%

0%

5%

<0.05§

0%

 

* HBeAg loss <32 wks vs. wk >52-78, Ą HBeAg-loss <32 wks vs. wk >32-≤52, § HBeAg loss <32 wks vs. wk >32-≤52 and wk >52-78

 

#996. Induction of CD4+ CD25+ Regulatory T-cells Is Associated with Non-Response to Pegylated Interferon-a Therapy for Chronic Hepatitis B Virus Infection

D. Sprengers; J. N. Stoop; R. S. Binda; J. G. Kusters; B. L. Haagmans; P. Carotenuto; R. G. van der Molen; A. D. Osterhaus; H. L. Janssen

 

Introduction:

Little is known about why treatment with interferon alpha (IFNα) leads to a response in only a minority of patients with chronic HBV. It was recently shown that in these patients CD4+ CD25+ regulatory T-cells (Treg) can suppress the HBV-specific immune response. We investigated whether in non-responders to IFN therapy Treg contribute to treatment failure by down-regulating the HBV-specific T-cell responses.

 

Method:

Fourteen HBeAg-positive patients, received pegylated IFNα-2b (100 μg weekly) monotherapy for 52 weeks and were followed-up for 26 weeks. Six patients (43%) responded to therapy (HBeAg negative at week 78). At baseline the HBV-specific Th-cell proliferation dnot differ between responders and non-responders (mean SI = 4.83 ± 0.63 and 4.43 ± 0.38, respectively). However, in non-responders at the end of therapy (EOT) the proliferation capacity of Th-cells had decreased by 76%, (p < 0.05), while 5 of 6 responders showed a profound increase in the Th-cell proliferative response (SI > 2 x baseline level). Whereas at baseline there was no difference in the frequencies of CD4+ CD25+ regulatory T cells (Treg) between responders and non-responders (2.23% ± 0.19 vs 2.21% ± 0.10, respectively), during therapy these frequencies decreased in responders (1.75% ± 0.09 at EOT, p = 0.031) and increased in non-responders (3.6% ± 0.18 at EOT, p = 0.008). In contrast to the responders, the non-responders showed a significant increase in frequency of IL-10 producing cells from 22.7 ± 4.0 / 1x105 PBMC at baseline to a mean of 48 ± 6.7 / 1x105 PBMC at EOT (p = 0.016). Treg depletion resulted in increased proliferation capacity and increased frequencies of HBV-specific INFγ-producing cells, but dnot affect the frequency of IL-10 producing cells measured during the course of the treatment.

 

Conclusion:

In conclusion, this study indicates that there may be an important role for regulatory T-cells, in HBV-persistence during and after treatment with pegylated IFNα-2b for chronic hepatitis B.

 

#981. Pegylated Interferon-alfa-2a Plus Adefovir Combination Therapy Is Superior to Pegylated Interferon-alfa-2a Alone or Adefovir Monotherapy in Reducing HBsAg Levels in HDV-Coinfected Patients with Low HBV Viremia

H. Wedemeyer; C. Yurdaydin; K. Zachou; A. Erhardt; U. Drebber; Y. Cakaloglu; H. Degertekin; S. Gurel; S. Zeuzem; T. Bock; G. Dalekos; M. P. Manns

 

Introduction:

Serum HBsAg levels are considered as a surrogate marker for intrahepatic HBV-cccDNA levels and have been shown to be reduced by adefovir therapy in HBV-monoinfected patients. The hepatitis D virus (HDV) uses the HBsAg for virion formation. Thus, the best treatment option for HDV infection would be clearance of HBsAg. So far, there are no data available on HBsAg-levels during pegylated-interferon alfa therapies alone or in combination with nucleos(t)es in HBV infection.

 

Methods:

We investigated HBsAg levels in 90 patients with HBV-HDV coinfection being treated for 48 weeks with 180µg PEG-interferon-alfa-2a qw plus 10mg adefovir dipivoxil qd (group A, n=31), 180µg PEG-interferon-alfa-2a qw plus placebo (group B, n=29,) or 10mg adefovir dipivoxil qd alone (group C, n=30). Patients were treated in the Hep-Net/International Delta Hepatitis Intervention Trial (H-IT) in Germany, Turkey and Greece. At week 48, HDV-RNA was negative in 21%, 30% and 8% of patients in the H-IT trial, respectively.

 

Results:

HBeAg tested positive in 14 patients at baseline. 48% of patients had HBV-DNA levels below 100 IU/ml, 37% had a HBV viremia between 101 and 10.000 IU/ml and 15% showed HBV-DNA levels above 10.000 IU/ml.

 

Mean baseline HBsAg-levels were 3.9±0.6, 4.0±0.6 and 4.0±0.5 log10-IU/ml in groups A, B and C, respectively, ranging from 184 to 79591 IU/ml. HBsAg levels dnot correlate with HBV viremia but were positively correlated with HDV-RNA levels (r=0.324, p=0.002). While patients receiving pegylated interferon alfa-2a alone or adefovir monotherapy had similar mean HBsAg levels at week 0 and week 48, the PEG-IFN alfa-2a/adefovir combination group showed a 1.0 log10-IU/ml decline of HBsAg levels by week 48 (p<0.001). 40% of patients in group A but only 5% of patients in group B and none of the patients treated in group C displayed at least a 10-times reduction of HBsAg in serum (p<0.001). Importantly, HBsAg was lost by week 48 in 2 patients, both patients were treated with a combination of PEG-IFN alfa-2a and adefovir and had also developed anti-HBs antibodies with titers of 58 and 413 IU/L, respectively.

 

Conclusion:

This is the first trial demonstrating that a combination therapy of pegylated interferon with a nucleote is superior to either monotherapy in reducing HBsAg levels in HBV-infected patients. HBsAg clearance can be achieved by combination therapy in some HDV-coinfected patients after only 48 weeks of therapy. Future trials will have to investigate whether longer treatment regimes can increase HBs-seroconversion rates in HDV-coinfected as well as in HBV mono-infected patients.

 

#1010. Early Viral Kinetics and Pharmacokinetics in HBeAg-Positive Chronic Hepatitis B Treated with Pegylated Interferon Alpha-2b with or without Lamivudine

M. J. ter Borg; B. E. Hansen; M. van Zonneveld; S. W. Schalm; B. L. Haagmans; H. L. Janssen

 

Biphasic and triphasic patterns of viral load decline have been observed in the early phase of treatment with (pegylated) interferons in chronic hepatitis C. In hepatitis B, little is known about viral decline during interferon treatment. To investigate early viral kinetics and pharmacokinetics of pegylated interferon alpha-2b (PEG-IFN-α2b) in HBeAg-positive chronic hepatitis B, we analyzed patients treated with PEG-IFN 100 µg/week with or without lamivudine 100 mg/day for 52 weeks.

 

Method:

Serum HBV DNA levels were measured by TaqMan PCR assay in 38 patients at the start of treatment (day 0) and at days 1, 2, 3, 4 and 7. IFN serum concentrations were measured using a quantitative sandwich IFN enzyme-linked immunosorbent assay (ELISA) in 96 patients at days 0, 1, 2, 3, 4 and 7. The detection limit of this assay is 35 pg/mL and is linear up to a concentration of 2000 pg/mL.

 

In the first week of treatment with PEG-IFN-α2b monotherapy (n=19), we observed a mean 0.48 log HBV DNA decline at day 4, followed by a 0.25 log rebound of HBV DNA thereafter to the end of the week. In patients treated with a combination of PEG-IFN-α2b and lamivudine (n=19), there was a continuous HBV DNA decline during the first week of treatment (mean 1.57 log). IFN levels peaked 1 day after administration of the drug in patients receiving PEG-IFN-α2b monotherapy (n=48), as well as in patients treated with PEG-IFN-α2b and lamivudine (n=48). After day 1, IFN serum levels declined and the IFN level was below the limit of detection in 52 out of 96 patients (54%) before the end of the first week.

 

Conclusions:

In conclusion, this study indicates that the observed rebound in HBV DNA at the end of the first week after administration of PEG-IFN-α2b monotherapy is related to the low levels of IFN observed 7 days after administration of the drug.

 

#1014. Modeling of Pharmacokinetics and Viral Kinetics in HBeAg-positive Chronic Hepatitis B Treated with Pegylated Interferon Alpha-2b

M. J. ter Borg; B. E. Hansen; E. Herrmann; S. Zeuzem; B. L. Haagmans; H. L. Janssen

 

Mathematical models to describe pharmacokinetics and viral kinetics may improve the understanding of the mechanisms of action of pegylated interferons and therefore contribute to the development of different treatment regimens.

 

Method:

In 96 HBeAg-positive chronic hepatitis B patients treated with pegylated interferon alpha-2b (PEG-IFN) 100 μg/week with or without lamivudine 100 mg/day, IFN concentrations were measured at day 0, 1, 2, 3, 4 and 7 of treatment. HBV DNA levels were measured in a subgroup of 19 patients in each treatment arm. The IFN concentration was analysed with a non-linear mixed model using an absorption and elimination model1. Mixed modeling uses a group-wise analysis with subject specific random effects for the rate of elimination (ke), the rate of absorption (ka), the bioavailability (F), the volume of distribution (Vd) and the delay between administration and maximal drug concentration (τ). Assuming that the effectiveness depends on the varying drug concentration in the first week of treatment, the predicted effectiveness over time could hereafter be incorporated in an expanded non-linear mixed model2,3 to fit the viral load in patients treated with PEG-IFN monotherapy.

 

There were no differences in IFN concentration in the PEG-IFN monotherapy and PEG-IFN plus lamivudine therapy group at any time point. Using this non-linear mixed modeling, we were able to adequately fit 95% (91/96) of the pharmacokinetics in either treatment arm and all (19/19) viral kinetics data in the PEG-IFN monotherapy arm. The population mean of ke was 0.42 per day (with an individual interquartile range of 0.36-0.48), of ka 2.36 per day (1.39-3.41), of F/Vd 1.02 (0.72-1.60) with a τ of 1.06 day (0.87-1.43). There was a correlation between pharmacokinetic constants ka and F/Vd and the body surface area (BSA) with correlation coefficients of -0.24 (p=.019) and -0.30 (p=.003), respectively. The mean maximal antiviral effectiveness of PEG-IFN monotherapy was 0.86 (0.79-0.93) with a mean viral clearance rate of 0.97 per day (0.88-1.12). Viral load was minimal 3.7 days (3.25-3.90) after administration of PEG-IFN alone, with a rebound thereafter.

 

Conclusion:

In conclusion, an adequate fit of pharmacokinetics can be made with non-linear mixed modeling techniques using IFN concentrations from the first week of PEG-IFN treatment and this model can be used to fit viral load during PEG-IFN therapy. Based on these findings, PEG-IFN administration every 4 days and weight-based dosing can be considered to optimize drug availability.

 

Monitoring HBV Infection

#978. A Line Probe Assay (LiPA) for Detecting Novel Hepatitis B Drug Resistance Mutations Associated with Entecavir, Tenofovir and Adefovir Dipivoxil Therapy

E. Sablon; J. Doutreloigne; E. Libbrecht; E. Van Assche; M. Van Brussel

 

A number of new antiviral drugs are now available or under evaluation for treatment of chronic hepatitis B virus-infected patients. As with lamivudine, these antivirals can induce viral escape mutants that may lead to viral non-responsiveness and treatment failure. Furthermore, some mutations seem to lead to cross-resistance for several drugs, as such limiting further treatment options. Early detection of these mutants during treatment may therefore play a key role in future selection and monitoring of patients.

 

Methods:

The current line probe assay, the INNO-LiPA HBV DR v2*, detects the wild-type and mutant motifs for lamivudine resistance and compensatory mutations and adefovir dipivoxil resistance mutations. A new prototype LiPA strip that detects the single reported tenofovir mutation A194T, the newly discovered mutation I233V for adefovir, and the drug resistance mutations for entecavir: I169T, T184 S/C/G/A/I/L/F/M, S202 G/C/I and M250V/I/L has been developed. A set of highly specific oligonucleote probes has been designed for both wild-type and mutant versions of these motifs and applied as lines on a membrane strip. The new LiPA strip is fully compatible with the single-round PCR encompassing the HBV polymerase domains A-F, previously developed for the INNO-LiPA HBV DR v2 assay.

The prototype strip has been evaluated with clinical samples obtained from patients infected with all known HBV genotypes (A-H), both untreated and treated with different antiviral drugs.

 

Conclusion:

Due to the nature of the reverse hybridization, the LiPA platform is capable of early detection of emerging HBV treatment-resistant viruses even before an increase in viral load is observed.

 

Similarly to the INNO-LiPA HBV DR v2, the new assay detects the complex quasispecies nature of HBV and can help to unravel the dynamics of emerging HBV resistance during treatment with different antiviral drugs and should prove to be a useful asset in monitoring and tailoring of current antiviral treatment for patients with chronic hepatitis B.

 

* For research use only in US.

 

#980. Can ALT and HBV DNA Replace Liver Biopsy for the Evaluation of Hepatitis B Trials?

G. Soon; K. Laessig; R. Fleischer

 

How to measure the drug efficacy for chronic hepatitis B infection has been a challenging issue for the regulatory agency as well as sponsoring companies for a long time. Given that the true clinical endpoint, death or liver carcinoma, is not feasible because the long trial duration it would require, liver biopsies have been used for the approval of the first three HBV anti-viral drugs that are currently on the market: lamivudine, adefovir, and entecavir. However, liver biopsies are invasive and cannot be done frequently. Therefore it is of great interest to investigate if the HBV DNA or ALT can be used as a substitute for the liver biopsies in clinical trials. In this paper we present the preliminary findings on their relationships.

 

Methods:

The analyses are based on four drug submissions: lamivudine, adefovir, entecavir, and peginterferon 2a. We integrated the data from these four drug submissions and explored the relationships of the following parameters: liver biopsies measured by Knodell scores or Ishak, HBV DNA measured by several assays, ALT levels, HBeAg, HBeAb, HBsAb, and HBsAg etc. We looked at their relationships over time to see how they change. A total of 10 Phase III studies with a total of 13 arms, over 3000 patients were included. At the patient level, each patient's own ALT (U/L) and HBV DNA does not predict his/her Knodell scores well, the correlations are generally low, averaging about 0.35.

 

At the trial level, we examined how the effect size on ALT, HBV DNA and other markers correlates with the effect size of liver biopsy. With the addition of the data from entecavir and peginterferon, the correlation has improved over the correlation based on only lamivudine and adefovir trials.

 

Conclusion:

Overall, the correlations of the HBV DNA and ALT with biopsies are weak, even when all the measurements of ALT and HBV DNA over time are used for the prediction. This raises the question of the suitability of ALT or HBV DNA as a replacement for biopsy as the primary endpoint for HBV trials.

 

Treatment With Vaccines

 

#984. Vaccination with Mature Dendritic Cells Induces Strong HBV Specific Th Cell and CTL Responses in HBV Trimera Mice

W. Bocher; R. Vuyyuru; N. Blust; S. Herzog-Hauff; P. R. Galle

 

Introduction:

Spontaneous resolution from hepatitis B is associated with strong and broad HBV core specific T cell responses. In contrast, viral persistence is associated with weak and narrow immune responses. Thus, induction of strong HBV-specific T cell reactivities might represent a new therapeutic strategy.

 

Methods:

We have shown in the humanized trimera mouse model, that vaccination with dendritic cells (DC) might represent an effective therapeutic vaccine. However, in viro maturation and pulsing with permanently HBV-transfected HepG2.215 cells might further improve the vaccine response in vivo. Methods: DC were generated from MACS-seperated blood monocytes by incubation in IL-4 and GM-CSF. After 5 days, DC were pulsed with UV-irradiated apoptotic permanently HBV-transfected hepatoma cells or control antigens, before maturation was induced by addition of IL-1b, IL-6, TNFa and PgE2 for 2 days. Lethally irradiated Balb/c mice, reconstituted with nod.scmouse bone marrow, were transplanted with human PBMC from chronic HBV carriers. Vaccination of such trimera was performed i.p. with mature or immature DC pulsed with apoptotic HBV-transfected HepG2.215 or non-transfected HepG2 cells, apoptotic HepG2.215 cells, HBcAg or HBc18-27 pepte; vaccination with tetanus toxoand EBV pepte280-288 served as controls. HBc, HBs, TT- and EBV- specific human T cell frequencies were analyzed from peritoneal lavage by IFNg ELISpot with autologous APC pulsed with recombinant antigens or CTL epitopes 10 days after vaccination. Results: Very stong HBc specific Th cell and CTL responses were induced in trimera mice vaccinated with DC pulsed with apoptotic HepG2.215 cells. In vitro maturation of DC significantly enhanced this immune stimulatory effect. In contrast, HBc pepte pulsed mature DC induced CTL responses only, while vaccination with apoptotic HepG2.215 cells (without DC) resulted in no detectable response.

 

Conclusions:

Our studies demonstrate that HBV core specific CTL, that are barely detectable in chronic HBV patients, can effectively be recovered in our system by vaccination with apoptotic HepG2.215 cell pulsed mature DC. Such an approach should further be studied in vivo.

 

Impact of Genotypes on Treatment

 

#987. Impact of Hepatitis B Genotype on Treatment Response: A Meta-Analysis of Controlled and Uncontrolled Trials

A. Rajendra; B. B. Shah; J. Wong

 

Background/Aim:

The significance of hepatitis B virus (HBV) genotype response to treatment is not well established. The aim of this study was to examine treatment response by genotype in patients with chronic hepatitis B HBeAg-positive infection.

 

Methods:

Studies were retrieved from MEDLINE between 1966 and 2006, abstracts of scientific meetings, and review of bibliographies of retrieved studies. Included treatments were peginterferon (with ribavirin in one study), lamivudine, telbivudine and entecavir. The primary end points were anti-HBe seroconversion, sustained loss of HBeAg, and undetectable HBV DNA. We used a DerSimonian and Laird random effects model to pool data.

 

Results:

We identified 9 randomized controlled trials (3407 patients) and 5 retrospective trials (439 patients) with genotypic response rate data. Anti-HBe seroconversion rates (95% CI) by genotype were 49% (40-57) for A, 35% (31-40) for B, 26% (23-29) for C, 23% (15-35) for D with any treatment in 8 studies of 1531 patients; 54% (43-64) for A, 31% (25-39) for B, 29% (25-34) for C, 27% (15-43) for D with peginterferon; and 48% (28-68) for A, 40% (32-47) for B, 21% (17-26) for C, 19% (6-42) for D with lamivudine. Sustained loss of HBeAg rates (95% CI) by genotype were 43% (36-51) for B and 28% (22-36) for C with any treatment in 5 studies of 343 patients. Undetectable HBV DNA level rates (95% CI) by genotype were 48% (39-58) for A, 48% (44-52) for B, 50% (46-54) for C, 42% (36-47) for D with any treatment in 8 studies of 1775 patients; and 44% (38-51) for B and 43% (38-48) for C with lamivudine. Statistically significant increased likelihood of response occurred for anti-HBe seroconversion for A vs D (OR 3.0, CI 1.4-6.6); HBeAg loss for B vs C (OR 2.3, CI 1.5-3.8), and undetectable HBV DNA for C vs D (OR 2.5, CI 1.6-3.9) and A vs D (OR 1.7, CI 1.1-2.8).

 

Conclusions:

Our analysis supports significant genotype-specific responses to treatment in chronic hepatitis B HBeAg positive infection. Genotype A appeared to have the highest response rates. When comparing response rates across different trials, the proportion of patients with each genotype should be examined.

 

#1009. Should Treatment of Hepatitis B Depend on HBV Genotypes? – A Hypothesis Generated from an Explorative Analysis of Published Evidence

J. Wiegand; D. Hasenclever; H. L. Tillmann

 

Therapy of hepatitis B is either based on interferon (IFN) or on nucleos(t)e analogues. We summarize the available evidence on treatment outcome by HBV-genotypes and pose the question whether genotypes determine HBV therapy.

 

Methods:

PubMed, EASL- and AASLD-abstracts were screened for publications reporting treatment results broken down by genotype. 18 reports with at least 30 patients were included.

 

Forest-plot techniques from standard meta-analysis were applied to visualize association of HBV-genotypes with treatment outcome. To assess the potential order of magnitude of a treatment by genotype interaction effect the difference of summary differences between treatment types with respective confidence interval was calculated. The analysis is explorative and hypothesis generating only.

 

Results:

1) Therapy with nucleos(t)e analogues HBV-genotypes do not display different responses to nucleos(t)e analogues (genotype A vs. D: random effect p=0.24; genotype B vs. C: random effect p=0.81).

 

2) IFN based therapies in HBeAg (+) patients. In contrast, HBeAg seroconversion or loss of HBeAg after IFN based therapies occur more often in patients with genotype A vs. D (random effect p<0.0001) and in cases with genotype B vs. C (random effect p=0.001).

 

3) Loss of HBsAg after IFN based therapies. Efficacy of IFN is further supported by higher HBsAg clearance rates for genotype A vs. D (random effect p<0.0001). There is no difference between genotype B vs. C (random effect p=0.372).

 

4) Difference of summary differences between treatment types.

 

IFN treatment seems to be effective in genotype A and B as opposed to genotype C and D. Calculating the difference of summary differences between treatment types, the interaction effect is estimated to be 15% resp. 13% in response rates.

 

Conclusion:

IFN compared to nucleos(t)e analogues may be more effective in genotypes A and B as opposed to genotypes D and C.

 

#989. Low Rates of Genotypic Resistance to Adefovir in Lamivudine-Resistant Patients Treated with Adefovir-Lamivudine Combination Therapy for 3 Years

P. Lampertico; M. Vigano; M. Iavarone; E. Manenti; G. Lunghi; E. Del Ninno; M. Colombo

 

Background and Aims:

Te risk of developing genotypic and clinical resistance to adefovir and virological breakthrough in lamivudine resistant patients treated long-term with a combination of adefovir and lamivudine, is unknown.

 

Patients and Methods:

Fifteen lamivudine resistant patients with chronic hepatitis B (84% HBeAg neg, 73% cirrhotics) were treated for more than 1 year (median: 30 months, range 12-65) with 10 mg/daily of adefovir added to ongoing lamivudine. HBV NA was assessed every two months by Versant 3.0 and drug resistance was assessed by INNO-LiPA HDR V2 assay in viremic patients every year.

 

Results:

Serum HBV-DNA became undetectable in 99/145 (68%), 70/92 (76%) and 43/52 (83%) patients after 1, 2 and 3 years, respectively. None of the patients who achieved undetectable HBV DNA or maintained persistently detectable viremia, showed >1 log rebound of HBV DNA compared to on-treatment nadir. Moreover, genotypic resistance for rtN236T was not identified in any patient. By converse, the rtA181T/V mutation was found in 4 (3%), 1 (1%), and 1 (2%) serum samples at 1, 2 and 3 years, respectively (overall, 6 patients, 4%). All the 5 patients with the rtA181T mutation, but not the one with the rtA181V, had a mixed viral population with the wild-type sequence rtA181A. The rtA181T/V mutants were already detected at baseline in 3 patients, as a mixed viral population with rtA181A. Despite the presence of HBV viral strains with rtA181T/V mutations, serum HBV DNA became undetectable in 4 of 5 patients during 6-12 months of follow-up. Overall, after 3 years of combined therapy, de-novo emergence of rtA181T mutation and persistence of > 4 log copies/ml of serum HBV DNA were observed in 1 patient (0.7%), only. By converse, lamivudine-associated resistance mutations were confirmed in 93% of the samples, the pattern being similar to baseline.

 

Conclusions:

Adefovir and lamivudine combination therapy is an effective strategy in lamivudine-resistant patients, since it minimizes the risk of genotypic resistance to ADV and prevents both virological rebound and clinical resistance up to 3 years.

 

Quality of Life and HBV

 

#1015. Development and Validation of a Disease-Targeted Health-Related Quality of Life (HRQOL) Instrument in Chronic Hepatitis B Infection: the HBQOL v1.0

B. M. Spiegel; R. Bolus; S. Han; M. Tong; E. Esrailian; J. Talley; T. Tran; J. Smith; H. A. Karsan; F. Durazo; B. Bacon; P. Martin; Z. Younossi; S. Ong; F. Kanwal

 

Background:

Despite the increasing realization that HRQOL is an important outcome in chronic hepatitis B virus (HBV) infection, there are no validated, disease-targeted instruments currently available. We sought to develop and validate the first disease-targeted HRQOL instrument in non-cirrhotic HBV: the HBQOL v1.0.

 

Methods:

We established content validity for the HBQOL v1.0 through a 4-step process, including (1) systematic literature review, (2) focus group of expert hepatologists, (3) cognitive interviews of 59 patients with chronic, non-cirrhotic HBV, and (4) development a priori hypotheses regarding relevant HRQOL domains. We administered the resulting questionnaire to a cohort of 138 geographically diverse patients with chronic HBV and no cirrhosis or hepatocellular cancer, and subsequently used item reduction to create the final questionnaire. We used factor analysis to test our hypotheses regarding HRQOL domains, and measured construct validity by comparing HBQOL v1.0 scores across several anchors, including: (1) viral response to treatment, (2) SF-36 scores, and (3) global health. Finally, we measured test-retest and internal consistency reliability.

 

Results:

Patient interviews revealed a range of striking disease-specific fears and concerns (e.g. “I’m afraid I will die young,” “I feel like a time bomb”), social sequelae (e.g. “I am contagious and some people shy away from me,” “I cannot establish intimate relationships”), and psychological consequences (“I was so depressed when I got my blood test result,” “I wonder if I will ever feel normal again”). Based on systematic review, expert panel, patient focus group feedback, we included 31 items in the HBQOL v1.0, which were grouped across 6 sub-scales: (1) Psychological Well-being, (2) Anticipation Anxiety, (3) Vitality, (4) Disease Stigma, (5) Vulnerability, and (6) Transmissibility.

 

Internal consistency reliability coefficients ranged from 0.73 to 0.96 across the sub-scales. Factor analysis empirically supported the validity of a single, higher order, “overall score.” Two weeks test-retest reliability was excellent (r=0.96). The HBQOL v1.0 discriminated between viral responders versus non-responders, and the overall score correlated highly with SF-36 mental and physical component scores and global health.

 

Conclusions:

Patients with chronic HBV attribute a wide range of negative psychological, social, and physical symptoms to their condition, even in the absence of cirrhosis or cancer. The HBQOL v1.0 is a valid and reliable measure that appears to capture this HRQOL decrement. This instrument may be used in everyday clinical practice and in future clinical trials.