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Meeting Report
Endpoints of therapy in chronic hepatitis B†
Article first published online: 27 APR 2009
DOI: 10.1002/hep.22977
Copyright © 2009 American Association for the Study of Liver Diseases
Supplement: NIH Consensus Development Conference: Management of Hepatitis B, October 20–22, 2008 — Guest Editors: Jay H. Hoofnagle and Edward Doo
Volume 49, Issue Supplement S5, pages S96–S102, May 2009
Additional Information
How to Cite
Feld, J. J., Wong, D. K. H. and Heathcote, E. J. (2009), Endpoints of therapy in chronic hepatitis B. Hepatology, 49: S96–S102. doi: 10.1002/hep.22977
- †
Potential conflict of interest: Feld: Nothing to declare; Wong: Hoffmann-La Roche–nursing support; Schering-Plough – nursing support; Heathcote: Gilead Sciences – research grant, speaker bureau, global medical advisory board; Bristol-Meyers Squibb – research grant; Hoffmann-La Roche – unrestricted and restricted research grants, global medical advisory board; Schering-Plough – unrestricted and restricted research grants, Debio pharm – research grant, Vertex – research grant, Novartis – research grant.
Publication History
- Issue published online: 27 APR 2009
- Article first published online: 27 APR 2009
- Manuscript Accepted: 10 MAR 2009
- Manuscript Received: 11 FEB 2009
Funded by
- American Association for the Study of Liver Diseases (AASLD)
- Canadian Institute for Health Research (CIHR)
- Physician Sciences Inc
- National Institutes of Health (NIH)
- Abstract
- Article
- References
- Cited By
Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly.At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B. (HEPATOLOGY 2009;49:S96–S102.)
The ultimate goal of treatment of any chronic infection is the eradication of the infectious agent, ideally before significant damage has been done to the host. In chronic hepatitis B, complete eradication of hepatitis B virus (HBV) infection is rarely achieved with currently available therapies. Even with prolonged suppression of viral replication for years, most patients remain positive for hepatitis B surface antigen (HBsAg) without antibody to HBsAg (anti-HBs), indicating the persistence of infection. Furthermore, even in those who clear HBsAg, HBV remains in infected hepatocytes in the form of covalently closed circular DNA (cccDNA) likely for the lifetime of the cell if not the individual, thus making it possible for reactivation to occur with the right stimulus. Consequently, true "cure" of hepatitis B with complete viral clearance is an unrealistic therapeutic goal.
Short of viral eradication, the goal of therapy is to prevent the complications of the disease. Unfortunately, in chronic hepatitis B, this goal is also not straightforward. It is estimated that 25%-35% of persons who acquire chronic HBV infection in early childhood will die of liver-related complications. Conversely, at least 65% will not. Thus, progression to cirrhosis and end-stage liver disease is common but far from invariable, and the progression is slow, generally requiring years or decades to become evident. For these reasons, clinically relevant endpoints in therapy of chronic hepatitis B, such as prevention of cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC), are impractical targets to assess therapy. Most clinical trials last for only 1-2 years during which few if any untreated subjects would be expected to reach one of these clinically relevant endpoints. Furthermore, these are negative endpoints (prevention of cirrhosis or its complications), rather than positive endpoints (loss of HBsAg or reversal of cirrhosis). Consequently, reliable surrogate biomarkers, with clear relevance to long-term outcomes, are needed. Although a number of such markers exist, the question of which markers provide the greatest utility in terms of long-term clinical significance is still unresolved.
Potential therapeutic targets include improvement in clinical, biochemical, virological, serological, or histological surrogate endpoints. Clinical endpoints might include symptoms; yet symptoms in chronic hepatitis B are uncommon and typically mild and nonspecific (fatigue, right upper quadrant discomfort) and are thus difficult to measure and unreliable in assessing benefits of therapy. Biochemical endpoints include serum aminotransferase levels, which are usually elevated in patients with chronic hepatitis B and are reasonable measures of disease activity. However, aminotransferase levels fluctuate considerably over time, and individual values are not useful for assessing long-term effects of therapy. The level of viral replication as reflected by serum levels of HBV DNA has become the predominant metric for assessing new oral treatments. Unfortunately, viral levels also fluctuate and the significance of a given viral level depends greatly on the stage of disease, degree of liver damage, and the type of therapy being used (i.e., oral nucleoside analogs versus peginterferon). The main serological markers used in assessing therapy include hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe) and, to a lesser extent, HBsAg and antibody (anti-HBs). Clearance of HBeAg and/or development of anti-HBe are associated with improved outcomes, provided that HBeAg loss is sustained after treatment is discontinued and the patient does not subsequently develop HBeAg-negative chronic hepatitis B with recurrent disease despite loss of HBeAg. Loss of HBsAg is the most convincing beneficial outcome of treatment of hepatitis B, because it is the most robust marker for lasting resolution of disease and is clearly associated with improved outcomes. The only drawback of relying on HBsAg loss is that it occurs very infrequently and therefore is unhelpful for the majority of treated patients. A final possible endpoint for therapy is liver histology. Liver biopsy is considered the gold standard for assessing liver injury and fibrosis; however, it too is not an ideal surrogate endpoint. Like serum aminotransferase levels, histological activity fluctuates over time and can improve or worsen rapidly. Hepatic fibrosis is perhaps a more stable marker for disease progression, but the assessment of fibrosis is problematic, because it is subject to sampling error, slow to change, and requires liver biopsy for accurate assessment. Liver biopsy is costly and invasive and cannot be repeated frequently to assess disease progression.
Clearly, none of the currently available biomarkers is an ideal measure of treatment efficacy on its own. Perhaps for this reason, approval of new therapies for hepatitis B by licensing authorities has usually depended on demonstration of significant improvements in two or more surrogate markers of disease progression with treatment. Typically, the surrogates are (1) biochemical (aminotransferase levels), (2) virological (HBV DNA levels, HBeAg, HBsAg), and (3) histological (based on histological scoring systems). Furthermore, the timing of assessment of these surrogate markers is defined as either "on-treatment" (maintained) or "off-treatment" (sustained or durable). In the approval of the initial agents for hepatitis B, comparisons were made to placebo-treated controls; more recently, newer agents are compared to standard, licensed therapies.
Evaluation of Biomarkers of Disease Status
Biochemical Endpoint: Serum Aminotransferase Levels.
Standard indirect markers of the "activity" of the underlying liver disease are levels of serum alanine and aspartate aminotransferases (ALT and AST). In an analysis of 142,055 Koreans who were 35 to 39 years of age and undergoing routine laboratory testing for insurance purposes, elevations in serum AST and/or ALT of greater than 30 U/L in men was associated with an increased relative risk of death from liver disease during the subsequent 8 years of follow-up.1 The mortality rate in women was too low for a comparable analysis. Those with a family history of liver disease (most likely chronic hepatitis B) had a higher relative risk of liver-related mortality. An observational cohort study of HBV-infected individuals from Hong Kong also observed that subjects with ALT levels below 0.5 × upper limit of normal were at lower risk for developing liver-related complications than those with even minor ALT elevations, in the range of 1× to 2× upper limit of normal.2 These findings suggest that normalization of ALT values has some utility as a surrogate endpoint, but because of the lack of specificity for HBV and the fluctuant nature over time, serum aminotransferase levels cannot be used as the only endpoint of therapy.
In addition to the lack of specificity for hepatitis B, ALT levels may also be insensitive. In individuals with advanced liver disease and cirrhosis, with or without signs of liver decompensation, ongoing viral replication may be present, yet not be associated with elevation in ALT.3 Thus, the context of the measurement of ALT needs to be taken into account, including other laboratory tests, HBV DNA levels, and background liver disease severity.
HBeAg Status.
Transmission of HBV at birth or in early childhood typically results in chronic infection in the infant, characterized by a pattern of immune tolerance with extremely high levels of HBV DNA in serum, circulating HBeAg, normal ALT levels, and minimal liver injury.4 Most, but not all such patients, move from the immune-tolerant phase to the immune-active HBeAg-positive phase between the second and fourth decade of life, at which time disease activity and liver injury become evident.
Because of the dynamic nature of the disease, an individual's HBeAg status at a single point in time cannot, on its own, be considered a marker of disease severity. The REVEAL-HBV (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV) cohort of Taiwanese men aged 30-65 reported a higher relative risk of cancer in those who were HBeAg-positive than in those who were HBeAg-negative at baseline, with a relative risk of HCC of 60.2 for those who were HBeAg-positive compared to 9.6 for HBeAg-negative persons, using HBsAg-negative individuals as the reference.5 To interpret these data correctly, the age and sex of the patient must be considered. Whether persistent HBeAg-positivity is as clearly related to the absolute risk of cancer in young individuals or women is not known. Indeed, many persons become HBeAg-negative in adolescence or young adulthood (< age 30) and would therefore fall into the "lower risk" HBeAg-negative category at age 30.
HBeAg Seroconversion to Anti-HBe.
For poorly understood reasons, immune-tolerant HBeAg-positive individuals enter the immune-active phase of disease, during which they eventually lose HBeAg and with time seroconvert to anti-HBe. When this occurs spontaneously, loss of HBeAg is associated with a fall in HBV DNA to low levels (generally <1000 IU/mL), normalization of serum ALT levels, and resolution of active necroinflammatory injury on liver biopsy. When sustained, these changes are associated with excellent long-term prognosis.6 For these reasons, HBeAg loss has been used as a surrogate marker for treatment efficacy and is considered a potential sign that therapy might be stopped in patients who were initially HBeAg-positive. HBeAg seroconversion (loss of HBeAg and development of antibody to HBeAg [anti-HBe]) has been considered a more reliable marker for a durable disease remission than simple loss of HBeAg; however, this is based on minimal evidence and as a result, most therapeutic trials have used loss of HBeAg as a therapeutic endpoint. Unfortunately, loss of HBeAg with or without HBeAg seroconversion is not always associated with resolution of disease. In some patients, HBeAg reappears in the serum once treatment is withdrawn and the disease returns to its initial level of activity. In other patients, virological, biochemical, and clinical relapse of disease occurs without reappearance of HBeAg (so-called HBeAg-negative chronic hepatitis B), which may be as severe as HBeAg-positive disease. Because HBeAg loss and associated disease quiescence are not always durable, the potential for sustained clinical benefit following this occurrence cannot be relied on, making it an imperfect endpoint in assessing therapy. Relapse in disease either due to return of HBeAg or evolution into HBeAg-negative hepatitis appears to be more common in responders to oral nucleoside analog therapy than in those responding to interferon or peginterferon. Recent data suggest that a fall in HBeAg concentration during peginterferon therapy predicts subsequent HBeAg loss, but HBeAg titers are not widely available.7 There are also genotypic differences, because patients with genotype C and D HBV infection are more likely to progress to HBeAg-negative hepatitis after HBeAg loss/seroconversion whereas patients with genotype A are more likely to achieve a durable disease remission. Unfortunately HBeAg loss, even with seroconversion to anti-HBe, may only mark the transition from immune-active HBeAg-positive to immune-active HBeAg-negative hepatitis. Therefore, although the presence or absence of HBeAg is still a useful marker in both the natural history and treatment of chronic HBV infection, it is not adequate as an endpoint in and of itself.
Serum HBV DNA Concentration.
Serum HBV DNA levels reflect the level of hepatic HBV replication but do not necessarily indicate the presence of ongoing HBV-related liver injury. Individuals in the immune-tolerant phase of infection usually have little or no liver injury despite very high levels of viral replication (usually >107 IU/mL),4 while those with HBeAg-negative disease may have progressive liver disease with much lower viral levels (<105 IU/mL). Therefore, it is critical to interpret HBV DNA levels in the context of the natural history of infection and other measures of disease activity.
The observation that patients in the REVEAL-HBV study8 with HBV DNA concentrations > 105 copies/mL (∼ 20,000 IU/mL) were at increased risk of HCC (odds ratio = 8.9) has led some to suggest that viral suppression should be the main goal of therapy for all patients, irrespective of other factors. It is critical to recognize that the majority of the REVEAL-HBV cohort were men, all were over the age of 30, probably infected since childhood, and 85% were HBeAg-negative at study entry. The absolute risk of HCC in younger individuals with very high HBV DNA levels is known to be low. Furthermore, none in the REVEAL-HBV observational cohort was treated, and it is important to stress that this study did not show a reduction in HCC with HBV-suppressive therapy. Clearly, HBV DNA level is an important consideration, but different levels have different implications at different times in different individuals. Until a therapy with no toxicity and no risk of resistance is developed, targeting HBV DNA as the only therapeutic endpoint in all infected individuals is not a realistic or appropriate strategy.
Even less clear than the significance of high levels of HBV DNA is the potential importance of lower levels of viremia. As the sensitivity of assays improves, lower and lower levels of serum HBV DNA can be detected. However, whether very low but detectable viral replication leads to progressive liver disease, HCC, or even antiviral resistance in those on oral antiviral therapy is unclear. The outcome of individuals who spontaneously seroconvert to anti-HBe and remain with low level HBV DNA (<103 IU/mL) without reactivation is significantly better than that of patients who remain HBeAg-positive. Whether outcomes such as HBsAg loss would improve further with complete viral suppression is not known.
Although HBV DNA alone cannot be used to determine the need for therapy, it may be a useful marker to follow during oral antiviral therapy. With suppression of viral replication, liver biochemistry, and more importantly, histology, both inflammation and fibrosis improve. Furthermore, failure to achieve viral suppression increases the risk of the development of antiviral resistance. However, although viral suppression is a necessary condition, it is not sufficient on its own as a lasting treatment endpoint. For HBeAg-positive patients who do not achieve HBeAg loss/seroconversion, HBV DNA and disease activity will rebound promptly if treatment is discontinued. Unfortunately, the pattern of decline of HBV DNA during antiviral therapy in patients with HBeAg-positive hepatitis does not reliably predict HBeAg loss/seroconversion whether interferon or nucleoside analog-based therapy is administered.9, 10 If HBeAg loss occurs with nucleoside analog treatment, guidelines suggest a period of consolidation before stopping therapy. However, even with a further 6 months of treatment, reactivation with or without reappearance of HBeAg may occur in a proportion of patients.11 Reactivation can be severe, and therefore all patients should continue to be followed after stopping treatment, particularly those with advanced fibrosis. In HBeAg-negative disease, reactivation if treatment is stopped is almost universal even after prolonged viral suppression, unless HBsAg loss occurs. In one small study, HBsAg loss was reported in 18 of 33 (55%) patients treated with adefovir for 4-5 years.12 Thus, sustained suppression of HBV DNA is necessary for full clinical benefit, but is not a sufficient measure of treatment efficacy unless it is sustained and durable when therapy is stopped.
Drug Resistance and HBV DNA.
Maintained suppression of HBV DNA on treatment with oral antiviral agents is required to minimize the risk for selecting drug resistance mutations. Rise of HBV DNA on antiviral therapy (excluding interferon) suggests either drug resistance or noncompliance (which may increase the likelihood of resistance). Genotypic evaluation of HBV DNA is needed to establish the presence of mutations in the polymerase/reverse transcriptase gene. Presence of resistance mutations can limit treatment efficacy and if allowed to persist, can be associated with worsening of disease (occasionally associated with fatality).13, 14
Liver Biopsy.
Liver biopsy has, to date, been a prerequisite for almost all trials designed to evaluate new antiviral agents in chronic hepatitis B prior to licensing. Pretreatment and end-of-treatment liver biopsies have been required to demonstrate that treatment improved histological activity and was not associated with worsening of fibrosis (little attention has been paid to regression of fibrosis). The size of the liver biopsy specimen is important in assessing fibrosis, because biopsies less than 2.5 cm can lead to an underestimation of hepatic fibrosis.15 In most clinical trials, a minority of biopsies meet this standard. There are a number of scoring systems designed to report the degree of fibrosis and inflammatory activity. Although the scores are numerical, it is incorrect to assume that they are linear; a change in METAVIR activity from 1 to 2 does not necessarily have the same implication as a change from 2 to 3. The scoring system with the greatest range of values, namely the Ishak score (18 points for necroinflammation and 6 for fibrosis), is more discriminating by virtue of the larger range, and thus it is more sensitive for detecting smaller degrees of change. However, the increase in sensitivity may come at the expense of a decrease in reproducibility.
The development of cirrhosis greatly increases the risk of HCC and the other complications of advanced liver disease, and therefore prevention of this outcome is an important and clinically meaningful goal of therapy. By extrapolation, it seems reasonable to assume that improvement in lesser degrees of fibrosis or inflammation might be beneficial; but this has been difficult to demonstrate objectively. Furthermore, it is impossible to be certain that patients with lesser degrees of fibrosis at baseline are destined to progress to advanced liver fibrosis if left untreated.
In addition to assessment of histology, liver biopsy allows for measurement of levels of hepatic cccDNA (present in the nucleus), which may predict the likelihood of subsequent HBsAg loss. Other viral measurements within hepatocytes have not been extensively examined in terms of predicting outcome. Liver biopsy is an invasive procedure and is not always accurate in assessing fibrosis because sampling errors may occur, particularly if the specimen is inadequate in length. As a result, a great deal of effort has been put into the development of valid biomarkers for both hepatic fibrosis and liver disease "activity", i.e., necroinflammation.
Noninvasive Markers of Hepatic Fibrosis.
Several serum markers have been developed and compared to liver biopsy. Many of these tests were developed initially for chronic hepatitis C. These tests may not be as reliable in chronic hepatitis B, where serum aminotransferase levels can fluctuate widely. Noninvasive approaches to assessing fibrosis using conventional blood tests such as the AST-to-platelet ratio index (APRI),16 Forns,17 Fibrotest,18 ELF (European Liver Fibrosis Group),19 and the platelet count20 have been evaluated in hepatitis B (Table 1).
|APRI; (AST-to-Platelet Ratio Index)
|(AST/AST ULN) divided by (Platelet count/1000) × 100
|AUC = 0.80 for advanced fibrosis APRI < 0.5 − NPV for absence of advanced fibrosis = 0.85 APRI > 1.5 − PPV for presence of advanced fibrosis = 0.88
|Score = 7.811 − 3.131×ln(platelet count) + 0.781×ln(GGT) + 3.467×ln(age) − 0.014× (cholesterol)
|AUC = 0.81 for advanced fibrosis If <4.2 − NPV for absence of advanced disease = 0.96 If >6.9 − PPV for presence of advanced disease = 0.66
|ELF (European Liver Fibrosis Group)
|Score = −0.014×ln(age) + 0.616×ln(hyaluronic acid) + 0.586×ln(PIIINP) + 0.472×ln(TIMP1) − 6.38
|AUC = 0.801 for advanced fibrosis If <0.102 − NPV for absence of advanced fibrosis = 0.92 If >0.82 − PPV for presence of advanced fibrosis = 0.90
|Platelet Count
More recently, transient elastography has been developed as a means of assessing hepatic fibrosis. This approach depends on a device that measures the speed at which ultrasonic waves of low amplitude and frequency move through the liver, which can be measured with a high degree of reproducibility and which reflect hepatic "elasticity". Scores obtained with elastography have been compared to results of liver biopsy and serum-based noninvasive scores and have been found to be equally if not more reliable than the serum-based tests.21, 22 In some individuals (about 10%), reliable elastography measurements cannot be made, particularly in persons who are overweight or obese. Transient elastography scores can be affected by edema and acute hepatic inflammation as occurs in acute hepatitis, disease relapses, and even acute cholangitis.23 Clearly, measurement of hepatic elasticity shows great promise as a noninvasive means of assessing hepatic fibrosis. To date, most studies have been conducted in patients with chronic hepatitis C, and its utility in evaluating outcomes of therapy and longitudinal progression in hepatitis B await further definition. Transient elastography measurements may be particularly helpful in assessing persons with normal results on standard blood tests. In a study from China, 18% of subjects with normal values for ALT, AST, and gamma glutamyl transpeptidase had elastography scores in the range associated with cirrhosis.24 Unfortunately, transient elastography ultrasound systems have not been approved for use and licensed in North America, whereas serum markers are both inexpensive and widely available.
Indirect Measures of Disease Complications.
In patients with advanced liver disease, measures of portal hypertension and hepatic synthetic dysfunction can be assessed as markers of progression of disease. These range from simple evaluations such as the decline in platelet count over time as a measure of progressive portal hypertension, to calculation of either the Child-Turcotte-Pugh (CTP) or Model for End-Stage Liver Disease (MELD) scores. The CTP and MELD scores have been repeatedly validated as predictors of hepatic decompensation and survival. The CTP score incorporates clinical (ascites and encephalopathy) and laboratory (albumin, international normalized ratio, bilirubin) parameters that are objective markers of hepatic synthetic dysfunction, portal hypertension, and liver failure (Table 2). As a result, the use of such measures as endpoints in clinical trials has the advantage of demonstration of clear clinical utility; however, they are only useful in populations of patients with advanced disease at baseline.
|Controlled with medication
|Mild asterixis only Grade I-II
|Confusion or coma Grade III-IV
HBsAg Status.
Natural history studies of chronic hepatitis B stretching over many decades have shown that loss of HBsAg is associated with improved survival25 and reduced risk of HCC26 (particularly if the loss occurs before the age of 50). Recent data indicate that measurement of HBsAg concentration may be a reliable predictor of HBsAg loss while an individual is on antiviral therapy.27 Furthermore, long-term treatment and follow-up of patients treated with interferon or nucleoside analogs indicate that rates of HBsAg loss can rise to 10%-20% over time. It is unclear whether development of anti-HBs is an essential element in documenting effective disease resolution. Reactivation of chronic hepatitis B is possible even after HBsAg loss but only with profound and sustained immune suppression. Furthermore, in rare occasions, clinical outcomes including HCC can arise in patients with chronic hepatitis B after they have cleared HBsAg.
Although loss of HBsAg is clearly a reliable marker of resolution of clinically significant HBV-related disease and is therefore a useful surrogate endpoint, its relatively rare occurrence limits its utility for evaluation of new therapies. To date, it has been difficult to determine the treatment-related predictors of HBsAg loss because it occurs too infrequently in even relatively large cohorts. Because HBsAg loss should be the goal of therapy, a better understanding of the factors predicting this occurrence should be a focus of future research.
The avoidance of progressive liver disease and the development of HCC are the true goals of anti-HBV therapy; however, the time necessary to observe an improvement in these outcomes, in the absence of advanced liver disease,3 makes them unrealistic endpoints for studies or clinical practice. The alternative to using these hard clinical endpoints are various surrogates ranging from serologic markers and viral levels to measures of hepatic fibrosis. These surrogates, while imperfect, are useful as indicators of the need for and efficacy of antiviral therapy. Unfortunately none, with the exception of HBsAg loss, can be considered an accurate and reliable clinical outcome on its own (Table 3). Until therapy improves rates of HBsAg loss or better surrogates are developed, a combination of existing markers of disease activity will have to suffice.
|Surrogate Endpoint
|Control of symptoms
|• Relevant to patients
|• Often asymptomatic even with advanced disease
|• Nonspecific
|Normalization of ALT/AST
|• Inexpensive
|• Significant fluctuation
|• Correlation with disease activity
|• Not specific to HBV
|• Imprecise correlation with histology
|HBeAg loss +/− Development of anti-HBe
|• Predicts favorable outcome if maintained off therapy without HBeAg negative hepatitis
|HBsAg loss +/− Development of anti-HBs
|• Associated with excellent prognosis (particularly if before age 50)
|HBV DNA suppression
|• Unclear significance of low level titers
|Improvement in liver inflammation and/or fibrosis
|• Slow to change (esp fibrosis)
|Improvement in noninvasive tests of fibrosis• serum markers• elastography
|Liver Function
|Improvement in CTP or MELD scores
|• Clinically relevant association with outcome
|• Only relevant in cirrhosis
- 1Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004; 328: 983., , , , , .
- 2Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005; 54: 1610–1614., , , , , , et al.
- 3Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004; 351: 1521–1531., , , , , , et al.;
- 4Need to strictly define hepatitis B virus immunotolerant patients to avoid unnecessary liver biopsy. Gastroenterology 2008; 135: 2155–2156., , , .
- 5Taiwan Community-Based Cancer Screening Project Group. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002; 347: 168–174., , , , , , et al.;
- 6Host and environmental factors influencing hepatitis B e antigen seroconversion in children. J Hepatol 2008; 49: 1079–1080., .
- 7HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. HEPATOLOGY 2008; 47: 428–434., , , , , , et al.
- 8REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65–73., , , , , , et al.;
- 9HBV 99-01 Study Group. Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. HEPATOLOGY 2006; 44: 721–727., , , , , , et al.;
- 10Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352: 2682–2695., , , , , , et al.;
- 11Virological and biochemical relapse after discontinuation of lamivudine monotherapy for chronic hepatitis B in Japan: comparison with breakthrough hepatitis during long-term treatment. Intervirology 2005; 48: 174–182., , , , , , et al.
- 12Predictors/determinants of sustained virological response (and of HBsAg loss following long term adefovir dipivoxil therapy for HBeAg negative chronic hepatitis B) [Abstract]. HEPATOLOGY 2008; 48: A874., , , .
- 13Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003; 125: 1714–1722., , , , , , et al.
- 14Fatal hepatitis B reactivation following discontinuation of nucleoside analogs for chronic hepatitis B. Gut 2002; 51: 597–599., , , , .
- 15Sampling variability of liver fibrosis in chronic hepatitis C. HEPATOLOGY 2003; 38: 1449–1457., , .
- 16A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. HEPATOLOGY 2003; 38: 518–526., , , , , , et al.
- 17Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. HEPATOLOGY 2002; 36: 986–992., , , , , , et al.
- 18MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001; 357: 1069–1075., , , , , ;
- 19European Liver Fibrosis Group. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004; 127: 1704–1713., , , , , , et al.;
- 20Portal Hypertension Collaborative Group. Platelet count is not a predictor of the presence or development of gastroesophageal varices in cirrhosis. HEPATOLOGY 2008; 47: 153–159., , , , , , et al.;
- 21Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128: 343–350., , , , , , et al..
- 22Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006; 55: 403–408., , , , , , et al.
- 23Liver stiffness in the hepatitis B virus carrier: A non-invasive marker of liver disease influenced by the pattern of transaminases. World J Gastroenterol 2008; 14: 6154–6162., , , , , , et al.
- 24Prevalence of fibrosis and cirrhosis in chronic hepatitis B: implications for treatment and management. Am J Gastroenterol 2008; 103: 1421–1426., , , , , .Direct Link:
- 25Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut 2008; 57: 84–90., , , , , .
- 26HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. HEPATOLOGY 2007; 45: 1187–1192., .
- 27Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response. Clin Gastroenterol Hepatol 2007; 5: 1462–1468., , , , , , et al.


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Annual fashion event will benefit Boys and Girls Clubs of Grand Rapids.


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Welcome to the September edition of What's Hoppenin' at eZanga. This month, we're going to school you on everything that's been going on in our office over the past month. We're gearing up for a very busy fall, so without further adieu, let's get to it!
Intern Manifesto: What Tanner's Internship Was Like
When I first stepped through the doors of the eZanga office, I was told I looked lost. And this was a fair and accurate observation. I had no idea what I was doing, where I was going, or what to expect. I was the sole intern this season and it was honestly a little intimidating. But any fear or apprehension I had coming in quickly dissipated as I learned what the people at eZanga were all about.
Please Take Our Ad Fraud Survey
At eZanga, we strive to continuously grow within the industry, and one way to stay ahead of the curve is to listen to the concerns of our clients and colleagues. In an effort to improve our service, we'd like to get your feedback through a survey regarding the effect ad fraud has had on your business. Your responses will aid eZanga in ensuring our offerings coincide with the needs of your business and your fight against ad fraud.
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Monetize Your Blog With eZanga InText
If you have a WordPress site, you have a source of income. Are you looking to monetize traffic to your WordPress blog? Do you want to do it without disrupting your readers' experience? That's where eZanga InText comes in.
eZanga Cools off With a Pool Party!
Here at eZanga, we're itching for a reason to party. It's the middle of summer, it's hot, and the sun is shining bright. Sounds like the perfect time for another pool party at the Kahn-pound!
What's Hoppenin' at eZanga In July?
Welcome to another edition of What's Hoppenin' at eZanga. This month, I'm going to give you the low-down on what's going on around our office. You'll get an inside look at the office gossip, our latest newsworthy moments, and maybe even a prank or two! Let's get to it, shall we?
Rich Kahn Takes Over the Airwaves
Rich Kahn recently sat down with Kevin Price of the Price of Business Radio Show to discuss eZanga's business model, online advertising, and how eZanga eliminates click fraud.
Playlist of the Month: Born in the U.S.A
Happy (almost) Fourth of July!
Is it hot enough for you yet? Summer is just getting started, and it's time to give three cheers for the red, white, and blue.
So this month, we take it from the mountains, to the prairies, and everything in between. Here are the best songs our 50 states have to offer.


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Citi Compensates Bondholders For Pain And Suffering Of Worrying That Citi Might Default
Back in the pre-Lehman days Citigroup owned a lot of things that, in hindsight, turned […]
Should You Mourn For JPMorgan's Trust Preferred Securities?
I spend a good 40% of my day mindlessly refresing JPMorgan's page at the SEC […]
High-Frequency Monitoring: A Short-Sighted Behavior
The more frequently you monitor your portfolio, the more likely you are to observe a loss.
This is likely to cause short-sighted decisions and could hurt your investment performance.
If you are checking your portfolio more than once per quarter, you're doing it too much.
Click to read more.
Dan Egan, Betterment Director of Behavioral Finance and Investing


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Durable Goods Slump Is Bad for Workers, But Stocks Aren't Doomed
Durable goods are in a prolonged slump, which contributes to the widespread misconception that the U.S. is still in recession. Read Article
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Financial Advice – 5 Spring Cleaning Money Tips
Financial advice isn't normally something many people seek out, so take a look at key money issues this spring and refine your plans. Read Article
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The Federal Reserve moved its 'dot plot' estimates south, surprising Wall Street and leading to strong gains on Wednesday. The question now: Will the gains stick? Read Article
Stocks Mixed as Wall Street Awaits the Fed
It's been almost a decade since the price of money actually increased; but in as little as three months, it could start rising again. Read Article
Monday's Stock Market Game: Bad News Is Good News
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FOMC: Why You Should Just Shut Down Your Trading Console
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Lower-than-expected retail sales weren't enough to keep down stocks Thursday, though Intel Corporation (INTC) took a hefty spill. Read Article
Stocks Dribble Lower as Fed Fears Grow
Growing fears that an eventual interest-rate hike is on the way continued swinging the market pendulum in the other direction on Wednesday. Read Article
Strong Dollar, Interest-Rate Fears Crush Wall Street
The U.S. dollar is strengthening to levels seen in two previous recessions, and job openings data point to increased likelihood of a June interest-rate hike. Watch out below! Read Article
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Stocks Mixed on Crude Schizophrenia
Mergers and acquisitions and corporate action resulted in some excitement in select stocks, but it was largely a quiet day as Janet Yellen's remarks failed to move the markets. Read Article


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14905 Views 6 Replies Latest reply: Mar 30, 2009 1:46 PM by gert7
Niel Jan 22, 2009 9:28 AM
Re: Can't quit iPhoto in response to matthijsenPress the Option, Command, and Escape keys, and force quit iPhoto.
matthijsen Jan 22, 2009 9:33 AM
Re: Can't quit iPhoto in response to NielThank you Neil!!!
LarryHN Jan 22, 2009 9:34 AM
Re: Can't quit iPhoto in response to matthijsenMatt
Welcome to the Apple user to user assistance forums
the key combination is command(alt)/option(apple)/escape
and it is important to figure out what the problem is - force quitting iPhoto (are any program) can lose data and in iPhoto's case if that data is the database information it can create problems with the library
You might post back with more details on what i going on
gert7 Mar 30, 2009 1:14 PM
Re: Can't quit iPhoto in response to LarryHNSame here. iPhoto is unwilling to quit since a few days. Obviously Force-Quit works but this is not the way I would like it to be. By the way looking in
Terminal - Top
Doesn't show any activity within iPhoto. Anyone knows what is going on?
Terence Devlin Mar 30, 2009 1:30 PM
Re: Can't quit iPhoto in response to gert7Any messages in the Console?
gert7 Mar 30, 2009 1:46 PM
Re: Can't quit iPhoto in response to Terence DevlinSome lines like:
30-03-09 22:03:18 /Applications/iPhoto.app/Contents/MacOS/iPhoto[691] open on /Users/gert_MBP/Library/Application Support/iLifeSlideshow/Effects/Simple3DTransition.qtz: File exists
I just got rid of a Flickr-slideshow or what-is-it-called like and then my iPhoto wouldn't activate anymore. A Force-Quit and a restart and I'm able to do a normal 'quit' again!
Seems everything back to normal. No idea if it's related to Flickr. I saved the full console messages if you're interested.


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Recent Meetups
July 14 · 6:30 PMDUKALE'S DREAM Film Screening & Artisan Chocolate TastingJoin us for a sneak preview of the film: DUKALE'S DREAM directed by Josh Rothstein and a special artisan chocolate tasting by Luxx Chocolat! Luxx will be serving a... Learn more
February 7 · 5:00 PMChocoVin Chocolate & Wine Tasting @ Mohonk Mtn HouseJoin us 2/7/15 @ Mohonk Mountain House for a special ChocoVin chocolate & wine tasting celebrating their annual Art of Chocolate weekend! ChocoVin Chocolate and Wine... Learn more
January 23 · 7:00 PMChocoVin chocolate & wine tasting @Upper Saddle River LibraryChocoVin chocolate & wine tasting @Upper Saddle River Library Perfect Pairings - A Chocolate and Wine Tasting Experience Join us for the Friends fundraiser and indulge... Learn more
Jan 30, 2013 · 6:30 PMPrivate Film Screening with Artisan Chocolate Tasting by Luxx ChocolatJoin us for the first Cinémonde soiree of the New Year on Wednesday evening, Jan. 30 as we host filmmaker Olivia Silver with a sneak preview of her award-winning feature... Learn more
Jul 14, 2012 · 6:30 PMPrivate French Film Screening with Artisan Chocolate Tasting by Luxx ChocolatCinemonde is a private screening series of thought-provoking movies for film, media and entertainment professionals (and anyone else who loves great food, drink, people... Learn more
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Hotel was in a nice location, just in the beach with walking distance to South Beach!!! Rooms are little bit dated but very clean and well maintained, comfy beds, nice and clean linen Friendly staff, affordable price
Hotel was in a nice location, just in the beach with walking distance to South Beach!!! Rooms are little bit dated but very clean and well maintained, comfy beds, nice and clean linen Friendly staff, affordable price
Review collected in partnership with Best Western
love this hotel and its employees.. Jose the front desk supervisor really went out of his way help me.. I would recommend this hotel to my friends and family. the rooms are wonderful the pool is nice and the breakfeast was delicious......
Review collected in partnership with Best Western
Clean Rooms with comfortable beds. Good facilities, Nice area, amazing ocean view from balcony, direct access to the Beach The staff throughout the hotel are all extremely nice, especially our Room Attendant and The guys at Front Desk Overall, a great stay and I will definitely stay again in the near future.
Review collected in partnership with Best Western
Ok so my experience at this hotel was overall great. No, it is not luxurious, to the point that it even looks quite old. However the location is fantastic, right on the beachfront. You can even access the beach from the back of the hotel lobby. The concierge was very helpful as was the rest of the staff who were... More
This Best Western is a very nice hotel right on the beach. I have read reviews on here and they are quite misleading. Often so many people go online to type negative things but never when it's positive. And most of the travelers reviews are extremely unfair. There are so many other properties to choose from. If you don't like... More
Dear guest: Thank you! Thank you! I cannot express enough how much your review means to us. Your honesty is very much appreciated and we are so grateful for your comments regarding our staff. These gentleman along with others go above and beyond each day to make sure our guests have a wonderful stay. I wanted to mention that we... More
HOW A PROFESSIONAL MANAGER ON DUTY SOLVED THE PROBLEM.. purchase a glass of chardonay at 659opm and the cost is a little over seven dollars Do it at 7 01 and its more than fourteen dollars for one glass. While the ambience is adequate its nothing special , no comfortable chairs not a nut in sight. With the knowledge that... More
Dear guest: We are pleased that you enjoyed much of your stay with us but anything less than perfect calls for improvement on our part. It seems we did not meet your expectations in a few areas of our service and we appreciate you taking the time to notify us of your concerns. We want to ensure that our guests... More
The hotel is in a great location, very close to the south Beach in quite area is affordable and very clean. The hotel staff were very friendly and charming Great Bar at the pool area, direct access to the beach We had a great stay
Review collected in partnership with Best Western
Dear guest: Thank you for the wonderful review. We are always so pleased to hear that our guests had a wonderful time in this great city and our Hotel. We look forward to your visit with us once again. Best Regards, Barbara Romano General Manager More
Hotel staff uncaring, rooms unclean, pay to use everything! $30 a day to park $30 for shuttle $14 a person for breakfast. Don't waste your time. The area does not look very nice, The bed sheets had small blood stains droplets on them (a sign of bed bug bites) The staff was very uncaring when it came to issues that... More
Review collected in partnership with Best Western
Dear guest: I am so sorry to hear that you were not pleased with your stay. It is concerning to hear your comments on cleanliness as we are always complimented on how clean our hotel is. We value your opinion and will definitely use your comments to make any necessary changes in our daily operations. We hope that you will... More
This was our once-in-a-lifetime trip to Miami Beach, so getting a room that faced another building and overlooked a rooftop, was quite a let-down from the ocean view we had requested! The hotel was clean and the beach was right behind it, so that was nice. We learned that it was so far north from all the South Beach action... More
Dear Guest: Thank you for your review. I am very sorry to hear that you were not given a room with the view you expected. I hope that we will were able to make it up to you with our amenities and service. Please reach out to us directly next time so that we can make sure we give you... More
We stayed at Best Western Atlantic Beach three nights, we were very pleased with everything: the staff is nice, the rooms are really clean, the location is perfect just in front of the beach, you can get beach towels anytime. I recommend this hotel 100%.
Review collected in partnership with Best Western
Dear guest: Thank you for the wonderful review. We are always so pleased to hear when guests have a great time and take the time out of their schedule to let us know. Thank you, Thank you! Barbara Romano General Manager More
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hi is there any convience stores or such close by....or subway other fast food options...is there a liquor store close by...
We leave for our cruise the morning after our stay, what transportation is available and do I need to make arrangements in advance?
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My favorite drug stock right now is Merck (NYSE:MRK). I'm excited about the cost savings that I think can be achieved by its planned merger with Schering-Plough (NYSE:SGP). Moreover, according to a March 9 Schering press release, "Post-transaction, the combined company will have a strong balance sheet with a cash and investments balance of approximately $8 billion." This gives the company options to perhaps - and I'm speculating - buy back shares, up its dividend or make acquisitions.
IN PICTURES: Biggest Stock Scams
With that in mind, my second-favorite drug stock for the long haul is Pfizer (NYSE:PFE). Trouble is, I'm not super excited about the stock's potential in the near term. Here's why I think it could struggle over the next few months, and what makes it attractive to me for the long run:
Short Term Issues?
April 28, the New York-based company disseminated its first-quarter earnings report. It earned 54 cents per share, which was well ahead of the 49 cents Wall Street had expected. However, in that same release, in the "financial guidance" section, it indicated it was looking for adjusted diluted earnings per share (in 2009) of "$1.85 to $1.95." That's a bit of a disappointment in that the estimate from Thomson Financial Networks is $1.95 per share. In short, we could see estimates tick down as a result, which I think would be a negative. (Learn how this key metric is calculated and how it is used to judge market performance in Earnings Forecasts: A Primer.)
Another concern I have is Pfizer's planned acquisition of Wyeth (NYSE:WYE), which is expected to close in either the third or fourth quarter. Wyeth is an extremely large company that booked $22.8 billion in revenue in 2008. I worry that because it is so large, Pfizer, which generated 2008 revenue of $48.3 billion, could have trouble bringing it under its wing, and that it could take a couple of quarters for it to fully appreciate what it's buying.
An article in BusinessWeek earlier this year offered an interesting take on Pfizer's (prior) acquisition of Pharmacia. According to the article, "The Pharmacia acquisition turned out to be a disappointment because its biggest drug, the Cox-2 inhibitor Celebrex, was severely damaged by the fallout over Merck's similar drug, Vioxx, which was pulled from the market due to safety concerns." Again, the point is that sometimes you don't know what you will get. (Learn more in Measuring The Medicine Makers.)
Long-Term Likes
In spite of the pessimistic attitude I displayed above, I think a merger with Wyeth has the potential to bear tangible fruit down the line. After all, because of its sheer size, logic seems to dictate plenty of cost savings to be realized. Furthermore, I do think it can add big-time to earnings down the line. Per the Pfizer press release, "The deal is expected to be accretive to Pfizer's adjusted diluted earnings per share in the second full year after closing."
Another thing that caught my attention in that same January 26 release was this comment: "It is expected that no drug will account for more than 10 percent of the combined company's revenue in 2012." In short, I think that such diversification could be a big plus for both the company and shareholders. Compare this to Novartis (NYSE:NVS), where Diovan, its high blood pressure product, represented 14.4% of sales in its first quarter.
Bottom Line
I am concerned that Pfizer could have its hands full with the Wyeth acquisition in the near term. I also think that some may be disappointed with its earnings outlook for 2009. However, I like this company for the long run and believe that combining forces with Wyeth will pay off down the line. I particularly like the product diversity the combined company is expected to have and the potential for cost savings.
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Description from the owner
Description from the owner
Bedrooms: 2/
Bathrooms: 3/
Sleeps: 4/
Type: Villa
This luxury two bedroom (all en-suite) villa was originally an antique wooden joglo from Java which was transported to Canggu in Bali and rebuilt to our own specification. The building and interior design was completed in August 2012.
There's lots of space for you to hang out and relax in the large living area. There are also plenty of bean bags and sofas to sit and read or catch a movie from. The kitchen and dining area is fully equipped and ready for expert and novice chefs alike! The villa was designed specifically for laid back fun. Villa Sena also has super-fast wireless internet throughout.
Our guest accommodation consists of 2 private ...Read more
About the owner
About the owner
Rachel F.
Rachel F.
- Response rate: 78%
- Response time: Within 2 days
- Calendar updated: 2 months ago
Overall rating:
Additional Location Information
We are located in Berawa, Canggu, within walking distance to Desa Seni the world class yoga resort. Canggu is a wonderful village just out of the hustle and bustle of Seminyak. We are close to the beach & the local convenience store. There are an abundance of amazing cafes and restaurants in Canggu. There are numerous world class surf breaks close by to Villa Sena. The world famous Echo Beach is just a 10 minute drive away. The airport is 35 minute drive away. Taxis are an affordable way to get around and also scooter hire is inexpensive.
More About This Location
Beach or lakeside relaxation, City vacations, Warm winter getaways
Getting There
Nearest ferry port: Sanur, 15 miles
Nearest airport: Denpasar, 9 miles
Car is not necessary
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"A Song that Defines Love." Shelter, from Ray LaMontagne.
A love song worthy of its subject.
I met him a year ago—was going to see him at Macky [Auditorium in Boulder] that night, ran into him and a band member (who was very nice) at Boulderado [Hotel]. He was super shy, reserved, something like that. Then, that night on stage, he avoided the spotlight, even faced away from the audience…and then he unleashed that voice, that's not shy or reserved at all. Whew!
Incorrect source, offensive, or found a typo? Email us (please put title in subject bar of email so we'll be able to fix). Or do you want to write for Elephant?
{Waylon H. Lewis C Enterprises 2015: Use Rights in perpetuity. Ownership remains with author.}
2 Responses to ""A Song that Defines Love." Shelter, from Ray LaMontagne."
His new album is amazing.
Great song, great voice, great band, great arrangement, beautiful location…
Thanks for the tip.
ps – u gotta love the BBC too.


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Cobblestone Manor Luxury Historic Inn
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The Beginning of the Blog
... of Light orphanage and Ministry. This will be my first international mission trip. I am really excited to see God move in this country. Thank you for your support and stay tuned. Please pray for our safety, financing, and that we achieve our ...
Day 56 Caro, MI To Capac, MI Mile 3,016
... and vintage display cases. I was greeted by old Gus and a group of men sipping on their first coffee of the day and munching on donuts. Gus was laying dollar bills on the counter in neat little stacks, meticulously counting his cash drawer. When I paid for my second breakfast, he looked up ...
Reaching for the Stars
So, I should have started this a week or two ago when I first had the idea, when I first decided to throw my lasso up to sky and try to actually capture a dream. I guess a part of me has always wanted to travel and to see the world, to be free. Although it never seemed a possibility because even setting one toe outside my comfort zone would turn me into a hyperventilating mess.
Today is a hard day. A day I know will happen more than once whilst I am saving up and ...
The Avengers
... our shopping we headed back to the apartment were Andy cooked us a nice Chinese meal before we got ready for the evenings entertainment.
We had decided, prior to my arrival, that we would go to the Movies In The Moonlight event in Rochester as they were showing The Avengers (one of my favourite films). We managed to park in the car park right next to the event so we could be away sharpish. There was a fancy dress event for kids dressed in ...
A relaxing Sunday
... the same. I also loved that communion and the words amen an alleluia were universal. After every song the entire congregation said amen, instead of clapping or cheering. I loved that this is the same in all languages. After over three hours of service, we walked around downtown, headed home for lunch, relaxed for the afternoon and then headed out to see one of the local beaches. The beach was beautiful! ...


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December 11, 2012 The American carrier is hoping to crack into the lucrative New York-to-London route. The deal, which needs regulators' approvals, would also let Delta's passengers connect with Virgin's flights out of London.
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|Reviews for CC Academy
| Guest chapter 6 . 3/27
This is really good please continue
| Guest chapter 6 . 7/2/2014
Awesome story!
| Guest chapter 6 . 5/14/2014
Don't make an enemy appear gohan's dreams mean nothing please where's his tail pwease and make mari trunks come him and lime love Gohan and videl bound Hercule forbids freak out Gohan and mari train videl lime erasa sharpener all figure out who and what Gohan and mari are tails for all sayians please
| Imma Gokuu chapter 6 . 10/14/2013
come on man, please continue the story!
| Guest chapter 6 . 4/28/2013
i like the story,except the dreams.
| GohanSSJ2x chapter 6 . 4/23/2010
i love this story so far dont quit on it now its been 3 years
| blueyblonde chapter 6 . 6/14/2008
i love it
| Rohan777 chapter 6 . 2/9/2008
Great story. I really enjoyed reading the first 6 chapters. _ Great formatting, spelling and grammar too. Well, I'm curious to see what those dreams mean. And what'll happen on the Cell anniversary. Anyway, I hope you'll eventually post another chapter. Good luck writing it. _
| Neco-chan chapter 6 . 1/15/2008
This is a really GREAT story! I'm a HUGE fan Gohan and Videl fanficts. I hope that this story isn't discontinued and I hipe that you update soon
| Meca Vegeta chapter 6 . 12/11/2007
| LinkOOT chapter 6 . 4/5/2007
I really like the foreshadowing your doing. It makes you wonder whats going to happen and who this mysterious villain is. The videl/gohan relationship seems to be going quite well too. So yeah, Im lokking forward to reading your next update. See ya!
| Ookii Mamoru chapter 6 . 4/3/2007
Videl, and flowery dress?
Ya right!
Great fic, I look forward to seeing more.
| TheRomanticNerd chapter 6 . 4/3/2007
I have NO idea what happened in all the previous chapters... But it was enjoyable reading this one. .
| SamuraiGirl7 chapter 6 . 4/3/2007
Overall I like this story. It seems pretty interesting and the whole Lime/Videl and Gohan situation adds some flavor to it. I look forward to the next chapter.
| lime-hater chapter 1 . 1/5/2007
Gohan would NEVER even LOOK at another is the ONLY girl for are the ultimate to my strong personal conviction on this subject,I cannot condone your portrayal of this SICK 'love triangle'as some would call it.
Also,DEATH TO LIME !DEATH TO LIME! DEATH TO LIME! DEATH TO LIME!
I can't STAND the ugly,fat and grotesquely freckled BITCH!


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.@TommySmythESPN and @alexisenunes make their predictions for this weekend's matches, including #USAvMEX: es.pn/1huQaTa
.@TommySmythESPN and @alexisenunes make their predictions for this weekend's matches, including #USAvMEX: es.pn/1huQaTa
Marco Reus is on Barcelona's list of "most wanted" for the summer of 2016. Transfer Talk: es.pn/1P4MvtX pic.twitter.com/qW2Eq9NZqx
Kyle Beckerman. Jurgen Klinsmann's midfield destroyer. es.pn/1LE6Vtp (@DougMacESPN) #USAvMEX pic.twitter.com/fJD6WKF7nb
Sir Alex Ferguson is confident that Jose Mourinho will get Chelsea back on track. » es.pn/1VJKxy7
Will the United States or Mexico win on Saturday? VOTE: es.pn/1PlfJ79 #FCDebate pic.twitter.com/PVdMlRs2bB
The FC crew make #USAvMEX predictions, we'll have Euro qualifying highlights & Stevie gets excited about Jurgen Klopp. 6 ET on ESPNEWS!
England's win was mostly dull, with Walcott & Barkley the exceptions. @AlexShawESPN: es.pn/1P4xuIB pic.twitter.com/KUzuNHBSuU
Have a question for @SteveNicol61, @AleMorenoESPN and @JanuszMichallik? Use #FCExtraTime!
#EURO2016 FT: Slovenia 1-1 Lithuania Liechtenstein 0-2 Sweden Slovakia 0-1 Belarus Moldova 1-2 Russia
Switzerland qualify for #EURO2016 after beating San Marino, 7-0.
FT: Spain 4-0 Luxembourg Spain clinch #EURO2016 qualification but lose David Silva and Alvaro Morata to injury. pic.twitter.com/12xVCsrM1t
FT: England 2-0 Estonia England stay perfect in #EURO2016 qualifying. pic.twitter.com/Ee0hWgd0k0
Santi Cazorla with his second of the day! His low strike makes it 4-0! #EURO2016
GOAL, ENGLAND! Raheem Sterling doubles the lead! 2-0! #EURO2016
Goal, Spain! Paco Alcacer with a nice run and cool finish. Assist from Cesc Fàbregas. 2-0 #EURO2016
Theo Walcott slides the ball in after a great pass from Ross Barkley. Watch: es.pn/1FWP6Dw (U.S. only) pic.twitter.com/7iJUwqhqfQ
HT: Spain 1-0 Luxembourg David Silva and Álvaro Morata both leave the game injured. #EURO2016 pic.twitter.com/tEHp2oFxMp
HT: England 1-0 Estonia Theo Walcott's 45th-minute goal separates the sides at the break. #EURO2016
GOAL, England! Theo Walcott gives England the lead just before half-time! 1-0! #EURO2016
GOAL, Spain! Santi Cazorla scores the opener after Pedro's shot is saved! 1-0! #EURO2016
Santi Cazorla hits the crossbar! #EURO2016


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NARS Laos Matte Multiple ($39.00 for 0.26 oz.) is described as a "rose coral." It's a brightened, medium-dark pink-coral with a satin-matte finish. theBalm Pie (P) is lighter, warmer. Chanel Intonation (69) (LE, $38.00) is also lighter, less pink, but sheered out, they're very similar applied. NARS Soulshine #3 (LE, $29.00) is more shimmery, darker. MAC Simmer (LE, $25.00) is more shimmery, slightly lighter. MAC Mocha (P, $21.00) is less warm-toned, pinker, powder. See comparison swatches.Read Full Review
Urban Decay Native Naked Flushed Palette
Urban Decay Native Naked Flushed Palette ($30.00 for 0.49 oz.) is a new trio that features a bronzer, highlighter, and blush. It is a follow up to Naked Flushed. This one seems to [attempt to] match the blush to the colors of Native Lipstick and Native Lip Pencil, which are both light-medium pinks. I don't think it's a great match for either the lipstick or pencil, as it is distinctly cool-toned, whereas the lipstick is warm-toned and the pencil more neutral-to-warm-toned. To me, the color is a better match for Obsessed Lipstick. I didn't like the original Naked Flushed palette, as I felt like the texture was firm and drier, but I didn't love this one either, as it was powdery–makes me feel a bit like Goldilocks. Though you'll see excess powder as you grab product onto your applicator, it doesn't seem to look powdery on the skin, so that's definitely a plus. It's not ideal to have so much excess sitting on the surface of the pan when there are three shades that sit next to each other. The highlighter emphasizes pores/skin texture, which is a drawback. If used lightly, that effect can be lessened, but some care is required–it's not foolproof.Read Full Review
NARS Siam Matte Multiple
NARS Siam Matte Multiple ($39.00 for 0.26 oz.) is described as a "warm poppy red." It's a bright, deep red with warm undertones and a satin-matte finish–it is very true-to-description. theBalm Cobbler (P) is similar in color but has more of a sheen. Kevyn Aucoin Fira (P) is more orange, powder. NARS Exhibit A (P, $29.00) is more orange, powder. See comparison swatches.Read Full Review
NARS Exumas Matte Multiple
NARS Exumas Matte Multiple ($39.00 for 0.26 oz.) is described as a "pink apricot." It's a medium-dark, coral-orange with a smidgen of pink and a satin-matte finish. Sleek MakeUP Pink Mint (P, $6.99) is more shimmery, powder. NARS Final Cut (LE, $29.00) is lighter, powder. Make Up For Ever #410 HD Blush (P, $26.00) is pinker. Fyrinnae Nordic Angel (P, $6.50) is lighter, powder. Illamasqua Sleek (P, $26.00) is darker, pinker. Chanel Presage (62) (LE, $38.00) is slightly darker. theBalm Swiss Dot (P, $22.00) is more orange, powder. MAC Early Morning (LE, $25.00) is darker, powder. MAC Fiery Impact (LE, $25.00) is darker, more shimmery, powder. See comparison swatches.Read Full Review
NARS Cappadoce Matte Multiple
NARS Cappadoce Matte Multiple ($39.00 for 0.26 oz.) is described as a "golden bronze." It's a medium-dark, orange-toned brown with strong, warm orange-yellow undertones and a semi-matte finish. Guerlain Moyen Brunettes (05) (LE, $75.00) is lighter, less warm-toned. MAC Exotic Ember (LE, $25.00) is darker, more shimmery. MAC Hibiscus Kiss Bronzer (LE, $25.00) is lighter. Clarins Splendours (LE, $35.00) is lighter. MAC Billionaire Bronze (LE, $29.50) is darker, shimmery. Le Metier de Beaute Sun Drenched (P, $55.00) is very similar but a powder product. See comparison swatches.Read Full Review
NARS Anguilla Matte Multiple
NARS Anguilla Matte Multiple ($39.00 for 0.26 oz.) is described as a "ginger pink." It's a light-medium pink with warm, yellow undertones and a satin-matte finish. Hourglass Radiant Magenta (P, $35.00) is lighter. NARS Love (LE, $29.00) is darker, less pink. Physicians Formula Natural (P, $11.99) is more shimmery. Chanel Revelation (63) (P, $38.00) is brighter, pinker. See comparison swatches.Read Full Review


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Last month I had the great pleasure of meeting Raphaella Bilski, author of My Street Cats: Their Personalities and Social Behavior, on Facebook. Her love of stray cats, and her mission to help them for over 16 years touched my … Continue reading
Are you surprised to see a book on this blog about cats? Well, I may only have a dog right now, and Rescue Me may only be about dogs, but I love cats, too. One of my favorite things to … Continue reading
We are very excited to announce that our book, Rescue Me was honored by the Dog Writers Association of America as the winner of the Maxwell Medallion in the Human-Dog Bond Books Category. The Dog Writers Association of America awards banquet … Continue reading
About Amy: Amy Burkert runs the award-winning pet travel website, GoPetFriendly.com, which makes it easy for you to plan trips with your entire family- including your pets. Amy's blog, Take Paws, is an encyclopedia of pet travel tips, pet friendly destination advice, … Continue reading
Welcome fellow pet bloggers and readers. A big hello from me and Teddy. 1. How long have you been blogging? For anyone stopping by for the first time, please give us a quick description of what your blog is about. … Continue reading
Outraged dog lovers and pit bull advocates reacted to recent remarks made by Dr. Laura Schlessinger about pit bulls. In a nut shell, she said that shelters are full of pit bulls and pit mixes no one wants, so they should … Continue reading
Ghost Dogs and Spirits – a true Halloween Story When I rented a furnished home for a few months, the last thing I expected to see were ghost dogs and spirits. But it happened to me. One sunny fall morning … Continue reading


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Yellowstone Part 2, Jackson Hole and Park City
... doing this trip for two years and only seen one bear in the wild from a few hundred metres away, so we were very lucky. Following on from an additional couple of hours in Yellowstone, we continued onto Jackson Hole, Wyoming via a brief stop at the Teton National Park. It goes to prove though that the American Indians had dirty minds, because roughly translated Teton means big breasts. Having said that, the mountains in the Teton National Park were ...
Unexpected religion
... with no real intent, yelling out at people across the street with shady visitors coming in and out. We passed several 'adult' clubs and shops and even were yelled at by a seemingly homeless guy while on our drive to Walmart where we finally experienced the famous American discounted store. Where are all the nicely dressed, prim and proper Mormons that this city is so well known for? Probably in bed sleeping since it was 8pm but I no longer had a strong desire to move ...
Arches and Canyonlands
... a rare kind of organism that lives in some of the "potholes" in the park that fill with water. They are called tardigrades and experiments have been done on them to try to kill this organism and seems ...
A Corner Turned
... way to Salt Lake City was a long long drive with very few signs of life along the way. There aren't many towns, no trees and very barren landscape. As we drove past Lovelock we noticed a big 'L' carved into the hillside above the town and I said to Elvis 'L for London' and took a photo. The next town we came to was Carlin and there above the town a 'C' in the hillside. We looked at each other and ...
Nevada in a Day
... horizon but we drove and drove and drove and drove to finally reach it. The desert is completely flat so you could see things far off in the distance, but it took forever to reach them. We made it to Salt Lake City in time to make dinner and for Morgan and I to get some much needed retail therapy. Yes!
Tommy caught up on emails and work stuff and Clay worked on his school work. Then is was time for a little TV and bed.Tomorrow we get to explore Salt Lake City. ...


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Blog: Weather is cooling down in Hampton Roads
It was a warm day for some and a cool day for others depending on when the cold front moved through your neighborhood.
It was a warm day for some and a cool day for others depending on when the cold front moved through your neighborhood.
The couple filed a claim in 2008 with their insurance company, State Farm, and a lawsuit against the home's previous owners for not disclosi…
The guided-missile destroyer was attacked a small boat laden with explosives during a brief refueling stop in
Police say the parents, Adam and Jasmyne Alexander, both age 21, left their girl unattended in her crib from 8:30 p.m. Saturday to 12:30 p.m…
What looked like a Halloween trick was actually an array of treats being served up Saturday at the Audubon Butterfly Garden and Insectarium …
Dispatch confirmed the accident happened around 4:30 p.m. on Saturday.
The run/walk event was Saturday, Oct. 11.
A 21-month-old girl is the first person in Michigan to die from the virus that has caused severe respiratory illness across the country, sta…
The flames on the 6000 block of Camellia Drive in Suffolk were under control within a half an hour, according to fire officials.
WAVY Sports Director Bruce Rader presents Friday Night Flights with co-host Anita Blanton.
Photos from high school football games in Hampton Roads, Va. on Oct. 10, 2014
It's week six of the Old Dominion Football Show with Bruce Rader and Coach Bobby Wilder.
The infestation on the second floor was found Thursday.
The Band of the Week for October 10, 2014 is Grafton High School.
The man overdosed the night of the sale, according to authorities.
A new condition for the electronic toll collection company says: You agree not to dispute charges that are more than six months old.
Three former leaders of a Norfolk-based destroyer received non-judicial punishments on Thursday.
The man walked through the door of the business Thursday night with a mask on demanding money.
Some $4.8 million in federal homeland security funding is headed to 79 projects around Virginia.
Gov. Terry McAuliffe has become the first Virginia governor to preside over a same-sex wedding ceremony.
A woman concerned about a public utilities project has succeeded in getting the city to go back to the drawing board.


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For over 30 years I have successfully resolved thousands of injury claims for my clients
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Attorneys offering services in personal injury, premises liability, medical malpractice, dangerous drugs, wrongful death, construction, and car accidents.
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Welcome to the Southern Highland Craft Guild
Since 1930, artists from Maryland to Alabama have come together to create a network and market for mountain craftspeople. Today, Guild membership stands at more than 900 artisans selected by a jury for the high quality of design and craftsmanship. The Southern Highlands continues to inspire and lead the craft revival movement.
Discover Handmade Originals TodayShop Online
Shop Our Retail Stores
Bauman Mountain Heart Earrings - oxidized
Celebrate your love of the mountains with these heart-shaped landscape earrings by Pat and Tom Bauman of Asheville, NC.
Featured Member
Steve Noggle
Steve has been working with trees and wood since finishing a degree in Forestry in 1976 from LSU in Baton Rouge. After a few years as a timber cruiser in the Pacific Northwest, Steve returned home to North Carolina and began his career as an engineer in the furniture industry. He has been building fine furniture for himself and friends and family since college at first out of necessity and later purely for pleasure.


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Select Local Merchants
A&W RestaurantRead MoreAs an iconic American brand, A&W stands for good times had over classic American food & treats. It all started in 1919 at Roy Allen's Root Beer stand, celebrating the return of World War I veterans. After partnering with Frank Wright, the good times never stopped, as A&W became the first major food franchise, growing along with the country over the course of the next several decades. Today, A&W remains a place for friends, families & communities to gather over the simple pleasures of great food & great company. We make quality food fresh just for you! Our Burgers are cooked-to-order with your choice of toppings, & our Hand-Breaded Chicken Tenders are 100% all-white meat, lightly breaded, & cooked to juicy, mouth-watering perfection. Our Root Beer is still made fresh in our restaurants with real cane sugar - top it off with our creamy vanilla soft serve for one of our signature Root Beer Floats!717 E Wisconsin StPortage, WI US
Tamarack PizzaRead MoreIf you have yet to eat at Tamarack, now is the perfect time to check out the popular pizza place. It's a popular restaurant for customers that want outstanding food. Thanks to its outdoor seating, the restaurant is a fantastic option when the Wisconsin weather cooperates. There's no specific recommended attire, so feel free to dress casually and comfortably. Also, though the overall price can be a bit on the low side, you won't be sacrificing any quality. In fact, you should be able to enjoy a good meal for $11 or $12, and can probably get in and out for $8 if you try. When you get there, think about ordering the pizza, as it's frequently raved about. In terms of the restaurant itself, if you're on the lookout for the perfect spot for family or friends, it's been reviewed as a solid option for large groups and kids. If you don't feel like eating in, you can always grab your food to go, or just place an order for delivery. Or, if you just want to pop in for a beverage, the restaurant does have a pretty decent selection at its bar. A staple in the community for more than four decades, Tamarack definitely won't leave you disappointed, no matter how you slice it.412 E Wisconsin StPortage, WI US
Jimmy John'sRead MoreOne of the better-priced fast food restaurants in Portage, customers of Jimmy John's won't break the budget for a satisfying meal and enjoyable experience. Come by for the great quality and stay for friendly service. You'll be a regular at Jimmy John's before you know it. There's no specific recommended attire, so feel free to dress casually and comfortably. Also, though the overall price may be low, you can bank on the ingredients being fresh. In fact, you should certainly be able to enjoy a good meal for nine or ten bucks, and can probably get in and out for just a fiver if you try. There really is something for everyone, with gluten-free options, as well as low-fat and vegetarian items on the robust menu. Plus, most local parents will tell you that it's a good place to bring the kids, as well. In addition to its quick service (take-out is available), the restaurant also offers delivery, and can even cater an event for you. One of the better fast-food chains in the area, this Jimmy John's definitely serves up subs so fast you'll freak.2643 New Pinery RdPortage, WI US
Mike and Cathy's Good Old DaysRead MoreOne of the highest-rated bars in Montello, Mike and Cathy's Good Old Days delivers a relaxed vibe with a deeply flavorful menu that features seafood. It's a local favorite for customers seeking excellent food. Defined by its outdoor seating, the restaurant is a fantastic option when the Wisconsin weather cooperates. There's not really a recommended attire, so feel free to dress comfortably. Also, it's common knowledge that the background noise can get a little loud here. There really is something for everyone, with gluten-free options, as well as low-fat and vegetarian items on the robust menu. Plus, if you're searching for the perfect spot for a family gathering, it's been reviewed as a great local option for big groups and families with kids. If you just feel like stopping by for a beverage, the restaurant has helpful bar staff (and a good selection behind the bar). All things considered, Mike and Cathy's Good Old Days definitely won't leave you disappointed.W995 W North Shore DrMontello, WI US
Cimaroli's Supper ClubRead MoreCatch up with your friends over a bite to eat at Cimaroli's Supper Club, a local American bistro. Cautious diners will appreciate the low-fat and gluten-free fare at Cimaroli's Supper Club. Find time to peruse the wine list here — Cimaroli's Supper Club offers a variety of drink options. Youngsters are more than welcome to join mom and dad at Cimaroli's Supper Club. Warm weather brings out Cimaroli's Supper Club's highly coveted patio seating. Cimaroli's Supper Club is a prime location to dine with a group. The music and crowds can create quite a racket at Cimaroli's Supper Club — noise levels can reach the upper registers. Business casual dress, tasty food and a classic atmosphere makes this a great place for any occasion. For those in a hurry, the restaurant lets you take your grub to go. null Meals at Cimaroli's Supper Club are incredibly tasty and reasonably priced around $30.W11793 State Road 127Portage, WI US
Pheasant InnRead MoreAt Pheasant Inn in Briggsville, you can treat yourself to a hearty meal of steak and potatoes. Low-fat food isn't on the menu, so diners come to Pheasant Inn to enjoy their every bite. Pheasant Inn is a fine restaurant for those with large and small parties. Casual dining at its best, Pheasant Inn customers are free to enjoy themselves in jeans and a T-shirt. Feed the gang at your next get-together with catering from Pheasant Inn as well. In addition to street parking, there is a lot right around the corner, so finding a space shouldn't be an issue for drivers dining at the restaurant. Prices are a bit on the higher side, so this might be a good pick for a special night out. Pheasant Inn serves breakfast, lunch, and dinner, so stop by whenever is most convenient for you. Whether you're a party animal or an early riser, the restaurant will be open to serve you 24 hours a day.N415 County Road ABriggsville, WI US


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No. 14 Louisville 89, BYU-Hawaii 79
LAIE, Hawaii (AP)—Louisville coach Rick Pitino wanted a tuneup before the Maui Invitational. Division II Brigham Young-Hawaii provided much more.
Taquan Dean and Larry O'Bannon each scored 18 points and No. 14 Louisville rallied in the second half to beat BYUH 89-79 Saturday in its season opener.
"I wanted this game to prepare us for the Maui Classic," Pitino said. "They were a scary opponent to play with your first game. We knew we had to play our hearts out to get a victory."
The game also marked the return of Pitino to Hawaii. He began his coaching career at Hawaii as a graduate assistant in 1974-75 and was an assistant coach in 1975-76.
The Cardinals rallied from a 45-38 second-half deficit behind tough defense and the scoring of Dean, who had 11 of his 18 points in the final 20 minutes. Louisville forced 24 turnovers and scored 15 points off 12 turnovers in the second half.
"I think our full-court press was able to wear them out," Pitino said. "(BYUH) played a lot of consecutive games. To go against that type of pressure, playing all those games, I think they had tired legs down the stretch."
Louisville trailed at halftime and faced a 59-54 deficit in the second half before using a 10-4 run, capped by a 3-pointer by Brandon Jenkins, to take a 64-63 lead. The Cardinals extended their lead to 78-71 with just over four minutes left.
BYUH (2-1) closed within 80-77 with 2:36 remaining but couldn't get closer. Dean made a 3-pointer and the Cardinals closed the game with a 9-2 run.
"Taquan was very important today," Pitino said. "If I can get him more time at the (shooting guard) spot I think you'll see that a lot."
Ellis Myles scored 14 points and Francisco Garcia added 10 for Louisville.
Austin Smylie scored a game-high 27 points for BYUH.
Louisville outrebounded BYUH 39-31, including 21-10 on the offensive glass.
"I think rebounding was a trouble for us," Smylie said. "They're so much bigger than us and so much more athletic. Without rebounding, it's pretty hard to win games."
Paul Peterson, starting point guard for BYUH, did not play in the second half.
The Cardinals are making their 10th visit to Hawaii, and first since the 2000-01 season. They faces Iowa in the first round of the Maui Invitational on Monday at the Lahaina Civic Center.


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Personal Info
I am currently a Ph.D candiate at The College of William and Mary. I am particularly interested in intelligent systems and networks. "Creativity is contagious pass it on".- Albert Einstein.
- Name Daniel Graham
- Advisor Gang Zhou
- InterestIntelligent Systems
- Email dggraham[@]cs[.]wm[.]edu
- Hobbiesphotography and racket ball
- Awards W & M Graduate Board Fellowship
Recent Work
I have worked on a collection of papers on networking and embedded systems
Research Assistant
William and Mary (2011- present)
Wrote papers and submitted them to conferences
PM Intern
Microsoft (2014)
Wrote specifications for microsoft office products
Imagination is more important than knowledge. For knowledge is limited to all we now know and understand, while imagination embraces the entire world, and all there ever will be to know and understand
Beware of the person who can't be bothered by details.William Feather
Think left and think right and think low and think high. Oh, the thinks you can think up if only you tryDr. Seuss
Creativity is contagious, pass it onAlbert Einstein
William and Mary (2011 - Present)
Computer Science: Intelligent Systems and Networks
University of Virginia (2006 - 2011)
System Engineering, Computer Engineering, Electrical Engineering and Engineering Science
M.Eng, B.Sc
Skill set
My publications are listed below in chronological order.
Get in touch
View Larger Map
Contact details
- Address McGlothlin-Street Hall
- Email dggraham[@]cs[.]wm[.]edu


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YMCA Camp McConnell
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Commuter Bikes - MensWorried about the environment? Want to start improving the air you breathe? Start pedaling yourself to work instead of sitting in a car like everyone else. Our selection of commuter bikes provides the lightest and most durable two-wheeled delights to get you from Point A to Point B on a day-to-day basis. Get exercise as a bike commuter instead of sitting in traffic and adding pollutants to the air. You deserve to feel the satisfaction in improving your health and our environment!
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- Price: 250.00 - 279.99
Framed X300 3 Speed Bike
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SE Draft BikeReg: $329.00 On Sale: $259.95 - $269.95
Size: 52cm, 55cm, 58cm


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