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Results for “Endpoint Determination”

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PubMed2006

A brief symptom index for advanced renal cell carcinoma.

BACKGROUND: Our objective was to test a brief, symptom index for advanced renal cell carcinoma, a disease affecting over 38,000 Americans each year and often diagnosed in late stages. METHODS: We conducted secondary data analyses on patient-reported outcomes of 209 metastatic renal cell carcinoma patients participating in a Phase III clinical trial. Patient-reported outcomes, obtained from the FACT-Biological Response Modifier (FACT-BRM) scale, were available at baseline, 2, and 8 weeks. We analyzed data from eight FACT-BRM items previously identified by clinical experts to represent the most important symptoms of advanced renal cell carcinoma. Items comprising this index assess nausea, pain, appetite, perceived sickness, fatigue and weakness, with higher scores indicating fewer symptoms. We determined reliability and validity of the index and estimated a minimally important difference. RESULTS: The index had excellent internal reliability at all three time points (alphas > or = 0.83). Baseline scores were able to discriminate patients across Karnofsky performance status, number of metastatic sites, and risk group categories (ps < .01). Mean index scores declined over time likely indicative of the toxic nature of the administered treatments. Distribution- and anchor-based methods converged on a minimally important difference estimate of 2 to 3 points. CONCLUSION: The 8-item index of patient-reported symptoms of renal cell carcinoma appears to be a psychometrically sound measure. It is a brief, reliable, and valid measure that can easily be adapted for use in clinical trials and observational studies.

Antineoplastic Agents↗

PubMed1998

Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response. Copyright 1998 Academic Press.

Journal Article↗

PubMed1998

Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?

Animals↗

PubMed2003

Identifying predictive and surrogate markers of erlotinib antitumor activity other than rash.

The identification of predictive or surrogate markers of response to HER1/epidermal growth factor receptor (EGFR) inhibitor treatment would permit selection of patients most likely to respond to such treatment. Markers could consist of tumor characteristics (e.g., characteristics of the receptor or downstream signaling molecules and determinants of resistance) or host characteristics (e.g., pharmacokinetic parameters and toxicities). The occurrence of rash may constitute a surrogate marker of response to erlotinib (Tarceva) treatment in patients with non-small-cell lung cancer and other cancers. The erlotinib marker identification program has been designed to identify and investigate other candidate markers by analysis of a large number of clinical samples from patients enrolled in erlotinib trials in non-small-cell lung cancer, including the phase III TALENT and TRIBUTE trials of erlotinib combined with chemotherapy and the phase III BR.21 trial of erlotinib monotherapy in advanced non-small-cell lung cancer. This program should both contribute to understanding of the molecular biology of HER1/EGFR inhibition and result in identification of potential markers that can be evaluated in the clinical setting.

Biomarkers↗

PubMed2005

Principles of early stopping of randomized trials for efficacy: a critique of equipoise and an alternative nonexploitation ethical framework.

Recent controversial decisions to terminate several large clinical trials have called attention to the need for developing a sound ethical framework to determine when trials should be stopped in light of emerging efficacy data. Currently, the fundamental rationale for stopping trials early is based on the principle that equipoise has been disturbed. We present an analysis of the ethical and practical problems with the "equipoise disturbed" position and describe an alternative ethical framework based on the principle of nonexploitation. This framework acknowledges the need for balancing the dual ethical obligations of clinical research, the protection of human subjects and the generation of new medical knowledge. Based on this framework, we put forward a proposal to make early stopping guidelines more stringent under specified conditions. The temporary withholding of apparent benefits in certain circumstances is justified by achieving a fair contract with the research participants, one that protects them from undue harm and exploitation while reducing the many uncertainties surrounding new investigational treatments that arise when trials are stopped prematurely.

Endpoint Determination↗

PubMed1999

Changes in the skin's capacitance after damage to the stratum corneum in humans.

BACKGROUND: Wound healing is a complex process to study, especially in humans, because the endpoint(s) of wound-induction and healing are subjective and, therefore, difficult to quantitate. Experiments were performed to establish quantifiable endpoints during the wound-induction process in 15 humans (11 women, 4 men). OBJECTIVE: Measurement of the skin's capacitance was used as a marker for the three stages of wound healing: 1) establishment of a wound, 2) the healing process, and 3) complete re-epithelialization. METHODS: Superficial wounds in the epidermis were generated by tape stripping the skin on the arm of 15 healthy volunteers. The skin's capacitance was measured before tape stripping, at various time points during the induction of the wound, immediately after glistening of the epidermis was achieved, and when the wound had healed according to clinical assessment. RESULTS: The values of the skin's capacitance at the point of removal of the stratum corneum varied from one individual to the next. Furthermore, the number of adhesive cellophane-tape strips needed to remove the stratum corneum and achieve glistening, due to accumulation of moisture, differed greatly from one volunteer to the next. These experiments suggest that the number of tape strips needed to remove the stratum corneum varies with age, sex, and possibly ethnicity of the subject. By contrast, during the wound healing process when a scab could be visualized, the skin's capacitance measured -122 picofarads (pF). Moreover, when the scab had disappeared, the skin's capacitance returned to baseline values (0 pF). CONCLUSION: Measurement of the skin's capacitance is a useful tool to determine two endpoints in the wounding and healing processes. The presence of a scab and the re-establishment of an intact stratum corneum can be quantitated easily. Less amenable to quantitation is the exact pF value that correlates to a specific type of wound.

Adult↗

PubMedDate not supplied

Development of California Public Health Goals (PHGs) for chemicals in drinking water.

As part of a program for evaluation of environmental contaminants in drinking water, risk assessments are being conducted to develop Public Health Goals (PHGs) for chemicals in drinking water, based solely on public health considerations. California's Safe Drinking Water Act of 1996 mandated the development of PHGs for over 80 chemicals by 31 December 1999. The law allowed these levels to be set higher or lower than federal maximum contaminant levels (MCLs), including a level of zero if data are insufficient to determine a specific level. The estimated safe levels and toxicological rationale for the first 26 of these chemicals are described here. The chemicals include alachlor, antimony, benzo[a]pyrene, chlordane, copper, cyanide, dalapon, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 2,4-D, diethylhexylphthalate, dinoseb, endothall, ethylbenzene, fluoride, glyphosate, lead, nitrate, nitrite, oxamyl, pentachlorophenol, picloram, trichlorofluoromethane, trichlorotrifluoroethane, uranium and xylene(s). These risk assessments are to be considered by the State of California in revising and developing state MCLs for chemicals in drinking water (which must not exceed federal MCLs). The estimates are also notable for incorporation or consideration of newer guidelines and principles for risk assessment extrapolations.

Algorithms↗

PubMed2001

Frequency of behavioral symptoms characterizes agitation in Alzheimer's disease.

This study describes two well-characterized groups of Alzheimer's disease (AD) patients with similar levels of cognitive functioning, but with different overall behavioral disturbance levels. We sought to determine the nature of this difference-whether AD patients with higher levels of behavioral disturbance (n = 148) differ from less disturbed AD patients (n = 235) in terms of (a) the range of symptoms exhibited, (b) the frequency of occurrence of these symptoms, or (c) both of these. We defined and operationalized 'diversity of behaviors' and 'frequency' with respect to the item-level responses on the Cohen-Mansfield agitation inventory (CMAI). We found that, in these two samples of AD patients, differences occurred in the frequency of 10 out of 21 behaviors, rather than in a variety of endorsed behaviors. These 10 behaviors, observed at different frequencies in both groups, may be useful for monitoring change in studies of drugs or behavioral interventions for behavioral disturbance in persons with AD.

Aged↗

PubMed2006

Effects of a rate smoothing algorithm for prevention of ventricular arrhythmias: results of the Ventricular Arrhythmia Suppression Trial (VAST).

BACKGROUND: Rate smoothing, which is available in some pacemakers and implantable cardioverter defibrillators (ICDs), has been used to prevent Torsades de Pointes in patients with long QT syndrome. Its efficacy in general ventricular arrhythmia prevention has not been determined. OBJECTIVES: The purpose of the Ventricular Arrhythmia Suppression Trial (VAST) was to prospectively investigate whether rate smoothing could significantly reduce the incidence of ventricular tachyarrhythmias in a large, broad population of patients with ICDs. METHODS: Five hundred sixty-nine patients were enrolled at 57 participating centers and implanted with a commercially available Guidant ICD. A single-blinded crossover design was used in which each patient was randomized at implant to one of two treatment sequences: either rate smoothing on (RS On) followed by rate smoothing off (RS Off), or RS Off followed by RS On. This mode sequence was randomly determined and assigned in a 1:1 fashion using randomized permuted blocks by site. Each mode was followed for 6 months. Programming of rate smoothing was prescribed as 12% Down and 12% Up for the duration of the RS On period. RESULTS: Of enrolled patients, 281 were randomized to RS Off followed by RS On, and 288 to RS On followed by RS Off. With RS On, 75 (23%) patients experienced a reduction in arrhythmias, 76 (23%) saw an increase in arrhythmias, and the remaining 176 (54%) had no difference. No significant difference (P = .58) in frequency of arrhythmias with RS On vs RS Off was found. CONCLUSION: Rate smoothing does not result in a reduction in ventricular arrhythmias in a heterogeneous population of patients receiving ICDs.

Adult↗

PubMed2005

Link between platelet activity and outcomes after an ischemic stroke.

BACKGROUND: Platelets play an important role in atherosclerosis and thromboembolic events. We examined the relationship between platelet activity and outcomes after an ischemic stroke. METHODS: Using flow cytometry, we serially measured the fractions of circulating platelet activity (CD62p expression) after an ischemic stroke in early (<48 h), recent (day 7), convalescent (day 21) and chronic (day 90) phases in 92 consecutive patients with an ischemic stroke. Patients were classified into high (CD62p expression >3.16%) and low (CD62p expression < or =3.16%) platelet activity groups according to the median value of CD62p expression in the early phase of a stroke. RESULTS: The composite end point--death, recurrent stroke and severe neurological impairment (alive in care), defined as a score of >13 on the National Institutes of Health Stroke Scale--within the first 30 days and at an interval of 8.2 +/- 1.5 months of follow-up was determined for each group. In the first 30 days, the composite end point occurred in 37.0% of patients in the high platelet activity group as compared with 6.5% in the low platelet activity group (p = 0.0004). At a mean follow-up of 8.2 +/- 1.5 months, the composite end point occurred in 36.6% of patients in the high platelet activity group as compared with 10.9% in the low platelet activity group (p = 0.0044). Multiple stepwise logistic regression analysis displayed that high platelet activity (p = 0.011), age (p = 0.013) and the presence of coronary artery disease (p = 0.021) were independently associated with adverse outcomes at the intermediate-term follow-up. CONCLUSIONS: Results of this study showed that high platelet activity is strongly associated with adverse clinical outcomes after an early ischemic stroke.

Aged↗

PubMed2001

Protection against pyrimidine dimers, p53, and 8-hydroxy-2'-deoxyguanosine expression in ultraviolet-irradiated human skin by sunscreens: difference between UVB + UVA and UVB alone sunscreens.

As DNA damage induced by ultraviolet radiation plays an essential role in skin cancer induction, we pursued the measure of several DNA lesions induced by ultraviolet radiation in human skin for determining the efficacy of different topical photoprotectors. Non-exposed skin (buttocks from 20 individuals) was exposed to 10 doses of ultraviolet, which corresponded to three to four minimal erythema doses of solar-simulating radiation, and biopsies were taken at 24 h within the half and one minimal erythema dose sites and a nonirradiated, adjacent control area. We report that even suberythemal doses of ultraviolet radiation are capable of inducing substantial DNA damage, namely pyrimidine dimers, p53 induction, and the DNA base-modified product generated by oxidative stress, 8-hydroxy-2'-deoxyguanosine. All three lesions are induced in a dose-dependent manner. An additional eight individuals were treated with either ultraviolet B or ultraviolet B + ultraviolet A sunblock (sun protection factor 15) and exposed to 71/2 and 15 times the minimal erythema dose on each individual, with biopsies taken at 24 h post-ultraviolet. Pyrimidine dimer and p53 expression were rarely seen in nonirradiated skin but occasional staining was seen in all normal skin for 8-hydroxy-2'-deoxyguanosine. Applications of sunscreens to human skin before irradiation were shown to attenuate erythema but did not completely eliminate all three types of cellular damage when tested up to their sun protection factor 15. Furthermore, ultraviolet B + ultraviolet A sunscreens were less efficient than the ultraviolet B alone formulation for protection against all three lesions. These results suggest that DNA damage assessed in vivo by immunohistochemistry provides a very sensitive endpoint for determining the efficacy or photosensitivity of possible different protective measures in human skin.

8-Hydroxy-2'-Deoxyguanosine↗

PubMedDate not supplied

An Item Response analysis of the Hamilton Depression Rating Scale using shared data from two pharmaceutical companies.

Although the Hamilton Depression Rating Scale (HAMD) remains the most widely used outcome measure in clinical trials of Major Depressive Disorder, the psychometric properties of the individual HAMD items have not been extensively studied. In the present paper, data from four separate clinical trials conducted independently by two pharmaceutical companies were analyzed to determine the relationship between scores on the individual HAMD items and overall depressive severity in an outpatient population. Option characteristic curves (the probability of scoring a particular option in relation to overall HAMD scores) were generated in order to illustrate the relationship between scoring patterns for each item and the range of total HAMD scores. Results showed that Items 1 (Depressed Mood) and 7 (Work and Activities), and to a lesser degree, Items 2 (Guilt), 10 (Anxiety/Psychic), 11 (Anxiety/Somatic), and 13 (Somatic/General) demonstrated a good relationship between item responses and overall depressive severity. However, other items (e.g. Insight, Hypochondriasis) appeared to be more problematic with regard to their ability to discriminate over the full range of depression severity. The present results illustrate that co-operative data sharing between pharmaceutical companies can be a useful tool for improving clinical methods.

Clinical Trials as Topic↗

PubMed2003

Comparison of in-hospital and one-year outcomes in patients with left ventricular ejection fractions or=50% having percutaneous coronary revascularization.

Outcome studies of percutaneous coronary intervention (PCI) with conventional balloon angioplasty have established increased in-hospital and 1-year mortality in patients with left ventricular (LV) dysfunction compared with others. It is unclear whether recent PCI practice innovations, including stents and adjunctive pharmacotherapy, have made PCI safer and more effective in patients with LV dysfunction. We evaluated the influence of LV ejection fraction (EF) indexes on in-hospital and 1-year outcomes in 1,458 patients within the National Heart, Lung, and Blood Institute-sponsored Dynamic Registry. Patients (n = 300) with acute myocardial infarction were excluded. The remaining 1,158 patients were subdivided into 3 categories: group 1, EF or=50% (n = 866). We determined the frequency of individual and composite adverse events (death/myocardial infarction [MI]/coronary artery bypass grafting) at discharge and 1 year. In the Dynamic Registry patients, mean EF in the 3 groups was 32%, 45%, and 62% and in-hospital mortality was 3.0%, 1.6%, and 0.1%, respectively (p <0.001). The composite end point of death/MI was also significant, but other in-hospital adverse events did not differ between groups. The respective mortality rates were 11.0%, 4.5%, and 1.9% (p <0.001) after 1 year. The composite end points of death/MI and death/MI/coronary artery bypass grafting also occurred more frequently in group 1 patients. Thus, significant LV dysfunction was still associated with increased in-hospital and 1-year mortality in patients having contemporary PCI.

Aged↗

PubMed2005

Research strategy for developing key information on bromate's mode of action.

Bromate is produced when ozone is used to treat waters that contain trace amounts of bromide ion. It is also a contaminant of hypochlorite solutions produced by electrolysis of salt that contains bromide. Both ozone and hypochlorite are extensively used to disinfect drinking water, a process that is credited with reducing the incidence of waterborne infections diseases around the world. In studies on experimental animals, bromate has been consistently demonstrated to induce cancer, although there is evidence of substantial species differences in sensitivity (rat>mouse>hamster). There are no data to indicate bromate is carcinogenic in humans. An issue that is critical to the continued use of ozone as a disinfectant for drinking water in bromide-containing waters depends heavily on whether current predictions of carcinogenic risk based on carcinogenic responses in male rats treated with bromate are accurate at the much lower exposure levels of humans. Thiol-dependent oxidative damage to guanine in DNA is a plausible mode of action for bromate-induced cancer. However, other mechanisms may contribute to the response, including the accumulation of alpha2u-globulin in the kidney of the male rat. To provide direction to institutions that have an interest in clarifying the toxicological risks that bromate in drinking water might pose, a workshop funded by the Awwa Research Foundation was convened to lay out a research strategy that, if implemented, could clarify this important public health issue. The technical issues that underlie the deliberations of the workshop are provided in a series of technical papers. The present manuscript summarizes the conclusions of the workgroup with respect to the type and timing of research that should be conducted. The research approach is outlined in four distinct phases that lay out alternative directions as the research plan is implemented. Phase I is designed to quantify pre-systemic degradation, absorption, distribution, and metabolism of bromate and to associate these with key events for the induction of cancer and develop an initial pharmacokinetic (PK) model based on preliminary studies. Phase II will be implemented if it appears that there is a linear relationship between external dose and key event responses and is designed to gather carcinogenesis data in female rats in the absence of alpha2u-globulin-induced nephropathy which the workgroup concluded was a probable contributor to the responses observed in the male rats for which detailed dose-response data were collected. If the key events and external dosimetry are found not to be linear in Phase I, Phase III is initiated with a screening study of the auditory toxicity of bromate to determine if it is likely to be exacerbated by chronic exposure. If this occurs, auditory toxicity will be further evaluated in Phase IV. If auditory toxicity is determined unlikely to occur, an alternative chronic study in female rats to the one identified in Phase II will be implemented to include exposure in utero. This was recommended to address the possibility that the fetus may be more susceptible. One of the three options are to be implemented in Phase IV depending upon whether preliminary data indicated that chronic auditory toxicity, reproductive and/or developmental toxicities, or a combination of these outcomes is necessary to characterize the toxicology of low dose exposures to bromate. Each phase of the research will be accompanied by further development of pharmacokinetic models to guide collection of appropriate data to meet the needs of the more sophisticated studies. It is suggested that a Bayesian approach be utilized to develop a final risk model based upon measurement of prior observations from the Phase I studies and the set of posterior observations that would be obtained from whichever chronic study is conducted.

Animals↗

PubMed2005

Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals.

PURPOSE: The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa. PATIENTS AND METHODS: Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered. RESULTS: The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69). CONCLUSION: It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).

Antineoplastic Agents, Hormonal↗

PubMed2006

Estimation of the Bath Ankylosing Spondylitis Disease Activity Index cutoff for perceived symptom relief in patients with spondyloarthropathies.

OBJECTIVE: To estimate the best Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) cutoff based on patients' perceptions of symptom relief collected in a large population of patients with spondyloarthropathies (SpA), in comparison to the BASDAI cutoff determined by experts. METHODS: A survey of patient perceptions about current disease control was conducted among the members of Spondylis, one of the main not-for-profit SpA patient organizations in France. BASDAI was among data collected by the questionnaire. To estimate the best BASDAI cutoff for discriminating between poor and well perceived controlled groups, we plotted the receiver operating characteristic (ROC) curve. We also determined the cutoff separately in male and female patients. RESULTS: Of the 1000 mailed questionnaires, 485 were returned without any missing data regarding perceived disease control and the BASDAI. Of these patients, 55.3% perceived inadequate control of their disease. The mean BASDAI in the overall population was 43.5 +/- 22.9, 30.4 +/- 19.9 in the well controlled group and 54 +/- 19.4 in the poorly controlled group (p < 0.001). The best BASDAI cutoff for discriminating between patients in the 2 groups was 39 (sensitivity 74.6% and specificity 72.4%). According to gender, the best cutoff was 44 for women and 36 for men. CONCLUSION: The best BASDAI cutoff of 39 based on patients' perceptions was very similar to that selected by international experts, i.e., 40. Gender affected the cutoff for perceived symptom relief in our study. These results need to be confirmed by further studies collecting the opinions of both patients and physicians.

Antirheumatic Agents↗

PubMed2004

Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker.

Intracellular macromolecules are released from dying tumor cells and may subsequently be detected in patient blood. In this review, we will discuss the use of cytokeratin-18 as a serum biomarker for monitoring therapy-induced cell death. Cytokeratins are abundant intracellular proteins expressed by most types of carcinoma, but not by treatment-sensitive cells from bone marrow and other tissues. Release of cytokeratins into blood is therefore expected to show some specificity for tumor cell death. Cytokeratin-18 (CK18) is cleaved by caspases specifically during apoptosis, and the molecular form of this protein (caspase-cleaved vs. non-cleaved) released from dying tumor cells is therefore diagnostic as to the type of cell death (apoptosis vs. necrosis). Analyses of different CK18 forms in patient sera have suggested that tumor apoptosis may not necessarily be the dominating death mode in many tumors in vivo. Measurements of increased levels of CK18 in serum during therapy of prostate and breast cancer patients have been encouraging with regard to the possible future use of CK18 as a biomarker for monitoring therapy efficiency.

Antineoplastic Agents↗

PubMed2003

Treatment of HBeAg-negative chronic hepatitis B.

The goals of therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are to abolish or efficiently suppress viral replication, which represents the main determinant of underlying liver necroinflammation and fibrosis. Currently available agents include interferon-alfa (IFN-alpha), lamivudine, and soon adefovir dipivoxil. A > or = 12-month course of IFN-alpha treatment or retreatment achieves sustained biochemical responses in 15 to 25% of patients with eventual hepatitis B surface antigen (HBsAg) loss and anti-HBs development in a proportion of them. Lamivudine induces initial virologic and biochemical responses in 70 to 90%, but breakthroughs due to lamivudine-resistant mutants accumulate with continuation of therapy and thus only one third of patients may remain in remission after the third year of therapy. Adefovir dipivoxil also achieves on-therapy responses in the majority of cases. Adefovir dipivoxil and entecavir appear to be effective against lamivudine-resistant strains. Many other antiviral agents and immunomodulatory approaches are currently evaluated for CHB, but, besides IFN-alpha, none has yet been convincingly shown to induce sustained off-therapy responses.

Adenine↗