Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin

OBJECTIVE: Patient- and virus-related factors influence the response of patients with chronic hepatitis C to interferon-based therapy. The purpose of this study was to model the probability of achieving a sustained virological response in individual patients, taking into consideration various predictive factors. MATERIAL AND METHODS: We combined data from two randomized, multinational trials in which patients received peginterferon alfa-2a (40KD) plus ribavirin. The logistic regression model for patients infected with hepatitis C virus genotype 1 included age, viral load, histology, alanine aminotransferase quotient, body mass index, treatment duration, ribavirin dose and adherence. RESULTS: In the genotype 1 model, varying baseline factors had a striking effect on the probability of sustained virological response. A dramatic difference in the probability of sustained virological response was seen in a series of hypothetical patients in whom five factors were varied to represent best and worst case scenarios. The best case scenario (age 20 years; no cirrhosis/bridging fibrosis; alanine aminotransferase quotient=7; body mass index 20 kg/m2; viral load 40,000 IU/mL) was associated with a 97% probability of sustained virological response, compared with 7% in the worst case scenario (age 60 years; cirrhosis/bridging fibrosis; alanine aminotransferase quotient=1; body mass index 30 kg/m2; viral load 9,000,000 IU/mL). Both adherence to treatment and achieving an early virological response increased the probability of sustained virological response. CONCLUSIONS: In treatment-na?ve patients with chronic hepatitis C, host factors play a major role in determining treatment outcome and the logistic regression model is useful for predicting the probability of sustained virological response in individual patients.     

Social anxiety and ruminative self-focus

Studies of rumination have supported the differentiation of self-focus into distinct modes of self-attention with distinct functional effects. Given that self-focused attention and rumination have been implicated in the maintenance of social anxiety, the present study investigated the effects of these two distinct forms of self-focused attention on mood and cognition in social anxiety. High and low socially anxious individuals (n=29 in each group) either thought analytically about, or focused on their momentary experience of, identical symptom-focused induction items from [Nolen-Hoeksema, S., & Morrow, J. (1993). Effects of rumination and distraction on naturally occurring depressed mood. Cognition and Emotion, 7, 561-570] rumination task. As predicted, in high socially anxious individuals, the experiential (low analysis) self-focus condition decreased ratings of anxious mood pre- to post-manipulation and was associated with more positive thoughts on a thought-listing exercise, whereas the analytical (high analysis) self-focus condition resulted in no significant effects on mood and cognition. Theoretical and clinical implications of these findings are discussed.     

The effect of surgically induced anterior disc displacement of the temporomandibular joint on the midface and cranial base

This investigation studies the development of mandibular and cranial base asymmetries with the aid of an animal model. The effect internal derangement of the temporomandibular joint (TMJ) might have on the asymmetric development of the cranial base is not known. The purpose of this study was to investigate the consequences of unilateral TMJ disc displacement on the midface and cranial base. Thirteen 10-week-old rabbits, eight controls and five experimental were included in this study. The five experimental rabbits had surgically created unilateral disc displacement. Animals were sacrificed at 22 weeks and frontal, occlusal and lateral oblique radiographs were made of the skulls. The occlusal radiograph demonstrated that the glenoid fossa on the experimental side was located more anteriorly. Whereas, the oblique radiograph revealed the root of the zygomatic arch on the experimental side to be more inferior. Finally, the anterior aspect of the fossa was seen to be more inferior on the frontal radiograph. A previous study suggested a shortening in the ramal height. This study points to an alteration of the cranial articular fossa. Thus, it may be concluded that disc displacement is capable of producing asymmetry in both the developing mandible and the cranial base.     

Elective use of nasal continuous positive airways pressure following extubation of preterm infants

The aim of this study was to determine whether elective use of nasal continuous positive airways pressure (CPAP) following extubation of preterm infants was well tolerated and improved short- and long-term outcomes. A randomized comparison of nasal CPAP to headbox oxygen was undertaken and a meta-analysis performed including similar randomized trials involving premature infants less than 28 days of age. A total of 150 infants (median gestational age 30 weeks, range 24–34 weeks) were randomized in two centres. Fifteen nasal CPAP infants and 25 headbox infants required increased respiratory support post-extubation and 15 nasal CPAP infants and nine headbox infants required re-intubation (non significant). Eight infants became intolerant of CPAP and were changed to headbox oxygen within 48 h of extubation; 19 headbox infants developed apnoeas and respiratory acidosis requiring rescue nasal CPAP, 3 ultimately were re-intubated. Seven other trials were identified, giving a total number of 569 infants. Overall, nasal CPAP significantly reduced the need for increased respiratory support (relative risk, 0.57, 95% CI 0.43–0.73), but not for re-intubation (relative risk 0.89, 95% CI 0.68–1.17). Nasal CPAP neither influenced significantly the intraventricular haemorrhage rate reported in four studies (relative risk 1.0, 95% CI 0.55, 1.82) nor that of oxygen dependency at 28 days reported in six studies (relative risk 1.0, 95% CI 0.8, 1.25). In two studies nasal CPAP had to be discontinued in 10% of infants either because of intolerance or hyperoxia. Conclusion Elective use of nasal continuous positive airways pressure post-extubation is not universally tolerated, but does reduce the need for additional support. Received: 12 August 1999 / Accepted: 15 December 1999     

Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine

We determined the clinical outcome of hepatitis e antigen (HBeAg)-negative chronic hepatitis B patients treated with long-term nucleos(t)ide analog therapy starting with lamivudine. We evaluated 201 such patients treated for 3.8 +/- 1.4 years and 2 historical similar cohorts: 1 treated with interferon-alfa (n = 209) and 1 untreated (n = 195). Virological or biochemical remission rate at 48 months under lamivudine was 34% or 36%, respectively, whereas adefovir was administered in 79 patients with virological-biochemical breakthroughs or no response. Of the lamivudine-treated patients, 4 died, 1 underwent a transplantation, and another 8 developed major events, all having advanced fibrosis at baseline and all but 1 having experienced breakthroughs or no response. At 5 years, survival was 96%, and major event-free survival was 93%. The major event-free survival was significantly better in patients with than in those without virological remission under lamivudine. At the end of follow-up, both survival and major event-free survival were independently associated with type of and response to treatment, being significantly better in patients under long-term antiviral therapy or interferon sustained responders than in interferon non-sustained responders or untreated cases (5-year survival: 96% or 98% vs. 88% or 90%, respectively). In conclusion, in HBeAg-negative chronic hepatitis B, long-term nucleos(t)ide analog therapy starting with lamivudine significantly improves survival and reduces the risk of major complications, compared with interferon non-sustained responders or untreated patients. In such patients with advanced fibrosis, close follow-up for lamivudine resistance and prompt onset of additional antiviral therapy is required or the ab initio use of agent(s) with low resistance rates should be considered.     

Prediction of treatment-related HBsAg loss in HBeAG-negative chronic hepatitis B: a clue from serum HBsAg levels

BACKGROUND: Quantification of HBsAg in serum may be of clinical importance in predicting HBsAg seroconversion and complete response to treatment. METHODS: Serum HBsAg was quantified by ADVIA Centaur in 63 patients with HBeAg-negative chronic hepatitis B (CHBe-). A total of 42 had received interferon-alpha2b (IFN-alpha2b) (median 12.1 months; 19 sustained responders including 12 HBsAg-seroconvertors; 23 non-sustained responders) and 21 were on lamivudine (LAM) (median 33.0 months). Measurements were done at baseline, during and at the end of treatment, and during and at the end of follow-up. RESULTS: Baseline median [interquartile range (IQR)] HBsAg levels in all patients were 3286 (1602-7458) IU/ml, not different between IFN- and LAM-treated (P = 0.139). IFN significantly depressed HBsAg in all patients except IFN non-responders, but HBsAg decline persisted only in sustained responders. Low pretreatment HBsAg level was the only significant prognostic variable of HBsAg seroconversion by multivariate analysis. LAM treatment also suppressed HBsAg levels but at a significantly slower rate compared with IFN (P = 0.022). The median (IQR) estimated time to HBsAg undetectability (ETU-HBsAg), derived from best curve fitting, was 127 (87.6-263.5) months for LAM virological responders and 65.3 (36.3-95.0) months for IFN sustained responders (P = 0.002). In 12 HBsAg seroconvertors, ETU-HBsAg was similar to the real time of HBsAg loss (P = 0.525) and seroconversion (0.056). CONCLUSIONS: In CHBe-, IFN induces a sharper decrease in serum HBsAg compared with LAM and low pretreatment levels are significantly associated with HBsAg serocon-version. Serial HBsAg measurements may be useful for prediction of HBsAg loss and our data suggest that to achieve this, 5.4 years of sustained response to IFN or 10.6 years of effective LAM therapy are probably needed.     

Natural history of chronic hepatitis B in Euro-Mediterranean and African countries

Data derived from population, case-control, and cohort studies conducted in several Euro-Mediterranean and African countries disclose impressive similarities in the age and modes of hepatitis B virus (HBV) transmission and in the prevalence, duration, and outcome of the four phases of the natural history of chronic infection. Perinatal HBV infection is rare while the vast majority of chronic infections originate from horizontal HBV transmission to infants and children. HBeAg loss and seroconversion to anti-HBe occur in a few years time, usually during the second decade of life. HBeAg-negative/anti-HBe-positive chronic hepatitis B (CHB), predominates in these countries being 7-9 times more frequent than HBeAg-positive CHB. The predominance of HBeAg-negative CHB is largely linked to the molecular characteristics of HBV genotype D prevailing in European and African countries of the Mediterranean basin and of genotype E and subgenotype A1 that prevail in the other parts of Africa. The molecular characteristics of the African subgenotype A1 differ from those of European subgenotype A2 explaining the fact that patients infected subgenotype A1 demonstrate an earlier loss of HBeAg and seroconversion to anti-HBe during the natural course of HBV infection compared to those infected with subgenotype A2. It is proposed that the molecular characteristics of HBV genotypes and subgenotypes prevailing in Euro-Mediterranean and African countries acting in concert with host and environmental factors largely determine the natural history of chronic HBV infection and its significant differences from countries of HBV genotype C and B and of subgenotype Ae predominance. The knowledge of the natural history of chronic HBV infection in Euro-Mediterranean and African countries combined with wide screening programs for prompt recognition and treatment of chronic HBV infection both in its HBeAg-positive and -negative immune reactive phases can be expected to increase the efficacy of current and future therapeutic strategies.     

Impact of biphasic electrical cardioversion of atrial fibrillation on early recurrent atrial fibrillation and shock efficacy

INTRODUCTION: Early recurrent atrial fibrillation (ERAF) after external cardioversion of atrial fibrillation (AF) occurs in 12% to 26% of patients. Whether biphasic cardioversion has an impact on the incidence of ERAF after cardioversion of AF is unclear. METHODS AND RESULTS: Consecutive patients (n = 216, mean age 66 years, 71% male, 88% with structural cardiovascular disease or hypertension) underwent cardioversion with a biphasic (Bi) or monophasic (Mo) shock waveform in randomized fashion. Energies used were 120-150-200-200 Ws (Bi) or 200-300-360-360 Ws (Mo). The two study groups (Bi vs Mo) did not differ with regard to age, sex, body mass index, underlying cardiovascular disease, left atrial diameter, left ventricular ejection fraction, duration of AF fibrillation, and antiarrhythmic drug therapy. Mean delivered energy was significantly lower in the Bi group (Bi: 186 +/- 143 Ws vs Mo: 324 +/- 227 Ws; P < 0.001). Overall incidence of ERAF (AF relapse within 1 minute after successful cardioversion) was 8.9% and showed no difference between the two groups (Bi: 8.1% vs Mo: 9.7%, P = NS). Cardioversion was successful in 95.4% of patients. The success rate was comparable in both groups (Bi: 94.3% vs Mo 96.8%; P = NS). First shock efficacy did not differ between Bi and Mo (76.4% vs 67.7%; P = NS). Mean number of shocks were 1.4 shocks per patient in both groups. CONCLUSION: Biphasic cardioversion allows comparable success rates with significantly lower energies. However, the incidence of ERAF is not influenced by biphasic cardioversion. With the energies used, biphasic and monophasic shock waveforms are comparable with regard to first shock and cumulative shock efficacy.     

Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients

Purpose

To investigate the durability of response to peginterferon alfa-2a up to 5 years post-treatment and factors associated with response in hepatitis B e-antigen (HBeAg)-negative patients.

Methods

HBeAg-negative patients received peginterferon alfa-2a (180 μg/week) ± lamivudine (100 mg/day) for 48 weeks as part of a multicenter, randomized study. The planned 5-year efficacy analysis included patients (n = 230) enrolled in the long-term follow-up study. On-treatment hepatitis B surface antigen (HBsAg) decline kinetics were analyzed retrospectively in a subgroup of patients with HBsAg data available at baseline, weeks 12, 24, and 48 on-treatment, and 6 months post-treatment (n = 120). Receiver operating characteristic analyses identified the on-treatment HBsAg levels associated with response at 1 and 5 years post-treatment.

Results

HBV DNA ≤2,000 IU/mL and HBsAg clearance at 5 years post-treatment were achieved by 23 and 12% of patients, respectively. High rates of HBsAg clearance at 5 years post-treatment were achieved by patients with HBV DNA ≤2,000 IU/mL at 1 year post-treatment (28%). Rates of HBV DNA ≤2,000 IU/mL at 1 year post-treatment were 47.2 and 43.4% in patients with ≥10% decline from baseline at weeks 12 and 24, respectively, compared with 16.4% (p = 0.0003) and 13.2% (p < 0.0004) in patients with a <10% decline. Rates of HBsAg clearance at 5 years post-treatment were 22.6 and 22.4% in patients with ≥10% decline at weeks 12 and 24, respectively, compared with 7.5% (p = 0.0161) and 3.8% (p < 0.0001) in patients with <10% decline.

Conclusions

Peginterferon alfa-2a results in increasing rates of HBsAg clearance during post-treatment follow-up in HBeAg-negative patients. On-treatment decline in HBsAg is significantly associated with long-term post-treatment response.