Determinants for sustained HBeAg response to lamivudine therapy

There are inconsistent data on the durability of hepatitis B e antigen (HBeAg) seroconversion after lamivudine is discontinued. The aim of this study was to examine the determinants for sustained HBeAg response to lamivudine therapy. Both host and viral factors as well as the drug factor were compared between 43 patients with sustained HBeAg response and 39 patients whose response was not sustained. All of them received a mean period of 16 months (range, 3-55 months) lamivudine therapy and had achieved complete response (HBeAg seroconversion plus HBV DNA seroclearance by hybrid capture assay and normal alanine aminotransferase [ALT]) and were followed-up for a mean period of 44 months (range, 12-88 months). Stepwise logistic regression model was used to estimate the sustained response on the presence of the following variables: age; gender; pretherapy ALT; total bilirubin and HBV DNA levels; time to HBeAg seroconversion; additional lamivudine treatment after HBeAg seroconversion; total duration of treatment; hepatitis activity index scores; periportal, intralobular, and portal inflammation and fibrosis scores; scores excluding fibrosis; status of precore mutation; basal core promoter mutation; and genotype. The results showed that genotype (OR, 5.922; 95% CI, 1.611-21.768; P =.007), age (OR, 0.943; 95% CI, 0.891-0.997; P =.040), and additional treatment (OR, 1.097; 95% CI, 1.028-1.171; P =.005) were independent factors to sustained HBeAg response. Further categorical analysis disclosed that patients with genotype B, age < or =36 years, and additional lamivudine treatment over 8 months have higher sustained response. In conclusion, HBV genotype, age, and additional treatment are the major determinants for the sustained HBeAg response to lamivudine therapy.     

Community-acquired pneumonia due to gram-negative bacteria and pseudomonas aeruginosa: incidence,risk, and prognosis

BACKGROUND: Initial empirical antimicrobial treatment of patients with community-acquired pneumonia (CAP) is based on expected microbial patterns. We determined the incidence of, prognosis of, and risk factors for CAP due to gram-negative bacteria (GNB), including Pseudomonas aeruginosa. METHODS: Consecutive patients with CAP hospitalized in our 1000-bed tertiary care university teaching hospital were studied prospectively. Independent risk factors for CAP due to GNB and for death were identified by means of stepwise logistic regression analysis. RESULTS: From January 1, 1997, until December 31, 1998, 559 hospitalized patients with CAP were included. Sixty patients (11%) had CAP due to GNB, including P aeruginosa in 39 (65%). Probable aspiration (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.02-5.2; P =.04), previous hospital admission (OR, 3.5; 95% CI, 1.7-7.1; P<.001), previous antimicrobial treatment (OR, 1.9; 95% CI, 1.01-3.7; P =.049), and the presence of pulmonary comorbidity (OR, 2.8; 95% CI, 1.5-5.5; P =.02) were independent predictors of GNB. In a subgroup analysis of P aeruginosa pneumonia, pulmonary comorbidity (OR, 5.8; 95% CI, 2.2-15.3; P<.001) and previous hospital admission (OR, 3.8; 95% CI, 1.8-8.3; P =.02) were predictive. Infection with GNB was independently associated with death (relative risk, 3.4; 95% CI, 1.6-7.4; P =.002). CONCLUSIONS: In our setting, in every tenth patient with CAP, an etiology due to GNB has to be considered. Patients with probable aspiration, previous hospitalization or antimicrobial treatment, and pulmonary comorbidity are especially prone to GNB. These pathogens are also an independent risk factor for death in patients with CAP.     

A novel ex vivo assay of interferon-based suppression, to predict the outcome of antiviral therapy for hepatitis C

An ex vivo liver slice-culture method was used to develop a novel assay of pretherapy interferon-based suppression. To evaluate its clinical application, 45 consecutive patients with chronic hepatitis C were included. They underwent the ex vivo antiviral assay, followed by a 24-week course of therapy with peginterferon and ribavirin. A stepwise logistic regression model was used to estimate the relationship between sustained virological response and the presence of various clinicopathological parameters. The results indicated that the presence of an interferon-based suppression effect in the ex vivo assay (odds ratio [OR], 12.454 [95% confidence interval {CI}, 1.115-139.090]; P=.0405), clinically diagnosed liver cirrhosis (OR, 0.081 [95% CI, 0.011-0.584]; P=.0126), and the portal-inflammation score (OR, 4.220 [95% CI, 1.264-14.085]; P=.0192) were independent determinants of sustained virological response. In conclusion, this new assay serves as an independent predictor of sustained virological response in interferon-based antiviral therapy.     

Hepatitis B virus genotype B is associated with better response to thymosin alpha1 therapy than genotype C

Hepatitis B virus (HBV) genotype has been reported to correlate with response to interferon treatment in several studies. The relationship between HBV genotype and thymosin alpha1 (T-alpha1) treatment is unknown. We retrospectively examine HBV genotypes, precore and core promoter mutations in patients treated with Talpha1 and analyse the correlation between complete response [alanine aminotransferase (ALT) normalization plus seroclearance of HBeAg and HBV-DNA] and HBV genotype. It consisted 98 patients with chronic hepatitis B randomly allocating to three groups: (i) T6 group (n = 32) received a 26-week course of Talpha1 1.6 mg two times a week; (ii) T12 group (n = 34) received the same regimen as T6 group, but Talpha1 therapy extended for 52 weeks; (iii) T0 group (n = 32) served as a control and was followed up for 18 months without specific treatment. Stepwise logistic regression analysis showed that genotype (OR, 3.747; 95% CI, 1.066-13.170; P = 0.039), precore mutation (OR, 6.285; 95% CI, 1.874-21.086; P = 0.003) and Talpha-1 treatment (OR, 12.045; 95% CI, 2.220-65.354; P = 0.004) as independent factors associated with complete response. The complete response of Talpha-1 therapy was higher in patients with genotype B compared to patients with genotype C (52%vs 24%; P = 0.036) and in patients with precore mutation (64%vs 19%; P = 0.002). In conclusion, genotype, presence of precore mutation and Talpha-1 therapy were independent predictors to complete response. Genotype B, compared to genotype C, is associated with a higher response rate to T-alpha1 therapy.     

慢性丙型肝炎抗病毒治疗应答独立预测因子的研究

目的 通过对应用不同干扰素(IFN)剂型的大样本慢性丙型肝炎患者的治疗,对可能与IFN疗效相关的因子进行多因素回归分析,探讨慢性丙型肝炎IFN治疗应答的预测因子。方法 对入选聚乙二醇干扰素α-2a治疗慢性丙型肝炎的随机、开放、多中心对照研究的患者随机分组,分别应用聚乙二醇干扰素α-2a和干扰素α-2a治疗24周,停药后随访24周。在用药前对患者血清中的HCV RNA进行定量和基因分型检测,治疗和随访结束时检测血清HCV RNA含量,以HCV RNA阴转作为IFN治疗应答的主要评价指标,并对患者临床特征、病毒学特征进行多因素logistic回归分析。 结果 按意愿治疗分析人群208例,按方案分析人群197例,在对按方案分析人群的分析中,治疗24周结束时,女性、年龄<50岁、非输血感染途径、IFN治疗后复发者、天冬氨酸氨基转移酶/丙氨酸氨基转移酶(AST/ALT)<1、HCV RNA 含量<8×105U/ml,非基因1型HCV感染和聚乙二醇干扰素α-2a治疗患者的病毒应答率分别高于男性、年龄≥50岁、输血感染途径、IFN初治患者、AST/ALT比值≥1、HCV RNA含量≥8×105U/ml、基因1型HCV感染和干扰素α-2a治疗患者的应答率。但随访结束时,AST/ALT≥1和HCV RNA含量≥8×105U/ml患者的持续应答率却大于AST/ALT<1和HCV RNA含量<8 × 105U/ml患者。经多因素logis     

Adherence and plasma drug concentrations are predictors of confirmed virologic response after 24-week salvage highly active antiretroviral therapy

Data from 197 patients for whom highly active antiretroviral therapy (HAART) failed, who started a new regimen chosen under the guide of resistance testing results interpreted by experts, were retrospectively studied, provided that at least 2 determinations of adherence and plasma drug concentrations were performed during the follow-up. Univariate and multivariable logistic regression analyses were conducted, using confirmed virologic response at week 24 as outcome measure (i.e., achievement of undetectable HIV plasma viral load at any time point before week 24 and its maintenance up to week 24). Suboptimal drug concentrations (odds ratio [OR]: 0.3; 95% confidence interval [CI] 0.2-0.7; p = 0.006) and suboptimal adherence (OR: 0.4; 95% CI 0.2-0.8; p = 0.014) were both negative independent predictors of sustained virologic response, while the use of boosted protease inhibitor-containing regimens resulted to be protective (OR: 2.4; 95% CI 1.1-5.3; p = 0.032).     

Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy

Approximately one third of hepatitis C virus (HCV) genotype 1 patients achieved a sustained virological response (SVR) after 24 weeks of treatment with peginterferon alpha-2a (40 kd) plus ribavirin in a randomized, multinational trial. We aimed to identify factors associated with a rapid virological response (RVR) at week 4 (HCV RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL at the end of follow-up) in these patients. Stepwise multiple logistic regression analysis was used to explore the prognostic factors for a RVR and SVR in genotype 1 patients treated for 24 weeks. Fifty-one of 216 (24%) genotype 1 patients in the 24-week treatment groups had a RVR. SVR rates were considerably higher in patients with than without [corrected] a RVR (89% vs. 19%, respectively). Patients with a baseline HCV RNA of less than 200,000 IU/mL (OR 9.7, 95% CI 4.2-22.5; P < .0001) or 200,000-600,000 IU/mL (OR 5.6, 95% CI 1.5-9.1; P = .0057) were more likely to achieve a RVR than those with HCV RNA greater than 600,000 IU/mL. HCV subtype (1b vs. 1a) was also independently associated with RVR (OR 1.8, 95% CI 0.9-3.7; P = .0954). RVR (OR 23.7 vs. no RVR, 95% CI 9.1-61.7) and baseline HCV RNA less than 200,000 IU/mL (OR 2.7 vs. > 600,000 IU/mL, 95% CI 1.1-6.3; P < .026) were significant and independent predictors of SVR in patients treated for 24 weeks. In conclusion, patients infected with HCV genotype 1 and treated with peginterferon alpha-2a/ribavirin sustained a RVR 24% of the time. This portends an 89% probability of a SVR after 24 weeks of treatment.     

Exercise: a potential contributing factor to the relationship between folate and dementia

OBJECTIVES: To investigate whether exercise confounds the relationship between folate and cerebrovascular events, all-cause dementia, and Alzheimer's disease. DESIGN: Prospective cohort study. SETTING: Multiple centers in Canada. PARTICIPANTS: In the Canadian Study of Health and Aging, 466 people reported exercise levels, had folate measurements, and were not demented at baseline. After 5 years, 194 had adverse cerebrovascular events, and 65 had dementia (Alzheimer's disease in 47). MEASUREMENTS: Associations between folate and cerebrovascular outcomes were examined using logistic regression in the presence and absence of exercise and other confounders. RESULTS: Folate was associated with greater risk of Alzheimer's disease (odds ratio (OR)=2.12, 95% confidence interval (CI)=1.01-4.54) and cerebrovascular outcomes (OR=2.05, 95% CI=1.11-3.78) in adjusted analyses before the inclusion of exercise and neared significance with all-cause dementia (OR=1.80, 95% CI=0.94-3.45). After the inclusion of exercise, the association between folate and dementia and Alzheimer's disease was 29% and 25% lower, respectively, and neither association was any longer significant (Alzheimer's disease: OR=1.91, 95% CI=0.89-4.11; all-cause dementia: OR=1.62, 95% CI=0.84-3.15). Exercise was a significant confounder in the relationship between folate and Alzheimer's disease (P=.03) and dementia (P=.003) but not cerebrovascular outcomes (P=.64). Unlike folate, exercise was significantly associated with Alzheimer's disease (OR=0.43, 95% CI=0.19-0.98) and dementia (OR=0.35, 95% CI=0.17-0.72) in adjusted analyses. CONCLUSION: Exercise seems to account for much of the relationship between folate and incident dementia and Alzheimer's disease.     

Predictors for successful angioplasty of chronic totally occluded coronary arteries

AIMS: Reevaluation of clinical and angiographic predictors for percutaneous recanalization of coronary chronic total occlusion (CTO) using current techniques with conventional PTCA wires and balloons. METHODS AND RESULTS: We studied 253 consecutive patients with 283 lesions who underwent attempted PTCA of CTO (mean time since occlusion 33 months, range 3-150 month). Immediate procedural success rate was 84.8% (95% CI = 80.3%-88.6%). Multiple clinical and angiographic characteristics were evaluated as possible predictors of success/failure. Multiple logistic regression analysis revealed that a tapered morphology (P < 0.001, OR = 6.1; 95% CI = 2.1-18.2), 相似文献   

Serum insulin levels and the prevalence of adenomatous and hyperplastic polyps in the proximal colon.

BACKGROUND & AIMS: Obesity and diabetes mellitus are associated with an increased incidence of proximal colon cancer. Colonic adenoma that has been reported to be associated with elevated serum insulin levels and subsets of hyperplastic polyps might serve as a precursor of colon cancer. In this study, we sought to determine segment-specific associations between serum insulin levels and the prevalence of adenoma and hyperplastic polyps in the proximal and distal colon. METHODS: We studied 343 consecutive patients who underwent colonoscopy in our hospital. All medical information, including fasting serum insulin, was obtained at colonoscopy. We performed multinomial logistic regression models by using the outcome categories of none (reference), proximal-only, distal-only, and both-segment lesions for the presence of adenoma/hyperplastic polyp with serum insulin, age, gender, lifestyle characteristics, and the presence of other types of lesions as predictors. Odds ratios (ORs) and 95% confidence intervals (CIs) are provided for a 5-muU/mL increase in serum insulin. RESULTS: Overall, serum insulin levels were significantly associated with adenoma (OR, 1.5; 95% CI, 1.1-2.0; P = .005) and borderline associated with hyperplastic polyps (OR, 1.3; 95% CI, 1.0-1.7; P = .075). In multinomial logistic regression models, elevated serum insulin levels were significantly associated with proximal-only adenoma (OR, 1.8; 95% CI, 1.2-2.5; P = .002), both-side hyperplastic polyp (OR, 1.7; 95% CI, 1.1-2.5; P = .015), and proximal-only hyperplastic polyp (OR, 1.5; 95% CI, 1.0-2.1; P = .048) and borderline associated with distal-only adenoma (OR, 1.5; 95% CI, 1.0-2.1; P =.059) but not with distal-only hyperplastic polyp. CONCLUSIONS: Serum insulin levels directly correlate with the presence of adenoma and hyperplastic polyps in the proximal colon and might also less strongly correlate with the presence of distal adenoma.     

Adherence is not a barrier to successful antiretroviral therapy in South Africa

OBJECTIVE: To determine adherence of an indigent African HIV-infected cohort initiating antiretroviral therapy (ART); to identify predictors of incomplete adherence (< 95%) and virologic failure (> 400 HIV RNA copies/ml). DESIGN: Prospective monitoring of adherence in a poor HIV-positive cohort, attending a public sector hospital and receiving ART through phase III studies. METHODS: Adherence to ART was determined over 48 weeks by counting tablet-returns. Logistic regression models including age, WHO HIV stage, home language, socio-economic status, complexity and type of regimen were fitted to determine predictors of incomplete adherence and virologic failure at 48 weeks. RESULTS: 289 patients were recruited between January 1996 and May 2001. Median (mean) adherence of the cohort was 93.5% (87.2%). Three times daily dosing [risk ratio (RR), 3.07; 95% confidence interval (CI), 1.40-6.74], speaking English (RR, 0.41; 95% CI, 0.21-0.80) and age (RR, 0.97; 95% CI, 0.94-0.99) were independent predictors of incomplete adherence. Socio-economic status, sex and HIV stage did not predict adherence. Independent predictors of virologic failure included baseline viral load (RR, 2.57; 95% CI, 1.57-4.22) and three times daily dosing (RR, 2.64; 95% CI, 1.23-5.66), incomplete adherence (RR, 1.92; 95% CI, 1.10-3.57), age (RR, 0.96; 95% CI, 0.92-0.99) and dual nucleoside therapy (RR, 2.69; 95% CI, 1.17-6.15). CONCLUSION: The proportion of individuals achieving viral suppression matched results from the developing world. Speaking the same language as site staff and simplified dosing frequency were beneficial. Socio-economic status had no impact on adherence and should not be used as a limitation to ART access.     

Association of polymorphisms in human leukocyte antigen class I and transporter associated with antigen processing genes with resistance to human immunodeficiency virus type 1 infection

To examine the relationship of human leukocyte antigen (HLA) class I and transporter associated with antigen processing (TAP) genes with resistance to human immunodeficiency virus type 1 (HIV-1) infection, 100 HIV-seronegative men who had been exposed repeatedly to HIV-1 were compared with 184 men who had seroconverted to HIV positive and had lower risk. In the univariate analysis, the HLA-A2 supertype, excluding A*0201 (HLA-A2/6802 supertype; odds ratio [OR], 4.45; 95% confidence interval [CI], 1.33-4.84; P=.009) was associated with resistance to HIV-1 infection; the effect was the result of the presence of the A*0205 subgroup alleles. Susceptibility was associated in univariate analysis with the B*35 Px alleles (OR, 0.29; 95% CI, 0.08-0.99; P=.037), which suggests that differential preferences for amino acids at the C terminus may influence peptide-binding capacity. TAP2 Ala665 was also associated with resistance (OR, 2.26; 95% CI, 1.35-3.79; P=.002), perhaps because of its higher efficiency in transporting peptides, thus eliciting a greater CD8(+) T cell response, or because of linkage disequilibrium. In multivariate logistic analysis, only the A*0205 subgroup (OR, 5.56; 95% CI, 1.34-23.10; P=.018) and the TAP2 Ala665 (OR, 2.22; 95% CI, 1.28-3.84; P=.005) were associated with resistance.     

Efficacy of 5 MU of interferon in combination with ribavirin for naïve patients with chronic hepatitis C virus: a randomized controlled trial

BACKGROUND: In chronic hepatitis C the schedule of interferon (IFN), 3 MU thrice weekly (tiw) plus ribavirin (1000-1200 mg/daily) needs further evaluation, as IFN dosages >3 MU achieve better responses. AIMS: To compare the efficacy of 5 MU tiw of IFN with (96 patients) or without ribavirin (96 patients) for 12 months in na?ve patients, to evaluate the effect of baseline features on the response to therapy, and to determine a reliable point in time during treatment to predict non-response. RESULTS: Sustained virologic response was 20.8% (95% CI 13-29) with IFN monotherapy and 54.2% (95% CI 44-64) with combination (P = 0.0001), the relapse rate 39.4% (95% CI 23-56) and 9% (95% CI 1-16) (P = 0.0007), and the combined rate of sustained biochemical and virologic response 22.7% (95% CI 14-31) and 60.5% (95% CI 50-71) (P = 0.0001), respectively. Patients given combination therapy were more likely to respond regardless of baseline features. Apart from genotype non-1, predictive factors for IFN monotherapy were ineffective in predicting response to combination therapy. Using logistic regression analysis, IFN-ribavirin was the strongest predictor of response (X2 = 21.3; P = 0.0001). Viral persistence at month 3 of therapy was a more accurate predictor than aminotransferase values for non-response to IFN monotherapy but not to combination therapy (positive predictive values of 98 and 82%, respectively). CONCLUSION: In this study, 5 MU of IFN combined with a standard dose of ribavirin has yielded the highest rate of sustained response reported to date. Further dose finding studies are warranted.     

Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data

Multicenter randomized trials have shown that once-weekly pegylated interferon (peginterferon) alfa-2a is more efficacious than conventional interferon alfa-2a (IFN) in patients with chronic hepatitis C. We performed a meta-analysis of 1,013 previously untreated patients (from 3 randomized trials) with pretreatment and post-treatment liver biopsies to assess the differences between peginterferon alfa-2a and IFN in terms of their effects on liver histology. Reported values were standardized mean differences (SMD) between patients receiving peginterferon alfa-2a and those receiving IFN (post-treatment value minus baseline value for each group). We used a random-effects model to quantify the average effect of peginterferon alfa-2a on liver histology. Peginterferon alfa-2a significantly reduced fibrosis compared with IFN (SMD, -0.14; 95% CI: -0.27, -0.01; P =.04). A reduction in fibrosis was observed among sustained virologic responders (SMD, -0.59; 95% CI: -0.89, -0.30; P <.0001) and patients with recurrent disease (SMD, -0.34; 95% CI: -0.54, -0.14; P =.0007), whereas no significant reduction was observed among nonresponders (SMD, -0.13; 95% CI: -0.32, 0.05; P =.15). Logistic regression analysis indicated that patients with sustained virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI: 1.14, 2.29) for reduction in fibrosis compared with patients without SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m(2)) had an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal-weight (BMI < 25 kg/m(2)) and overweight patients (BMI, 25-30 kg/m(2)). In conclusion, in patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa-2a (relative to IFN) significantly reduced fibrosis. The beneficial effects of peginterferon on liver histology are closely related to virologic response.     

Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers

In infants born to hepatitis B surface antigen (HBsAg)-positive mothers, failure after passive-active immunization still occurs. The role of maternal hepatitis B DNA level and other risk factors in this setting remains unclear. This study retrospectively evaluated virologic and other risk factors associated with immunoprophylaxis failure in infants born to HBsAg-positive mothers. Between January 2007 and March 2010, we reviewed the clinical and virologic tests in 869 mother-infant pairs. All infants received the identical passive-active immunization schedule after birth. The failure infants (HBsAg positive at 7-12 months of age) were compared to infants who were HBsAg negative when tested during this time period. Among 869 infants, 27 (3.1%) infants were immunoprophylaxis failures and the other 842 (96.9%) infants remained HBsAg negative. When mothers' pre-delivery HBV DNA levels were stratified to <6, 6-6.99, 7-7.99 and ≥ 8 log(10) copies/mL, the corresponding rates of immunoprophylaxis failure were 0%, 3.2% (3/95), 6.7% (19/282) and 7.6% (5/66), respectively (P < 0.001 for the trend). All failure infants were born to hepatitis B e antigen (HBeAg)-positive mothers. Multivariate logistic regression analysis identified maternal HBV DNA levels [odds ratio (OR) = 1.88, 95% confidence interval (CI): 1.07-3.30] and detectable HBV DNA in the cord blood (OR = 39.67, 95% CI: 14.22-110.64) as independent risk factors for immunoprophylaxis failure. All failure infants were born to HBeAg-positive mothers with HBV DNA levels ≥ 6 log(10) copies/mL. The presence of HBV DNA in cord blood predicted failure to passive-active immunization.     

Independent clinical predictors of impaired response to hepatitis B vaccination in HIV-infected persons

Protective response rates to hepatitis B (HB) vaccination have been reported as low as 18-62% in HIV-infected persons. The relative importance of various predictors for this poor response has not been fully characterized. In this retrospective cohort study, we examined the relationship between clinical characteristics and vaccine non-response (HB surface antibody <10 IU/L) among patients attending an urban HIV clinic. Among the 97 patients who met the inclusion criteria, 43 (44%) developed a protective antibody response. In multivariate analyses, age >40 years (odds ratio [OR] 3.03 [95% confidence interval [CI], 1.14-8.06]; P = 0.026) and alcohol abuse (OR 4.92 [95% CI, 1.72-20.89]; P = 0.007) were independent predictors of failure to develop vaccine response. In addition, CD4 nadir <200 (OR 7.24 [95% CI, 1.91-27.41]; P = 0.004), rather than CD4 current to vaccination, remained a strong independent risk factor. Patients with HIV viral suppression on highly active antiretroviral therapy had a significantly lower rate of vaccine failure (OR 0.31 [95% CI, 0.11-0.91]; P = 0.033), after adjusting for these other covariates. Our findings underscore the importance of confirming seroconversion after HB vaccination in HIV-infected patients and initiating vaccination early in the course of HIV infection.