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A major challenge in tuberculosis is identifying correlates of a protective immune response. The Mycobacterial Growth Inhibition Assay (MGIA) is a functional assay providing an integrated measure of the host immune response to mycobacteria. However, its feasibility is limited by reliance on biosafety level 3 facilities, and its performance has not been widely evaluated in TB-endemic settings. Here, we compared two mycobacterial strains (M. tuberculosis H37Rv versus attenuated M. bovis BCG) in the performance of whole-blood MGIA in 30 TB-exposed children (median age 2 years) in Chennai, India. The time-to-positivity in both assays was similar (5.7 days vs 6 days) and the mycobacterial growth of M. tuberculosis H37Rv and M. bovis BCG were correlated (r = 0.64, p < 0.0001). In Bland-Altman analysis, the bias was −0.54 days (95% limit of agreement −2.08, 0.99). Collectively, our results indicate that M. tuberculosis H37Rv can be substituted with the less virulent M. bovis BCG strain to improve feasibility of the MGIA assay, particularly in low-income settings. [ABSTRACT FROM AUTHOR]

Background & Aims: No information is available about the frequency or factors that predict spontaneous increases in alanine aminotransferase (ALT) levels in asymptomatic Indian patients with chronic hepatitis B virus (HBV) infection who are HB e antigen (HBeAg) negative and have normal ALT levels. Methods: We followed 217 asymptomatic patients with chronic HBV who were HBeAg negative, anti-HBe antigen (anti-HBe) positive, and had normal ALT levels. Spontaneous increases in ALT levels (ALT flares) were considered to be >2-fold the upper limit of normal (ULN) and were accompanied by HBV DNA levels ≥105 copies/mL or a 100-fold increase from the previously measured level. Results: During a median follow-up period of 69.0 months, spontaneous ALT flares occurred in 43 patients (an annual rate of 4.3%), with cumulative probabilities of 10.8% and 47.3% after 5 and 10 years, respectively. Based on multinomial logistic regression, the probability of an ALT flare correlated with age ≥30 years at presentation (odds ratio [OR], 5.31; 95% confidence interval [CI]: 1.53–18.39; P = .008), male sex (OR, 4.54; 95% CI: 1.01–20.76; P = .05), and presence of a precore mutation (OR, 10.99; 95% CI: 3.67–32.92; P < .001). The median time to spontaneous ALT flare after enrollment was 25 months (range, 1–128 months; 10th percentile = 3.4 months). Conclusions: In asymptomatic patients with chronic HBV infection who have normal ALT levels and are HBeAg negative, the annual rate of ALT flares was 4.3%. Precore mutants, male sex, and age ≥30 years at presentation are independent predictors for an ALT flare. A follow-up every 3 months can capture up to 90% of flares and would help identify patients who require antiviral therapy. [Copyright &y& Elsevier]

Background & Aims: There is a paucity of data on hepatitis B virus (HBV) DNA levels and histologic lesions in patients with chronic HBV (CHBV) infection and persistently normal alanine aminotransferase (ALT) levels (PNALT). We studied the ALT, HBV DNA levels, and spectrum of histologic lesions in such patients. Methods: One thousand three hundred eighty-seven incidentally detected asymptomatic hepatitis B surface antigen (HBsAg)-positive patients with ≥1-year follow-up and either PNALT (n = 189; hepatitis B e antigen [HBeAg+], 73; HBeAg−, 116) or persistently or intermittently elevated ALT (PIEALT; n = 1198; HBeAg+, 530; HBeAg−, 668) were included. Results: In the PIEALT and PNALT patients, baseline DNA ≥5-log copies/mL was seen in 73.8% and 60.3% in HBeAg+ (P = .018) and 76% and 35.3% in HBeAg− (P < .001) patients and histologic fibrosis stage ≥2 in 65.5% and 40.2% in HBeAg+ (P < .001) and 63.9% and 13.8% in HBeAg− (P < .001) patients, respectively. Approximately 21% of HBeAg− patients with PNALT and HBV DNA <5-log copies/mL had histologically active liver disease (histologic activity index ≥3 and/or fibrosis stage ≥2). Conclusions: A fair proportion of patients with CHBV infection with PNALT have HBV DNA ≥5-log copies/mL and significant histologic fibrosis. Use of ALT and HBV DNA levels without resorting to liver biopsy to define “inactive carrier state” in HBeAg− PNALT patients may miss histologically significant disease in a proportion of patients. [Copyright &y& Elsevier]

Abstract: The non-response to hepatitis B vaccine in health care workers (HCWs) is reported to vary between 5 and 40%. The underlying cellular and molecular events for unresponsiveness to HBV vaccine have not yet been characterized at any great extent. In the current study, we examined the CD150 surface expression levels and its association with polyclonally activated and HBV specific stimulated cellular proliferations in responders and non-responders. CD150 was identified as upregulated expression marker with suppressive regulatory cell function on all activated T cells by gene chip analysis. We found the overall weak cellular proliferation in response to specific and non-specific agents in non-responders. This is significantly associated with enhanced surface expression of CD150 in the non-responders. A strong expression of CD150 with weak cellular proliferation could be used as a predictive marker for non-responsiveness. [Copyright &y& Elsevier]