Hepatitis B remains a significant health issue and a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Transmission of the hepatitis B virus, despite the availability of the vaccine, ...still occurs, particularly in the perinatal setting. Studies have shown that mothers with active viremia especially those with very high viral levels (>10⁸ copies/mL or >10⁷ IU/mL) are at increased risk of hepatitis B virus transmission, even with appropriate immunoprophylaxis at birth. With the development of new and relatively safe oral antiviral therapies, assessment with the mother about the risks and benefits of antiviral therapy should be discussed in those with highest transmission risk.
Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma, globally. Most individuals infected with HCV are asymptomatic. The introduction of the newer ...direct-acting antiviral (DAA) therapies has led to achievement of treatment success rates of more than 90%. Sustained virologic response is the end point of therapy, and is considered a virologic cure. It is defined as undetectable HCV RNA 12 weeks after end of therapy. This article reviews current approved non-interferon-based therapy and data from clinical trials in treatment-naive patients with chronic HCV infection.
Genetic studies have established that lysis inhibition in bacteriophage T4 infections occurs when the RI antiholin inhibits the lethal hole‐forming function of the T holin. The T‐holin is composed of ...a single N‐terminal transmembrane domain and a ∼20 kDa periplasmic domain. It accumulates harmlessly throughout the bacteriophage infection cycle until suddenly causing permeabilization of the inner membrane, thereby initiating lysis. The RI antiholin has a SAR domain that directs its secretion to the periplasm, where it can either be inactivated and degraded or be activated as a specific inhibitor of T. Previously, it was shown that the interaction of the soluble domains of these two proteins within the periplasm was necessary for lysis inhibition. We have purified and characterized the periplasmic domains of both T and RI. Both proteins were purified in a modified host that allows disulfide bond formation in the cytoplasm, due to the functional requirement of conserved disulfide bonds. Analytical centrifugation and circular dichroism spectroscopy showed that RI was monomeric and exhibited ∼80% alpha‐helical content. In contrast, T exhibited a propensity to oligomerize and precipitate at high concentrations. Incubation of RI with T inhibits this aggregation and results in a complex of equimolar T and RI content. Although gel filtration analysis indicated a complex mass of 45 kDa, intermediate between the predicted 30 kDa heterodimer and 60 kDa heterotetramer, sedimentation velocity analysis indicated that the predominant species is the former. These results suggest that RI binding to T is necessary and sufficient for lysis inhibition.
The prevalence of hepatitis B virus (HBV) infection in the Asian American population is disproportionately high compared with
the US population as a whole. Effective management is difficult because ...of cultural barriers, which can be better understood
with recognition of the diversity of the Asian continent in terms of language and spiritual beliefs. Barriers to care among
the Asian American population include educational deficits, low socioeconomic status, lack of health insurance, noncitizenship,
inability to communicate in English, negative perceptions of Western medicine, and underrepresentation among health care professionals.
Given the diversity of the population, some subpopulations may be more directly affected by certain barriers than others.
The resulting delays in seeking care can lead to poor outcomes and risk of HBV transmission to household members. Health care
providers are obligated to educate themselves regarding cultural sensitivity and to advocate for improved access to care.
Key points Some Asian Americans have limited proficiency in English and are isolated linguistically, limiting their ability to communicate
with health care providers.
Key points Asian Americans may view Western medicine with suspicion, causing delays in seeking care and making it difficult to successfully
manage chronic HBV infection.
Key points Sensitivity to cultural attitudes may enhance communication and the likelihood that immigrant patients will accept health
care providersâ recommendations; cultural sensitivity training may be helpful.
It is uncertain whether differences in
(
virulence defined
influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the ...virulence of
isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5-90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (
= 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (
= 0.002 and 0.0005, respectively), but higher concentration of IL-1β (
= 5.1 × 10
) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage
= 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68-11.13. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent
. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage.
Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the ...rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co‐infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24 weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24–48 weeks. HBeAg loss was defined as first HBeAg‐negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg‐negative values ≥24 weeks apart. During a median follow‐up of 1.8 years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8–13.3) per 100 person‐years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre‐core mutations versus wild type. Additionally, during follow‐up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies.
Introduction
Chronic hepatitis C (CHC) infection is associated with extrahepatic manifestations (EHMs) which can affect renal, cardiovascular and other comorbidities. The effect of CHC treatment with ...short-duration regimens on these EHMs is not well defined. Hence, we examined longitudinal estimated glomerular filtration rate (eGFR), triglycerides and glucose values to assess the impact of short-duration CHC therapy on renal, cardiovascular and metabolic diseases, respectively.
Methods
We conducted analyses of all patients without cirrhosis treated with glecaprevir and pibrentasvir (G/P) for 8 weeks in two phase 3 clinical trials. In addition, one phase 3 trial was carried out to explore the effects of treatment on renal EHMs in patients with advanced renal impairment at baseline. As a sensitivity analysis, we included all CHC patients treated with G/P for 8 or 12 weeks enrolled across five phase 3 trials. Adjusting for baseline demographics and clinical properties via mixed regression models enabled evaluation of changes in EHMs through end of treatment.
Results
G/P treatment for 8 weeks resulted in statistically significant declines in triglycerides (− 28.6 mg/dl) and glucose (− 11.2 mg/dl), while there was no statistically significant decline in eGFR. Biomarker improvements were greatest among patients with elevated triglycerides and elevated glucose at baseline. Similar effects were observed across all patients treated with G/P for 8 or 12 weeks.
Conclusion
Short-duration treatment with G/P resulted in stable renal function and improvements in cardiovascular and metabolic EHM markers, especially in patients with severe EHMs at baseline.
Funding
AbbVie Inc.
Chronic hepatitis B virus infection remains a global health concern, with perinatal transmission still a problem in many countries. Several new therapies for chronic hepatitis B virus infection have ...recently been introduced that can safely and effectively suppress viral replication with a low risk of resistance; thus, it has become increasingly tempting for many clinicians to treat patients in the immune tolerant stage of infection who have high levels of viremia yet persistently normal levels of transaminases. However, understanding the natural history of hepatitis B virus infection and how it pertains to disease progression, as well as how current therapies alter or do not alter this natural history, is important when deciding whether to treat these patients. This article will review the definition and natural history of immune tolerance, the current world guidelines and recommendations for treatment of immune tolerant patients, and data on the effectiveness of current therapies in this patient population.
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