Hepatitis B Reactivation in the DAA Era: Minding the Gap Between the Black Box and Clinical Practice

Purpose of Review

The US Food and Drug Administration recently issued a black box warning regarding the risk of hepatitis B virus (HBV) reactivation with direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-coinfected individuals. The warning included all HBV infection, active and resolved, which, along with the lack of consensus among the gastroenterology and hepatology guidelines, have left clinicians unsure on how to proceed. Recent data have filled some knowledge gaps regarding the true risk of HBV reactivation in HCV treatment. The clinical data pertaining to the risk of reactivation in active and resolved HBV infection are reviewed, and potential prevention and management strategies are proposed, noting there are still some knowledge gaps remaining.

Recent Findings

Recent large prospective studies of HBV/HCV-coinfected patients, along with the largest meta-analysis of such patients to date, provide additional insight into the risk of HBV reactivation with HCV antiviral treatment. Subclinical HBV reactivation is not uncommon, occurring in about 25% of patients, but the risk of clinically significant events such as hepatitis remains low in HBsAg-positive individuals, and even lower in isolated HBcAb-positive patients. However, recent case reports have brought to light particular situations, such as concomitant immunosuppression, as potential pitfalls to the previous low risk of reactivation attributed to resolved infection.

Summary

Recent prospective data and a large meta-analysis confirm that clinically significant HBV reactivation remains an uncommon event with the use of DAAs in HBsAg-positive patients, and even rarer in isolated HBcAb-positive cases.

     

Diagnosing breast cancer by using Raman spectroscopy

We employ Raman spectroscopy to diagnose benign and malignant lesions in human breast tissue based on chemical composition. In this study, 130 Raman spectra are acquired from ex vivo samples of human breast tissue (normal, fibrocystic change, fibroadenoma, and infiltrating carcinoma) from 58 patients. Data are fit by using a linear combination model in which nine basis spectra represent the morphologic and chemical features of breast tissue. The resulting fit coefficients provide insight into the chemical/morphological makeup of the tissue and are used to develop diagnostic algorithms. The fit coefficients for fat and collagen are the key parameters in the resulting diagnostic algorithm, which classifies samples according to their specific pathological diagnoses, attaining 94% sensitivity and 96% specificity for distinguishing cancerous tissues from normal and benign tissues. The excellent results demonstrate that Raman spectroscopy has the potential to be applied in vivo to accurately classify breast lesions, thereby reducing the number of excisional breast biopsies that are performed.     

Spectral diagnosis of atherosclerosis using an optical fiber laser catheter

This communication demonstrates that fluorescence spectra of human aorta with good S/N ratios can be collected using an optical fiber laser catheter. The performance of this catheter is compared to a non-fiber optic collection system with an equivalent delivery/collection geometry. For a given sample, fluorescence lineshapes obtained using the two systems are identical; differences in peak fluorescence intensity are related to the different collection efficiencies of the two systems. It is shown that the fluorescence lineshape of arterial tissue depends on the delivery/collection geometry of the detection system, and that this is due to the interaction of absorption and fluorescence within the artery wall. This effect is investigated systematically using a specially designed collection system. Results are analyzed qualitatively using a simple, one-dimensional model of tissue fluorescence. With this analysis, we present design requirements for a collection system in which such geometric effects are eliminated, and show that our optical fiber laser catheter satisfies these requirements.     

Diffuse vasospasm following stenting of a free gastroepiploic artery graft: Resolution with balloon angioplasty and intensive medical therapy

Vasospasm following balloon angioplasty of gastroepiploic artery bypass grafts can be prevented or reversed with vasodilators. In our patient, stent deployment for ostial stenosis of a free gastroepiploic artery graft was accompanied by severe, diffuse spasm and a change in graft configuration that required both intensive medical therapy and balloon angioplasty for resolution. © 1995 Wiley-Liss, Inc.     

Conduction Velocity Around the Tricuspid Valve Annulus During Type 1 Atrial Flutter: Defining the Location of Areas of Slow Conduction by Three-Dimensional Electroanatomical Mapping

Background: Conduction velocity (CV) around the tricuspid valve annulus (TVA) during type 1 atrial flutter (AFL) has been shown to be slowest in the tricuspid valve-inferior vena cava (TV-IVC) isthmus, compared to the septal or free wall segments of the TVA. However, fiber orientation in the triangle-of-Koch suggests that the inferior septum and medial TV -IVC isthmus should be the most slowly conducting segments around the TVA. Methods: To test this hypothesis we evaluated CV around the TVA during type 1 atrial flutter in 11 patients, using an electro-anatomical mapping system (Carto). CV was first calculated in 4 segments around the TVA including the TV-IVC isthmus, lateral free wall, superior free wall and septum, and then calculated in 8 segments around the TVA including medial (MI) and lateral isthmus (LI), inferior (IL) and superior lateral (SL) free wall, lateral (LS) and medial superior (MS) free wall, and superior (SS) and inferior septum (IS). Statistical comparison of CV from these multiple segments was made by one-way analysis of variance. Results: Measured in 4 segments around the TVA, mean CV (m/sec) in the TV-IVC isthmus (0.81 ± 0.23) and the septum (0.93 ± 0.18) was significantly slower than CV in the lateral free wall (1.16 ± 0.23) and superior free wall (1.10 ± 0.20), and CV in the TV-IVC isthmus was significantly slower than in the septum (p < 0.05). However, when analyzed in 8 segments, mean CV in the MI (0.56 ± 0.16) and IS (0.59 ± 0.24) was significantly (p < 0.05) slower than in all other segments including the LI (1.06 ± 0.46), IL (1.17 ± 0.40), SL (1.15 ± 0.40), LS (1.04 ± 0.25), MS (1.15 ± 0.28), and SS (1.26 ± 0.36) segments. Conclusions: Consistent with previous reports, CV around the TVA during type 1 AFL was slowest in the TV-IVC isthmus, compared to the septum, superior and lateral free wall regions. However, when the TVA was further subdivided into 8 segments, CV in the MI and IS segments was significantly slower than in all other segments around the TVA. These observations more precisely define the regions of slow conduction in human type 1 AFL, and are consistent with the known anisotropy and slow conduction in the Triangle of Koch.     

Empiric therapy for infections in granulocytopenic cancer patients: continuous infusion of amikacin plus cephalothin.

A combination of amikacin sulfate given by continuous infusion (800 mg/sq m/24 hr) plus cephalothin sodium (2 g every four hours) was used as initial empiric therapy for the treatment of 65 evaluable febrile (greater than 38.5 degrees C) episodes in 54 granulcoytopenic (neutrophils, less than 1,000/microliter) adult cancer patients. Carbenicillin disodium (5 g every four hours) was substituted for cephalothin in patients with Pseudomonas infections and in patients in whom the initial regimen was unsuccessful. Thirty-two of the 38(84%) identifiable infections responded to therapy, including all of the eight septicemias and eight of 11 pneumonias. Three additional infections responded to the substitution of carbenicillin for cephalothin, for a total response rate of 92% (35/38). Nephrotoxicity occurred in five patients (7.1%), most commonly in patients over 60 years of age. Ototoxicity, highly correlated with a duration of greater than 19 days and a total dosage of greater than 25 g of amikacin sulfate, occurred in four patients (5.6%). Amikacin given by continuous infusion plus cephalothin is a safe and efficacious empiric therapy for infections in granulocytopenic cancer patients.     

Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias

Sotalol is a unique beta-blocker that lengthens cardiac repolarization and effective refractory period (ERP). Its efficacy after intravenous (1.5 mg/kg) and oral (160 to 480 mg bid) administration was therefore evaluated in 37 patients with refractory recurrent ventricular tachycardia/fibrillation (VT/VF). Thirty-five patients, 33 with inducible VT/VF, underwent electrophysiologic testing. Intravenous sotalol lengthened the ERP in the atrium (+24.6%, p less than .01), atrioventricular node (+24.9%, p less than .01), and ventricle (+14.9%, p less than .01). It also significantly lengthened sinus node recovery time, corrected QT interval (QTc), and the AH interval, but not the HV interval. Sotalol prevented reinduction of VT/VF in 15 patients (45.5%). Twenty-five of the 33 patients (15 with positive results of electrophysiologic tests; 10 with negative results) were given oral sotalol. The drug was ineffective in seven (26.9%) and aggravated arrhythmia in one (3.8%). In four patients sotalol was withdrawn because of side effects; arrhythmias recurred late in two (7.7%). Eleven patients (42.3%) have continued on oral sotalol over a mean follow-up period of 9.2 +/- 8.6 months. Sotalol reduced (n = 21) total premature ventricular complex (PVC) count on the Holter electrocardiogram by 73% (p less than .01), paired PVCs by 89% (p less than .01), and beats of ventricular tachycardia by 95% (p less than .01). In 52% (n = 11), total reduction in PVCs was at least 85%, and incidence of paired and tachycardiac beats was reduced at least 90% (group A). In the remainder (n = 10), PVC suppression was not significant (group B). Group A included nine patients with nonreinducible VT/VF and two in whom it was reinducible; in group B, eight of 10 patients had reinducible VT/VF. The difference between the two groups (Fisher exact test) was significant (p less than .01). The prevention of reinduction of VT/VF by intravenous sotalol and suppression of spontaneously occurring arrhythmias by the oral drug were both predictive of long-term drug efficacy. Sotalol is a significant advance in the short- and long-term management of life-threatening ventricular tachyarrhythmias.     

A comparative trial of sisomicin therapy by intermittent versus continuous infusion

One hundred and thirty-nine febrile episodes in 120 patients were treated with sisomicin after a combination of carbenicillin and a cephalosporin antibiotic had failed. These patients were randomized to receive sisomicin either by continuous or by intermittent infusion. The response rate for patients treated with sisomicin was 61 percent by continuous infusion and 46 percent by intermittent infusion, which was not statistically significant. Pneumonia, septicemia, and soft tissue infections were the most frequent infections. Most (96 percent) of the identified pathogens were gram-negative bacilli with the most frequent being Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. The response rate was higher in those patients whose neutrophil count increased or remained the same while on therapy. The worst response was obtained if there was a decrease in the neutrophil count during therapy. The major toxicity of sisomicin was found to be azotemia and occurred in 17 percent of episodes treated by continuous infusion and in 21 percent treated by intermittent infusion. Hearing loss in the high frequency range occurred in five patients. Sisomicin is effective in the treatment of gram negative infections in neutropenic cancer patients.