There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV).
IgG4-related disease is a rare, systemic fibroinflammatory condition characterized by lymphoplasmacytic infiltrates and often times elevated serum IgG4 levels. Multiple organs are implicated in the disease and although the pathogenesis is not entirely understood, genetic risk factors and autoimmune dysregulation have been associated. Pathology from biopsied lesions is varied and can range from a dense lymphoplasmacytic infiltrate to fibrosis. Currently, there are limited reports of IgG4-related disease in the literature. A 69 year-old female with a past medical history significant for salivary gland tumor (s/p resection and radiation), rheumatoid arthritis (on Methotrexate), alcohol use (2-3 glasses of wine for several years) presented to hepatology clinic for evaluation of elevated liver function tests noted on routine blood work. ALP was 367 IU/L, ALT 162 IU/L and AST 67 IU/L. CA 19-9 was also elevated to 45 U/mL, however MRI and EUS were unremarkable. Liver biopsy showed portal fibrosis, lymphocytic, neutrophilic and eosinophilic portal and lobular hepatitis with bile ductular proliferation. After an unrevealing extensive workup for other causes of abnormal liver tests, it was thought the abnormal tests and biopsy finding may be secondary to ethanol abuse and methotrexate. Over the subsequent year, the patient continued to have elevated liver function tests, a thirty-five pound weight loss, jaundice and pruritus. MRI of the abdomen revealed an infiltrating peri-choledochal, peripancreatic, porta hepatic and retroperitoneal soft tissue mass, narrowing the common bile duct and multiple enlarged retroperitoneal and pericardial lymph nodes. EUS showed an irregular, 2.3 x 2.3 cm, poorly defined area within the region of the head of the pancreas, dilation of the pancreatic duct and distal common bile duct stricture. Biopsies were not performed, and cytology from FNA revealed only benign pancreatic acini. IgG4 levels were ordered to evaluate for IgG4 related autoimmune pancreatitis/sclerosing cholangitis and were elevated to 125 mg/dL. Given the elevated IgG4, and multiple organ dysfunction, a presumed diagnosis of IgG4-related disease was made. Although glucocorticosteroids are the mainstay of therapy, the patient has not since returned to clinic. IgG4-related disease is a rare yet potentially treatable entity that can mimic primary organ disease or malignancy, yet should always remain in the differential diagnosis. Close follow up and cognizance of this disease entity is critical as a lag in treatment can have significant implications.
BackgroundRecent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.MethodsIn this ongoing, double-blind, phase 1–3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19–related medically attended visit through day 29. Safety was assessed in all patients.ResultsData from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% confidence interval [CI], −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.ConclusionsIn this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)
High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.
Introduction: Ledipasvir/Sofosbuvir (LDV/SOF) is approved to treat patients infected with hepatitis C virus (HCV) genotype 1 (GT1). The current standard of care for patients infected with HCV GT2 through GT6 varies in regimen (interferon-free or interferon-containing) and duration (12, 16, or 24 weeks). Here we summarize the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for patients with HCV GT2, 3, 4, 5 or 6 infection. Methods: In the LEPTON Study (GS-US-337-1468), 26 GT2 patients received LDV 90 mg/SOF 400 mg daily for 12 weeks. In the ELECTRON-2 Study (GS-US-337-0122), 51 treatment-naïve (TN) GT3 patients were randomized to receive LDV/SOF or LDV/SOF + weight-based dosed (WBD) RBV daily for 12 weeks. In addition, 50 treatment-experienced (TE) GT3 patients received LDV/SOF + WBD RBV daily for 12 weeks and 25 GT6 patients received LDV/SOF daily for 12 weeks. In the SYNERGY Study, 21 GT4 patients received LDV/SOF daily for 12 weeks. In the GS-US-337-1119 (1119) Study, 44 GT4 and 41 GT5 patients received LDV/SOF daily for 12 weeks. Results: Two-hundred fifty-eight patients with HCV non-GT1 were enrolled in the above-listed arms of LEPTON, ELECTRON-2, SYNERGY, and Study 1119 in New Zealand, France, and the United States. In LEPTON, the majority of patients were male (17, 65%), white (24, 92%), and were treatment-naïve (21, 81%). Two patients (8%) had cirrhosis. In ELECTRON-2, the majority of patients were male (79, 63%), white (88, 70%), and were treatment naive (74, 59%). Thirty-two (25%) patients had cirrhosis. In SYNERGY, the majority of patients were male (14, 67%), white (12, 57%), and were treatment naive (13, 62%). Seven patients (33%) had cirrhosis. In Study 1119, the majority of patients were male (49, 58%), white (77, 91%), and were treatment naive (43, 51%). Sixteen (19%) patients had cirrhosis. SVR12 data are reported in the table below. Treatment was well-tolerated. Most common adverse events (>20% reported in any arm) were fatigue, headache, nausea, upper-respiratory tract infection, and insomnia. Two patients discontinued treatment due to an adverse event. Conclusion: LDV/SOF for 12 weeks is a safe, well-tolerated, and highly effective treatment option for patients with HCV GT2, 4, 5, or 6 infection. The addition of RBV may benefit patients with GT3 infection.Table 1: Primary Efficacy Results (SVR12%)
The authors describe a case of presumed endogenous fungal endophthalmitis in an immunocompetent pediatric patient with acute lymphoblastic leukemia. A 15-year-old boy with a history of high-risk B-cell acute lymphoblastic leukemia status post-chemotherapy presented with acute changes in vision in his left eye. Fundus examination revealed a white bi-lobed chorioretinal lesion with overlying vitritis and associated subretinal fluid. Magnetic resonance imaging of the brain revealed small ring-enhancing lesions in the right parietal and left occipital lobes. Blood, cerebrospinal fluid, aqueous, and vitreous cultures were all negative. Bone marrow and vitreous cytology were negative for malignant cells. The patient was treated for presumed fungal endophthalmitis with systemic and intravitreal voriconazole, followed by pars plana vitrectomy with intravitreal voriconazole and amphotericin B injections. The chorioretinal lesion resolved and visual acuity recovered to 20/20. Chorioretinal infiltrates in a patient with leukemia may require treatment even in the absence of a definitive diagnostic test result. Intervention should be guided by risk analysis and clinical judgment. [J Pediatr Ophthalmol Strabismus. 2017;54:e42-e46.].
There is a major unmet need for accurate, readily available, noninvasive tests (NITs) to identify patients with advanced fibrosis due to NASH. Our goal was to evaluate sequential NIT algorithms to minimize the requirement for biopsy and improve accuracy overuse of single tests.
Methods
The STELLAR studies (NCT03053050, NCT03053063) enrolled NASH patients with bridging fibrosis (F3) or compensated cirrhosis (F4). Baseline liver biopsies were read using the NASH CRN fibrosis classification and noninvasive fibrosis markers: FIB-4 index, ELF test, and FibroScan® (FS). The performance of these tests to discriminate advanced fibrosis was evaluated using AUROCs with 5-fold cross-validation repeated 100x. Thresholds were obtained by maximizing specificity given ≥85% sensitivity. The cohort was divided (80%/20%) into evaluation/validation sets. The evaluation set was further stratified 250x into training and test sets (66%/33%). Optimal thresholds were derived as the average across training sets, and applied sequentially (FIB-4 followed by ELF and/or FS) to the validation set. Data are from an interim analysis on 26 July 2018.
Results
All patients with available liver histology (N=3202, 71% F3-F4) and NIT results were included. While single tests were able to discriminate advanced fibrosis (AUROCs of 0.78, 0.80, and 0.80 for FIB-4, ELF, and FS in validation cohort), up to 32% of patients had an indeterminate result. Using thresholds derived from STELLAR data, FIB-4 followed by FS or ELF in those with indeterminate FIB-4 values (1.23 to 2.1) reduced indeterminate results to as low as 13% (table 1). Published NIT thresholds yielded similar results (data not shown). Adding a third test (FIB-4 then ELF then FS) reduced the rate of indeterminate results to 8%. Misclassification occurred at rates similar to biopsy (15–21%). The majority of misclassifications (63–81%) were false negatives; among false positive cases (19–27% of misclassifications) up to 70% had F2 fibrosis.
Conclusions
FIB-4 followed by ELF and/or FS nearly eliminated the need for liver biopsy and accurately identified patients with advanced fibrosis due to NASH with misclassification rates similar to liver biopsy.
We explored 2 novel scores, Agile 3+ and 4, to identify advanced fibrosis (≥F3) and cirrhosis (F4), respectively, in NAFLD and compared their diagnostic performances to liver stiffness measurement (LSM) by vibration-controlled transient elastography and fibrosis-4 index (FIB-4) (for Agile 3+).This multicenter study included 548 NAFLD patients with laboratory testing, liver biopsy, and vibration-controlled transient elastography within 6 months. Agile 3+ and 4 were applied and compared with FIB-4 or LSM alone. Goodness of fit was evaluated using a calibration plot and discrimination using area under the receiver operating curve. Area under the receiver operating curves was compared using the Delong test. Dual cutoff approaches were applied to rule out and rule in ≥F3 and F4. Median (interquartile range) age was 58 (15) years. Median body mass index was 33.3 (8.5) kg/m2. Fifty-three percent had type 2 diabetes, 20% had F3, and 26% had F4. Agile 3+ demonstrated an area under the receiver operating curve of 0.85 (0.81; 0.88) similar to that of LSM [0.83 (0.79; 0.86), p=0.142] but significantly higher than that of FIB-4 [0.77 (0.73; 0.81), p<0.0001). Agile 4's area under the receiver operating curve [0.85 (0.81; 0.88)] was similar to that of LSM [0.85 (0.81; 0.88), p=0.065). However, the percentage of patients with indeterminate results was significantly lower with Agile scores compared with FIB-4 and LSM (Agile 3+: 14% vs. FIB-4: 31% vs. LSM: 13%, p<0.001; Agile 4: 23% vs. LSM: 38%, p<0.001).Agile 3+ and 4 are novel vibration-controlled transient elastography-based noninvasive scores that increase accuracy in the identification of advanced fibrosis and cirrhosis respectively and are ideal for clinical use due to a lower percentage of indeterminant outputs compared with FIB-4 or LSM alone.
