Summary Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In ...a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov , number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0·73 log IU/mL in group 1 (95% CI 0·17–1·31; p=0·03) and −1·54 log IU/mL in group 2 (1·21–1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change ( r2 =0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days SE 0·24), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 SE 0·06 vs 0·739 0·05, p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. Funding National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health , and Eiger Biopharmaceuticals Inc.
Because of the severity of some of the infections, such as the risk of meningitis with Coccidioides exposure, strong consideration should be given to antifungal prophylaxis for those at heightened ...risk. Meningitis (Cryptococcus) Ketoconazole (ND; Histoplasma); amphotericin B (ND), fluconazole (ND; Cryptococcus) Lobectomy for Histoplasma-related bronchiectasis Cr1 18/M/A R423Q (DNA binding) Cryptococcus gattii C gattii C gattii meningitis Liposomal amphotericin B, flucytosine, voriconazole Papilledema and increased opening pressures without vision changes Cr2E7 29/F/B ND Cryptococcus neoformans N Colon, perirectal abscess Amphotericin B (10 wk) and 5-flucytosine (ND) ND Cr3E8 31/M/W ND C neoformans N Esophageal Amphotericin B (6 wk) and 5-flucytosine (6 wk) ND Cr4E9 13/M/ND ND C neoformans N Meningitis Amphotericin B (10 wk), 5-flucytosine (6 wk), dexamethasone (12 wk), fluconazole (6 mo) Myeloperitoneal shunt Co1 4/F/W V713M (transactivation) Coccidioides immitis Y Meningitis Liposomal amphotericin, fluconazole Stroke, hydrocephalus, bilateral VP shunt, hypercalcemia Co2E10 17/F/ND T412S (DNA binding) C immitis Y Meningitis, cerebral abscess Amphotericin B (3 wk), fluconazole (lifelong) Altered mental status requiring temporary intubation Co3E11 4/F/ND ND Cimmitis N Meningitis Amphotericin B (ND), fluconazole (ND) Strokes Table E1 Cases and literature review of patients with HIES with endemic fungal infections A, Asian; B, black; N, no; ND, not documented; W, white; Y, yes.
To describe the ophthalmic and systemic autoimmune findings after successful adoptive cell transfer of ex vivo expanded, autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) for metastatic ...melanoma.
Retrospective, interventional case report.
A 35-year-old man who underwent immunotherapy for metastatic melanoma with adoptive cell transfer of tumor-reactive TIL.
A 35-year-old man with metastatic melanoma was treated with TIL plus interleukin-2 (IL-2) therapy after a lymphodepleting regimen of cyclophosphamide and fludarabine for metastatic melanoma, which led to a complete and durable remission. Bilateral panuveitis, hearing loss, vitiligo, poliosis, and alopecia developed in the patient, requiring local ophthalmic immunosuppressive therapy. The clinical course, diagnostic testing, and therapeutic interventions over a 2-year period are reviewed.
Visual acuity, anterior chamber and vitreous inflammation, optical coherence tomography findings, serial electro-oculograms (EOGs), microperimetry (MP-1) testing, flow cytometric analysis of cells derived from the aqueous humor, and aqueous humor cytokine profiles were evaluated.
After melanoma immunotherapy, complete tumor regression was achieved at 5 months after treatment with a durable, ongoing, complete remission at 24 months. Early in the treatment course, a high fever, a diffuse rash, hearing loss, and bilateral anterior uveitis developed acutely in the patient. Late autoimmune sequelae included the development of alopecia, vitiligo, poliosis, and bilateral panuveitis with diffuse retinal pigment epithelium (RPE) hypopigmentation, reminiscent of Vogt-Koyanagi-Harada (VKH) syndrome. Bilateral cystoid macular edema also developed that was responsive to acetazolamide. Serial EOGs showed alterations in RPE standing potentials in dark conditions, and MP-1 testing revealed diminished foveal and perifoveal sensitivity. An aqueous humor aspirate revealed a high concentration of melanoma tumor antigen-reactive T cells compared with that of peripheral blood samples, as well as a proinflammatory aqueous cytokine profile. At the time of cataract surgery 22 months after immunotherapy, a repeat aqueous humor sample showed the disappearance of the previously seen melanoma differentiation antigen-reactive lymphocytes, but the proinflammatory cytokine profile persisted.
Ocular and systemic autoimmune sequelae resembling VKH may develop after successful melanoma immunotherapy. This report provides insight into the pathogenesis of VKH disease. The patient's clinical course illustrates the fine balance between tumor-specific immunity and loss of self-tolerance.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Survivors of Ebola virus disease (EVD) experience decreased intraocular pressure (IOP) relative to unaffected close contacts during the first year of convalescence. Whether this effect persists over ...time and its relationship to intraocular pathology are unclear. We sought to determine whether IOP remained lower in survivors of EVD over 4 years of follow-up and to identify associated risk factors.
Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) III is a 5-year, longitudinal cohort study of survivors of EVD and their close contacts and is a collaboration between the Liberian Ministry of Health and the United States National Institutes of Health.
Participants who enrolled in PREVAIL III at John F. Kennedy Medical Center in Liberia, West Africa from June 2015 to March 2016 who underwent comprehensive ophthalmic evaluation annually for 5 consecutive visits.
Intraocular pressure was measured at each visit by a handheld rebound tonometer using sterile tips. Comparisons are made between antibody-positive survivors and antibody-negative close contacts.
Intraocular pressure, measured in mmHg, at each study visit.
Of 565 antibody-positive survivors and 644 antibody-negative close contacts enrolled in the study at baseline, the majority of participants returned annually, with 383 (67.8%) and 407 (63.2%) participants, respectively, presenting for the final study visit at a median of 60 months after symptom onset. A sustained, relative decrease in IOP was observed in survivors relative to close contacts, with mean difference of −0.72 mmHg (95% confidence interval CI −1.18 to −0.27) at the final study visit. This difference remained constant throughout the study period (P = 0.4 for interaction over time). Among survivors, physical examination findings of vitreous cell and OCT findings of vitreous opacities both demonstrated a significant association with decreased IOP at baseline (P < 0.05 for both). After adjusting for such factors, the difference throughout the follow-up (−0.93 mmHg, 95% CI, −1.23 to −0.63) remained significant.
Survivors of EVD experienced a sustained decrease in IOP relative to close contacts over a 5-year period after EVD. The results highlight the importance of considering long-term sequelae of emerging infectious diseases within a population.
Proprietary or commercial disclosure may be found after the references.
Introduction Despite many recommended strategies for obesity prevention during infancy, effectively delivering recommendations to parents in clinical settings is challenging, especially among ...high-risk populations. This study describes and compares mothers’ and clinicians’ priorities for obesity prevention during infancy, to facilitate more-effective obesity prevention messaging. Methods A discrete choice experiment using maximum difference scaling was administered in 2013 and analyzed in 2013−2014. Twenty-nine low-income, obese mothers of infants and 30 pediatric clinicians from three urban primary care practices rated the relative importance of 16 items relevant to obesity prevention during infancy, in response to this question: Which topic would be most helpful for new mothers to learn about to prevent your their child from becoming overweight? Response options encompassed the domains of feeding, sleep, parenting (including physical activity and screen time), and maternal self-care. Results Mothers (all Medicaid-enrolled and black; mean age, 27 years; mean BMI, 35 kg/m2 ) and clinicians (97% female, 87% pediatricians, 13% nurse practitioners) both highly prioritized recognizing infant satiety and hunger cues, and appropriate feeding volume. Mothers rated infant physical activity and maintaining regular routines as 3.5 times more important than clinicians did ( p <0.001). Clinicians rated breastfeeding as 3.4 times more important than mothers did ( p <0.001). Neither group prioritized learning about screen time or maternal self-care. Conclusions Low-income, obese, black mothers of infants highly prioritized learning about many effective obesity prevention strategies, including recognizing hunger and satiety cues, promoting infant activity, and maintaining regular routines. Clinicians may frame preventive guidance to be responsive to these priorities.
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