Transcriptome analysis of Burkitt lymphoma cells treated with anti-convulsant drugs that are inhibitors of Epstein-Barr virus lytic reactivation.

Herpesviruses have two distinct life cycle stages, latency and lytic replication. Epstein-Barr virus (EBV), a gamma-herpesvirus, establishes latency in vivo and in cultured cells. Cell lines harboring latent EBV can be induced into the lytic cycle by treatment with chemical inducing agents. In the Burkitt lymphoma cell line HH514-16 the viral lytic cycle is triggered by butyrate, a histone deacetylase (HDAC) inhibitor. Butyrate also alters expression of thousands of cellular genes. However, valproic acid (VPA), another HDAC inhibitor with global effects on cellular gene expression blocks EBV lytic gene expression in Burkitt lymphoma cell lines. Valpromide (VPM), an amide derivative of VPA, is not an HDAC inhibitor, but like VPA blocks induction of the EBV lytic cycle. VPA and VPM are the first examples of inhibitors of initial stages of lytic reactivation. We compared the effects of VPA and VPM, alone and in combination with butyrate, on host cellular gene expression using whole transcriptome analysis (RNA-seq). Gene expression was analyzed 6 h after addition of the compounds, a time before the first EBV lytic transcripts are detected. The results address two alternative, yet possibly complementary, mechanisms for regulation of EBV lytic reactivation. First, cellular genes that were up- or down-regulated by butyrate, but no longer altered in the presence of VPA or VPM, represent genes that correlated with EBV lytic reactivation. Second, genes regulated similarly by VPA and VPM in the absence and presence of butyrate are candidates for suppressors of EBV reactivation. Two genes upregulated by the lytic cycle inhibitors, CHAC1 and SLC7A11, are related to redox status and the iron-dependent cell death pathway ferroptosis. This study generates new hypotheses for control of the latency to lytic cycle switch of EBV and provides the first description of effects of the anti-convulsant drug VPM on global human cellular gene expression.

Biologic Therapy Carries a Very Low Risk of Reactivation in Hepatitis B Surface Antigen-Negative Phase of Hepatitis B.

BACKGROUND: The risk of hepatitis B reactivation in hepatitis B surface antigen-negative phase of hepatitis B virus-infected patients exposed to biologic agents is not clear. We aimed to investigate the reactivation rate in hepatitis B surface antigen-negative phase of hepatitis B virus-infected patients after biologic therapy. METHODS: Patients followed at gastroenterology, rheumatology, and dermatology clinics with a diagnosis of immune-mediated inflam matory diseases were screened. Immune-mediated inflammatory diseases patients exposed to biologic agents with a negative hepatitis B surface antigen and positive hepatitis B core immunoglobulin G antibody were included in the study. RESULTS: We screened 8266 immune-mediated inflammatory disease patients, and 2484 patients were identified as exposed to biologic agents. Two hundred twenty-one patients were included in the study. The mean age was 54.08 ± 11.69 years, and 115 (52.0%) patients were female. The median number of different biologic subtype use was 1 (range: 1-6). The mean biologic agent exposure time was 55 (range: 2-179) months. One hundred and fifty-two (68.8%) patients used a concomitant immunomodulatory agent, and 84 (38.0%) patients were exposed to corticosteroids during biologic use. No hepatitis B reactivation with a reverse seroconversion of hepatitis B surface antigen positivity was seen. Antiviral prophylaxis for hepatitis B was applied to 48 (21.7%) patients. Hepatitis B virus-DNA was screened in 56 (25.3%) patients prior to the biologic exposure. Two patients without antiviral prophylaxis had hepatitis B virus-DNA reactivation with a negative hepatitis B surface antigen during exposure to the biologic agent. CONCLUSION: We found 2 reactivations and no hepatitis B surface antigen seroconversion in our cohort. Antiviral prophylaxis for patients exposed to biologic agents may need to be discussed in more detail.

Meta-analysis: hepatitis B reactivation in patients receiving biological therapy.

BACKGROUND: The use of biologics poses a moderate to high risk for hepatitis B virus reactivation (HBVr) in chronic carriers. AIM: To determine the prevalence of HBVr with TNF alpha inhibitors, ustekinumab and vedolizumab METHOD: We followed the MOOSE guidelines and conducted a comprehensive literature search. We conducted a systematic search of EMBASE (Ovid), MEDLINE (Ovid) and PubMed. The studies included patients who were chronic and occult HBV carriers with various rheumatological, dermatological or gastroenterological conditions. We used a random effects model using pooled estimates (prevalence of HBVr with 95% confidence intervals (CI)). RESULTS: We included 29 studies with 1409 patients infected with HBV. The prevalence of HBVr in chronic carriers of HBV was 17.1% (95% CI: 7.0-35.9, n = 5), 16.6% (95% CI: 9.5-27.5%, n = 6), 40.5% (95% CI: 20.3-64.5%, n = 4) and 19.1% (95% CI: 7.3-41.2%, n = 2), respectively, for adalimumab, etanercept, infliximab and ustekinumab. The respective prevalence for reactivation in patients with occult HBV infection was 5.0% (95% CI: 2.8-8.7%, number of studies: n = 18), 2.6% (95% CI: 1.4-4.7%, n = 18), 4.4% (95% CI: 2.2-8.7%, n = 12) and 6.4% (95% CI: 2.2-16.8, n = 5). There were 39 HBVr (26 in chronic HBV and 13 in the occult group) without any hepatic failure or death. In the chronic HBVr group, only three of 24 patients received antiviral prophylaxis. CONCLUSIONS: HBVr prevalence rates differ between the chronic carrier state and the occult carrier state. The uptake of prophylactic antiviral therapy in high-risk groups was low, contrary to clinical practice guidelines.

HPLC-Based Purification and Isolation of Potent Anti-HIV and Latency Reversing Daphnane Diterpenes from the Medicinal Plant Gnidia sericocephala (Thymelaeaceae).

Despite the success of combination antiretroviral therapy (cART), HIV persists in low- and middle-income countries (LMIC) due to emerging drug resistance and insufficient drug accessibility. Furthermore, cART does not target latently-infected CD4+ T cells, which represent a major barrier to HIV eradication. The "shock and kill" therapeutic approach aims to reactivate provirus expression in latently-infected cells in the presence of cART and target virus-expressing cells for elimination. An attractive therapeutic prototype in LMICs would therefore be capable of simultaneously inhibiting viral replication and inducing latency reversal. Here we report that Gnidia sericocephala, which is used by traditional health practitioners in South Africa for HIV/AIDS management to supplement cART, contains at least four daphnane-type compounds (yuanhuacine A (1), yuanhuacine as part of a mixture (2), yuanhuajine (3), and gniditrin (4)) that inhibit viral replication and/or reverse HIV latency. For example, 1 and 2 inhibit HIV replication in peripheral blood mononuclear cells (PBMC) by >80% at 0.08 µg/mL, while 1 further inhibits a subtype C virus in PBMC with a half-maximal effective concentration (EC50) of 0.03 µM without cytotoxicity. Both 1 and 2 also reverse HIV latency in vitro consistent with protein kinase C activation but at 16.7-fold lower concentrations than the control prostratin. Both 1 and 2 also reverse latency in primary CD4+ T cells from cART-suppressed donors with HIV similar to prostratin but at 6.7-fold lower concentrations. These results highlight G. sericocephala and components 1 and 2 as anti-HIV agents for improving cART efficacy and supporting HIV cure efforts in resource-limited regions.

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation.

Latency reversing agents (LRAs), such as protein kinase C (PKC) agonists, constitute a promising strategy for exposing and eliminating the HIV-1 latent reservoir. PKC agonists activate NF-κB and induce deleterious pro-inflammatory cytokine production. Adjuvant pharmacological agents, such as ruxolitinib, a JAK inhibitor, have previously been combined with LRAs to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 reactivation in vitro. Histone deacetylase inhibitors (HDACi) are known to dampen pro-inflammatory cytokine secretion in the context of other diseases and synergize with LRAs to reactivate latent HIV-1. This study investigates whether a panel of epigenetic modifiers, including HDACi, could dampen PKC-induced pro-inflammatory cytokine secretion during latency reversal. We screened an epigenetic modifier library for compounds that reduced intracellular IL-6 production induced by the PKC agonist Ingenol-3,20-dibenzoate. We further tested the most promising epigenetic inhibitor class, HDACi, for their ability to reduce pro-inflammatory cytokines and reactivate latent HIV-1 ex vivo. We identified nine epigenetic modulators that reduced PKC-induced intracellular IL-6. In cells from aviremic individuals living with HIV-1, the HDAC1-3 inhibitor, suberohydroxamic acid (SBHA), reduced secretion of pro-inflammatory cytokines TNF-α, IL-5, IL-2r, and IL-17 but did not significantly reactivate latent HIV-1 when combined with Ingenol-3,20-dibenzoate. Combining SBHA and Ingenol-3,20-dibenzoate reduces deleterious cytokine production during latency reversal but does not induce significant viral reactivation in aviremic donor PBMCs. The ability of SBHA to reduce PKC-induced pro-inflammatory cytokines when combined with Ingenol-3,20-dibenzoate suggests SBHA can be used to reduced PKC induced pro-inflammatory cytokines but not to achieve latency reversal in the context of HIV-1.

Importance of Compliance With Guidelines for the Prevention of Varicella-Zoster Virus Reactivation in Multiple Myeloma.

BACKGROUND/AIM: The importance of compliance with National Comprehensive Cancer Network (NCCN) guidelines for preventing varicella-zoster virus reactivation (VZVr) in multiple myeloma (MM) in a clinical setting has not been well investigated. PATIENTS AND METHODS: We retrospectively studied the clinical characteristics and outcomes of 118 patients with MM treated with proteasome inhibitors. RESULTS: Thirty-nine episodes of VZVr were observed in 37 patients (VZVr group). The proportion of prophylactic antiviral prescriptions and compliance with antiviral prophylaxis based on the NCCN Clinical Practice guidelines was 76% and 30% in the VZVr group, and 88% and 74% in the non-VZVr group, respectively. Multivariate analysis showed that compliance with the NCCN guidelines was the only independent risk factor for VZVr (p=0.0017). CONCLUSION: It is important that prophylactic antivirals are prescribed for an appropriate duration of time to prevent the reactivation of VZV in compliance with existing guidelines.

Hepatitis B (HBV) reactivation in patients receiving biologic therapy for chronic inflammatory diseases in clinical practice.

INTRODUCTION AND AIM: Biologic treatment - particularly with the anti-TNF molecules - is frequently used in clinical practice to treat the severe form for both chronic rheumatic diseases and inflammatory bowel diseases. The immunosuppression induced by biologic therapies increases the risk of infections, including tuberculosis, as well as hepatitis B virus (HBV) reactivation may occur in inactive carriers or occult HBV infection (OBI) subjects during biologic therapy. This study aimed to update data on HBV prevalence and reactivation in patients receiving biologic therapy for either chronic rheumatic diseases or IBD, and to describe their management in clinical practice. MATERIALS AND METHODS: This study was performed in 6 Italian centers (3 Rheumatology Units and 3 Gastroenterology Units). Clinical, biochemical and virological data, as well as follow up information, were recorded and analyzed. RESULTS: 984 patients were considered, including 817 with rheumatic disease and 167 with IBD. A total of 43 showed HBV infection (38 OBI and 5 carriers) accounting for a prevalence of 4%. Among OBI patients, 1 (2.6%) case of HBV reactivation occurred in a male patient with Crohn disease. Among the 5 HBV carriers, two patients (1 with spondyloarthritis and 1 with rheumatoid arthritis) did not received HBV antiviral therapy, and both experienced flare of hepatitis at 47 and 49 months following biologic therapy starting. DISCUSSION: Data of our study highlight that guidelines on management of HBV patients treated with biologic therapies should be still implemented in clinical practice when considering that, although infrequent, HBV reactivation could be potentially life-threatening.

Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways.

The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4+ T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4+ T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4+ T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.

Safety, tolerability of ES16001, a novel varicella zoster virus reactivation inhibitor, in healthy adults.

PURPOSE: Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults. METHOD: Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants' treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests. RESULTS: In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration. CONCLUSION: ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ. TRIAL REGISTRATION: CRIS, KCT0006066. Registered 7 April 2021-Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071 ).

COVID-19 pandemic as a risk factor for the reactivation of herpes viruses.

The appearance on the skin of herpes virus lesions, concomitantly with the coronavirus disease 2019 (COVID-19) pandemic, leads us to suspect an underlying infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Diagnostic reverse transcriptase polymerase chain reaction tests and immunoglobulin M (IgM) and IgG seroconversion studies have therefore been carried out. We present three cases of herpes virus infections in immunocompetent patients: one of the infections was herpes simplex 1 in a 40-year-old woman, and the other two were herpes varicella-zoster infections in a 62-year-old man and a 25-year-old woman. The patients were in the care of the southern health district of Seville of the SAS (Andalusian Health Service) during the Spanish state of alarm over the COVID-19 pandemic. The SARS-CoV-2 infection was confirmed in only one of the three cases. In this study, we briefly review the etiopathogenic role of the COVID-19 pandemic situation, whereby immunodeficiencies are generated that favour the appearance of other viral infections, such as herpes virus infections.

An extract of Stephania hernandifolia, an ethnomedicinal plant, inhibits herpes simplex virus 1 entry.

Stephania hernandifolia (Nimukho), an ethnomedicinal herb from rural Bengal, has been used traditionally for the management of nerve, skin, urinary, and digestive ailments. Here, we attempted to confirm the antiviral potential of aqueous, methanol, and chloroform extracts of S. hernandifolia against herpes simplex virus type 1 (HSV-1), the causative agent of orolabial herpes in humans, and decipher its underlying mechanism of action. The bioactive extract was standardized and characterized by gas chromatography-mass spectroscopy, while cytotoxicity and antiviral activity were evaluated by MTT and plaque reduction assay, respectively. Two HSV strains, HSV-1F and the clinical isolate VU-09, were inhibited by the chloroform extract (CE) with a median effective concentration (EC50) of 4.32 and 4.50 µg/ml respectively, with a selectivity index (SI) of 11. Time-of-addition assays showed that pre-treatment of virus-infected cells with the CE and its removal before infection reduced the number of plaques without lasting toxicity to the cell, indicating that the CE affected the early stage in the viral life cycle. The number of plaques was also reduced by direct inactivation of virions and by the addition of CE for a short time following attachment of virions. These results together suggest that modification of either the virion surface or the cell surface by the CE inhibits virus entry into the host cell.

Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: An economic evaluation using a dynamic transmission model.

OBJECTIVES: Comprehensive cost-effectiveness analyses of introducing varicella and/or herpes zoster vaccination in the Swedish national vaccination programme. DESIGN: Cost-effectiveness analyses based on epidemiological results from a specifically developed transmission model. SETTING: National vaccination programme in Sweden, over an 85- or 20-year time horizon depending on the vaccination strategy. PARTICIPANTS: Hypothetical cohorts of people aged 12 months and 65-years at baseline. INTERVENTIONS: Four alternative vaccination strategies; 1, not to vaccinate; 2, varicella vaccination with one dose of the live attenuated vaccine at age 12 months and a second dose at age 18 months; 3, herpes zoster vaccination with one dose of the live attenuated vaccine at 65 years of age; and 4, both vaccine against varicella and herpes zoster with the before-mentioned strategies. MAIN OUTCOME MEASURES: Accumulated cost and quality-adjusted life years (QALY) for each strategy, and incremental cost-effectiveness ratios (ICER). RESULTS: It would be cost-effective to vaccinate against varicella (dominant), but not to vaccinate against herpes zoster (ICER of EUR 200,000), assuming a cost-effectiveness threshold of EUR 50,000 per QALY. The incremental analysis between varicella vaccination only and the combined programme results in a cost per gained QALY of almost EUR 1.6 million. CONCLUSIONS: The results from this study are central components for policy-relevant decision-making, and suggest that it was cost-effective to introduce varicella vaccination in Sweden, whereas herpes zoster vaccination with the live attenuated vaccine for the elderly was not cost-effective-the health effects of the latter vaccination cannot be considered reasonable in relation to its costs. Future observational and surveillance studies are needed to make reasonable predictions on how boosting affects the herpes zoster incidence in the population, and thus the cost-effectiveness of a vaccination programme against varicella. Also, the link between herpes zoster and sequelae need to be studied in more detail to include it suitably in health economic evaluations.

Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity.

We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.

The Efficacy of Natural Bioactive Compounds for the Treatment of Nasopharyngeal Carcinoma.

The death toll associated with cancer worldwide is constantly on the increase. Efforts to combat and treat the different forms of this disease is also evolving. Nasopharyngeal carcinoma (NPC) is a lethal form of cancer, which is prevalent in Southern China, that is normally treated by using radiotherapy. Here, we will review products obtained from natural sources that have potential cytotoxic and apoptotic properties against NPC. These include grifolin, dihydroartemisinin, luteolin, honokiol, indole-3-carbinol, caffeic acid phenethyl ester, 6-O-angeloylenolin, cucurbitacin E, genistein, helenalin, celastrol, coronarin D, quercetin, trans-cinnamaldehyde, 5'-epimer episilvestrol, silvestrol, arnicolide D, brevilin A, and baicalin hydrate. Ethyl acetate extracts of Wedelia chinensis and aqueous extracts of Ajuga bracteosa are also included although the bioactive compounds involved have yet to be identified. The known mechanism of action of these products is discussed. It is anticipated that one or more of these substances may provide the general population with alternative and cost-effective ways to combat this fatal disease.

Prevalence of hepatitis B virus infection and risk of reactivation in rheumatic population undergoing biological therapy.

OBJECTIVES: Hepatitis B (HBV) is a common comorbidity among rheumatic patients. The prevalence of HBV infection and the rate of reactivation remain unclear. The literature data suggested a higher risk in chronic than in past infection. Currently, the literature data are mostly focused on anti-TNF and rituximab. This retrospective observational study aimed to analyse the prevalence of HBV infection and the risk of viral reactivation in a population of rheumatic patients undergoing anti-TNF and non-anti-TNF agents. METHODS: We analysed 1216 rheumatic patients, treated with both csDMARDs and bDMARDs between 2006 and 2017. Serologic markers for HBV (HBsAg, anti-HBs, anti-HBc) were performed prior and during biologic treatment. Patients with chronic or resolved infection were monitored every 3 months. RESULTS: The prevalence of HBV in our cohort was 15.7% (chronic infection: 0.4%, resolved infection: 12.6%, anti-HBc positivity alone: 2.6%). 12 (6.2%) out of 191 HBV infected patients experienced a reactivation. All of them showed markers of past infection. One patient experienced HBV reactivation despite lamivudine. Only one patient experienced acute hepatitis, probably due to the interruption of immunosuppressors in anticipation of surgery, not preceded by any HBV prophylactic treatment. CONCLUSIONS: HBV reactivation is a rare event in patients treated with a bDMARD and it can also occur while taking lamivudine, not only in chronic carriers (as per the literature data) but also in inactive ones. Regular screening followed by prompt treatment can prevent symptoms or complications. Due to the risk of hepatitis following the immune reconstitution, an antiviral therapy should be considered in the case of sudden discontinuation of csDMARDs or bDMARD.

Extracellular Vesicles as a New Promising Therapy in HIV Infection.

Combination antiretroviral therapy (cART) effectively blocks HIV replication but cannot completely eliminate HIV from the body mainly due to establishment of a viral reservoir. To date, clinical strategies designed to replace cART for life and alternatively to eliminate the HIV reservoir have failed. The reduced expression of viral antigens in the latently infected cells is one of the main reasons behind the failure of the strategies to purge the HIV reservoir. This situation has forced the scientific community to search alternative therapeutic strategies to control HIV infection. In this regard, recent findings have pointed out extracellular vesicles as therapeutic agents with enormous potential to control HIV infection. This review focuses on their role as pro-viral and anti-viral factors, as well as their potential therapeutic applications.

Evaluation of Hepatitis B Reactivation Among Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors.

Hepatitis B reactivation (HBVr) in cancer patients is a well-established complication due to chemotherapy-induced immunosuppression. Studies have reported HBVr associated with immunosuppressive medications, such as rituximab, methotrexate, and high dose steroids. There are different risks for different types of chemotherapy with rituximab carrying one of the highest risks for hepatitis B reactivation. Tyrosine kinase inhibitors (TKIs) are the standard of care in patients with chronic myeloid leukemia (CML). The risk of HBVr in chronic myeloid leukemia has been reported in many studies, but to this date, there are no clear guidelines or recommendations regarding screening and monitoring of HBV in CML patients receiving TKIs. We conducted this review to identify the risk of HBVr in patients with CML who are treated with tyrosine kinase inhibitors. We recommend testing for HBV status in patients who are to be treated with TKIs and to consider giving prophylaxis in those who are positive for HBsAg at baseline. More studies are needed to assess the risk of reactivation in patients with Hepatitis B core antibody positive receiving TKIs. Currently, monitoring such patients for reactivation may be the best strategy.

[Functional immunoassays in the setting of infectious risk and immunosuppressive therapy of non-HIV immunocompromised patients]. / Place des tests immunitaires fonctionnels dans la prise en charge du risque infectieux et de la gestion des thérapies immunosuppressives chez les patients immunodéprimés non-VIH.

The holistic approach of the human immune system is based on the study of its components collectively driving a functional response to an immunogenic stimulus. To appreciate a specific immune dysfunction, a condition is mimicked ex vivo and the immune response induced is assessed. The application field of such assays are broad and expanding, from the diagnosis of primary and secondary immunodeficiencies, immunotherapy for cancer to the management of patients at-risk for infections and vaccination. These assays are immune monitoring tools that may contribute to a personalised and precision medicine. The purpose of this review is to describe immune functional assays available in the setting of non-HIV acquired immune deficiency. First, we will address the use of theses assays in the diagnosis of opportunistic infections such as viral reactivation. Secondly, we will report the usefulness of these assays to assess vaccine efficacy and to manage immunosuppressive therapies.

[Biological therapy after COVID-19 infection : No reactivation of a COVID-19 infection with positive SARS-CoV-2 antibody status under biological therapy]. / Biologikatherapie nach COVID-19-Infektion : Keine Reaktivierung einer COVID-19-Infektion bei positivem Antikörperstatus SARS-CoV-2 unter Biologikatherapie.

A case with rheumatoid arthritis and insufficient compensation under disease-modifying combined long-term therapy with methotrexate and leflunomide is reported. After recovery from a COVID-19 infection, a tumor necrosis factor (TNF) inhibitor therapy was initiated. Until now no reactivation of the COVID-19 infection with positive SARS-CoV­2 antibody status has occurred.