RESUMEN
Treatment selection for patients with polycythemia vera (PV) is based on patient age and history of thrombosis. The standard treatment is low-dose aspirin and phlebotomy for low-risk PV, with cytoreductive therapy added for high-risk PV. Thrombotic events and disease progression due to PV clone expansion affect the prognosis of PV. Although phlebotomy is effective in controlling hematocrit level, it has no effect on disease progression or PV-related symptoms. In Western countries, interferon (IFN) has been used as a cytoreductive therapy for PV. Long-term IFN therapy has been shown to result in sustained hematologic remission and molecular responses. Ropeginterferon-α-2b (ropeg-IFN), which is administered every two weeks, has recently become available. Clinical trials in patients with PV have shown that ropeg-IFN treatment is safe and efficacious, reducing JAK2V617F allele burden. Ropeg-IFN could ultimately affect long-term hematologic remission and molecular response in younger patients with low-risk PV, and may even offer a cure.
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Policitemia Vera , Policitemia Vera/terapia , Humanos , Janus Quinasa 2/genética , Interferón-alfa/uso terapéutico , Interferón-alfa/administración & dosificación , Factores de RiesgoRESUMEN
Primary myelofibrosis (PMF) is the most aggressive of the myeloproliferative neoplasms and patients require greater attention and likely require earlier therapeutic intervention. Currently approved treatment options are limited in their selective suppression of clonal proliferation resulting from driver- and coexisting gene mutations. Janus kinase inhibitors are approved for symptomatic patients with higher-risk PMF. Additionally, most ongoing clinical studies focus on patients with higher-risk disease and/or high rates of transfusion dependency. Optimal treatment of early/lower-risk PMF remains to be identified and needs randomized clinical trial evaluations. Pegylated interferon alfa is recommended for symptomatic lower-risk PMF patients based on phase 2 non-randomized studies and expert opinion. Ropeginterferon alfa-2b (ropeg) is a new-generation pegylated interferon-based therapy with favorable pharmacokinetics and safety profiles, requiring less frequent injections than prior formulations. This randomized, double-blind, placebo-controlled phase 3 trial will assess its efficacy and safety in patients with "early/lower-risk PMF", defined as pre-fibrotic PMF or PMF at low or intermediate-1 risk according to Dynamic International Prognostic Scoring System-plus. Co-primary endpoints include clinically relevant complete hematologic response and symptom endpoint. Secondary endpoints include progression- or event-free survival, molecular response in driver or relevant coexisting gene mutations, bone marrow response, and safety. Disease progression and events are defined based on the International Working Group criteria and well-published reports. 150 eligible patients will be randomized in a 2:1 ratio to receive either ropeg or placebo. Blinded sample size re-estimation is designed. Ropeg will be administered subcutaneously with a tolerable, higher starting-dose regimen. The study will provide important data for the treatment of early/lower-risk PMF for which an anti-clonal, disease-modifying agent is highly needed.
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Interferón alfa-2 , Interferón-alfa , Polietilenglicoles , Mielofibrosis Primaria , Proteínas Recombinantes , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/administración & dosificación , Método Doble Ciego , Interferón-alfa/uso terapéutico , Interferón-alfa/efectos adversos , Interferón-alfa/administración & dosificación , Interferón alfa-2/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , AncianoAsunto(s)
Interferón-alfa , Humanos , Interferón-alfa/uso terapéutico , Masculino , Antivirales/uso terapéutico , FemeninoRESUMEN
INTRODUCTION: The treatment landscape of polycythemia vera (PV) has seen major advancements within the last decade including approval of ruxolitinib in the second line setting after hydroxyurea, ropegylated interferon-α2b, and advanced clinical development of a novel class of agents called hepcidin mimetics. AREAS COVERED: We provide a comprehensive review of the evidence discussing the risk stratification, treatment indications, role and limitations of phlebotomy only approach and pivotal trials covering nuances related to the use of interferon-α (IFN-α), ruxolitinib, hepcidin mimetics, and upcoming investigational agents including HDAC and LSD1 inhibitors. EXPERT OPINION: The research paradigm in PV is slowly shifting from the sole focus on hematocrit control and moving toward disease modification. The discovery of hepcidin mimetics has come as a breakthrough in restoring iron homeostasis, achieving phlebotomy-independence and may lead to improved thrombosis-free survival with stricter hematocrit control. On the other hand, emerging data with IFN- α and ruxolitinib as well as combination of the two agents suggests the potential for achieving molecular remission in a subset of PV patients and long-term follow-up is awaited to validate the correlation of molecular responses with clinically relevant outcomes of progression-free and thrombosis-free survival.
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Interferón-alfa , Nitrilos , Flebotomía , Policitemia Vera , Pirazoles , Policitemia Vera/tratamiento farmacológico , Humanos , Nitrilos/uso terapéutico , Pirazoles/uso terapéutico , Interferón-alfa/uso terapéutico , Pirimidinas/uso terapéutico , Hepcidinas/metabolismo , Interferón alfa-2/uso terapéutico , HematócritoRESUMEN
BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.
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Antivirales , Quimioterapia Combinada , Hepatitis B Crónica , Interferón-alfa , Polietilenglicoles , Proteínas Recombinantes , Tenofovir , Humanos , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Tenofovir/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Masculino , Femenino , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , Niño , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Polietilenglicoles/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/administración & dosificación , Interferón-alfa/uso terapéutico , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Preescolar , Resultado del Tratamiento , Interferón alfa-2/uso terapéutico , Interferón alfa-2/administración & dosificación , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacos , ADN Viral/sangre , Alanina/uso terapéutico , Alanina/análogos & derivadosRESUMEN
The mortality and hospitalization rate by COVID-19 dropped significantly currently, but its seasonal outbreaks make antiviral treatment still vital. The mortality and hospitazation rate by COVID-19 dropped significantly currently, but its seasonal ourbreaks make antiviral treatment still vital. In our study, syrian golden hamsters were treated with molnupiravir and interferons (IFNs) after SARS-CoV-2 infection. Their weight changes, pathological changes, virus replication and inflammation levels were evaluated. In the IFNs single treatment, only IFN-α group reduced viral load (p < 0.05) and virus titer in hamster lungs. The TNF-α expression decreased significantly in both IFNs treatment at 2dpi. Histological and immunofluorescence results showed lung damage in the IFNs groups were milder at 4dpi. In the molnupiravir/IFN-α combination treatment, weight loss and virus replication in lung were significantly decreased in the mono-molnupiravir group and combination group (p < 0.05), the expression of IL-6, TNF-α, IL-1ß and MIP-1α also decreased significantly (p < 0.05), but the combination treatment was not more effective than the mono-molnupiravir treatment. Histological and immunofluorescence results showed the lung damage and inflammation in mono-molnupiravir and combination groups were milder. In summary, IFNs treatment had anti-inflammatory effect against SARS-CoV-2, only IFN-α showed a weak antiviral effect. Molnupiravir/IFN-α combination treatment was effective against SARS-CoV-2 but was not superior to mono-molnupiravir treatment. IFN-α could be considered for immunocompromised patients to stimulate and activate early immune responses.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Hidroxilaminas , Pulmón , Mesocricetus , SARS-CoV-2 , Carga Viral , Replicación Viral , Animales , Antivirales/uso terapéutico , Antivirales/farmacología , Pulmón/virología , Pulmón/patología , Pulmón/efectos de los fármacos , Replicación Viral/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Carga Viral/efectos de los fármacos , Hidroxilaminas/uso terapéutico , Hidroxilaminas/farmacología , Cricetinae , Modelos Animales de Enfermedad , COVID-19/inmunología , COVID-19/virología , Citidina/análogos & derivados , Citidina/uso terapéutico , Citidina/farmacología , Quimioterapia Combinada , Interferón-alfa/uso terapéutico , Interferón-alfa/farmacología , Citocinas/metabolismo , Interferones/uso terapéutico , Masculino , Leucina/análogos & derivados , Leucina/uso terapéutico , Leucina/farmacologíaRESUMEN
BACKGROUND: Immune-checkpoint inhibitors are now used more commonly in combination than monotherapy as the first-line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first-line immune therapy. METHODS: We reviewed the clinical profiles of patients diagnosed with stage IIIC-IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti-PD-1 mono antibody plus interferon(IFN)-alpha 1b and anlotinib hydrochloride as the second-line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T-cells using mIHC staining in available tumor samples. RESULTS: Fifty-five patients were included in this study. The median follow-up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression-free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor-infiltrating T cells in patients without objective response. CONCLUSION: PD-1 monoclonal antibody plus interferon-alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second-line therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Indoles , Melanoma , Receptor de Muerte Celular Programada 1 , Quinolinas , Humanos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/mortalidad , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Indoles/uso terapéutico , Indoles/administración & dosificación , Indoles/efectos adversos , Anciano , Adulto , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Interferón-alfa/uso terapéutico , Interferón-alfa/administración & dosificación , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.5%) were inoculated, receiving a total of 79 inoculations. There were six Grade 4 and one Grade 5 adverse events noted (judged unrelated to SV-BR-1-GM). Disease control (stable disease [SD]) occurred in 8 of 16 evaluable patients; 4 showed objective regression of metastases, including 1 patient with near-complete regressions in 20 of 20 pulmonary lesions. All patients with regressions had human leukocyte antigen (HLA) matches with SV-BR-1-GM; non-responders were equally divided between matching and nonmatching (p = .01, Chi-squared), and having ≥2 HLA matches with SV-BR-1-GM (n = 6) correlated with clinical benefit. Delayed-type hypersensitivity (DTH) testing to candida antigen and SV-BR-1-GM generated positive responses (≥5 mm) in 11 (42.3%) and 13 (50%) patients, respectively. Quantifying peripheral circulating tumor cells (CTCs) and cancer-associated macrophage-like cells (CAMLs) showed that a drop in CAMLs was significantly correlated with an improvement in progression-free survival (PFS; 4.1 months vs. 1.8 months, p = .0058). Eight of 10 patients significantly upregulated programmed cell death ligand 1 (PD-L1) on CTCs/CAMLs with treatment (p = .0012). These observations support the safety of the Bria-IMT regimen, demonstrate clinical regressions, imply a role for HLA matching, and identify a possible value for monitoring CAMLs in peripheral blood.
Asunto(s)
Neoplasias de la Mama , Ciclofosfamida , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Interferón-alfa , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Adulto , Anciano , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Metástasis de la Neoplasia , Línea Celular Tumoral , Resultado del Tratamiento , Estados UnidosRESUMEN
Background and aims: Limited data have been reported on achieving functional cure using pegylated interferon (Peg-IFN) alpha-2b treatment for postpartum hepatitis B e antigen (HBeAg)-negative women with chronic hepatitis B virus (HBV) infection. This study was to assess the effectiveness and safety of Peg-IFN alpha-2b in HBV postpartum women without HBeAg and identify factors linked to the functional cure. Methods: A total of 150 HBeAg-negative postpartum women were retrospectively recruited.47 patients received Peg-IFN alpha-2b [Peg-IFN(+) group] and 103 patients did not [Peg-IFN(-) group]. Propensity score matching (PSM) was used to adjust the baseline imbalance between the two groups. The patients were followed for at least 48 weeks. The primary endpoints were hepatitis B surface antigen(HBsAg) loss and HBsAg seroconversion at 48 weeks. Logistic regression analysis was used to assess factors associated with HBsAg loss at 48 weeks. Results: At week 48,the HBsAg loss and seroconversion rate in Peg-IFN(+) group were 51.06%(24/47) and 40.43%(19/47), respectively. Even after PSM, Peg-IFN(+) group still showed higher HBsAg loss rate (50.00% vs 7.14%,p<0.001) and higher HBsAg seroconversion rate (38.10% vs 2.38%,p<0.001). Baseline HBsAg levels (Odds Ratio [OR]: 0.051, 95% Confidence Interval [CI]: 0.003-0.273, P=0.010), HBsAg at week 24 (OR:0.214, 95%CI:0.033-0.616, P=0.022), HBsAg decline at week 24 (OR:4.682, 95%CI: 1.624-30.198, P=0.022) and postpartum flare (OR:21.181, 95%CI:1.872-633.801, P=0.030) were significantly associated with HBsAg loss at week 48 after Peg-IFN alpha-2b therapy. Furthermore, the receiver operating characteristic curve (ROC) showed that the use of baseline HBsAg<182 IU/mL, HBsAg at week24 < 4 IU/mL and HBsAg decline at week24>12IU/mL were good predictors of HBsAg loss. No serious adverse events were reported. Conclusion: Peg-IFN alpha-2b treatment could achieve a high rate of HBsAg loss and seroconversion in HBeAg-negative postpartum women with reliable safety, particularly for patients experience postpartum flare and have low baseline HBsAg levels.
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Antivirales , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , Hepatitis B Crónica , Interferón alfa-2 , Interferón-alfa , Polietilenglicoles , Periodo Posparto , Proteínas Recombinantes , Humanos , Femenino , Hepatitis B Crónica/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Adulto , Antígenos e de la Hepatitis B/sangre , Antivirales/uso terapéutico , Interferón-alfa/uso terapéutico , Estudios Retrospectivos , Interferón alfa-2/uso terapéutico , Antígenos de Superficie de la Hepatitis B/sangre , Resultado del Tratamiento , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/efectos de los fármacos , Adulto Joven , SeroconversiónRESUMEN
The efficacy of different pegylated interferon (PEG-IFN) treatment strategies for achieving sustained hepatitis B surface antigen (HBsAg) clearance in chronic hepatitis B (CHB) remains controversial. This study assesses the efficacy of different PEG-IFN treatment regimens and factors influencing sustained HBsAg clearance after PEG-IFN discontinuation. PubMed , Embase , Web of Science , and the Cochrane Library databases were searched from inception to June 2023, regarding PEG-IFN therapy in CHB. Methodological quality was assessed using the Cochrane risk of bias tool. We explored sources of heterogeneity through univariate meta-regression. Frequentist network meta-analyses were used to compare the efficacy of different PEG-IFN treatment strategies. We analyzed 53 studies (including 9338 CHB patients). After PEG-IFN withdrawal, the annual rates of HBsAg clearance and seroconversion were 6.9% [95% confidence interval (CI), 5.10-9.31] and 4.7% (95% CI, 2.94-7.42). The pooled 1-, 3-, and 5-year sustained HBsAg clearance rates were 7.4%, 9.9%, and 13.0%, and the sustained HBsAg seroconversion rates were 6.6%, 4.7%, and 7.8%, respectively. HBsAg quantification, hepatitis B e antigen status, and PEG-IFN treatment protocols were major sources of heterogeneity. Baseline HBsAg quantification was significantly lower in patients with sustained HBsAg clearance versus those without ( P â <â 0.046). PEG-IFN combined with tenofovir has the highest probability of achieving HBsAg seroconversion (surface under the cumulative ranking of 81.9%). Sustained HBsAg clearance increased approximately linearly from years 1 to 5 after PEG-IFN discontinuation. Low baseline HBsAg quantification has a significant impact on sustained HBsAg clearance. PEG-IFN combined with tenofovir may be optimal in achieving sustained HBsAg seroconversion.
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Antivirales , Antígenos de Superficie de la Hepatitis B , Hepatitis B Crónica , Interferón-alfa , Metaanálisis en Red , Polietilenglicoles , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Antivirales/uso terapéutico , Polietilenglicoles/uso terapéutico , Interferón-alfa/uso terapéutico , Seroconversión , Respuesta Virológica Sostenida , Tenofovir/uso terapéutico , Virus de la Hepatitis B/inmunología , Proteínas Recombinantes/uso terapéutico , Quimioterapia Combinada , Resultado del TratamientoRESUMEN
OBJECTIVES: Exophytic Sinonasal Papilloma (ESP) is a benign tumor of the sinonasal tract. Complete surgical excision by endoscopic surgery is the treatment of choice. However, a high recurrence rate (36% at 5-year follow-up) is associated with this method, which may indicate the presence of microorganisms such as Human Papillomavirus (HPV). It is important to note that the standard treatment for ESP does not include antiviral drugs. In our study, we are testing the effectiveness of an interferon-containing drug in reducing recurrence and postoperative reactions in patients with ESP. METHODS: We included 78 patients aged 23-83 years with a confirmed diagnosis of ESP by rhinoscopy and nasal endoscopy and a positive PCR test for HPV in nasal scrapings. To compare the results, we divided the patients into main and control groups. The main group received recombinant human interferon after surgery, while the control group did not receive the drug. We performed a statistical analysis to compare the proportion of patients without reactive manifestations at different stages of the postoperative period, as well as to compare the proportion of patients with recurrent ESP at certain stages of observation. RESULTS: The introduction of recombinant human interferon accelerated the resolution of postoperative reactions and promoted the healing of the nasal mucosa after surgical removal of the ESP. We also found a statistically significant association between treatment with recombinant interferon and a reduction in the recurrence rate of ESP. CONCLUSION: According to the results of the study, it was found that in the main group of patients who received rhIFN-α2b (recombinant human Interferon alpha 2b) in the postoperative period, the frequency of relapses of ESP and the time of postoperative recovery were significantly lower than in patients in the control group who did not take the drug. LEVEL OF EVIDENCE: Cohort Study.
Asunto(s)
Interferón alfa-2 , Interferón-alfa , Papiloma , Infecciones por Papillomavirus , Humanos , Persona de Mediana Edad , Adulto , Anciano , Masculino , Femenino , Interferón alfa-2/uso terapéutico , Infecciones por Papillomavirus/tratamiento farmacológico , Anciano de 80 o más Años , Adulto Joven , Interferón-alfa/uso terapéutico , Resultado del Tratamiento , Papiloma/tratamiento farmacológico , Papiloma/cirugía , Papiloma/virología , Neoplasias Nasales/cirugía , Neoplasias Nasales/tratamiento farmacológico , Neoplasias Nasales/virología , Proteínas Recombinantes/uso terapéutico , Recurrencia Local de Neoplasia , Antivirales/uso terapéuticoRESUMEN
OBJECTIVE: Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on. DESIGN: 53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy. RESULTS: Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values. CONCLUSIONS: PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.
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Antivirales , Antígenos e de la Hepatitis B , Hepatitis B Crónica , Interferón-alfa , Células Asesinas Naturales , Polietilenglicoles , Proteínas Recombinantes , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/sangre , Interferón-alfa/uso terapéutico , Antivirales/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Femenino , Adulto , Masculino , Polietilenglicoles/uso terapéutico , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Persona de Mediana Edad , Antígenos e de la Hepatitis B/sangre , Antígenos del Núcleo de la Hepatitis B/inmunología , Antígenos del Núcleo de la Hepatitis B/sangre , Quimioterapia Combinada , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Resultado del Tratamiento , Nucleósidos/uso terapéuticoAsunto(s)
Interferón alfa-2 , Interferón-alfa , Policitemia Vera , Polietilenglicoles , Proteínas Recombinantes , Adulto , Humanos , Aberraciones Cromosómicas , Interferón alfa-2/uso terapéutico , Interferón-alfa/uso terapéutico , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéuticoRESUMEN
OBJECTIVES: Patients with haematologic malignancies (HM) COVID-19 have more severe disease, with increased risk of mortality. Therefore, this study aimed to evaluate the effect of SARS-CoV-2 RNAemia and the specific humoral immune responses on the clinical outcomes of patients with HM and COVID-19. METHODS: Interferon-α/γ (IFN-α/IFN-γ) serum levels, neutralizing antibodies and RNAemia at COVID-19 diagnosis, and persistent RNAemia during the follow-up were evaluated. RESULTS: Overall, 63 (58.9%) out of 107 patients had RNAemia, which was persistent in 26 (41.3%) patients. RNAemia at diagnosis and persistent RNAemia were associated with the need for high-flow nasal oxygen therapy during admission. Persistent RNAemia, age >70 years, and CURB-65 score ≥2 in patients with pneumonia were associated with increased 90-day mortality (P = 0.009, P = 0.030 and P = 0.001, respectively). The 90-day overall survival was lower (P = 0.006) in patients with persistent RNAemia. In addition, dexamethasone administration was associated with a COVID-19 episode with persistent RNAemia. CONCLUSION: Our results suggest that in patients with HM, RNAemia at the time of COVID-19 diagnosis and during the follow-up can be used to stratify patients with HM according to their clinical evolution and to guide clinical decisions tailored to the specific needs of each patient.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Neoplasias Hematológicas , ARN Viral , SARS-CoV-2 , Humanos , COVID-19/complicaciones , COVID-19/inmunología , Masculino , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Anciano , Persona de Mediana Edad , ARN Viral/sangre , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Interferón gamma/sangre , Interferón-alfa/uso terapéutico , Anciano de 80 o más Años , Adulto , Dexametasona/uso terapéutico , Dexametasona/administración & dosificaciónRESUMEN
PD-1 blockade therapy has revolutionized melanoma treatment, but still not all patients benefit and pre-treatment identification of those patients is difficult. Increased expression of inflammatory markers such as interleukin (IL)-6 in blood of patients correlates with poor treatment response. We set out to study the effect of inflammatory cytokines on PD-1 blockade in vitro. For this, we studied the effect of IL-6 and type I interferon (IFN) in vitro on human T cells in a mixed leukocyte reaction (MLR) in the absence or presence of PD-1 blockade. While IL-6 reduced IFN-γ secretion by T cells in both the presence and absence of PD-1 blockade, IFN-α specifically reduced the IFN-γ secretion only in the presence of PD-1 blockade. IFN-α reduced T cell proliferation independent of PD-1 blockade and reduced the percentage of cells producing IFN-γ only in the presence of PD-1 blockade. Next we determined the type I IFN score in a cohort of 22 melanoma patients treated with nivolumab. In this cohort, we did not find a correlation between clinical response and type I IFN score, nor between clinical response and IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade. We conclude that IFN-α reduces the effectiveness of PD-1 blockade in vitro, but that in this cohort, type I IFN score in vivo, nor IFN-γ secretion in vitro in a MLR in the presence of PD-1 blockade correlated to decreased therapy responses in patients.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Interferón-alfa , Melanoma , Nivolumab , Receptor de Muerte Celular Programada 1 , Linfocitos T , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Interferón-alfa/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos , Femenino , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Persona de Mediana Edad , Nivolumab/uso terapéutico , Nivolumab/farmacología , Anciano , Adulto , Proliferación Celular/efectos de los fármacosRESUMEN
BACKGROUND: Interferon-alpha (IFNα) is a common treatment for chronic hepatitis B virus (HBV) infection, but its efficacy varies widely among patients. GTPASE, an interferon-stimulated gene (ISG), has recently been identified as a factor in antiviral immunity, though its role in HBV infection is not fully understood. OBJECTIVE: This study investigates the role of GTPASE in enhancing the antiviral effects of IFNα against HBV and elucidates its mechanism of action. METHODS: We analyzed the impact of GTPASE overexpression and silencing on HBV replication and clearance in HBV-infected cells. Molecular docking studies assessed the interaction between GTPASE and HBV surface antigens (HBs). Clinical samples from HBV patients undergoing Peg-IFNα treatment were also evaluated for GTPASE expression and its correlation with treatment efficacy. RESULTS: Overexpression of GTPASE led to significant inhibition of HBV replication, increased HBeAg seroconversion, and enhanced HBsAg clearance. GTPASE directly bound to HBs proteins, reducing their levels and affecting viral particle formation. Silencing GTPASE reduced these effects, while combined treatment with Peg-IFNα and GTPASE overexpression further improved antiviral outcomes. Mutational analysis revealed that specific sites in GTPASE are crucial for its antiviral activity. CONCLUSIONS: GTPASE acts as a positive regulator in IFNα-induced antiviral immunity against HBV. It enhances the therapeutic efficacy of IFNα by targeting HBs and modulating viral replication. GTPASE levels may serve as a predictive biomarker for response to Peg-IFNα therapy, highlighting its potential for improving individualized treatment strategies for chronic HBV infection.
Asunto(s)
Antivirales , GTP Fosfohidrolasas , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Hepatitis B Crónica , Interferón-alfa , Replicación Viral , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Replicación Viral/efectos de los fármacos , Antivirales/farmacología , Antivirales/uso terapéutico , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Antígenos de Superficie de la Hepatitis B/metabolismo , Simulación del Acoplamiento Molecular , Adulto , Masculino , Antígenos e de la Hepatitis B/metabolismo , Células Hep G2 , Femenino , Resultado del TratamientoAsunto(s)
Antivirales , Humanos , Antivirales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Polietilenglicoles/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Interferón-alfa/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/tratamiento farmacológicoAsunto(s)
Antivirales , Humanos , Antivirales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Polietilenglicoles/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Interferón-alfa/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/tratamiento farmacológicoRESUMEN
The early and accurate identification of predictive biomarkers for antiviral treatment efficacy remains a significant clinical challenge, particularly in the management of chronic hepatitis B (CHB). This study aimed to assess whether the plasma metabolome could reliably predict the success of antiviral therapy in CHB patients. We conducted a retrospective analysis on 56 treatment-naive CHB patients at the First Affiliated Hospital of Zhejiang University from December 2013 to March 2016. Patients who underwent a 48-week treatment regimen of entecavir (ETV) and interferon-alpha (IFN-α) were randomly assigned to either a discovery cohort (n=29) or a validation cohort (n=27). Based on the outcome of the treatment, patients were classified as HBeAg seroconversion group (High responders, Hrp) or the non-remission group (Low responder, Lrp). Our methodology involved an untargeted analysis of the amine/phenol and carboxylic acid submetabolomes in the CHB patients under treatment, utilizing chemical isotope labeling (CIL) techniques with liquid chromatography-mass spectrometry (LC-MS). Several metabolites were identified as having significant diagnostic potential for distinguishing Hrp from Lrp, with areas under the receiver operating characteristic curve (AUC) exceeding those typical clinical indicators. Notably, four metabolites, namely 2-methyl-3-ketovaleric acid, 2-ketohexanoic acid, 6-oxo-1,4,5,6-tetrahydronicotinic acid, and α-ketoisovaleric acid, demonstrated exceptionally high sensitivity and specificity in both cohorts, nearing 100%. In contrast, the clinical indicators, including HBcAb, log(HBsAg), and HBeAb, demonstrated lower and inconsistent sensitivity and specificity between the discovery and validation cohorts. Using HBcAb as a marker, the sensitivity was 87.5% with 76.9% specificity in the discovery cohort; however, the sensitivity dropped to 46.7% with 91.7% specificity in the validation cohort. Using log(HBsAg), the sensitivity was 84.6% with 69.2% specificity in the discovery cohort, compared to 85.7% sensitivity and 83.3% specificity in the validation cohort. For HBeAb, the separation of Hrp and Lrp had a sensitivity of 87.5% with 69.2% specificity in the discovery cohort, while the validation cohort showed 86.7% sensitivity and 91.7% specificity.
Asunto(s)
Antivirales , Biomarcadores , Hepatitis B Crónica , Metaboloma , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/sangre , Hepatitis B Crónica/diagnóstico , Antivirales/uso terapéutico , Masculino , Femenino , Biomarcadores/sangre , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Resultado del Tratamiento , Interferón-alfa/uso terapéutico , Interferón-alfa/sangre , Guanina/análogos & derivados , Guanina/uso terapéutico , Virus de la Hepatitis B , Metabolómica/métodosRESUMEN
Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal erythrocytosis. A phase 2 study reported that ropeginterferon alfa-2b is a well-tolerated and effective treatment for PV in Japanese patients. This post hoc analysis of the phase 2 data further evaluated outcomes in patients at low risk of thrombosis (low-risk PV). Among 20 patients with low-risk PV, 60.0% (12/20) and 85.0% (17/20) achieved < 45% hematocrit by weeks 24 and 52, respectively. The proportion of responders with complete hematologic response (CHR) was 60.0% (12/20) at week 52, and the median time to response was 11.9 months. The mean JAK2 V617F allele burden decreased from 75.8% at baseline to 53.7% at week 52. No patient experienced thrombosis or bleeding episodes. All patients experienced treatment-emergent adverse events (TEAEs) related to ropeginterferon alfa-2b, but no grade ≥ 3 TEAEs or deaths related to ropeginterferon alfa-2b occurred, and no new safety concerns arose. This analysis indicated that ropeginterferon alfa-2b may be an effective treatment option for Japanese patients with low-risk PV.