Recurrence of hepatitis C virus after treatment with pegylated interferon and direct acting antivirals in Punjab Pakistan / Recorrência do vírus da hepatite C após tratamento com interferon peguilado e antivirais de ação direta em Punjab, Paquistão

Although increased response rates concomitant in hepatitis C virus but relapse after treatment is threatened. Therefore, it is terrible requirement to evaluate the response of Pegylated interferon and direct acting antivirals in Punjab Pakistan. The study was conducted to find the rate of recurrence of HCV infection after treatment with Pegylated Interferon and Direct Acting Antivirals in Punjab Pakistan. This study was conducted at Department of Pathology, Nawaz Sharif Medical College Gujrat, while treatment effects monitored in different Government and Private Hospitals of Punjab, Pakistan. Total 973 patients who administered the recommended dose and divided in two groups (i) Interferon based therapy (ii) direct acting antivirals (DAAs).Other parameters like ALT and viral load studied. The rate of recurrence was higher in female infected with genotype 2b and in male with mixed genotype 3a/2b after six month of antiviral therapy. Genotype 3a showed significant response to therapy after three month. 32 among 374 (8.5%) were positive after 24 weeks of treatment with interferon, 29 (7.7%) patients have same genotype while 3 patients were re-infected with different HCV strains. With DAAs, only 27 (4.8%) patients were positive among 558 after 2 weeks and one patient re-infected with different genotype. Early and sustained virological response noted in DAAs. ALT and viral load decreased faster with DAAs that not achieved after 4 weeks with pegylated interferon. Sustained virological response appears in DAAs and recurrence rate is high in interferon therapy compared to DAAs. Therefore, reinfection has implications for correct treatment efficiency and to select strategies for retreatment cases.

Embora aumentem as taxas de resposta concomitantes no vírus da hepatite C (HCV), há risco de recidiva após o tratamento. Portanto, é um requisito terrível avaliar a resposta do interferon peguilado e antivirais de ação direta em Punjab, Paquistão. O estudo foi conduzido para encontrar a taxa de recorrência da infecção por HCV após o tratamento com interferon peguilado e antivirais de ação direta em Punjab, Paquistão. Este estudo foi conduzido no Departamento de Patologia Nawaz Sharif Medical College Gujrat, enquanto os efeitos do tratamento foram monitorados em diferentes hospitais públicos e privados de Punjab, Paquistão. Total de 973 pacientes que administraram a dose recomendada foram divididos em dois grupos: (i) Terapia baseada em interferon, (ii) antivirais de ação direta (DAAs). Outros parâmetros como ALT e carga viral foram estudados. A taxa de recorrência foi maior em mulheres infectadas com o genótipo 2b e em homens com genótipo misto 3a / 2b após seis meses de terapia antiviral. O genótipo 3a mostrou resposta significativa à terapia após três meses. 32 entre 374 (8,5%) foram positivos após 24 semanas de tratamento com interferon, 29 (7,7%) pacientes têm o mesmo genótipo, enquanto 3 pacientes foram reinfectados com diferentes cepas de HCV. Com DAAs, apenas 27 (4,8%) pacientes foram positivos entre 558 após duas semanas e um paciente reinfectado com genótipo diferente. Resposta virológica precoce e sustentada observada em DAAs. ALT e carga viral diminuíram mais rapidamente com DAAs, que não alcançou após 4 semanas com interferon peguilado. A resposta virológica sustentada aparece em DAAs, e a taxa de recorrência é alta na terapia com interferon em comparação com DAAs. Portanto, a reinfecção tem implicações para a eficiência do tratamento correto e para selecionar estratégias para casos de retratamento.

Regression of liver fibrosis and hepatocellular carcinoma development after HCV eradication with oral antiviral agents.

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.Clinical trials registration: ClinicalTrials.gov (NCT02865369).

A randomized, phase II trial of adjuvant immunotherapy with durable TKI-free survival in patients with chronic phase CML.

PURPOSE: Chronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation. METHODS: TKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover. RESULTS: Thirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFN⟶vaccine: n = 9, vaccine⟶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7-66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5-43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9-92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %-79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation. CONCLUSION: Adjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early.

Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome.

Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in the absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in the absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial load by antibiotic treatment averted the TH17 bias and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.

Early Experiences with Triple Immunochemotherapy in Adolescents and Young Adults with High-Risk Fibrolamellar Carcinoma.

INTRODUCTION: There are no standard systemic therapies for the treatment of fibrolamellar carcinoma (FLC), as surgery remains the only definitive option. We share our experiences using systemic "triple therapy" (TT) with 5-fluorouracil, interferon, and nivolumab for the treatment of relapsed, refractory, metastatic, or unresectable FLC. METHODS: Data from all patients who received TT from May 2018 to July 2020 were reviewed to assess response, survival, and toxicity. RESULTS: A total of 22 patients were treated with TT, of which 14 (median age of 21 years) were evaluable. They received a median of 18 cycles (8-44). At the time of analysis, the median progression-free survival was 9 months (4.5-26), 29% longer than prior to TT, with 5 patients achieving clinical remission, 8 patients stable or improving, and 1 progression. Overall objective response (clinical remission + partial response) was 50% and tumor control rate (clinical remission + partial response + stable disease) was 93%. Two patients withdrew from treatment due to side effects. DISCUSSION/CONCLUSION: Our early results support TT as a promising medical option to slow disease progression and prolong survival in high-risk patients with FLC. TT can be administered in the outpatient setting and has shown good tolerability. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.

Direct acting antivirals are associated with more liver stiffness regression than pegylated interferon therapy in chronic hepatitis C patients.

OBJECTIVES: Extent of post-treatment fibrosis change in patients with different stages of fibrosis not fully known. We aimed to study changes in liver fibrosis in chronic hepatitis C patients who were treated with pegylated interferon/ribavirin (PEG/RBV) or direct acting antivirals (DAAs). METHODS: Retrospective evaluation of results of transient elastography (TE) was done before and 1 year after end of treatment for patients treated with PEG/RBV (n = 268) and DAAs (n = 245). RESULTS: The average age was 45.54 ± 10.64 years; mainly males. All patients in the DAAs group achieved sustained virological response (SVR), unlike 56.3% of the patients in the PEG/RBV group. F3-F4 fibrosis was predominant in the PEG/RBV nonresponder patients (51.3%) and DAAs responders (57.1%). TE decreased 1 year after end of treatment (p = 0.001) in the viral responders of the PEG/RBV group (7.44 ± 4.02 vs. 10.24 ± 7.29 kPa) and DAAs group (12.12 ± 9.21 vs. 16.81 ± 12.84 kPa) respectively. The delta TE change in the DAAs responders was higher than the PEG/RBV responders (p = 0.001) and PEG/RBV nonresponders (p = 0.001). The percentage of patients with liver fibrosis regression was higher in DAAs responders (52.5%) than in PEG/RBV responders (23.3%). CONCLUSION: Treatment with DAAs is associated with fibrosis improvement more than treatment with PEG/RBV in chronic hepatitis C patients.

Type I and III interferons disrupt lung epithelial repair during recovery from viral infection.

Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-ß) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-ß responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).

The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment.

This study was done to elucidate the influence of direct-acting antiviral (DAA) agents on the recurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC (HCV-HCC) after curative therapies. HCV-HCC patients who received curative therapies and obtained a complete response were analyzed. From January 2017 to September 2017, 112 HCV-HCC patients received DAA and obtained a sustained virological response (SVR). From January 2006 to December 2014, another 345 HCV-HCC patients received peg-interferon-based treatment and 118 obtained SVR. From January 2012 to December 2016, 248 HCV-HCC patients had complete HCC response and did not receive antiviral treatment. Patients were divided into DAA, IFN, and Untreated groups based on what antiviral treatment they received. There were 82 patients in the DAA group, 80 patients in the IFN group, and 160 patients in the Untreated group. During the follow-up period, the DAA group had 22 (26.8%) recurrent cases, whereas the IFN group had 46 (56.8%) cases after antiviral treatment. Among the 22 recurrent cases in the DAA group, 19 (86.9%) experienced HCC recurrence during 1 year after DAA initiation. Compared with the IFN group, the DAA group had poorer one-year recurrence-free survival (75.4% vs. 95%, p < 0.001), even after adjustment with propensity score matching (81.4% vs. 93.9%, p = 0.034). However, DAA was an improving factor for HCC recurrence compared with the Untreated group in the multivariate analysis. Among HCV-HCC patients with complete treatment, those with DAA-induced SVR had a higher one-year recurrence rate than those who received IFN-based antiviral therapy, but DAA did not seem to increase HCC recurrence compared to untreated patients.

Surface-Displayed Porcine IFN-λ3 in Lactobacillus plantarum Inhibits Porcine Enteric Coronavirus Infection of Porcine Intestinal Epithelial Cells.

Interferon (IFN)-λ plays an essential role in mucosal cells which exhibit strong antiviral activity. Lactobacillus plantarum (L. plantarum) has substantial application potential in the food and medical industries because of its probiotic properties. Alphacoronaviruses, especially porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV), cause high morbidity and mortality in piglets resulting in economic loss. Co-infection by these two viruses is becoming increasingly frequent. Therefore, it is particularly important to develop a new drug to prevent diarrhea infected with mixed viruses in piglets. In this study, we first constructed an anchored expression vector with CWA (C-terminal cell wall anchor) on L. plantarum. Second, we constructed two recombinant L. plantarum strains that anchored IFN-λ3 via pgsA (N-terminal transmembrane anchor) and CWA. Third, we demonstrated that both recombinant strains possess strong antiviral effects against coronavirus infection in the intestinal porcine epithelial cell line J2 (IPEC-J2). However, recombinant L. plantarum with the CWA anchor exhibited a more powerful antiviral effect than recombinant L. plantarum with pgsA. Consistent with this finding, Lb.plantarum-pSIP-409-IFN-λ3-CWA enhanced the expression levels of IFN-stimulated genes (ISGs) (ISG15, OASL, and Mx1) in IPEC-J2 cells more than did recombinant Lb.plantarum-pSIP-409-pgsA'-IFN-λ3. Our study verifies that recombinant L. plantarum inhibits PEDV and TGEV infection in IPEC-J2 cells, which may offer great potential for use as a novel oral antiviral agent in therapeutic applications for combating porcine epidemic diarrhea and transmissible gastroenteritis. This study is the first to show that recombinant L. plantarum suppresses PEDV and TGEV infection of IPEC-J2 cells.

Risk of De Novo Hepatocellular Carcinoma Following Use of Direct Acting Antiviral Medications for Treatment of Chronic Hepatitis C.

Direct-acting antivirals (DAA) are now the mainstay of treatment for patients with chronic hepatitis C virus (HCV); however, there is some controversy over whether use of DAAs for HCV, as compared with IFN-based regimens, leads to an increased risk for hepatocellular carcinoma (HCC) development. We investigated the association between use of DAAs and subsequent development of HCC in longitudinal data from patients with HCV from diverse backgrounds (various ages, ethnicities, and geographic regions) across the United States. The design was a retrospective study performed using medical and pharmacy claims from OptumLabs. HCV treatment exposure was categorized as DAA-only, DAA + IFN, any-DAA, or IFN-only. To account for confounding by indication, inverse probability of treatment weighting was performed. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). We identified 5,781 patients with HCV with no history of HCC at baseline. Compared with IFN-only regimen, no significant increase in HCC risk was found for use of DAA-only (HR, 1.53; 95% CI, 0.73-3.23), DAA + IFN (HR, 1.02; 95% CI, 0.51-2.06), or any-DAA (HR, 1.04; 95% CI, 0.65-1.65). When stratified by sustained virological response (SVR), we noted a higher HCC risk for DAA-only among patients who achieved SVR post-treatment (HR, 7.53; 95% CI, 1.48-38.34), but the CIs were wide, which might be due to the small sample size of the subgroups. Among those who did not achieve SVR, no association was found for use of DAA-only (HR, 0.59; 95% CI, 0.19-1.91). These findings do not provide compelling evidence for the conception that use of DAAs for HCV is associated with increased risk of HCC development.

European mitochondrial haplogroups predict liver-related outcomes in patients coinfected with HIV and HCV: a retrospective study.

BACKGROUND: Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients. METHODS: We carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk. RESULTS: The study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups (p = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values. CONCLUSIONS: European mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals.

The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic "scarring" of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome.

Essential thrombocythaemia treated with recombinant interferon: 'real world' United Kingdom referral centre experience.

Standard first-line therapy choice for essential thrombocythaemia (ET) requiring cytoreduction, supported by randomized trials, is low-dose aspirin with hydroxycarbamide, but the role of recombinant interferon-alfa (IFNα)-2a/2b and pegylated (PEG)-IFN-α-2a/2b is increasingly highlighted. Longer-term outcome data, however, remains somewhat scarce, particularly in the 'real world'. We hereby report on a large, well-annotated cohort of ET patients from a single referral centre undergoing therapy with either IFNα or (PEG)-IFN-α-2a/2b and demonstrate high rates of complete haematological responses, good tolerability and safety, low rates of thromboembolic events in compliant patients and confirm feasibility of long-term therapy in a significant proportion of patients.

Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life.

Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

Checkpoint inhibition immunotherapy for advanced local and systemic conjunctival melanoma: a clinical case series.

BACKGROUND: Herein, we describe the use of systemic immunotherapy for both locally advanced and metastatic conjunctival melanoma. Current treatments for advanced conjunctival melanoma typically result in poor local control leading to disfiguring orbital exenteration surgery. Locoregional spread of conjunctival malignant melanoma typically requires pre-auricular and cervical lymph node dissection with post-operative adjuvant radiation therapy. In addition, classic systemic chemotherapy has been unsuccessful in the treatment of metastatic disease. METHODS: This is a retrospectively analyzed clinical case series of 5 patients with biopsy proven conjunctival melanoma who were treated with checkpoint inhibition therapy. Of these, 3 patients were treated for residual ocular disease present after failing multiple local therapies and refusing orbital exenteration surgery and two (with local ocular control) for metastatic conjunctival melanoma. Both those with locally advanced disease and patients with metastatic disease received an anti-PD1 agent in combination with another immunotherapeutic agent. All 5 were given multiple cycles of systemic anti-PD1 therapy, 1 was initially treated with single agent ipilimumab (3 mg/kg) prior to approval of anti-PD1 agents and two received interferon eye drops. As part of each ophthalmic examination, photographs of all conjunctival and eyelid surfaces were obtained. Systemic evaluations involved initial staging scans as well as periodic re-imaging. RESULTS: All cases have shown responses. Of the 2 complete responses, 1 was a patient with systemic disease. No patients developed ocular toxicity or loss of vision. However, systemic adverse effects included adrenal insufficiency, Grade-III colitis, Grade-II dermatitis, Grade-II hepatotoxicity and Grade-II pneumonitis. CONCLUSIONS: This report suggests that systemic immunotherapy with or without topical interferon is effective in treatment of malignant melanoma of the conjunctiva. Therefore, it can be considered for patients with advanced local conjunctival melanoma, those who refuse orbital exenteration surgery and those with systemic metastasis.

Lymphomas associated with chronic hepatitis C virus infection: A prospective multicenter cohort study from the Rete Ematologica Lombarda (REL) clinical network.

Chronic hepatitis C virus (HCV) infection is related with an increased risk of non-Hodgkin lymphomas (NHL). In indolent subtypes, regression of NHL was reported after HCV eradication with antiviral therapy (AT). In 2008 in Lombardy, a region of Northern Italy, the "Rete Ematologica Lombarda" (REL, Hematology Network of Lombardy-Lymphoma Workgroup) started a prospective multicenter observational cohort study on NHL associated with HCV infection, named "Registro Lombardo dei Linfomi HCV-positivi" ("Lombardy Registry of HCV-associated non-Hodgkin lymphomas"). Two hundred fifty patients with a first diagnosis of NHL associated with HCV infection were enrolled; also in our cohort, diffuse large B cell lymphoma (DLBCL) and marginal zone lymphoma (MZL) are the two most frequent HCV-associated lymphomas. Two thirds of patients had HCV-positivity detection before NHL; overall, NHL was diagnosed after a median time of 11 years since HCV survey. Our data on eradication of HCV infection were collected prior the recent introduction of the direct-acting antivirals (DAAs) therapy. Sixteen patients with indolent NHL treated with interferon-based AT as first line anti-lymphoma therapy, because of the absence of criteria for an immediate conventional treatment for lymphoma, had an overall response rate of 90%. After a median follow-up of 7 years, the overall survival (OS) was significantly longer in indolent NHL treated with AT as first line (P = 0.048); this confirms a favorable outcome in this subset. Liver toxicity was an important adverse event after a conventional treatment in 20% of all patients, in particular among DLBCL, in which it is more frequent the coexistence of a more advanced liver disease. Overall, HCV infection should be consider as an important co-pathology in the treatment of lymphomas and an interdisciplinary approach should be always considered, in particular to evaluate the presence of fibrosis or necroinflammatory liver disease.

Interferon-based treatment is superior to nucleos(t)ide analog in reducing HBV-related hepatocellular carcinoma for chronic hepatitis B patients at high risk.

BACKGROUND: The effect of nucleos(t)ide analogs (NAs) versus interferon (IFN) on the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) is controversial. We assessed whether antiviral strategy affected HCC development in CHB patients at different HCC risks. METHODS: 1112 CHB patients with antiviral therapy were included in this retrospective study. Patients treated with NAs only were classified into NAs group (n = 682) while those received IFN treatment with or without NAs were defined as IFN group (n = 430). Propensity score matching (PSM) was applied to minimize baseline differences. RESULTS: Totally, 31 patients developed HCC during follow-up (median 5.41 years). The cumulative HCC incidence at 10 years was significantly lower in the IFN group than NAs group (2.7% vs 8.0%, p < 0.001). Similar results were obtained in the PSM-cohort. Patients with IFN-based treatment were less likely to develop HCC than those with NAs (Hazard ratio = 0.15; 95% CI 0.04-0.66; p = 0.012). Subgroup analyses demonstrated that this superiority of IFN in reducing HCC development was obvious in patients at high- but not low-risk of HCC. CONCLUSIONS: Reduction of HCC development was more significant in CHB patients at higher HCC risk with IFN-based therapy than NAs treatment.

Nebulized Mannitol, Particle Distribution, and Cough in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during drug inhalation can be affected by many factors, but some factors are fixed by the needs of the formulation and inflammatory disease in the airways. A component of the cough response may be related to sites of deposition, particularly upper and central airways. If deposition sites are important, then manipulating the particle distribution of the aerosol may mitigate coughing. To design a therapeutic formulation and delivery system for formulations that contain mannitol, we tested the effect of particle distribution on cough during mannitol inhalation in volunteers with idiopathic pulmonary fibrosis. METHODS: A solution of mannitol was formulated to match requirements for future interferon formulations (40 mg/mL, 220 mOsm/L). Mannitol aerosols were generated by using different nebulizers providing particle distributions that were expected to vary upper airway deposition. The nebulizer fill volume was adjusted to correct for differences in nebulizer efficiency with a target inhaled mass of 20 mg. Particle distributions were measured by cascade impaction (mass median aerodynamic diameters, 1.2 and 6.5 µm). Seven subjects with idiopathic pulmonary fibrosis participated in the study. To maximize deposition, the subjects were trained to inhale slowly and deeply (6 s inspiration). Spirometry was measured before and after inhalation. The study was carried out on separate days (day 1: 1.2 µm; day 2: 6.5 µm), and the pattern of coughing was observed. RESULTS: Coughing was often spontaneous and provoked by spirometry. When inhaling the 1.2-µm distribution, no subject coughed during inhalation. Six of the seven subjects coughed when inhaling the 6.5-µm particles. Spirometry was unaffected. CONCLUSIONS: In subjects with idiopathic pulmonary fibrosis, nebulized mannitol can cause coughing. Modifying the aerosol distribution prevents coughing during mannitol inhalation. Mannitol aerosols can be inhaled safely without bronchospasm. These data serve to inform future formulation and/or device combinations for planned interferon therapy.