Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon‐alfa for more than three decades. First studies to treat HDV‐infected patients with type 1 ...interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one‐quarter to one‐third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long‐term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon‐alfa will still have an important role in the management of hepatitis D – either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon‐based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development.
In the 2017 World Health Organization (WHO) classification, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), is included as one of 7 distinct diagnostic entities under the major ...category of myeloproliferative neoplasms (MPNs).1 WHO defining criteria for CEL, NOS include: (a) peripheral blood eosinophilia >1.5×109/L; (b) evidence of clonal cytogenetic or molecular genetic abnormality, and/or (c) presence of excess myeloblasts (<20%) in the peripheral blood (≥2%) or bone marrow (≥5%). In addition, other eosinophilia-associated hematolymphoid neoplasms require exclusion, particularly myeloid malignancies associated with eosinophilia such as acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) CBFB-MYH11, MPNs including chronic myeloid leukemia, myelodysplastic syndromes MDS, MDS/MPNs, and myeloid/lymphoid neoplasms with eosinophilia and fusion genes involving tyrosine kinases (e.g., PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2; see SOHO abstract by Reiter et al). CEL, NOS is a very rare neoplasm among patients presenting with eosinophilia. For example, in a Mayo Clinic series of 1416 patients with peripheral blood eosinophilia who were evaluated between 2008 and 2019, only 17 patients (1.2%) fulfilled the WHO diagnostic criteria for CEL, NOS.2 An analysis of the Surveillance, Epidemiology, and End Results (SEER) data between 2004 and 2015 revealed a stable incidence rate of 0.4 cases/1,000,000 persons.3
Chronic hepatitis B virus (HBV) infection continues to pose a serious global health threat and a significant socio‐economic burden in many areas of the world. Almost all current clinical practice ...guidelines on the management of chronic hepatitis B (CHB) infection recommend that eligible patients pursue the optimal treatment endpoint, which is defined as HBsAg loss with or without anti‐HBs seroconversion. This review describes the effects of various regimens containing pegylated interferon (peg‐IFN)‐alpha on functional cure and the outcome of hepatocellular carcinoma (HCC) in patients with CHB. Peg‐IFN‐α monotherapy is a treatment option recommended by local and international clinical practice guidelines to help more CHB patients achieve a sustained off‐treatment virological response, which is particularly appropriate for relatively young patients who demand a finite treatment approach. Peg‐IFN‐α add‐on or sequential therapy in patients who have achieved a suppressed viral load after nucleos(t)ide analog (NA) therapy may offer further benefits on HBeAg seroconversion and HBsAg decline, although the effects of de novo combination therapy with peg‐IFN‐α and NAs on long‐term outcomes remain unclear. Evaluation of baseline and on‐treatment predictors is useful for selecting the patients who are likely to achieve additional benefits. Furthermore, some recent studies have shown that peg‐IFN‐α–based therapy results in better prevention of HBV‐related hepatocellular carcinoma (HCC), especially in high‐risk patients.
Background & Aims We recently identified a polymorphism upstream of interleukin ( IL ) -28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated ...interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. Methods HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). Results In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1–6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). Conclusions In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.
There is no satisfactory standard for predicting HBeAg seroconversion during Pegylated interferon alpha (PegIFNα) treatment. Studies have shown that IFNα therapy in chronic hepatitis C patients could ...alter serum lipid profiles. However, there have been no studies on lipid changes that predict the outcome of PegIFNα monotherapy in treated‐naive chronic hepatitis B (CHB) patients. This retrospective study included 130 treated‐naive HBeAg‐positive CHB patients receiving PegIFNα monotherapy. The relationship between serum lipid changes and HBeAg seroconversion was analysed. The TC‐ALT‐HBsAg‐HBeAg‐Genotype‐Age (CASEGA) model was established to predict HBeAg seroconversion after PegIFN‐α monotherapy. Among 130 patients, 33 achieved HBeAg seroconversion (SR) and 97 did not achieve HBeAg seroconversion (NR). The decrease in serum total cholesterol (TC) in the NR group was significantly higher than in the SR group at Week 24 (−9.59% vs. −0.31%, p < 0.001). Multivariate logistic regression analysis showed that the change in TC at Week 24 (odds ratio = 1.065, p = 0.009) was an independent predictor of HBeAg seroconversion. The area under the receiver operating characteristic curve for the CASEGA model was 0.883. The model score at the maximum Youden index was 90, and the specificity, sensitivity, positive predictive value and negative predictive value were 0.727, 0.794, 0.546 and 0.895, respectively. The HBeAg seroconversion rate at Week 72 in patients with scores >90 was significantly higher than that in patients with scores <90 (54.55% vs. 10.47%, p < 0.001). This study indicated that the change in the TC level at 24 weeks in CHB patients treated with PegIFNα was associated with HBeAg seroconversion. The CASEGA prediction model based on the TC change rate of 24 weeks has good predictive efficiency for HBeAg seroconversion.
Hepatitis B surface antigen (HBsAg) loss or seroconversion is an ideal treatment endpoint for patients with chronic hepatitis B but is rarely achievable in hepatitis B e‐antigen (HBeAg)‐positive ...patients using existing treatment strategies. In this study, the effect of pegylated interferon (peg‐IFN) alfa‐2b plus tenofovir disoproxil fumarate (TDF), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and hepatitis B vaccine was evaluated. This randomized controlled trial was conducted at nine liver centers in Chinese university hospitals from May 2018 to July 2020. Patients (n = 303) enrolled were randomly administered peg‐IFN‐α‐2b combined with TDF, GM‐CSF, and hepatitis B vaccine (experimental group); peg‐IFN‐α‐2b plus TDF (control group 2); or interferon‐α‐2b alone (control group 1). The primary efficacy endpoint was HBsAg seroconversion at 48 weeks and the secondary endpoint included safety. No differences in baseline HBsAg levels were observed among the groups. The primary endpoint was achieved in three (3.0%), one (1.03%), and one (1.19%) patient in the experimental group, control group 2, and control group 1, respectively. The incidence of HBsAg seroconversion at week 48 was not significantly different among the three groups (p = 0.629). However, the decrease in serum levels of HBsAg at week 48 was significantly higher in the experimental and control group 2 compared with that in control group 1 (p = 0.008 and 0.006, respectively). No significant difference between the experimental and control group 2 was observed (p = 0.619). Adverse events were not significantly different among the groups except for the lower incidence of neutropenia in the experimental group. Peg‐IFN‐α‐2b combined with TDF, GM‐CSF, and hepatitis B vaccine is not superior to peg‐IFN‐α‐2b combined with TDF in HBeAg‐positive naïve patients. Clinical Trials Registration: ChiCTR1800016173.
The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. In some patients, the infection resolves spontaneously, whereas in others it develops into ...chronic disease. However, because acute hepatitis C is often asymptomatic, detection and diagnosis are usually difficult. What is more, there are no established treatment guidelines, leaving physicians to make several challenging decisions, such as whether to treat, when to treat and what treatment regimen to use. Pegylated interferon alfa monotherapy is most commonly used to treat patients with acute hepatitis C; the role of ribavirin has yet to be established. In this review, we discuss the epidemiology of acute hepatitis C, its risk factors and routes of transmission and current treatment practices. We also discuss data from published clinical studies and focus on unresolved issues for which additional studies are needed in order to establish standardized treatment guidelines for the management of acute hepatitis C.
Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we ...retrospectively analyzed 47 consecutive ATL (acute,
n
= 23; lymphoma,
n
= 14; chronic,
n
= 8; smoldering,
n
= 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response CR 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (
n
= 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (
n
= 14/19) and 89% (
n
= 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI,
n
= 11) included 2
Pneumocystis jirovecii
pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (
n
= 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months,
p
= 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.
Introduction. We evaluated the antiviral activities of ribavirin (RBV) and interferon (IFN) alfa as monotherapy and combination therapy against chikungunya virus (CHIKV). Methods. Vero cells were ...infected with CHIKV in the presence of RBV and/or IFN alfa, and viral production was quantified by plaque assay. A mathematical model was fit to the data to identify drug interactions for effect. We ran simulations using the best-fit model parameters to predict the antiviral activity associated with clinically relevant regimens of RBV and IFN alfa as combination therapy. The model predictions were validated using the hollow fiber infection model (HFIM) system. Results. RBV and IFN alfa were effective against CHIKV as monotherapy at supraphysiological concentrations. However, RBV and IFN alfa were highly synergistic for antiviral effect when administered as combination therapy. Simulations with our mathematical model predicted that a standard clinical regimen of RBV plus IFN alfa would inhibit CHIKV burden by 2.5 log₁₀ following 24 hours of treatment. In the HFIM system, RBV plus IFN alfa at clinical exposures resulted in a 2.1-log₁₀ decrease in the CHIKV burden following 24 hours of therapy. These findings validate the prediction made by the mathematical model. Conclusions. These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections.
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