Influence Of Antiviral Therapy Research Articles

Diverse facets of MDSC in different phases of chronic HBV infection: Impact on HBV-specific T-cell response and homing.

Chronic HBV infection (CHI) is associated with a diverse natural history that includes immune-tolerant (IT), HBeAg-positive chronic hepatitis B (CHB) (EP-CHB), inactive carrier, and HBeAg-negative CHB (EN-CHB) phases. A hallmark of CHI is impairment of HBV-specific T-cell response. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as key regulator of T cells, and their properties are sculpted by their microenvironment. Here, we investigated the distinctive features of MDSCs during CHI, identified factors responsible for their functional discrepancies, and studied their impact on HBV-specific T-cell response and homing. Influence of antiviral therapy on MDSC profile and T-cell response was also assessed. Flow cytometric analysis indicated that MDSCs in EP-CHB/EN-CHB patients had profound suppressive ability, expressing arginase 1 (Arg1)/inducible nitric oxide synthase (iNOS)/programmed death ligand 1 (PD-L1)/cytotoxic T lymphocyte-associated protein 4 (CTLA-4)/CD40 at significantly greater levels relative to healthy controls (HC). However, in IT, only Arg1+ MDSCs and in inactive carrier, iNOS+ and PD-L1+ MDSCs were higher than HC. In vitro assays demonstrated that high HBsAg titer in IT/CHB induced Arg1+ MDSC. Furthermore, elevated serum TNF-α and IL-4 in CHB potentiated Arg1/PD-L1/CD40/CTLA-4 expression, whereas increased IL-1β in CHB/IC triggered the expansion of PD-L1+ MDSCs and iNOS+ MDSCs. MDSCs, sorted from CHB/IC, greatly attenuated IL-2/interferon gamma (IFN-γ) production by HBV-specific CD8+ /CD4+ T cells, the effect being more pronounced in CHB. However, MDSCs of IT minimally affected the cytokine production by T cells. Adding Arg1-/iNOS-inhibitor restored only IFN-γ production, while neutralizing PD-L1 recovered both IL-2 and IFN-γ secretion by T cells. Moreover, MDSCs from IT/CHB disrupted virus-specific T-cell trafficking by down-regulating chemokine receptor type 5 on them via TGF-β signaling. One year of tenofovir therapy failed to normalize MDSC phenotype and HBV-specific T-cell response. Diversity of MDSCs during CHI affects HBV-specific T-cell response and homing. Hence, therapeutic targeting of MDSCs could boost anti-HBV immunity.

Dynamics of endogenous interferon-alpha and -gamma production under the influence of ingaron therapy in patients with chronic epstein – barr viral infection with chronic fatigue syndrome

The influence of antiviral therapy with ingaron on the dynamics of production of interferons and and clinical effects in patients with chronic viral Epstein Barr infection was studied. The study involved 51 patients (33 women and 17 men aged 35,27 1,28 years) suffering from chronic infection caused by the Epstein Barr virus. The duration of the disease from the appearance of the first complaints to laboratory confirmation of the Epstein Barr virus infection and diagnosis was 2,23 0,21 years. Determined the serum, spontaneous and induced production of cytokines interferons and in serum and in the culture of lymphocytes. Three months after the end of antiviral therapy, in patients with an initially low level of induced interferon-, the production of interferon- increased. The absence of an increase in the production of induced interferon- in patients one and three months after the end of therapy with ingaron indicates the absence of the effect of the drug on the level of endogenous interferon-. It has been established that the initially low level of induced interferon- can be a marker of the positive effect of the therapy with ingaron. Correlation analysis revealed the effect of baseline interferon- induced on the clinical picture of the disease. Thus, initially a high level of induced interferon- (2706 1058.94 pg/ml) inversely affects the development of sweating in patients (r = 0.506, p = 0,023; = 0.419, р = 0.021), and initially low level of the induced IFN- (287.2 64.65 pg/ml) on development of weakness (r = 0.405, р = 0.045; = 0.419, р = 0.037). In general, ingarone can be used in the therapy of patients with chronic Epstein virus Bar infection at a dose of 500,000 IU every other day, at least 10 injections.

Impact of antiviral therapy on risk prediction model for hepatocellular carcinoma development in patients with chronic hepatitis B.

Risk prediction models for hepatocellular carcinoma (HCC) development are available. However, the influence of antiviral therapy (AVT) on these models in patients with chronic hepatitis B is unknown. The dynamic changes in risk prediction models during AVT and the association between risk prediction model and the risk of chronic hepatitis B-related HCC development were investigated. Between 2005 and 2017, 4917 patients with chronic hepatitis B (3361 noncirrhotic, 1556 cirrhotic) were recruited. The mean age of the study population was 49.3years and 60.6% (n=2980) of the patients were male. The mean Chinese University-HCC (CU-HCC) score was 12.7 at baseline in the overall study population, and decreased significantly (mean, 8.7) after 1year of AVT (p<0.001). The score was maintained throughout 5years of AVT (mean, 8.4-8.8; p>0.05). The proportion of high-risk patients (CU-HCC score≥20) was 28.9% at baseline, and decreased significantly after 1year of AVT (5.0%; p<0.001), and remained stable through 5years of AVT (2.2%-3.6%; p>0.05). In addition to the score at baseline, the CU-HCC score at 1year of AVT independently predicted the risk of HCC development (hazard ratio=1.072; p<0.001), together with male gender and platelet count (all p<0.05). The CU-HCC score significantly decreased at 1year of AVT and was maintained thereafter. The CU-HCC score after 1year of AVT independently predicted the risk of HCC development in patients with chronic hepatitis B.

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Influence of antiviral therapy on the liver stiffness in chronic HBV hepatitis.

The aim of this study was to evaluate the effects of antiviral therapy on liver stiffness measurement (LSM). Two hundred HBV patients were enrolled from four hospital centers in southern Italy; median age was 50.7 (25-75) males were 68%; 171 patients underwent to liver biopsy and 200 patients had LSM at baseline and 189 at the end of follow-up. One hundred and forty-nine patients were treated with nucleos(t)ide analogs, while 51 patients were untreated. The cutoffs of the LSM, related to the fibrosis stages, were as follows: non-advanced fibrosis≤8.1kPa and advanced fibrosis≥8.2 Kpa. At baseline, the median value of LSM was 14.1kPa for advanced fibrosis/cirrhosis and 6.9kPa for non-advanced fibrosis. LSM was performed at 24months from the start of therapy. The treated patients (68% received Entecavir and 32% Tenofovir) showed a decrease in liver stiffness measurement of 1.5kPa (p<0.001) in non-advanced fibrosis and of 6kPa (p<0.001) in advanced fibrosis/cirrhosis. In the patients not undergoing antiviral treatment, no statistically significant change of the LSM was observed (p=0.26). A logistic binary regression model showed that the only independent factor associated with a significant change in the LSM was the liver stiffness value at baseline (odd ratio 2.855; 95% CI 1.456-5.788; (p=0.007). Long-term antiviral therapy induced a significant reduction of liver stiffness measurement and this result may be related to the reduction of liver fibrosis.

Influence of antiviral therapy on survival of patients with hepatitis B-associated hepatocellular carcinoma undergoing transarterial chemoembolization

Purpose: To examine the prognostic value of antiviral therapy among hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). Method: A total of 356 patients with HCC undergoing TACE were recruited for the purpose of current study. All the patients were categorized into two groups; antiviral ( n = 132) and non-antiviral group ( n = 224). All the clinical and laboratory parameters were noted at baseline. Patients were then followed up for five years. The mortality rates in two groups were evaluated with Kaplan-Meier estimate. Results: The average age of the participants was 51.2 ± 6.17 years. A majority (329; 92.4 %) of the patients were male while females constituted only 7.6 %. During five years follow-up period, a total of 274 (76.9 %) died, with 89 patients belonging to the antiviral group while the remaining 185 patients were in the non-antiviral group. Mortality rate significantly differed between the antiviral and non-antiviral groups (67.4 % versus 82.5 %, p = 0.028). The results of Cox regression demonstrated that being a smoker, low serum albumin, local ablation and resection decreased overall survival while female gender, antiviral therapy, and early tumor site-node-metastatis (TNM) staging increased overall survival. Conclusion: Antiviral therapy for underlying hepatitis B in HCC patients undergoing TACE prolongs overall survival and prevents or delays reactivation of tumor. Keywords: Cancer, Chemoembolization, Hepatitis, Hepatocellular carcinoma, Transarterial chemoembolization (TACE)

Association between recent herpes zoster but not herpes simplex infection and subsequent risk of malignancy in women: a retrospective cohort study.

The association between herpes zoster and subsequent cancer risk is still unclear. Consequently, doubts remain regarding the need for investigation of herpes patients for co-existing or subsequent malignancy. This is a retrospective cohort study comparing cancer risk in patients after herpes zoster and age-/sex-matched non-herpes zoster patients, in a primary care-based continuous morbidity database. We tested for interaction by gender, age, diabetes, HRT use or antiviral therapy. Analyses were repeated for patients with and without herpes simplex. The hazard ratio (HR) comparing cancer risk in herpes zoster vs. control patients was significant in all women, women aged > 65 years and subgroups of breast and colorectal cancer (HRs 1·60, 1·82, 2·14, 2·19, respectively). For men, a significant association was found for haematological cancers (HR 2·92). No associations were found with herpes simplex. No interaction was identified with antiviral therapy, diabetes or HRT treatment. We concluded that there was a moderate significant association between herpes zoster and subsequent cancer risk in women aged > 65 years, without any influence of antiviral therapy. No association was found with herpes simplex. There is insufficient reason for extensively testing older patients with herpes zoster or herpes simplex for the presence of occult cancer.

Influence of antiviral therapy in the long‐term outcome of recurrent hepatitis C virus infection following liver transplantation

Severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients (LTR) is variable and the influence of different factors, including the administration of antiviral therapy in the long-term outcome is controversial. We analyzed the outcome of a cohort of HCV-infected LTR who were transplanted in our institution. Patients were divided into 2 groups (severe and non-severe HCV disease) depending on the presence of a fibrosis score of F ≥ 2 in the Scheuer index and/or fibrosing cholestasic hepatitis (FCH) in a graft biopsy. Risk factors were studied using logistic regression analysis. Survival of patients was estimated using Kaplan-Meier plots. A total of 146 patients were followed for a mean of 58 months. Fifty-six (34%) patients developed severe HCV disease and showed shorter survival (P < 0.024). Donor age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.02-1.06) and pre-transplant viral load (VL) >10(6) UI/mL (OR: 3.5; 95% CI: 1.42-10.61) were the only factors associated with severe HCV infection. Over-immunosuppression (OR: 2.3; 95% CI: 1.2-4.41) was specifically associated with the development of FCH. Overall, patient survival in recipients who received a full course of anti-HCV therapy was higher than in patients who did not complete antiviral therapy (P = 0.004) or received no treatment (P = 0.007). Patients with non-severe HCV infection have a higher probability of receiving a full course of antiviral therapy (P = 0.033). In conclusion, donor age, pre-transplant VL, and over-immunosuppression were associated with the long-term development of severe HCV recurrence in liver grafts. Administration of a full course of antiviral therapy was associated with better survival.

A Prospective Evaluation of Pulmonary, Systemic and Hepatic Haemodynamics in HIV–HCV-Coinfected Patients before and after Antiviral Therapy with Pegylated Interferon and Ribavirin

Patients coinfected with HIV and HCV are at risk for developing portal hypertension (PHT), hyperdynamic circulation and pulmonary arterial hypertension (PAH). Data on the influence of antiviral therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV) are limited. Haemodynamic parameters, including hepatic venous pressure gradient (HVPG), pulmonary arterial pressure (PAP(mean)), cardiac output (CO) and systemic vascular resistance (SysVR), were prospectively evaluated before and after PEG-IFN-α+RBV therapy in 80 HIV-HCV-coinfected patients. Baseline evaluation showed a mean HVPG of 4.7 mmHg, CO of 6.15 l/min and PAP(mean) of 14.8 mmHg. PHT was present in 26% of patients, hyperdynamic circulation in 5% and PAH in 4%. Patients with advanced fibrosis (METAVIR stage F3/F4; n=32) had significantly higher CO (P=0.008), lower SysVR (P=0.035), higher PAP(mean) (P=0.018) and higher pulmonary vascular resistance (P=0.022) than patients with stage F0-F2 fibrosis (n=48). Both hyperdynamic circulation and PAH were significantly associated with liver stiffness, fibrosis stage and portal pressure; a non-significant trend was found for CD4(+) T-cell counts and HIV RNA levels. No significant changes in PAP(mean), CO and SysVR were observed after PEG-IFN-α+RBV treatment, although a significant decrease in HVPG was noted in patients with HCV eradication (P=0.013). The overall prevalence of hyperdynamic circulation and PAH in HIV-HCV coinfection is low. Advanced fibrosis, increased liver stiffness, elevated portal pressure and probably CD4(+) T-cell count and HIV viraemia represent risk factors for hyperdynamic circulation and PAH. PHT is present in 26% of HIV-HCV-coinfected patients evaluated for antiviral therapy. Successful HCV eradication significantly decreases HVPG.

Restoration of TLR3-Activated Myeloid Dendritic Cell Activity Leads to Improved Natural Killer Cell Function in Chronic Hepatitis B Virus Infection

There is increasing evidence that the function of NK cells in patients with chronic hepatitis B (CHB) infection is impaired. The underlying mechanism for the impaired NK cell function is still unknown. Since myeloid dendritic cells (mDC) are potent inducers of NK cells, we investigated the functional interaction of mDC and NK cells in CHB and the influence of antiviral therapy. Blood BDCA1(+) mDC and NK cells were isolated from 16 healthy controls or 39 CHB patients at baseline and during 6 months of antiviral therapy. After activation of mDC with poly(I · C) and gamma interferon (IFN-γ), mDC were cocultured with NK cells. Phenotype and function were analyzed in detail by flow cytometry and enzyme-linked immunosorbent assay. Our findings demonstrate that on poly(I · C)/IFN-γ-stimulated mDC from CHB patients, the expression of costimulatory molecules was enhanced, while cytokine production was reduced. In cocultures of poly(I · C)/IFN-γ-stimulated mDC and NK cells obtained from CHB patients, reduced mDC-induced NK cell activation (i.e., CD69 expression) and IFN-γ production compared to those in healthy individuals was observed. Antiviral therapy normalized mDC activity, since decreased expression of CD80 and CD86 on DC and of HLA-E on NK cells was observed, while poly(I · C)/IFN-γ-induced cytokine production by mDC was enhanced. In parallel, successful antiviral therapy resulted in improved mDC-induced NK cell activation and IFN-γ production. These data demonstrate that CHB patients display a diminished functional interaction between poly(I · C)/IFN-γ activated mDC and NK cells due to impaired mDC function, which can be partially restored by antiviral therapy. Enhancing this reciprocal interaction could reinforce the innate and thus the adaptive T cell response, and this may be an important step in achieving effective antiviral immunity.

The influence of antiviral therapy on psychiatric symptoms among patients with hepatitis C and schizophrenia

Antiviral therapy for chronic infection with HCV is associated with significant neuropsychiatric side effects. Research indicates that patients with mental illness are less likely to receive antiviral therapy, despite limited data regarding the influence of antiviral therapy on psychiatric symptoms in patients with specific psychiatric disorders. The aim of this study was to determine whether antiviral therapy is associated with higher rates of psychiatric symptoms in patients with schizophrenia (SCHZ). A regional Veterans Healthcare Administration database was used to identify veterans meeting criteria for this retrospective chart review. Patients confirmed to have SCHZ and to have received antiviral therapy for HCV between 1998 and 2006 (n=30) were compared with a control group of demographically matched (age, race and gender) patients with SCHZ who did not receive antiviral therapy (n=30). Clinicians blinded to antiviral therapy status used chart notes to evaluate whether patients exhibited prominent symptoms of SCHZ, depression or mania during a 6 month pre-treatment period, the treatment period and a 6 month post-treatment period (or during equivalent periods for the control group). Groups did not significantly differ in rates of symptoms of SCHZ, depression or mania during any study period. During the treatment period, groups did not significantly differ in rates of emergency room visits or inpatient hospitalizations. Our retrospective chart review suggests that patients with SCHZ experience similar rates of psychiatric symptoms on and off antiviral therapy. Despite limitations and constraints of the methods, our data suggest that SCHZ is not a contraindication to antiviral therapy for HCV.

Should antiviral therapy be offered to elderly patients?

relatively little information exists on the prognosis for elderly patients with chronic hepatitis C (CHC). Moreover, the majority of randomized, clinical trials of hepatitis C treatment exclude elderly patients. Findings from a 2009 clinical study address risk of hepatocellular carcinoma, life expectancy and the influence of antiviral therapy in elderly patients with CHC.

Natural history of chronic hepatitis B virus infection: What determines prognosis after cirrhotic decompensation?

Natural history of chronic hepatitis B virus infection: What determines prognosis after cirrhotic decompensation?

Therapy Insight: AIDS-related malignancies—the influence of antiviral therapy on pathogenesis and management

Patients with HIV infection are at an increased risk of a number of malignancies, including Kaposi's sarcoma (KS) and certain B-cell lymphomas. Most of these tumors are caused by oncogenic DNA viruses, including KS-associated herpesvirus and Epstein-Barr virus. HIV contributes to the development of these tumors through several mechanisms, including immunodeficiency, immunodysregulation, and the effects of HIV proteins such as Tat. The development of highly active antiretroviral therapy (HAART) has reduced the incidence of many HIV-associated tumors and has generally improved their responsiveness to therapy. However, the number of people living with AIDS is increasing, and it is possible that the number of AIDS-associated malignancies will rise and the pattern of tumors will change as more people live longer with HIV infection. The goal of KS therapy is long-term tumor control with minimal toxicity. HAART is an important component of this therapy, and some patients do not require other KS-specific therapies. By contrast, the goal of AIDS-related lymphoma therapy in most cases is the attainment of a complete response with curative intent, and the benefits of administering HAART during therapy must be weighed against possible disadvantages. The past decade has seen substantial improvements in the treatment of AIDS-related lymphoma, which is attributed partially to a shift in tumor type and more effective regimens. There is currently an interest in developing new therapies for HIV-associated malignancies, based on viral, vascular or other pathogenesis-based targets.

Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN

Background: The influence of hepatitis C virus (HCV) treatment on the course of HCV cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) is controversial. Methods: Twenty-five patients with nephrotic-range proteinuria, mixed cryoglobulinemia, MPGN proved by renal biopsy, and HCV infection were studied for their response to antiviral treatment. Results: After first-line treatment with prednisone, furosemide, or plasmapheresis, antiviral therapy with standard or pegylated interferon alfa and ribavirin was introduced in 18 patients. These patients were compared with 7 patients who did not receive antiviral treatment. Mean duration of antiviral treatment was 18 ± 10 months, with a follow-up of at least 6 months after treatment withdrawal. HCV RNA clearance (sustained virological response) was achieved in 12 of 18 patients. Compared with values before antiviral therapy, a decrease in proteinuria was observed in sustained virological responders at the end of combination therapy, as well as at the end of follow-up (mean, 2.85 ± 2.2 [SD] versus 1 ± 1.4 and 0.4 ± 0.8 g/d, respectively; P < 0.05). In sustained virological responders, cryoglobulin levels at the end of treatment (0.29 ± 0.4 g/L) and end of follow-up (0.25 ± 0.4 g/L) were decreased (P < 0.05) compared with pretreatment values (1.38 ± 2.2 g/L). Conversely, no changes in serum cryoglobulinemia levels were observed in nonresponders or controls. Serum creatinine levels remained stable in the 18 patients with antiviral therapy, regardless of response to treatment. Conclusion: Anti-HCV treatment improved HCV-associated cryoglobulinemic glomerulonephritis.

Influence of antiviral therapy on the natural history of hepatitis B virus recurrence after liver transplantation: retrospective study of 14 cases

Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon. An open, randomized trial study on the therapeutic effect of recombinant α-interferon (IFNα) in 40 patients with hepatitis B virus membranous nephropathy (HBVMN) was conducted. All were pathologically proven to have HBVMN which showed no response to corticosteroid treatment represented by persistent heavy proteinuria. Both HBeAg and HBsAg were positive in all. Group 1 was composed of 20 patients who were treated with recombinant IFNα (5 subjects, body wt < 20 kg; 8 subjects, body weight ≥ 20 kg) by subcutaneous (s.c.) injection three times a week for 12 months. In group 2 there were 20 patients who received supportive treatment only. At the end of the third month of treatment, all patients in Group 1 were free of proteinuria. In contrast, 10 patients (50%) in Group 2 had persistent heavy proteinuria and another 10 patients (50%) had light proteinuria with exacerbation during respiratory tract infection. At the end of the twelfth month, 8 patients (40%) in Group 2 still had persistent heavy proteinuria and 12 patients (60%) had light proteinuria with frequent relapses. Eight patients (40%) in Group 1 had HBeAg seroconversion between the fourth and sixth months and HBsAg seroconversion between the tenth and twelfth months. HBe seroconversion only [HBeAg (-)/HBsAg (+)] was found in four patients. Four patients had no change in HBV serological markers [HBeAg (+)/HBsAg (+)]. The remaining 4 patients had HBeAg (-)/ HBeAb (+) HBsAg (-)/HBsAb (-) at the end of the twelfth month. In contrast, there was no seroconversion of HBeAg (+)/HBsAg (+) in Group 2 patients. Flu-like symptoms were found in all patients during the first two weeks of IFNα treatment and disappeared spontaneously. Psychiatric problems were late side-effects found in 30% of patients which disappeared when the dosage of IFN was reduced. These results suggest that IFNα therapy is of value in complete resolution of heavy proteinuria, and provides some benefit in seroconversion of HBeAg (+)/HBsAg (+) in children with HBVMN.