Sequential analysis of hepatitis B virus core promoter and precore regions in cancer survivor patients with chronic hepatitis B before,during and after interferon treatment

We analysed the hepatitis B virus (HBV) core-promoter (CP) and precore (PC) regions before, during and after interferon treatment in young Caucasian cancer survivors who had acquired HBV infection during chemotherapy for malignancies. Fourteen patients with chronic hepatitis B [hepatitis B e antigen (HBeAg) /HBV-DNA positive] received α-2a interferon (IFN), 5  M U/m² t.i.w. for 12 months. HBV CP and PC region sequences were analysed following polymerase chain reaction (PCR) amplification. Sera from responders were studied at: T₀ (before starting IFN), T₁ [at alanine aminotransferase (ALT) peak preceding HBeAg seroconversion], T₂ (at ALT normalization), T₃ (at end of IFN) and T₄ (at one year after IFN) and in nonresponders at time points T₀, T₃ and T₄. Amplified HBV-DNA was cloned and sequenced automatically. Six of 14 patients (43%) responded to IFN treatment. Five of the six (83%) responders displayed the double CP mutation A1762T/G1764A always in association with a T1753C change. None of the nonresponders showed these mutations at any time point. The G1896A change creating the PC stop codon mutation was never detected in any of the patients. In our cancer survivors, IFN-induced HBeAg/anti-HBe seroconversion appeared to correlate with CP mutations and was not influenced by previous chemotherapy. These mutations in addition to low HBV DNA levels and elevated ALT can be considered favourable factors of response to IFN-induced anti-HBe seroconversion.     

Studies of interleukin-12 in chronic hepatitis B virus infection

Summary. Interleukin-12 is produced by antigen-presenting cells and regulates the balance between TH₁/TH₂ lymphocyte subsets, promoting cell-mediated immune reactions. Amongst patients with chronic hepatitis B undergoing interferon-alpha treatment, only those who clear hepatitis B virus show a substantial increase in the production of biologically active IL-12 and an inverse ratio between serum levels of IL-12p40 subunit and IL-12. The peak of serum IL-12 occurs after the hepatitis flare and precedes or coincides with the time of HBe seroconversion. These data indicate that IL-12 is an important element for establishing the host immune control on hepatitis B virus replication in patients with chronic hepatitis B virus infection.     

Combination low-dose lymphoblastoid interferon and thymosin α1 therapy in the treatment of chronic hepatitis B

SUMMARY. This open label study was initiated to assess the safety and efficacy of lymphoblastoid interferon-α (IFN-α) and thymosin α₁ (Tα₁) in the treatment of 11 patients with chronic hepatitis B, who had failed to respond to standard IFN-α2b therapy, and in four interferon naive patients. These fifteen hepatitis B surface antigen (HBsAg) positive and serum hepatitis B virus (HBV) DNA positive patients were given Tα₁ (1 mg) subcutaneously (sc) on 4 consecutive days. Low-dose lymphoblastoid IFN-α (3 MU) was administered intramuscularly (IM) on the fourth day. Beginning with the second and for the subsequent 25 weeks, patients self-administered Tα₁ twice weekly in the morning followed, 12 h later, by 3 million units (MU) lymphoblastoid IFN-α. Patients were followed-up for 12 months. Nine (60%) of the 15 patients, including six (55%) of the 11 patients previously treated with IFN-α2b, responded by losing serum HBV DNA and normalizing alanine aminotransferase (ALT) values. Six of the nine responders seroconverted to HBsAg negativity. Significant improvements in the Knodell histological activity index were observed in the responders and no significant adverse effects were observed. Combination low-dose lymphoblastoid IFN-α and Tα₁ treatment may provide a safe and potentially effective therapeutic approach in chronic hepatitis B. These results require confirmation in future randomized controlled studies.     

A phase I/II study of prostaglandin E1 for the prevention of hepatic venocclusive disease after bone marrow transplantation

Summary. We conducted a phase I/II trial of prostaglandin E₁ (PGE₁) for the prevention of hepatic venocclusive disease (VOD). Twenty-four patients at high risk for VOD received PGE₁ at four dose levels ranging from 1·25 to 10 ng/kg/min. Severe toxicity was experienced at all dose levels and was manifested as cutaneous erythema and desquamation, severe pain in dependent extremities, fluid retention and grade 4 oedema, or hypotension. In 12/24 patients, PGE₁ administration was stopped prior to day 15 due to severe toxicity attributed to the drug. Three of 12 patients who received PGE₁ for the entire course of treatment and 9/12 patients whose PGE₁ was stopped prior to day 15 developed severe toxicity which was attributed to PGE₁ ( P = 0·039). Severe toxicity attributed to PGE₁ was not related to either PGE₁ concentration or PGE₁, clearance. Six of 12 patients whose PGE₁ infusion was stopped prior to day 15 and 2/12 patients who received PGE₁ for the full course of treatment developed severe VOD ( P = 0·19). We conclude that PGE₁ causes significant toxicity in patients undergoing marrow transplantation. The ability of PGE₁ to prevent severe VOD in patients at high risk remains unproven.     

双环醇治疗慢性乙型肝炎的临床研究

初步探讨双环醇治疗慢性乙型肝炎的保肝、抗病毒效果 ,并比较双环醇对不同基因型的乙肝患者的疗效。选取 33例慢性乙型肝炎患者 ,口服双环醇 2 5mg每日 3次 ,6个月。治疗前测乙型肝炎病毒基因型 ,治疗结束后分析不同基因型乙肝患者ALT、AST、HBeAg、HBVDNA变化。复常率ALT2 1例 (6 3 6 % ) ,AST15例 (4 5 5 % ) ,转阴率HBeAg :11例 (33 3% ) ,HBVDNA :9例 (2 7 3% )。B型和C型抗病毒总有效率分别是 5例 (4 1 7% )、8例 (4 0 0 % )。双环醇治疗慢性乙型肝炎有较好的保护肝细胞抑制乙肝病毒的效果。基因型B型和C型患者对双环醇疗效比较无显著差异     

Long-term effects of interferon-α in five HIV-positive patients with chronic hepatitis B

Summary. Chronic hepatitis B viral infection is common in human immunodeficiency virus (HIV) carriers, but the effectiveness of interferon therapy is still unknown. We report the results of a long-term pilot study of five patients, who were infected with HIV and chronic hepatitis B, treated by interferon. Five males co-infected with HIV and hepatitis B virus (HBV) (mean age 2 7 years) were given a 6-month course of interferon (IFN)-α2b 5 million units (MU) three times weekly. On initiating the treatment, their CD4 lymphocyte count was 340–553 mm^-3, their CDC stage was IIa-III; all had histologically proven chronic hepatitis, with Knodell's score ranging from 6–10, and active HBV replication (HBV DNA and hepatitis B e antigen (HBeAg) were detectable). There was no associated hepatitis δ virus (HδV) or hepatitis C virus (HCV) infection. Follow-up was for 53 months on average (24–74 months). After the treatment, hepatitis B e antibody (HBeAb) and hepatitis B s antibody (HBsAb) sero-conversion was observed in one patient, HBeAb seroconversion alone in two patients, HBV DNA was absent from serum in three patients, and HBV DNA significantly decreased in one patient. The serum alanine aminotransferase (ALT) activity was normal in four patients. Histological improvement was obtained in four patients. The HIV stage remained unchanged in all patients during the whole follow-up. These preliminary results suggest that interferon can be successfully used in immunocompetent HIV carriers with chronic hepatitis B as well as in HIV-negative patients.     

Deficiency of endogenous prostanoids in gastric and duodenal ulcer diseases

The levels of prostaglandin E₂ (PGE₂), 6-keto-prostaglandin F₁α (PGF₁α) and thromboxane B₂ (TXB₂) in endoscopic biopsy specimens from the gastric and duodenal mucosa of healthy volunteers and ulcer patients were measured by radio-immunoassay. The PGE₂ and PGF₁α levels in the mucosa of the corpus of the stomach were lower and the TXB₂ level was higher in 10 patients with gastric ulcer in the corpus than in the 16 healthy subjects. The PGE₂ level in the antral mucosa of 14 patients with gastric ulcer in the antrum was lower than in the controls. In 18 patients with duodenal ulcer, PGE₂ deficiency was more widespread in the entire gastric and duodenal mucosa while the reduced PGF₁α level was limited in the gastric corpus. Lower levels of PGE₂ in patients with antral or duodenal ulcer and of PGE₂ and PGF₁α in patients with corpus ulcer in the anatomical mucosal area including the ulcer site may predispose the mucosa to ulceration.     

Beta interferon therapy for chronic hepatitis C in patients with haemophilia and other haemorrhagic disorders

Summary. Beta interferon therapy was given to seven chronic hepatitis C patients with haemophilia or other haemorrhagic disorders who had received clotting factor replacement therapy. Serum alanine aminotransferase (ALT) levels ranged from 82 to 275 UL^-1 and hepatitis C virus (HCV)-RNA ranged from 10⁶ to 10⁹ copies mL^-1. HCV-genotypes were I+II in one patient, II in one, II+III in four and IV in one. Patients received 6 mega units (MU) daily of natural type beta interferon by intravenous infusion for 6 weeks. In three of seven patients, the protocol was modified to intermittent administration because neutrocytopenia (under 500 × 10⁶ L^-1) developed in two patients and thrombocytopenia (under 50 × 10⁹ L^-1) was observed in one during treatment. No modification was necessary with regard to daily and total dose. All patients received administration without any haemorrhagic complications. Six of seven patients showed improvement in serum ALT levels, and one of the patients showed normalization of ALT levels for 6 months after treatment. HCV-RNA disappeared in four patients by the end of treatment, although no one remained negative 6 months after treatment. The results of our study were similar to those reported in previous papers which described the use of alpha interferon in haemophiliacs. The reason none of the patients showed sustained loss of HCV-RNA after therapy might be associated with high HCV-RNA levels, characteristics of the HCV-genotype and prolonged duration of the disease.     

Use of prostaglandin E1 for prevention of liver veno-occlusive disease in leukaemic patients treated by allogeneic bone marrow transplantation

Prostaglandin E1 (PGE₁) was used to prevent veno-occlusive disease (VOD) of the liver after allogeneic bone marrow transplantation (BMT) for leukaemia. It was given in continuous i.v. infusion from day – 8 to day 30 after BMT at a dose of 0.3 μg/kg/h. The patients were studied according to the risk factors for VOD: diagnosis, intensification of the conditioning and previous liver abnormalities. The diagnosis of VOD was made on at least two of the following factors: weight gain, hepatomegaly, jaundice, ascitis, pain of the right upper quadrant, increased platelet consumption. 109 patients were studied, 50 were treated by PGE₁ and 59 did not receive it. The actuarial incidence of VOD was 12.2% in the PGE₁ group and 25.5% in the non PGE₁ group ( P =0.05). In acute leukaemia, the incidence was 39.1% in the non-treated group and 12.8% in the PGE₁ treated group (P=0.02). Patients with previous hepatitis had an incidence of 62.5% in the non treated group and 15.5% in the treated group ( P =0.05). A positive cytomegalovirus (CMV) serology seemed to increase the risk of VOD: the incidence of VOD was 31.4% in non-treated patients and 22% in PGE₁ treated patients. The multivariate analysis of the risk factors for VOD shows that unfavourable factors were: recipient positive CMV serology ( P =0.06), hepatic disease prior to transplant ( P =0.02) and the absence of PGE₁ treatment ( P =0.02). This study suggests that prophylactic PGE₁ treatment may decrease the incidence of VOD in patients treated for leukaemia by allogeneic bone marrow transplantation.     

Thymosin-alpha 1 plus interferon-alpha for naive patients with chronic hepatitis C: results of a randomized controlled pilot trial

Summary.  In this pilot study, we evaluated the efficacy of interferon- α (IFN) plus Thymosin- α 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon- α _2b (3 million units three times a week) plus thymosin- α l (900  μ g/m² body surface area) and 19 received interferon- α _2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response ( P  = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.     

Plasma glutathione concentration in patients with chronic hepatitis C virus infection

Summary. It has recently been proposed that a depletion of glutathione (GSH) may be a contributing factor to viral persistence and resistance to interferon-α (IFN-α) therapy in chronic hepatitis C virus (HCV) infection. The aim of this study was: (1) to compare plasma GSH levels in patients with chronic HCV infection and normal healthy controls; and (2) to correlate GSH levels with liver histology and serum HCV RNA levels. Twenty-four patients with compensated chronic hepatitis C and 2 7 healthy subjects were studied. Serum and heparinized plasma were prospectively prepared and frozen within 1 h of collection. Plasma glutathione and glutathione peroxidase (GP) levels were measured spectrophotometrically. The serum HCV RNA level was quantitated by the branched chain DNA signal-amplification assay. Plasma GSH levels were not decreased in patients with chronic HCV infection but were actually greater than in controls (control 1.2 7 ± 0.12 μg ml^-1, HCV 1.62 ± 0.11 μg ml^-1, P < 0.05). There was also no difference in plasma GP activity between these two groups (control 0.233 ± 0.007 U ml^-1, HCV 0.230 ± 0.007 U ml^-1). Among the patients with chronic HCV infection, there was no correlation between either plasma GSH or GP levels and the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), serum HCV RNA level, or liver histology. This study demonstrates that chronic HCV infection does not decrease the plasma GSH and GP levels.     

慢性乙型肝炎2′，5′—寡腺苷酸合成酶活性与干扰素疗效的关系

探讨慢性乙型病毒性肝炎患者血液中单个核细胞的2′,5′-寡腺苷酸合成酶（2′,5′-OAS）活性与干扰素疗效的关系。为临床预测干扰疗效,避免盲目使用干扰素提供依据。将17例HBeAg、HBV-DNA双阳性的慢乙肝患者干扰素治前、治疗一周及治疗三月后进行2′,5′-OAS检测。结果示11例治前2′,5′-OAS活性较低,治疗一周有明显升高,其中8例HBeAg、HBV-DNA双项转阴,3例HBeAg单项转阴,其余6例治疗前2′,5′-OAS活性较高,治后1周升高幅度不大,双项均无转阴,提示2′,5′-OAS的水平可能是临床预测干扰素疗效的指标之一。     

Serum Thyroid Hormone, Triiodothyronine, Thyroxine, and Triiodothyronine/Thyroxine Ratio in Patients with Fulminant, Acute, and Chronic Hepatitis

The concentrations of triiodothyronine (T₃), thyroxine (T₄), T₃/T₄ ratio, free thyroxine index, and thyrox-ine-hinding glohulin were investigated in 114 viral hepatic disease patients and 36 controls. The T₃/T₄ ratio in healthy hepatitis B virus carriers was significantly greater than those in the controls and fulminant, acute, or chronic active hepatitis patients. The T₃/T₄ ratio in the fulminant hepatitis patients was significantly less than those in the controls and other liver disease patients. The correlation coefficient between the T₃/T₄ ratio and microsomal arylamidase activity in liver tissue from 30 patients was 0.78 (p < 0.001). The correlation coefficient between the T₃/T₄ ratio and the content of cholinesterase was 0.64 (p < 0.001). These results suggest that the T₃/T₄ ratio represents a marker of microsomal function and is useful for estimation of prognosis of fulminant hepatitis or differentiation of various viral hepatic diseases.     

Quantitative hepatitis B virus DNA assessment by the limiting-dilution polymerase chain reaction in chronic hepatitis B patients: evidence of continuing viral suppression with longer duration and higher dose of lamivudine therapy

Lamivudine, a novel cytosine analogue, exhibits potent antiviral activity against hepatitis B virus (HBV) in vitro and in vivo . The standard HBV DNA hybridization assay used in phase II clinical studies has a low sensitivity, the detection limit of HBV DNA levels being ≈ 10⁷ genome equivalents per ml (geq ml^–1). In this work we used a semiquantitative polymerase chain reaction (PCR) assay (detection limit ≈ 10³ geq ml^–1) to determine HBV DNA levels during a 24-week study of lamivudine in 51 stable chronic hepatitis B patients who were positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Patients were randomly allocated to receive oral doses of 25, 100 or 300 mg lamivudine once daily. At week 24 the median serum concentration of HBV DNA had fallen from 10⁸ to 10⁴ geq ml^–1, a 4-log median reduction. A trend towards more profound suppression of viral replication with an increased dose of lamivudine was observed. After 12 weeks of therapy, 12% of patients had an HBV DNA level that was undetectable in the PCR assay; this increased to 26% after 24 weeks, while in an additional 20% of patients, HBV DNA decreased to the level of detection of the PCR assay. We conclude that a 24-week course of lamivudine decreases serum HBV DNA to the level of PCR detection in 46% of patients. Such additional viral suppressive activity with higher doses and more protracted lamivudine may be of clinical utility prior to liver transplantation. Further studies are needed to define the degree of virus suppression required in clinical practice, and methods are required to increase the efficacy of virus suppression.     

Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: Phase II clinical study in Japan

Background and Aim:  Entecavir has demonstrated clinical efficacy for chronic hepatitis B. This study evaluated the efficacy and safety of entecavir in nucleoside-naive Japanese chronic hepatitis B patients.
Methods:  In this multicenter, double-blind study, 66 nucleoside-naive Japanese chronic hepatitis B patients were randomized to 0.1 mg entecavir ( n  = 32) or 0.5 mg entecavir ( n  = 34) daily for 52 weeks. The primary endpoint was the proportion of patients whose serum hepatitis B virus (HBV) DNA decreased from baseline by ≥2 log₁₀ copies/mL or became undetectable (<400 copies/mL by polymerase chain reaction assay) at week 48.
Results:  One hundred percent of patients in both treatment groups achieved the primary efficacy endpoint, with 81% and 68% of patients achieving undetectable HBV DNA in the 0.1 mg and 0.5 mg treatment groups, respectively. Mean changes from baseline in HBV DNA were −4.49 log₁₀ and −4.84 log₁₀ copies/mL for the 0.1 mg and 0.5 mg groups, respectively. Significant improvements in necroinflammation were seen in both groups, as assessed by Knodell and New Inuyama classifications. Most adverse events were transient and classified as grade 1 or 2. There were no clinically significant differences in adverse events across the two treatment groups and no discontinuations due to adverse events in either group.
Conclusions:  In Japanese nucleoside-naive patients with chronic hepatitis B, 0.1 mg or 0.5 mg entecavir daily provided excellent efficacy and was well tolerated. The 0.5 mg dose was selected for the treatment of nucleoside-naive patients.     

The natural history of chronic hepatitis B

Summary.  The natural history of chronic hepatitis B is dependent on the age of acquiring the hepatitis B infection. Those who are infected at adolescence or adulthood (including most of the Caucasians) tend to have stable disease after hepatitis B e antigen seroconversion with normal serum alanine aminotransaminase (ALT) and hepatitis B virus (HBV) DNA levels <10⁵ copies/mL (20 000 IU/mL). In contrast, those who are infected at birth or early childhood (including the majority of the world's hepatitis B carriers, i.e. Asians) have a prolonged immune tolerance phase followed by a prolonged immune clearance phase. A proportion of these patients have progressive disease after HBeAg seroconversion with HBV DNA <10⁴ copies/mL (<2000 IU/mL) and ALT between 0.5 and 2× upper limit of normal. Core promoter mutations may play a part in the development of cirrhosis-related complications. However, continuing viral replication, even at a relatively low level of <10⁴ copies/mL (<2000 IU/mL), is probably the most important factor for the development of complications.     

Hepatitis B in renal transplant recipients: An assessment of the relationship of viral replication to liver pathology

To determine the natural history of hepatitis B virus (HBV) infection in renal transplant recipients, 16 recipients who remained chronic HBsAg carriers were followed for 2–15 years by assaying hepatitis Be antigen (HBeAg) and hepatitis B viral DNA (HBV DNA). The results were compared with sequential liver biochemistry and histology. Similarly, nine HBsAg-negative renal transplant patients were studied for up to 10 years. It was found that different patterns of HBV replication were described in a majority of long-term HBsAg-positive renal transplant patients with intermittent virus replication being particularly common. A minority of patients with viral replication showed co-existing elevated transaminases. Development of liver disease was more common among HBsAg-positive patients, but when the various patterns of infection were correlated with long-term outcome, no one pattern was clearly more predictive of an adverse outcome.     

不同血清ALT水平的乙型肝炎病毒感染者肝纤维化指标变化

目的 研究不同血清谷丙转氨酶(ALT)水平的慢性HBV感染者肝纤维化指标的变化.方法 2018年4月～2020年4月我院诊治的68例慢性HBV感染者(HBV携带者21例,CHB患者47例),根据血清ALT水平不同将患者分为A组(ALT<40 U/L,n=21)、B组(40U/L≤ALT<80U/L,n=24)和C组(A...     

Interferon treatment in hepatitis B surface antigen-positive hepatitis B e antibody-positive chronic hepatitis B: role of hepatitis B core antibody IgM titre in patient selection and treatment monitoring

Chronic hepatitis B infection with the hepatitis B e antigen (HBeAg)-negative variant is associated with a severe clinical course and a low response rate to interferon (IFN). In an attempt to improve the chances of sustained response to interferon we designed a pilot study, using titres of IgM antibodies to hepatitis B core antigen (HBcAb IgM) to guide treatment initiation. Eighteen adults who were HBeAg-negative with biopsy-proven chronic active hepatitis (seven with cirrhosis) entered the study. They were followed-up bimonthly with routine liver function tests, and HBcAb IgM titres were also determined. Treatment (lymphoblastoid IFN 5 million units (MU) m^–2 three times weekly for 6 months) was started when the HBcAb IgM titre was increasing. Fifteen (83.3%) patients had normal alanine aminotransferase (ALT) levels and undetectable HBV DNA at the end of treatment. HBcAb IgM decreased in all responders. We observed a relapse in four patients (three with cirrhosis), in the first year after treatment, with an increase in ALT, HBV DNA and titre of HBcAb IgM. Eleven patients (61.1%) had a sustained response and eight of these 11 patients were followed-up for more than 18 months; two responders cleared hepatitis B surface antigen (HBsAg). Hence, the rate of sustained response to IFN in HBeAb-positive patients with chronic hepatitis is improved if treatment is started when HBcAb IgM levels are increasing.     

Long-term interferon-α treatment of children with chronic hepatitis delta: a multicentre study

Summary We assessed the efficacy of prolonged interferon-α (IFN) therapy in children with chronic hepatitis caused by hepatitis delta virus (HDV) by treating 26 paediatric cases with IFN-α2b(5 MU m^-2, then 3 MU m^-2 three times weekly for 12 (medium-term group, MTG) or 24 months (long-term group, LTG). Compliance and tolerability were acceptable. At the end of therapy a complete biochemical response [normalization of alanine aminotransferase (ALT)] occurred in 12 children (5/13 in MTG and 7/13 in LTG). A relapse occurred after stopping IFN in 10 cases (five in MTG and five in LTG). Two patients from the LTG had normal liver function tests during 12 months of follow-up. Six of the eight hepatitis Be antigen (HBeAg) positive children lost HBeAg, while all six hepatitis B virus (HBV) DNA positive patients lost HBV DNA during treatment. HBeAg reappeared later in two children. HDV RNA, present in 10/10 cases of MTG before treatment, persisted after 12 months IFN therapy in 3/10. One year after stopping therapy, 8/10 patients were again HDV RNA positive. Two children cleared hepatitis delta antigen (HDVAg) from the liver. No significant improvements in liver histology were seen in both groups. Our experience suggests that IFN-α treatment in children with chronic type D hepatitis has a transient effect, and long-term treatment does not appear to induce a greater therapeutic benefit in terms of biochemical and virological response.