Teruko Hino

A Randomized Study of Extended Treatment With Peginterferon α-2b Plus Ribavirin Based on Time to HCV RNA Negative–Status in Patients With Genotype 1b Chronic Hepatitis C

OBJECTIVES:The treatment of patients with hepatitis C virus (HCV) genotype 1 with peginterferon plus ribavirin treatment for more than 48 weeks demonstrated high sustained virological response (SVR) rates. Although many studies extended the duration of therapy from 48 weeks to 72 weeks, the optimal duration has not yet been determined.METHODS:A total of 113 genotype 1b patients with high viral load were randomized at baseline to the standard (n=56) or extended (n=57) treatment group. The standard group patients received 48 weeks of peginterferon plus ribavirin treatment. In the extended group, the treatment was performed for 44 weeks after patients became negative for HCV RNA (total duration 48–68 weeks).RESULTS:The SVR rate of the standard and extended group was 36% (20 of 56) and 53% (30 of 57; P=0.07). However, the extended group patients who became negative for HCV RNA between weeks 16 and 24 had a significantly higher SVR rate (78%; 7 of 9) than that of standard group (9%, 1 of 11; P=0.005). The predictive factors for the SVR were the treatment regimen (the standard vs. extended treatment) and the time to HCV RNA negative–status.CONCLUSIONS:The extended treatment significantly increased the SVR rate in patients who were HCV RNA negative at 16–24 weeks.

A real-time quantitative polymerase chain reaction method for hepatitis B virus in patients with chronic hepatitis B treated with lamivudine

OBJECTIVES:During treatment of chronic hepatitis B with lamivudine, changes in the level of hepatitis B virus (HBV) DNA were investigated using a real-time polymerase chain reaction (PCR) method with a detection limit of 1.7 log copies/ml (50 copies/ml) to clarify its clinical significance, particularly the association between HBV DNA levels and the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants.METHODS:Twenty-four patients who had received lamivudine therapy for >1 yr were studied. HBV DNA levels were determined using transcription-mediated amplification for sera with >3.7 log genome equivalents/ml, the Roche Monitor kit for sera with ≥2.6 log copies/ml, and real-time PCR for sera with < 2.6 log copies/ml (the detection limit was 1.7 log copies/ml). Patients were classified into three groups according to the minimal HBV DNA level attained during lamivudine therapy: the <1.7 log copies/ml group (eight patients), the 1.7–2.5 log copies/ml group (five patients), and the ≥2.6 log copies/ml group (11 patients).RESULTS:Pretreatment HBV DNA levels were significantly lower in the <1.7 copies/ml group than in the other two groups (p < 0.05). Neither the emergence of YMDD mutants nor a virological breakthrough of serum HBV DNA was observed in any of the eight patients in the <1.7 copies/ml group. In contrast, in the 1.7–2.5 copies/ml and ≥2.6 copies/ml groups, virological breakthroughs resulting from the emergence of YMDD mutants were observed in two of five patients and in all 11 patients, respectively (p < 0.001). Virological breakthroughs were observed at a mean of 49.6 ± 18.4 wk in 11 the patients in the ≥2.6 copies/ml group and at wk 107 and 115 in two patients in the 1.7–2.5 copies/ml group.CONCLUSION:The real-time PCR method is useful for predicting the emergence of YMDD mutants and the estimated time of their emergence.

Effect of interferon treatment on serum 2',5'-oligoadenylate synthetase levels in hepatitis C-infected patients.

Interferon (IFN) is widely used for patients with hepatitis C. Less than half of treated patients respond to IFN therapy, however, and increased resistance to IFN is particularly observed in genotype 1b patients. Recently, genotype 1b patients with the wild type sequence in the NS5A gene were shown to be resistant to therapy, suggesting that the NS5A protein may be involved to IFN resistance. Thus, we investigated the serum 2′,5′‐oligoadenylate synthetase (2′,5′‐OAS) levels before and during IFN treatment. In addition, other biochemical markers and NS5A mutations were also examined in 30 HCV genotype 1b‐positive patients. Before IFN treatment, 2′,5′‐OAS activity in sera was significantly lower in wild type patients than in mutant type patients. All patients were subsequently enrolled in IFN therapy, and 2′,5′‐OAS activity was elevated both in wild and mutant type patients, irrespective of the number of mutations in NS5A. Logistic regression analysis revealed that clearance of serum HCV RNA was independently related to the pretreatment viral load and NS5A mutations, but not to serum 2′,5′‐OAS activity. We concluded that the NS5A protein, that is associated with the outcome of IFN therapy, affects the kinetics of IFN‐induced molecules, such as 2′,5′‐OAS. 2′,5′‐OAS activity does not, however, seem to be related to long‐term virological response to IFN therapy. J. Med. Virol. 62:185–190, 2000.

Predicting Relapse after Cessation of Lamivudine Monotherapy for Chronic Hepatitis B Virus Infection

There have been reports of relapse after cessation of lamivudine monotherapy for hepatitis B virus (HBV) infection. The aim of this study was to examine factors that predict posttreatment relapse. Comparison 22 patients who experienced relapse with 11 who did not after cessation of therapy showed that predictive factors for nonrelapse were hepatitis B e antigen seroconversion and duration of undetectable HBV DNA load (<0.7 log IU/mL), as determined by HBV real-time detection direct testing. However, 7 of 12 patients with seroconversion experienced relapse after cessation of therapy. Multivariate analysis revealed that the duration of an undetectable HBV DNA load was the only independent predictive factor for nonrelapse (odds ratio, 0.50; 95% confidence interval, 0.27-0.9). More-prolonged lamivudine therapy is required after seroconversion, and persistent duration of an HBV DNA level of <0.7 log IU/mL for >6 months can more accurately aid in the decision of when to stop lamivudine therapy.

Transcription-mediated amplification is more useful in the follow-up of patients with chronic hepatitis B treated with lamivudine

Changes in the HBV DNA level during the treatment of patients with chronic hepatitis B with lamivudine were investigated by the transcription-mediated amplification (TMA) assay. Twenty-four patients treated with lamivudine (males:female= 20:4, age: 44.0+/-9.0 years, chronic hepatitis: 14, cirrhosis: 7, cirrhosis with hepatocellular carcinoma: 3) were investigated. The dosage of lamivudine was 75 mg/day in 3, 100 mg/day in 8, and 150 mg/day in 13 patients, and the administration period was 48+/-16 weeks (24-79 weeks). Sixteen patients were HBe antigen-positive before treatment, and the HBV DNA level was 7.4+/-1.2 (4.0- more than 8.7) LGE/ml. The HBV DNA level was measured every 1-6 months by the TMA assay and the branched DNA signal amplification technology (b-DNA assay). Serum HBV DNA disappeared in all patients by the b-DNA during the treatment period, while six patients had persistent HBV DNA by the TMA. The time of HBV DNA disappearance by the TMA in 18 patients was 2-5 months after initiation of treatment. The disappearance rate of HBV DNA was 3/8 (38%) in patients whose HBV DNA level before treatment was 8.0 LGE/ml or higher, 7/8 (88%) in those with 7-7.9 LGE/ml, and 8/8 (100%) in those with 6.9 LGE/ml or lower, showing that disappearance of HBV DNA became difficult when the HBV DNA level before treatment was high (P<0.01). In six patients, the HBV DNA level disappeared once, then increased thereafter. The present findings suggested that these increases in the HBV DNA level were due to an increase of YMDD mutant in three of these six patients, and due to a decrease in the dosage in two patients. In treatment with lamivudine, the TMA assay is more useful for understanding the changes in the HBV DNA level than b-DNA assay.

Interferon-γ brings additive anti-viral environment when combined with interferon-α in patients with chronic hepatitis C

Abstract T-cell hyporesponsiveness may lead to chronicity of hepatitis C virus (HCV) infection. We evaluated whether interferon (IFN)-γ injection can bring a Th1-dominant environment to patients with chronic hepatitis C. Seventeen patients with genotype 1b received natural IFN-α 5MU daily for the first 2 weeks and three times a week for the next 22 weeks followed by natural IFN-γ 1 MU daily for 2 weeks. In 4 of 17 patients (23.5%), alanine aminotransferase (ALT) was normalized and 3 of these 4 patients (75.0%) cleared HCV RNA. β2 microglobulin (BMG), neopterin and soluble (s) Fas increased with IFN-α and increased more with IFN-γ. Serum interleukin (IL)-12, CD4 and CD8 remained unchanged with IFN-α but increased after IFN-α was replaced by IFN-γ. IL-10 was not changed either with IFN-α or γ. Productions of IL-2, IFN-γ and tumor necrosis factor (TNF)-α by peripheral blood mononuclear cells did not change by IFN-α therapy, however, they were enhanced at the end of IFN-γ therapy. Productions of IL-2 and 4 were unaffected. These results show that some immune parameters become Th1-dominant by additional IFN-γ in patients with chronic hepatitis C. Combination of these two IFNs should be explored.

Lamivudine treatment‐related morphological changes of esophageal varices in patients with liver cirrhosis

Aim:  Many studies have reported the therapeutic effects of lamivudine on cirrhotic patients with hepatitis B; however, no study has investigated the morphological changes of esophageal varices after lamivudine treatment.

Adefovir Dipivoxil as a Treatment for Hepatic Failure Caused by Lamivudine-Resistant HBV Strains

Hepatitis B virus (HBV) infection is a serious worldwide problem because it is one of the major causes of cirrhosis and hepatocellular carcinoma in endemic areas. The number of people with chronic HBV infection is 350 million globally (1). Until recently, the therapeutic option for chronic HBV infection has been limited to interferon. Seroconversion from hepatitis B e antigen (HBeAg) to anti-hepatitis B e antibody (anti-HBe) occurs in up to about 40% of patients treated with interferon monotherapy (2–4). Recently, lamivudine, a nucleoside analogue, has become the main therapeutic option for chronic HBV infection. Some clinical trials showed that lamivudine suppressed HBV replication effectively and induced histological improvement (5–7). However, the prolonged therapy with lamivudine has been associated with the emergence of drug-resistant viruses with the mutations in the polymerase gene coding for the YMDD (tyrosine, methionine, aspartate, aspartate) motif (8, 9). The lamivudine-resistant HBV strains have been observed in 14 to 32% of patients undergoing a 1-year treatment regimen of 100 mg daily (6, 7). Several new nucleoside analogues are now under development. Adefovir dipivoxil, a prodrug of the acyclic deoxyadenosine monophosphate analogue adefovir, displays potent antiviral activity against HBV (10, 11) and an in vitro study demonstrated the antiviral activity to be against both wild-type and lamivudine-resistant strains of

Short term and two-step interferon therapy for chronic hepatitis C patients with low HCV RNA levels.

Objective: Chronic hepatitis C patients with low HCV RNA levels were treated with short term therapy and for patients in whom the virus was not eliminated in this short therapy, we designed a two-step IFN therapy. Subjects: There were 31 patients with chronic hepatitis C whose HCV RNA level before IFN therapy was <1.0 Meq/ml or 100 kcopies/ml. The HCV serotypes were serotype 1 in nine patients, serotype 2 in 21 and mixed type in one. A 9--10 MU per day of natural IFN was administered daily for 2 weeks, then three times weekly for 8 weeks (the first therapy), then the therapy was ended. For patients in whom the virus was not eliminated, an additional IFN therapy was administered during the decreasing phase of HCV RNA (second therapy). The historical control group consisted of 57 patients who fulfilled the above criteria and underwent IFN therapy for 24 weeks. Complete responders were defined as patients in whom HCV RNA was not detected in their serum for at least 6 months after the end of treatment. Results: Nineteen (61%) of 31 patients who completed the first therapy showed complete response to the first therapy. Eight patients underwent the second therapy and the complete response rates were 0/4 and 2/4 (50%) in the serotype 1 and 2 groups, respectively. The overall complete response rate was 44% (4/9) in the serotype 1 group, 76% (16/21) in the serotype 2 group and 100% (1/1) in the mixed type. The complete response rate in the historical control group was 70% (40/57), showing no difference in efficacy. However, the IFN dosage was significantly lower in the patients than in the control group (P<0.001). Conclusions: In patients with low HCV RNA levels and serotype 2, short term therapy is sufficiently effective. Furthermore, 50% of the complete response was obtained by an additional second therapy. This therapy design showed high efficacy and was cost-effective in these patients.

Clinical course of patients with chronic hepatitis B with viral breakthrough during long-term lamivudine treatment

BackgroundWe evaluated the clinical course of patients with chronic hepatitis B who showed viral breakthrough during long-term lamivudine therapy.MethodsWe initially studied 141 patients treated with lamivudine for 1 year or more, and 49 patients who showed viral breakthrough were the subjects of this study. Their mean lamivudine administration period was 2.3 ± 0.9 years.ResultsAfter viral breakthrough, breakthrough hepatitis occurred in 47 patients (95.9%), but did not occur in the other 2 (4.1%). Four of the 47 patients with breakthrough hepatitis were observed without further treatment, and the alanine transferase (ALT) level was normalized in 2 of them but fluctuated in the other 2. Breakthrough hepatitis was treated by injection of glycyrrhizin or ursodeoxycholic acid administration in 36 of the remaining 43 patients, and by antiviral drug administration in the other 7 (entecavir in 2 patients, adefovir in 2, and interferon in 3). The ALT level was normalized in 5 of the 36 patients treated with glycyrrhizin or ursodeoxycholic acid, but persistently fluctuated in the other 31. In those with normalized ALT after the occurrence of breakthrough hepatitis, the peak ALT level at that point was significantly lower (86 ± 47 IU/l) than that in the patients without normalization (206 ± 167 IU/l).ConclusionsThese results showed that there were a few patients who did not develop breakthrough hepatitis after showing viral breakthrough, and some who showed normalization of the ALT level after the occurrence of breakthrough hepatitis, but in many patients, ALT continuously fluctuated.