Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease

We studied the course of virologic breakthroughs detected by a quantitative polymerase chain reaction (PCR) assay in 32 of 78 patients with hepatitis B e antigen (HBeAg)-negative precore mutant hepatitis B virus (HBV) chronic liver disease under long-term lamivudine monotherapy. Serum HBV DNA levels were measured every 3 months and on every biochemical breakthrough. YMDD mutants were detected in 30 of the 32 patients with virologic breakthroughs. Among these 32 patients, biochemical remission rate was 44% at 6 months, 21% at 12 months, and 0% at 24 months after the onset of virologic breakthrough. Development of biochemical breakthroughs was associated with a significant increase of serum HBV DNA levels, which exceeded 100,000 copies/mL in 19 of 20 patients (95%) with biochemical breakthroughs and in only 1 of 8 patients (12.5%) remaining in biochemical remission for at least 6 months after the onset of virologic breakthrough (P <.001). Alanine aminotransferase (ALT) level peaked within 0 to 3 months after the onset of biochemical breakthrough and decreased at 6 months but remained abnormal in all but 2 patients. Follow-up liver histologic lesions in patients with biochemical breakthroughs did not differ from baseline findings, although they were significantly improved in patients remaining in virologic and biochemical remission. In conclusion, the frequent emergence of viral resistance under long-term lamivudine monotherapy in HBeAg-negative precore mutant HBV chronic liver disease is followed by increasing viremia levels culminating in the development of biochemical breakthroughs in most cases. ALT activity peaks close to the onset of biochemical breakthrough, decreasing thereafter but remaining persistently abnormal with fluctuating levels.     

Short report: hepatitis b infection and severe Plasmodium falciparum malaria in Vietnamese adults

We investigated the prevalence of infection with hepatitis B virus among adult Vietnamese patients hospitalized for severe Plasmodiumfalciparum malaria. Sera from patients admitted with severe malaria in Ho Chi Minh City, Vietnam, between May 1991 and January 1996 were assayed for hepatitis B surface antigen (HB(s)Ag) by a commercial enzyme-linked immunosorbent assay kit. The overall prevalence of HB(s)Ag was 23.77% (77 of 324). This was higher than reported estimates of prevalence in the general catchment population for the study hospital (mean, 9.8%; range, 9-16%). No association was found between risk of death caused by severe malaria and HB(s)Ag. Patients admitted with cerebral malaria had a slightly greater risk of registering positive for HB(s)Ag (relative risk, 1.28; 95% confidence interval, 1.04-1.58) relative to other manifestations of severe malaria. Chronic infection with hepatitis B virus may be a risk factor for severe malaria.     

Incidence and clinical significance of hepatitis B virus precore gene translation initiation mutations in e antigen-negative patients

Hepatitis Be antigen (HBeAg)-negative chronic hepatitis B (CHB) is associated with hepatitis B virus (HBV) variants harbouring changes in the precore region. Most commonly, a G to A point mutation at nucleotide 1896 (m1896) creates a novel translation stop codon that prevents HBeAg production. In the Mediterranean region the m1896 mutation prevails in greater than 98% of HBeAg-negative CHB patients. In this study the prevalence of additional mutations in the precore region was investigated among patients with chronic HBV infection. Precore sequences were determined by sequencing serum HBV DNA amplified by polymerase chain reaction (PCR) with primers flanking the precore/core region. Thirty-one HBeAg-negative and five HBeAg-positive individuals were studied. All HBeAg-negative patients (100%) harboured the m1896 mutation and 20 (64.5%) also had a G to A mutation at nucleotide 1899 (m1899). Additional mutations affecting the translation initiation of the precore gene were found in seven (22.5%) patients, all with active liver disease, five of whom had episodes of HBV reactivation. HBeAg-positive patients had no mutations in these positions and neither did any of the five HBeAg-negative patients with normal levels of liver enzymes, representing the healthy carrier state of HBV infection. Serial sample analysis from one patient revealed that the initiation codon mutation developed following HBeAg seroconversion and the appearance of m1896. During periods of high HBV replication, the ratio of mutant to wild-type ATG was found to increase in parallel with HBV DNA levels. These data show that a significant proportion of HBeAg-negative patients who already harbour the 1896 stop codon mutation may subsequently develop precore translation initiation mutations, which appear to be associated with enhanced HBV replication and severe liver disease.     

The unique riverine ecology of hepatitis E virus transmission in South-East Asia.

The ecology of hepatitis E virus (HEV) transmission in South-East Asia was assessed from a review of 6 published and 3 unpublished NAMRU-2 reports of hepatitis outbreak investigations, cross-sectional prevalence studies, and hospital-based case-control studies. Findings from Indonesia and Viet Nam show epidemic foci centred in jungle, riverine environments. In contrast, few cases of acute, clinical hepatitis from cities in Indonesia, Viet Nam and Laos could be attributed to HEV. When communities in Indonesia were grouped into areas of low (< 40%), medium (40-60%), and high (> 60%) prevalence of anti-HEV antibodies, uses of river water for drinking and cooking, personal washing, and human excreta disposal were all significantly associated with high prevalence of infection. Conversely, boiling of river drinking water was negatively associated with higher prevalence (P < 0.01). The protective value of boiling river water was also shown in sporadic HEV transmission in Indonesia and in epidemic and sporadic spread in Viet Nam. Evidence from Indonesia indicated that the decreased dilution of HEV in river water due to unusually dry weather contributed to risk of epidemic HEV transmission. But river flooding conditions and contamination added to the risk of HEV infection in Viet Nam. These findings attest to a unique combination of ecological and environmental conditions predisposing to epidemic HEV spread in South-East Asia.     

Hepatitis C among child transfusion and adult renal dialysis patients in Indonesia

Hepatitis C virus (HCV) prevalence among high-risk pediatric and adult patients was evaluated. The study included 269 adults and 150 children in a case-control research design. Risk factors of HCV exposure in Indonesia were assessed among adult renal dialysis patients and pediatric patients who received multiple blood transfusions. A high prevalence of anti-HCV was found among the adult renal dialysis patients, measured by second-generation electroimmunoassay tests. Family members of dialysis patients, who served as a comparison group for dialysis patients, were found to have a 9.0% seroprevalence. The prevalence of anti-HCV among pediatric patients with hematological disorders was found to be 39.0%. The comparison group seroprevalence (pediatric patients and family members) was 4.3% among sera available for confirmatory testing. Patients with history of hospitalization (odds ratio [OR] = 7.94, 95% confidence interval [CI]: 4.06-15.51, P = 0.0001), blood transfusion (OR = 6.85, 95% CI: 3.95-11.88, P = 0.0001), circumcision (OR = 2.39, 95% CI: 1.43-3.99, P = 0.0001), or marital partner/family member history of jaundice (OR = 3.62, 95% CI: 1.97-6.62, P = 0.0001) were found to have an increased odds of HCV exposure compared with individuals without similar histories.     

Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: synthesis, structure-activity relationship, and action mechanism studies

Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC(50) values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.     

Naphthyl and coumarinyl biarylpiperazine derivatives as highly potent human beta-secretase inhibitors. Design, synthesis, and enzymatic BACE-1 and cell assays

Twenty novel beta-secretase inhibitors containing biarylpiperazine moieties belonging to naphthyl and coumarinyl series were designed for their potential use in Alzheimer's disease therapy. Enzymatic and cell-based assays have been carried out. The biological results clearly demonstrate that specific substituents located at the N(4)-position of the piperazine ring result in excellent in vitro inhibitory potency (IC(50) values ranging between 40 and 70 nM). Variable temperature NMR and modeling studies are consistent with the obtained biological data, since these studies confirmed that introduction at the N(4)-position of the piperazine ring allows productive interactions within the BACE-1 active site, which appear to be determinative for high BACE-1 inhibitory activity. These results are of particular interest since some of the new analogues belonging to the naphthyl series are almost one log more active than the best inhibitor of the similar family recently reported.