Chronic hepatitis C in HIV infection: feasibility and sustained efficacy of therapy with interferon alfa-2b and tribavirin.

BACKGROUND: The role combination therapy with interferon alfa-2b and tribavirin (US: ribavirin) plays in producing sustained virological responses in patients with HIV and chronic hepatitis C (HCV) infection is still unknown. OBJECTIVES: To determine the feasibility and sustained response of interferon alfa-2b and tribavirin combination therapy. DESIGN: Phase II study. METHODS: Seventeen patients were enrolled at the National Cancer Institute, Aviano, Italy and received combination therapy with interferon alfa-2b 3 MIU subcutaneously three times a week plus tribavirin 1000-1200 mg/day for 24 weeks. Antiretroviral therapy was concomitantly given in all but one patient. RESULTS: At the end of treatment, five (31%) patients achieved clearance of HCV RNA and 11 (69%) showed normalized liver function enzyme levels. In three patients, serum HCV RNA concentration was still undetectable 24 weeks after treatment, with an overall sustained virological response rate of 19% The serum liver enzymes were still normal in 10 patients 24 weeks after treatment, the overall sustained biochemical response rate being 62% All patients with HCV RNA clearance at the end of treatment and 24 weeks after treatment had a concomitant biochemical response. Overall the combination treatment was well tolerated. CONCLUSIONS: Our data confirm that the combination of interferon alfa-2b and tribavirin is well tolerated and feasible in patients with HIV-HCV co-infection and it can be associated safely with highly active antiretroviral therapy. The sustained response achieved with the drug combination does not seem to be any better than that achieved with 12 months of monotherapy with interferon alfa-2b.

Atrophic gastritis and intestinal metaplasia in Helicobacter pylori infection: the role of CagA status.

OBJECTIVE: Helicobacter pylori (H. pylori) is a major factor in determining the risk for development of gastric adenocarcinoma through the intermediate steps of atrophic gastritis and intestinal metaplasia. Because H. pylori infection is highly prevalent in asymptomatic populations and only a few people develop cancer, additional factors may influence the risk for development of cancer, once infection is established. Some factors may pertain to differences among bacterial strains. Because infection by H. pylori strains possessing cagA (cytotoxin-associated gene A), a gene encoding a high-molecular-weight immunodominant antigen (CagA), is associated with enhanced induction of gastritis, the aim of our study was to evaluate potential differences in the prevalence and intensity of atrophy and intestinal metaplasia between CagA-positive and CagA-negative H. pylori-infected patients. METHODS: Eighty H. pylori-infected patients among 120 consecutive dyspeptic patients referred for upper gastrointestinal endoscopy were studied. Six bioptic specimens were taken from the gastric antrum: five for histological examination, and one for urease test. The H. pylori status was determined by histology, CLO test, and serology (in a standardized ELISA) for serum IgG and IgA directed to H. pylori. The CagA status was determined by Western blotting to detect serum IgG antibodies to CagA. Gastritis was classified according to the Sydney System. A score from 0 to 3 was assigned to each of the following morphological variables: atrophy, intestinal metaplasia, and mononuclear and neutrophilic cell infiltration. The association between CagA status and histological features was assessed by means of the chi2 test for trend. RESULTS: Among the 80 H. pylori-infected patients 53 (66%) were CagA seropositive and 27 (34%) were CagA seronegative. The mean age of the two groups was similar. CagA-positive patients had significantly higher scores for atrophy (p = 0.006), intestinal metaplasia (p = 0.01), and mononuclear (p < 0.001) and polymorphonuclear (p = 0.002) cell infiltration than did CagA-negative patients. No differences in contrast, were found for H. pylori density. CONCLUSION: Infection with CagA-positive H. pylori strains is associated with an increased prevalence and intensity of antral atrophy and intestinal metaplasia, in addition to higher degrees of gastritis. Our results seem to suggest that the CagA status could be a helpful parameter to define a subgroup of H. pylori-infected patients at increased risk of developing gastric adenocarcinoma.

Retinoids irreversibly inhibit in vitro growth of Epstein-Barr virus-immortalized B lymphocytes.

Natural and synthetic retinoids have proved to be effective in the treatment and prevention of various human cancers. In the present study, we investigated the effect of retinoids on Epstein-Barr virus (EBV)-infected lymphoblastoid cell lines (LCLs), since these cells closely resemble those that give rise to EBV-related lymphoproliferative disorders in the immunosuppressed host. All six compounds tested inhibited LCL proliferation with no significant direct cytotoxicity, but 9-cis-retinoic acid (RA), 13-cis-RA, and all-trans-RA (ATRA) were markedly more efficacious than Ro40-8757, Ro13-6298, and etretinate. The antiproliferative action of the three most effective compounds was confirmed in a large panel of LCLs, thus appearing as a generalized phenomenon in these cells. LCL growth was irreversibly inhibited even after 2 days of treatment at drug concentrations corresponding to therapeutically achievable plasma levels. Retinoid-treated cells showed a marked downregulation of CD71 and a decreased S-phase compartment with a parallel accumulation in Gzero/ G1 phases. These cell cycle perturbations were associated with the upregulation of p27 Kip1, a nuclear protein that controls entrance and progression through the cell cycle by inhibiting several cyclin/cyclin-dependent kinase complexes. Unlike what is observed in other systems, the antiproliferative effect exerted by retinoids on LCLs was not due to the acquisition of a terminally differentiated status. In fact, retinoid-induced modifications of cell morphology, phenotype (downregulation of CD19, HLA-DR, and s-Ig, and increased expression of CD38 and c-Ig), and IgM production were late events, highly heterogeneous, and often slightly relevant, being therefore only partially indicative of a drug-related differentiative process. Moreover, EBV-encoded EBV nuclear antigen-2 and latent membrane protein-1 proteins were inconstantly downregulated by retinoids, indicating that their growth-inhibitory effect is not mediated by a direct modulation of viral latent antigen expression. The strong antiproliferative activity exerted by retinoids in our experimental model indicates that these compounds may represent a useful tool in the medical management of EBV-related lymphoproliferative disorders of immunosuppressed patients.