tretinoin and Hepatitis-C--Chronic

More than 18 million adults in the United States abuse alcohol, a prevalence 5 times higher than that of hepatitis C. Chronic alcohol use of greater than 80 g/day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) approximately 5-fold; alcohol use of less than 80 g/day is associated with a nonsignificant increased risk for HCC. The risk for HCC in decompensated alcohol induced cirrhosis approaches 1% per year. The risk does not decrease with abstinence, and HCC can occur in a noncirrhotic liver. Alcohol use in chronic hepatitis C doubles the risk for HCC as compared with the risk in hepatitis C alone. Furthermore, there may be synergism between alcohol and hepatitis C in the development of HCC, and in these patients HCC may occur at an earlier age and the HCC may be histologically more advanced. Studies in the United States and Italy suggest that alcohol is the most common cause of HCC (accounting for 32%-45% of HCC). The mechanisms by which alcohol causes HCC are incompletely understood, but may include chromosomal loss, oxidative stress, a decreased retinoic acid level in the liver, altered DNA methylation, and genetic susceptibility. Alcohol use is increasing in many countries, suggesting that alcohol will continue to be a common cause of HCC throughout the world.

Topics: Alcohol Drinking; Carcinoma, Hepatocellular; Chromosome Aberrations; DNA Methylation; Hepatitis C, Chronic; Humans; Incidence; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Oxidative Stress; Risk Factors; Tretinoin; United States

Preclinical data suggested all-trans retinoic acid (tretinoin) as a potential antiviral agent against chronic hepatitis C infection.. To assess efficacy, safety, and tolerability of tretinoin in combination with peg-interferon and ribavirin in genotype-1 infected patients with prior non-response.. We performed an open-label multicentre clinical trial. Patients were randomised to either receive additional tretinoin (45mg/m(2)/day) for 12 weeks (arm A), or peg-interferon and ribavirin alone (arm B). Primary endpoint was the slope of the third phase of viral decline (Mδ) as determined in an established kinetic model known to correlate with treatment outcome. Secondary endpoints were additional kinetic parameters, viral response rates, safety, and tolerability.. 27 patients in arm A and 30 patients in arm B were treated per protocol until week 12. Viral kinetic parameters did not differ. Rates of early virological response (>2log10 drop at week 12) were similar (10/27 versus 11/30 patients). In arm A, patients experienced a higher rate and intensity of adverse events, most commonly skin and mucosal dryness, and headache.. Addition of tretinoin was safe and acceptably well tolerated. However, it did not influence viral kinetics and thus cannot be further considered as a treatment option.

Topics: Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Tretinoin; Viral Load

In vitro studies in the subgenomic hepatitis C virus (HCV) replicon system have identified all-trans retinoic acid (ATRA) as a potential therapeutic against hepatitis C. Thus, the antiviral potential of this drug should be assessed in vivo.. Twenty highly treatment experienced serotype 1 patients with non-response to conventional or pegylated interferon-alpha (Peg-/IFN-alpha) and ribavirin were randomly assigned to 12 weeks of monotherapy with ATRA (group A) or a combination of ATRA and PegIFN-alpha2a (group B). HCV RNA was assessed by bDNA assay and if negative by highly sensitive polymerase chain reaction.. During treatment, five of 10 patients in group A had a drop of viraemia >1log, while in group B after 8 weeks five of 10 dropped >2log, and three of 10 cleared HCV RNA from serum. Viraemia relapsed after treatment cessation. ATRA was rather well tolerated, with transient headache, dry skin and mucosa representing the most common side effects.. The viral load reduction under ATRA monotherapy, although limited and transient, supports the antiviral activity of ATRA. However, the rapid loss of HCV RNA in three of 10 previous non-responders under ATRA and PegIFN-alpha2a treatment demonstrates a strong additive or synergistic ATRA effect and calls for a controlled trial to assess the therapeutic potential of this drug.

Topics: Adult; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; RNA, Viral; Time Factors; Tretinoin