Hepatitis C: epidemiology, diagnosis, natural history and therapy.

With an estimated prevalence of 3% in the world population (around 170 million infected individuals worldwide), hepatitis C virus (HCV) heavily burdens public health. Even though the incidence of new infections is declining, at least in industrialized countries where they are mainly restricted to intravenous drug users, morbidity and mortality (which means also HCV-induced costs) associated with HCV infection are expected to increase over the next decade. Models suggest that the incidence of hepatocellular carcinoma and HCV-related mortality will still increase until about 2015. The prevalence of the disease, the risk of progression of fibrosis to cirrhosis or hepatocellular carcinoma, mainly but not only in patients with liver comorbidities such as metabolic syndrome and/or heavy alcohol intake, evidences: (1) the need for a screening of chronic HCV infection as defined by both anti-HCV antibodies and detectable HCV RNA, (2) the evaluation of the extrahepatic (cryoglobulinemia-related vasculitis) or liver impact of chronic infection (by liver biopsy or noninvasive markers of fibrosis) and (3) the discussion of an antiviral treatment which is mainly the combination of pegylated interferon (one weekly subcutaneous injection) and ribavirin, a nucleosidic analogue with a twice daily oral intake. This 'standard of care' results in a mean of 60% of sustained virologic response corresponding to viral eradication, which allows the inactivation of necroinflammation and the remodeling of fibrosis. New antiviral treatments (direct-acting anti-virals like protease NS3/4, polymerase NS5B, NS5A, entry inhibitors or other drugs like cyclophilin inhibitors, new interferons, immune modulators or therapeutic vaccine) are being rapidly developed (the approval of the first generation protease inhibitors is expected for spring 2011). The next step appears to be the combination of these oral drugs allowing a better safety and efficacy of the treatment.

Acquired protein S deficiency leads to obliterative portal venopathy and to compensatory nodular regenerative hyperplasia in HIV-infected patients.

OBJECTIVE: To identify the mechanism of nodular regenerative hyperplasia in HIV-infected patients. DESIGN: Case-control study. SETTING: The hepatology and the infectious disease units of two tertiary care centers in France. PATIENTS: We compared 13 consecutive HIV-positive patients with unexplained nodular regenerative hyperplasia to 16 consecutive HIV-positive patients without nodular regenerative hyperplasia, to eight HIV-negative patients with nodular regenerative hyperplasia from an identified cause and to 10 anonymous healthy blood donors. MAIN OUTCOME MEASURE: Patients and controls were screened for diminished protein S activity and antiprotein S immunoglobulin G (IgG) antibodies. The antiprotein S activity of purified IgG from patients and controls was assessed in a functional test of activation of protein C in which protein S serves as a cofactor. A full liver CT portography was realized on the liver explant of a case patient. RESULTS: The CT portography disclosed diffuse obliterative portal venopathy. Levels of protein S activity were lower among patients with HIV-associated nodular regenerative hyperplasia when compared with HIV-positive patients without nodular regenerative hyperplasia and when compared with HIV-negative patients with nodular regenerative hyperplasia (P < 0.005 for all comparisons). HIV-positive patients with nodular regenerative hyperplasia had significantly higher levels of antiprotein S IgG than HIV-positive patients without nodular regenerative hyperplasia and healthy controls. Purified IgG from patients with HIV-associated nodular regenerative hyperplasia specifically inhibited the protein S-dependent protein C activation. CONCLUSION: Acquired autoimmune protein S paucity and secondary thrombophilia appear to be causes of obliterative portal venopathy and compensatory nodular regenerative hyperplasia in HIV-positive patients.

Reversibility of cirrhosis in HIV/HBV coinfection.

HIV infection worsens the course and the natural history of chronic hepatitis B (HBV) leading to rapid progression to cirrhosis and to end-stage liver disease. Highly active antiretroviral therapy (HAART) regimens including nucleoside and/or nucleotide analogues with activity against both HIV reverse transcriptase and hepatitis B virus polymerase have clearly improved the survival rates of HIV/HBV-coinfected patients. How HAART beneficially affects the natural course of chronic hepatitis B in coinfected patients is not known. We report a biopsy-proven case of reversal of HBV-related cirrhosis in a coinfected patient, paralleling long-term suppression of HBV replication with tenofovir disoproxil fumarate as part of a HAART. Pathological reversibility of cirrhosis was ascertained by normalization of biochemical (platelet count) and morphological (abdominal ultrasonography and gastrointestinal endoscopy) tests as well as non-invasive markers of fibrosis. In conclusion, a HAART regimen including tenofovir disoproxil fumarate in a HBV/HIV-coinfected cirrhotic patient might lead to sustained HBV viral suppression and result in cirrhosis reversal.

Improving anti-hepatitis C virus therapy.

The estimated prevalence of hepatitis C virus (HCV) infection is 2%, representing 123 million infected individuals worldwide. HCV infection burdens public health in relation to hepatic (cirrhosis and its complications in 20% of patients) and extrahepatic (vasculitis) complications, and lessens quality of life. Major progress has been made in the last two decades for the diagnosis and treatment of HCV, including more appropriate screening strategies for HCV infection (improved sensitivity of serological and virological tests); a better evaluation of the impact of chronic HCV infection on the liver (semi-quantitative scoring systems of necro-inflammation and fibrosis on liver biopsy, non-invasive evaluation of fibrosis with biochemical markers and elastometry); and improved therapeutic regimens. This progress provides a better definition of who to treat (clinical impact or significant fibrosis); how to treat; tailoring therapies for doses and durations of the pegylated interferon plus ribavirin combination according to virological (mainly genotype and early viral kinetics, but also baseline viral load) and hosts factors (fibrosis, immune status, weight); and how to monitor efficacy and tolerance of therapy. The progress has now resulted in a 50% rate of complete HCV eradication, ranging 45 - 90% according to the genotype and especially in those patients with early viral response. New therapies, specifically HCV protease or polymerase inhibitors, in combination with pegylated interferon, or more potent and less toxic new formulations of interferons or ribavirin, will increase these encouraging results in the future.

Improving anti-HCV therapy.

Hepatitis C virus (HCV) infects about 2% of the world population or approximately 123 million people. The disease causes a significant level of morbidity and mortality among those afflicted. The combination of interferon and ribavirin is effective in many patients. However, the right treatment doses and duration, among other attributes, have a large impact on the treatment outcome.

High levels of catalytic antibodies correlate with favorable outcome in sepsis.

Sepsis is the leading cause of death in intensive care units and results from a deleterious systemic host response to infection. Although initially perceived as potentially deleterious, catalytic antibodies have been proposed to participate in removal of metabolic wastes and protection against infection. Here we show that the presence in plasma of IgG endowed with serine protease-like hydrolytic activity strongly correlates with survival from sepsis. Variances of catalytic rates of IgG were greater in the case of patients with severe sepsis than healthy donors (P < 0.001), indicating that sepsis is associated with alterations in plasma levels of hydrolytic IgG. The catalytic rates of IgG from patients who survived were significantly greater than those of IgG from deceased patients (P < 0.05). The cumulative rate of survival was higher among patients exhibiting high rates of IgG-mediated hydrolysis as compared with patients with low hydrolytic rates (P < 0.05). An inverse correlation was also observed between the markers of severity of disseminated intravascular coagulation and rates of hydrolysis of patients' IgG. Furthermore, IgG from three surviving patients hydrolyzed factor VIII, one of which also hydrolyzed factor IX, suggesting that, in some patients, catalytic IgG may participate in the control of disseminated microvascular thrombosis. Our observations provide the first evidence that hydrolytic antibodies might play a role in recovery from a disease.

Conditional cell ablation by tight control of caspase-3 dimerization in transgenic mice.

Studying the effects of the loss of a specific cell type is a powerful approach in biology. Here we present a method based on the controlled activation of the apoptotic machinery. We expressed a modified caspase-3-containing chemical inducer of dimerization (CID)-binding sites in the livers of transgenic mice. In the absence of CID, no liver injury was detectable, underlining the absence of leakage in our system. In contrast, injection of the CID produced activation of the chimeric caspase-3, which led to a dose-dependent pure hepatocyte ablation with subsequent regeneration. This method is effective in both growing and nongrowing cells, and is therefore applicable to a wide range of cells and tissues. Moreover, because apoptosis has been described in numerous pathological circumstances, this system is useful for generating mouse models of human disorders as well as for studying the recovery or regeneration of tissues after cell loss.

Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo.

Cell-based therapy may some day be a therapeutic alternative to liver transplantation. Recent observations indicating that hematopoietic stem cells can differentiate into hepatocytes have opened new therapeutic prospects. However, the clinical relevance of this phenomenon is unknown. We have previously developed a strategy based on the protective effect of Bcl-2 against Fas-mediated apoptosis to selectively amplify a small number of hepatocytes in vivo. We now show that this approach can be used to amplify a minor population of bone marrow-derived hepatocytes. Normal mice were transplanted with unfractionated bone marrow cells from transgenic animals expressing Bcl-2 under the control of a liver-specific promoter. Recipients were then submitted to weekly injections of the anti-Fas antibody, Jo2. Upon sacrifice, the liver of the recipients showed bone marrow-derived clusters of mature hepatocytes expressing Bcl-2, which showed that the hepatocyte progeny of a genetically modified bone marrow can be selectively expanded in vivo. In contrast, no Bcl-2 expression could be detected without the selective pressure of Jo2, suggesting that differentiation of bone marrow cells into mature hepatocytes is very inefficient under physiologic conditions. We conclude that a selection strategy will be required to achieve a therapeutic level of liver repopulation with bone marrow-derived hepatocytes.

Liver repopulation by Bcl-x(L) transgenic hepatocytes.

Liver repopulation could constitute a potential therapeutic alternative to liver transplantation in the future. Therefore, the development of liver repopulation strategies is of major interest. We have previously reported that Bcl-2-expressing hepatocytes are resistant to Fas-mediated apoptosis and that these hepatocytes, when transplanted into the spleen, are able to repopulate the liver of normal mice submitted to Fas-mediated apoptosis. We now show that Bcl-x(L)-overexpressing hepatocytes are able to repopulate up to 10% of a normal mouse liver treated with successive injections of anti-Fas antibody. We show that a twofold overexpression of Bcl-x(L) is sufficient to confer a selective advantage to hepatocytes submitted to anti-Fas antibody. Moreover, repopulation percentages obtained here were comparable to those obtained when Bcl-2 hepatocytes were transplanted, suggesting that both proteins are equivalent in conferring a selective advantage to hepatocytes submitted to anti-Fas antibody.