Other Issues

Epidemiology of viral hepatitis (Dr Miriam Alter, Centers for Disease Control and Prevention, Atlanta, US).

In addition to transmission by percutaneous exposure to blood, HBV, HCV and HIV are transmitted perinatally and sexually, but HBV and HIV are more efficiently transmitted by these routes than HCV. Nevertheless, clusters of acute HCV among homosexuals in large urban areas have been recently reported [34]. In the perinatal setting, co-infection with HIV facilitates the transmission of HCV to newborns. Viral hepatitis prevention should be provided to HIV-infected patients, including counseling, testing, HAV and HBV immunizations, and medical management for the chronically infected.

Virology of HBV and HCV and antiviral targets (Dr Jean-Michel Pawlotsky, Hôpital Henri Mondor, Créteil, France).

The complex HBV life cycle partly takes place in the nucleus, where covalently circled circular DNA (cccDNA) is produced and remains as a form of persistence of the viral genetic information.  The ultimate goal of therapy is to reduce, and eventually clear, the pool of cccDNA.

Specific antiviral molecules include the currently in use polymerase inhibitors (NRTI), and the potential attachment, entry, transcription, and viral packaging inhibitors. Among immunomodulatory approaches, the currently used IFN, but also cytokines and therapeutic vaccines deserve mention.

Specific anti-HCV drugs are under development: RNA ploymerase inhibitors, NS3 protease inhibitors, and inhibitors of the internal ribosome entry site. The combination of specific HCV inhibitors, RBV and RBV-like molecules, interferons, and immune therapy can be envisaged for the treatment of HCV. Both HCV and HBV are better approached combining antivirals and immune therapy. Contrary to HBV, HCV infection is curable.

Immunopathogenesis of hepatitis C (Dr. Margaret J. Koziel, Beth Israel Deaconess Medical Center, Boston, US).

The prevailing hypothesis of liver injury in HCV is that CD4+ and CD8+ T cells responses mediate liver damage while engaged in an ineffectual effort to clear the chronic infection. Vigorous intrahepatic CD4+ responses that produce IFN gamma early in infection are correlated with slower disease progression in HCV-monoinfection.

In a recent study performed in HIV/HCV-coinfected subjects, Dr. Koziel found a relationship between CD4+ immune responses and liver histology. She has also proven that there are qualitative differences in the CD4+ response in HIV/HCV-coinfected compared to HCV-monoinfected patients [35].

Predictors of disease severity in viral hepatitis (Dr. Thierry Poynard (Groupe Hospitalier Pitié-Salpêtrière, Paris, France).

Several factors have been clearly shown to be associated with fibrosis progression rate: duration of infection, age, male gender, alcohol consumption, HIV coinfection, and low CD4 counts.

Metabolic conditions such as steatosis, overweight, and diabetes are emerging as independent cofactors of fibrogenesis. Non-invasive biomarkers should facilitate the study of fibrosis progression in large populations.

Update on highly active antiretroviral therapy (HAART) in HIV (Dr. Patrick Yeni, Hôpital Bichat-Claude Bernard, Paris).

NNRTI are prescribed more often than PI both in the US and in Europe. The field is moving to decrease toxicity and to increase convenience of the HAART combinations (e.g., once a day regimens). Regarding the NRTI backbones, AZT+3TC, abacavir (ABC)+3TC, and TDF+FTC are currently the most popular [fixed-dose] combinations.

HBV treatment monitoring (Dr. Fabien Zoulim, Hôtel Dieu Hospital, Lyon, France).

The assessment of efficacy of anti-HBV treatment should rely firstly on plasma HBV DNA monitoring. During long-term treatment, the increase in HBV viral load ³ 1 log₁₀ copies/mL compared to nadir values defines the occurrence of HBV drug resistance. Specific HBV polymerase gene mutations can be detected by genotypic analysis.

Future research directions include the determination of factors predicting response, the effect of anti-HBV therapy on liver disease severity (liver biopsy versus non-invasive techniques), the impact of long-term treatment on HBsAg clearance and intrahepatic DNA, the impact of HBV drug resistance on liver disease and the role of cross-resistance testing of HBV strains in patients with HBV treatment failure.

HCV treatment monitoring (Dr. Raymond T. Chung, Massachusetts General Hospital, Massachusetts).

While further long-term studies of SVR in HIV/HCV-coinfection are required, the traditional SVR end-point for virological response appears to be valid also in this setting. The use of higher sensitivity assays is warranted. Early virological response (EVR), defined as a ³ 2 log₁₀ decrease in HCV RNA levels at 12 weeks of therapy, has a 100% negative predictive value for response to therapy [21].

Dr. Chung pointed out that there may be dissociation between virological and histological response, which supports the use of maintenance monotherapy with pegylated IFN. Liver histology should be frequently checked in these patients, and therefore the validation of serum markers of fibrosis in HIV/HCV-coinfection in order to use them in this setting would be of great interest.

Quality of life and cost-efectiveness of anti-HCV therapy in HIV-infected patients (Dr. María Buti, Hospital General Universitario Valle de Hebrón, Barcelona, Spain).

The questionnaires used to examine symptoms that affect quality of life in mono-infected patients are not well adapted for HIV/HCV-coinfected patients and need to be redesigned. Cost-effectiveness studies in HIV/HCV-coinfected patients will have to take into account some specific variables such as CD4 counts, increased fibrosis progression rate, and the use of expensive drugs (i.e., epoetin and G-CSF) for the management of side effects.

Access to anti-HCV therapy in HIV-coinfected patients (Mauro Guarinieri, European AIDS Treatment Group). Despite the high prevalence of HCV-coinfection in HIV-infected injection drug users, access to treatment for HIV and HCV is a significant problem for this population. Collaborative efforts by all levels of government, community organizations, healthcare providers, researches and people affected by HCV are required for an effective management of this infection.

Prevention of viral hepatitis in HIV-infected patients. Dr. Gary Brook (Central Middlesex Hospital, London, UK)

Dr. Brook recommended giving up to six double doses of hepatitis B vaccination, and if there is no response, vaccination should be repeated after CD4 counts rise (ideally to > 500 cells/mm³) with antiretroviral therapy. There is no utility in increasing the HAV vaccine doses, but response may be achieved with revaccination after CD4 counts increase.

Multiple viral infection (Dr. Giovanni B. Gaeta, Second University of Naples, Italy).

HIV-infected patients with concomitant HBV (±HDV) and HCV infections have poorer outcomes than patients with HIV alone or, to a lesser extent, than patients with a single hepatitis co-infection. Studies are needed to understand the dynamics of the hepatitis viral infections and to define through multicenter trials treatment strategies to better mange these patients with HIV and multiple hepatitis. There are conflicting results as to the impact of hepatitis G virus (GBV-C) on the course of HIV disease.

Orthotopic liver transplantation (OLT) (Dr. José María Miró, Hospital Clínic, University of Barcelona, Spain).

HIV-infected patients undergoing orthotopic liver transplantation (OLT) have similar in-hospital mortality and short/medium-term survival than non-HIV patients. However, increased incidence of acute rejection episodes has been reported. Main criteria are CD4 > 100 cells/mm³ and prospects for good control of HIV replication under HAART.

There is a debate regarding the exclusion patients with a history of a “C event” from transplant programs, and Dr. Miró stated that decisions should be individualized. Given the high mortality while waiting for OLT, HIV-infected subjects should be screened for OLT after the first hepatic decompensation. The prognosis of subjects transplanted because of HCV due to recurrence of the infection, have worse prognosis than those undergoing OLT to treat HBV-related liver disease.

Management of hepatocellular carcinoma (HCC) (Raffaele Bruno, University of Pavía, Italy).

Concurrent HIV infection may increase the incidence of hepatocellular carcinoma (HCC) in cirrhotic patients with HBV and/or HCV. HIV-infected cirrhotic patients should be screened for HCC at 6-month intervals using ultrasonography and measurement of alpha-fetoprotein levels. Percutaneous ethanol injection can be indicated for small tumors in patients who are not candidates for surgery. Chemoembolization may improve survival in cases with late-stage HCC. HIV-infected patients with HCC do not qualify for OLT.

At the end of the conference, Dr Michael Manns, from the Medical School of Hannover (Germany), nicely summarized in a 20-minute session the most relevant issues discussed during the 2-full days meeting.

HIV, HBV and HCV are the three top viral killers in the world. However, after years of investigation, there is now a better understanding of these infections, and more importantly, we currently have active drugs and many others are currently under development, which brings hope to those working in the field.

Members of the jury panel

Presidents:

        Alfredo Alberti (Italy)

        Natham Clumeck (Belgium)

Members:      

       Rondolphe Thiebaut (France)

       Simon Collins (UK)

       Wolfram Gerlich (Germany)

      Jens Lundgren (Denmark)

      Giorgio Palú (Italy)

      Peter Reiss (The Netherlands)

      Ola Weiland (Sweden)

      Yazdan Yazdanpanah (France)

      Stefan Zeuzem (Germany)

03/14/05

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