Conference Reports for NATAP  
  40th Annual Meeting of the
European Association
for the Study of the Liver
April 13-17, 2005
Paris, France

Tenofovir in HIV/HBV Coinfection
  Reported by Jules Levin
There are many reports from the 40th annual meeting of EASL archived on the NATAP website. The "new kid on the block" is HBV & HBV/HIV coinfection as there is a big pipeline of new HBV drugs. Adefovir, peginterferon, entecavir & tenofovir are used to treat HBV although tenofovir is not yet approved for use against HBV. A number of additional drugs are in development including LdT & LdC. There are a number of questions that need to be addressed regarding HBV treatment in mono & coinfected. Treatment guidelines are often discussed but questions remain. What affect will be the development of HBV drug resistance in future treatment? Our understanding of this is limited since so many new drugs are in developmental stages & research has just started addressing this question. Will combination therapy be useful? So far the only benefit with the current drugs that have been studied is a prevention or delay in HBV drug resistance? Should peginterferon be the first treatment option for HBV? It is a time limted treatment with good seroconversion rates vs the potential for having to continue ongoing with oral antivirals. In HBV/HIV coinfection, when should you begin therapy & with what? Research & discussions about treatment guidelines are in early stages, as more research needs to be conducted. There appears to be controversy regarding which HBV DNA (viral load) level is the best time to start therapy. As more treatment options become available, sequencing therapy will be more widely discussed. In the meantime, HBV will be getting increasingly more attention. HBV care, treatment, & diagnosis is complex, perhaps more complex than HIV & HCV. It is important to educate yourself & in particular understand the diagnostic serum markers such as HBeAg & HBsAg, and how they are used in evaluation & in making treatment decisions. The NATAP website has an HBV section where you can find many articles & conference reports on HBV, and there are a number of articles that explain these serum markers along with discussions about when to begin therapy as well as discussions about additional key issues.
S. Mauss1, T. Lutz2, F. van Boemmel3, F. Berger1, T. Berg3, A. Stoehr4, A. Carlebach2, G. Schmutz1
1 Center for HIV and Hepatogastroenterology, Duesseldorf, Germany
2 HIV-Cohort, Frankfurt, Germany
3 Medical Clinic Charite, Berlin, Germany
4 Institute for Interdisciplinary Infectiology and Immunology, Hamburg, Germany
Objective: Sequential monotherapy is the standard of care in the treatment of chronic hepatitis B. In contrast in HIV- or HCV-infection antiviral combination therapy has been proven to be superior to monotherapy.
Methods: Patients with HBV/HIV-coinfection never pretreated with tenofovir (TDF) and lamivudine (3TC) starting antiretroviral therapy on TDF in combination with 3TC were compared to patients who had highly replicative hepatitis B under treatment with 3TC and were switched to TDF as the only active HBV-polymerase inhibitor. All patients were HBe-antigen positive. All patients who switched to TDF as monotherapy for HBV had highly replicative chronic hepatitis B despite 3TC therapy defined as >500.000 copies/ml indicating 3TC resistance. The lower limit of detection of HBV-DNA was <1000 copies/ml.
At baseline patients on TDF + 3TC (n = 8) had a median HBV-DNA of 49.000.000 copies/ml compared to 187.000.000 copies/ml on TDF (n = 24).
After 3 months on treatment median HBV-DNA decreased to 140.000 copies/ml on TDF + 3TC compared to 30.000 copies/ml on TDF.
After 12 months on therapy median HBV-DNA was 2200 copies/ml in patients on TDF + 3TC and <1000 copies/ml on TDF.
A sustained undetectable HBV-DNA <1000 copies/ml was achieved in 6/8 (75%) patients on 3TC + TDF and in 19/24 (79%) patients on TDF.
Viral rebound was observed in 0/8 and 2/24 patients, respectively.
ALT normalised in 5/8 (63%) and 16/24 (67%) patients. ALT >2_ upper limit of normal was observed in 0/8 and 2/24 patients.
A loss of HBe-antigen was observed in 1/8 patients on TDF + 3TC and in 6/24 patients on TDF. HBs-antigen loss was found in 0/8 and 2/24 patients.
Author Discussion
In this cohort of HBe-antigen positive HBV/HIV-coinfected individuals full virologic suppression of HBV-DNA was achieved in the majority of patients independent of treatment allocation. HBe-antigen loss and ALT normalisation were not in favour of the combination therapy. From these preliminary data monotherapy with TDF seems as effective as TDF + 3TC in coinfected patients with highly replicative hepatitis B.
Note from Jules Levin: an increasing number of studies are showing that combination therapy appears to delay or prevent HBV drug resistance. So, although studies so far conducted in combination therapy may not be additive for HBV DNA suppression or seroconversion, HBV drug resistance may be a benefit. As new HBV drugs are developed and become available in a sequential fashion, as is occurring, prevention of drug resistance may be important; particularly because treatment with oral antivirals for HBV may be ongoing for many patients once they start HBV therapy. So, in theory if a patient has 3TC resistance, tenofovir+entecavir may be more effective in preventing HBV drug resistance. The combination of LdT+LdC has shown an additive effect in reducing HBV DNA in the woodchuck animal model & is being studied in humans by Idenix. In addition, several more drugs for HBV are in early stages of development. One last question to consider: what is the utility of peginterferon in HBV. A study at EASLŐs 40th annual meeting this year in Paris showed that previous treatment with interferon or lamivudine (3TC) did not substantially affect HBeAg seroconversion rates.

O. Schildgen1, U.C. Wend7, C.K. Schewe4, M. Vogel2, M. Daeumer3, R. Kaiser3, L. Weitner4, M. Helm5, H. Hartmann6, B. Matz1, J.K. Rockstroh2, W. Gerlich7
1 University of Bonn, Institute for Medical Microbiology and Immunology, Bonn, Germany
2 University of Bonn, Medizinische Klinik und Poliklinik 1, Bonn, Germany
3 University of Cologne, Institute for Virology, Cologne, Germany
4 Praxis St. Georg, Hamburg, Germany
5 Praxis Abelein & Helm, Nuernberg, Germany
6 Innere Medizin, Hepatologie, Krankenhaus Duderstadt, Duderstadt, Germany
7 University of Giessen, Institut fuer Medizinische Virologie, Giessen, Germany
Introduction: Within the adefovir early access program (EAP) for treatment of chronic hepatitis B three HBV/HIV coinfected patients were observed who did not respond to adefovir therapy virologically within the first 6 months of treatment with respect to HBV load (Schildgen et al., AIDS, in press). Three additional HBV-monoinfected patients infected with lamivudine resistant HBV strains displayed no virologic reaction on adefovir; a therapy switch to tenofovir was succesful also in these patients. After changing the treatment to tenofovir all patients receiving tenofovir responded with a significant drop of viral load.
Methods: HBV-DNA was isolated and the DNA-polymerase gene was amplified by PCR for sequencing. Sequencing was carried out using the BigDye terminator reaction (Applied Biosystems). Genotyping and lamivudine-resistance testing were carried out with the INNO-LiPA assay (Innogenetics) or by sequencing of PCR products (Schildgen et al., AIDS, in press).
Adefovir was useless in all six patients. Sequencing analysis of all HBV strains analysed from the six patients revealed no amino acid exchange at the aa position rt236 nor at position rt181, the positions described to mediate resistance to Adefovir.
All 3 HIV infected patients were infected with HBV genotype A accompanied by identical lamivudine resistance pattern (rtL180M/rtYVDD) at baseline, but were epidemiologically not related. In case of the HIV infected patients we identified mutations in a nonconserved HBV polymerase-region (aa rt217) that might mediate Adefovir resistance. In contrast, the HBV monoinfected patients were infected with HBV genotype D, accompanied by the unusual pattern yw4, and displayed a unique mutation.
Author Conclusion
Based on our data we draw the conclusions, that (a) the polymerase/reverse-transcriptase domain aa 215 to aa 236 might mediate adefovir resistance, (b) the combination of the lamivudine resistance plus HBV genotypes A or D predestinates resistance to Adefovir, and (c) a therapy change to tenofovir should be considered in the case of adefovir non-responders.