• HBV resistance more likely with a higher "body mass index" (weight divided by height, squared).
• HBV mutations are detected develop before HBV viral rebound.
• HIV/HBV co-infected patients taking HAART that includes 3TC risk developing HBV-resistance to the drug.

Second Presentation About HIV/HBV Co-Infected Patients

A poster at the 36th EASL by L.M.M. Wolters, MD and colleagues of Rotterdam University Hospital in The Netherlands partly addressed the issue of 3TC resistance to HBV in HIV/HBV co-infected patients. Dr. Wolters reported that after a median of 97 weeks in 46 patients, HBV resistance developed in 25% after 1 year and 52% after 2 years, with a trend towards an increased risk for those with a lower CD4 count. She reported that HBV resistance to 3TC was linear and time-dependent. The only significant factor associated with the development of HBV resistance was "body mass index" (BMI, weight divided by height, squared). She concluded, "It might be considered to increase the dose of 3TC in patients with a higher BMI" and that "surveillance of co-infected patients may be indicated." There are no data whether a higher dose of 3TC among those with a higher BMI might prevent the development of HBV mutations.

Third Presentation About HIV/HBV Co-Infected Patients

A third presentation about HIV/HBV co-infected patients was presented by Dr. A. Rogue Afonso of Hospital Paul Brosse in France. The report included analyses about 14 co-infected patients taking HAART with 3TC. Dr. Rogue Afonso found that "co-existence of [HBV] 'wild type' [without mutations] and polymerase mutants could be detected [after a marked HBV DNA decrease, but] before viral escape" [rebound]. "The emergence of YMDD [specific HBV] mutants before detectable viral escape claim for [suggests the need for] therapies associating [with] 2 or more antiviral agents." HBV mutations were detected using the Innogenetics line probe assay (INNO Lipa). Neil Parkin, PhD and colleagues at ViroLogic in South San Francisco, California have reported similar findings at last year's HIV Salvage Workshop regarding HIV mono-infected patients. Specifically, Dr. Parkin detected new HIV mutations using the PhenoSense HIV phenotypic drug resistance test prior to an increase in HIV RNA.

What Does It All Mean?

One relevant issue that arises when discussing HIV/HBV co-infected patients is whether 3TC should be a part of their HAART regimen in the first place. Some informed physicians might include 3TC in attempt to treat the HBV infection ("2 birds with 1 stone"). However, as has been learned the hard way in HIV patients, monotherapy (or here the HBV-equivalent of monotherapy) commonly leads to resistance. Therefore, one approach might be to avoid 3TC in HIV/HBV co-infected patients, until such time that 2 anti-HBV drugs might be included, e.g., 3TC and adefovir. Other informed physicians have addressed this issue by including 3TC as a part of HAART and famciclovir (Famvir), an FDA-approved drug to treat herpes virus infection that also has anti-HBV activity. However, the potential for negative drug interactions exists. Yet, one study at the 7th Retrovirus Conference reported some benefits with this strategy in one patient who added both drugs simultaneously and not sequentially (Matthews reference).

Also, it should be mentioned that the long term, clinical significance of HBV resistance to 3TC has not yet been fully elucidated. Some (but not all) HBV mono-infected patients with 3TC resistance still maintain lower HBV DNA levels and lower ALT levels (than baseline, pre-3TC), suggesting an altered "replication capacity" of the dominant HBV "strain," similar to what occurs in many HIV patients with multi-drug resistance. However, this has not been proven, and the clinical outcome (liver failure, primary liver cancer) with HBV resistance to 3TC in HIV/HBV co-infected patients is unknown. Some of this might be answered by comparing pre-3TC liver biopsies in the 23 patients who had biopsies within the 18 months before starting adefovir in Dr. Benhamou's study and including new biopsies after 48 weeks of adefovir. It might even be possible that liver histology (seen on biopsy) might improve even without an undetectable HBV DNA, similar to what has been observed in some HCV mono-infected patients who do not achieve an undetectable HCV RNA. Regardless, it is likely that the ultimate goal in HBV mono-infected (and one goal in HIV/HBV co-infected) patients will be total eradication of HBV infection in the liver and blood, with an undetectable HBV DNA.

Whether routine monitoring to detect HBV mutations before viral rebound (as suggested by Dr. Rogue Afonso) will provide any clinical benefit remains to be determined, when there are additional anti-HBV drugs available for new treatment options because with more and/or different drugs viral suppression to undetectable is possible. (There are many under development.) Hopefully, future research will be able to address these various issues.

References
Benhamou Y and others. An open label, pilot study of the safety and efficacy of adefovir dipivoxil in HIV/HBV co-infected patients with lamivudine resistant HBV. Abstract and oral presentation 1253 (session S28) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic. Journal of Hepatology 2001 April;34(suppl 1):24.

Benhamou Y and others. An open label, pilot study of the safety and efficacy of adefovir dipivoxil in HIV/HBV co-infected patients with lamivudine resistant HBV. Abstract and oral presentation 36 at the 8th Conference on Retroviruses and Opportunistic Infections. February 4-8, 2001; Chicago, Illinois.

Matthews G. Failure of sequential nucleoside analog therapy for HBV in HIV/HBV co-infected individuals. Abstract and poster 286 at the 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000; San Francisco, California.

Parkin NT and others. Detection of reduced drug susceptibility at low viral loads (<1,000 copies/mL) prior to virological failure during salvage therapy. Abstract and poster presentation 31 at the 3rd International Workshop on Salvage Therapy for HIV Infection and Antiviral Therapy 2000;5(suppl 2).

Rogue Afonso A and others. HBV viral load monitoring in HIV co-infected patients on lamivudine therapy: early emergence of HBV polymerase mutants. Abstract 212 (board number 542) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic. Journal of Hepatology 2001 April;34(suppl 1):137.

Wolters LMM and others. Development of hepatitis B virus resistance for lamivudine in a Dutch cohort of HIV-HBV co-infected patients. Poster board presentation 585 (abstract 675) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic. Journal of Hepatology 2001 April;34(suppl 1):155.