By Ronald Baker, PhD

There are limited data on how best to treat chronic hepatitis B patients coinfected with HIV. The issue is complicated by the fact that some agents used to treat hepatitis B and some antiretroviral drugs for HIV are active against both viruses, and using them inappropriately can lead to drug resistance.

Traditionally, entecavir (Baraclude) has been recommended for the treatment of hepatitis B in coinfected patients who did not require antiretroviral therapy. Recently, however, it was demonstrated that entecavir does have anti-HIV activity and can promote emergence of drug-resistant HIV.

J. Sasadeusz and colleagues have recommended avoiding entecavir as a single agent for chronic hepatitis B in HIV-HBV coinfected patients [1]. Their findings reflect those of other recent reports concerning entecavir use in the treatment of chronic hepatitis B in HIV-infected patients [2]. They showed the significant anti-HIV effect of entecavir and its ability to select for the M184V lamivudine-resistant mutation in HIV [1,2].

In a letter to the editor published in the November 30, 2008 issue of AIDS, French researchers noted a drop in HIV viral load and the selection of the M184V mutation during entecavir monotherapy in 4 HIV positive men. These patients had HBeAg positive chronic hepatitis B and did not require combination antiretroviral therapy, according to recent guidelines [3].

Following are edited excerpts from the French group's report:

Results

Discussion

Like Sasadeusz and colleagues [1], the French researchers recommended avoiding entecavir as a single agent for chronic hepatitis B in HIV-HBV coinfected patients.

How then should clinicians manage chronic hepatitis B in patients who do not require anti-HIV therapy?

According to guidelines from the European AIDS Clinical Society (EACS) [3], the 4 French patients should have received HBV therapy based on 3 of them having an HBV DNA level greater than 6.0 log10 IU/mL and Metavir fibrosis score greater than F3. However, they did not require antiretroviral therapy because of high CD4 cell counts (547-1033 cells/mm3) and low HIV viral load (3.0-4.2 log10 copies/mL), wrote the French authors.

"In patients with a CD4 cell count less than 500 [cells/mm3]," they continued, "the best option, according to current recommendations, is to consider earlier initiation of combination antiretroviral therapy, including 2 drugs with dual anti-HBV and HIV activity."

Along these lines, the current U.S. antiretroviral therapy guidelines recommend that all HIV-HBV coinfected patients who require treatment for hepatitis B should receive a full HAART regimen that includes dually active agents.

However, the French authors stated, "Recommending the same strategy in patients with CD4 cell counts greater than 500 cells/[cells/mm3] is questionable," especially if their HIV viral load is less than 100,000 copies/mL.

Pegylated interferon (Pegasys or PegIntron) may be an option for HBeAg positive patients with HBV genotype A, elevated alanine transaminase (ALT), and/or low HBV DNA, according to the EACS guidelines [3].

But unlike HBV monoinfection, data on the use of pegylated interferon in HIV-HBV coinfected patients are scarce, according to the authors.

"Two of our patients were placed on pegylated interferon alfa-2a [Pegasys] before initiation of entecavir," they wrote. "Pegylated interferon was discontinued after 7 months in one patient because of depression. The other patient was treated with pegylated interferon for 48 weeks and achieved HBeAg seroconversion upon treatment, which was not sustained after treatment discontinuation."

Regarding the use of 10 mg adefovir (Hepsera) for hepatitis B treatment, there is a theoretical risk of inducing HIV resistance mutations. (A higher dose of adefovir was once studied as an anti-HIV drug, but was abandoned due to toxicity concerns.)

"Recent data suggest that this risk is negligible," wrote the authors [4]. Still, they emphasized, "Adefovir should not be used alone." They cited data from studies of HBV monoinfected patients showing that the risk of selecting an HBV resistance mutation when using adefovir monotherapy reaches 29% by year 5 [5].

Telbivudine (Tyzeka) could also be considered [6], although the authors acknowledged that, "The absence of [telbivudine] anti-HIV activity remains to be confirmed."

In contrast to EACS guidelines, the French authors believe that telbivudine should not be used as monotherapy, because in HBV monoinfected patients the risk of HBV resistance mutations is 18% in HBeAg positive and 7% in HBeAg negative patients at year 2 [7,8].

"One acceptable option may be the use of an adefovir-telbivudine combination in these patients," the authors suggested.

Conclusions

In conclusion, the authors wrote, "Entecavir monotherapy should be avoided in HBV-HIV coinfected patients. In those who are not eligible for combination antiretroviral therapy, earlier initiation of combination antiretroviral therapy, which includes two drugs with dual activity against HBV and HIV, can be considered."

"This strategy is, however, questionable in patients with CD4 cell counts more than 500 [cells/mm3], and especially in those patients with low HIV viral load and no other comorbidities where pegylated interferon or a combination of potent nucleos(t)ide analogues such as adefovir and telbivudine may be of interest. Additional data concerning the safety of this combination are needed."

Service des Maladies Infectieuses et du Voyageur, CH de Tourcoing, Tourcoing, France; Laboratoire de Virologie, CHRU de Lille, Lille, France ; Laboratoire de Virologie, Centre Hospitalier de La Timone, France ; Service d'Hépatologie, Hôpital Saint-Joseph, Marseille, France.

Reports on Entecavir at AASLD 2008

Other Articles on Entecavir Posted on HIV and Hepatitis.com

11/25/08

Reference

H Castel, L Bocket, C Tamalet, and others. How should chronic hepatitis B virus infection be managed in HIV-hepatitis B virus-coinfected patients not eligible for concomitant antiretroviral therapy? [Correspondence]. AIDS 22(18): 2551-2552. November 30, 2008.

Other citations

1. J Sasadeusz and others. The anti-HIV activity of entecavir: a multicentre evaluation of lamivudine-naive patients. AIDS 22: 947-955. 2008.

2. MA MacMahon and others. The HBV drug entecavir effects on HIV-1 replication and resistance. New England Journal of Medicine 356: 2641-2721. 2007.

3. N Clumeck and others (EACS Executive Committee). European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults. HIV Medicine 9: 65-71. 2008.

4. JA Sheldon and others. Risk of selecting K65R in antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir. AIDS 9: 2036-2038. 2005.

5. S Locarnini and others. Incidence and predictors of emergence of adefovir resistant HBV during four years of adefovir dipivoxil (ADV) therapy for patients with chronic hepatitis B (CHB). Journal of Hepatology 42: A36. 2005

6. CL Lai and others. Two-year results from the GLOBE trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LdT) vs. lamivudine. Hepatology 44(S1): 222A. 2006.

7. DN Standring and others. HBV resistance determination from the telbivudine GLOBE registration trial. Journal of Hepatology 44(Suppl 2): S191. 2006.

8. SJ Matthews. Telbivudine for the management of chronic hepatitis B virus infection. Clinical Therapy 29: 2635-2653. 2007.