By Ronald Baker, PhD

Treatment and management of HIV-HBV coinfection represents a growing concern both in the US and worldwide, where health authorities estimate >300 million persons are living with chronic hepatitis B, 40 million with HIV-1 infection, and an unknown number living with both these viral infections. 

Due to the heightened risk for liver disease progression and for liver toxicity from anti-HIV drugs,  formulating a treatment regimen for HBV in HIV coinfected patients is important. Yet the optimal choice of regimens is far from clear.

In an article that appears in the October 1, 2005 issue of Clinical Infectious Diseases [1], Chloe Thio, MD, and colleagues at Johns Hopkins University in Baltimore review the treatment options for HIV-HBV coinfected individuals and encourage “thinking outside the Black Box” when choosing a drug regimen for hepatitis B patients coinfected with HIV.

FDA-approved Therapies for Chronic Hepatitis B

Antiretroviral agents active against hepatitis B virus infection include lamivudine (Epivir-HBV), emtricitabine (Emtriva) and tenofovir DF (Viread). Among these three anti-HIV drugs, only lamivudine is FDA-approved for HBV in persons with hepatitis B monoinfection [See Table 1 below].

Other drugs that have anti-HBV activity are adefovir dipivoxil (Hepsera), standard interferon alfa (Intron A) and pegylated interferon alfa (Pegasys). These three drugs are also FDA-approved for treatment of HBV in persons without HIV infection. Entecavir has an FDA indication for the treatment of HIV positive individuals who have had prior therapy with lamivudine.

Table 1: FDA-approved Drugs for Chronic Hepatitis B

The FDA now requires that HBV-related concerns be added to the black box warnings for the antiretroviral drugs active against both HIV and HBV. These warnings primarily concern the possibility of clinically significant hepatitis B relapse if the patient stops using them.

In the case of tenofovir, the black box warning further states that this drug is "not indicated" for the treatment of chronic hepatitis B (see Viread Package Insert This is “FDA speak” for the fact that tenofovir is not FDA-approved for the treatment of hepatitis B. The authors of the current study believe there is a danger that clinicians will misunderstand the FDA warning and interpret it to mean that tenofovir is not active against HBV and is contraindicated for individuals with hepatitis B.

On the contrary, argue the study authors, tenofovir has potent activity against HBV and the data are increasing that tenofovir may have an important role in the treatment of hepatitis in HIV positive persons. The use of tenofovir is supported in two sets of treatment guidelines (Bendon et al. [3], as well as European guidelines reported by Alberti et al. [4] on the treatment of HBV-HIV coinfection.

HBV Drugs to Consider in Choosing a Treatment Regimen for HIV-HBV Coinfection

Standard Interferon Alfa

The efficacy of standard interferon alfa-2b (Intron A), the first medication approved for treatment of chronic hepatitis B, appears to be quite low [5], with a response rate of about 14.3%.   There is greater confidence in, and more data for the efficacy of peginterferon alfa-2a (Pegasys) for treatment of chronic hepatitis B monoinfection [6]. There are no published data as yet for the effectiveness of peginterferon alfa in HIV-HBV coinfected persons.

Lamivudine

While lamivudine is a potent inhibitor of HBV in HIV-HBV individuals, the 12-month incidence of lamivudine resistance in this population is 25 percent [7], which leads to a resurgence of HBV DNA levels and higher concentrations of liver enzymes (ALT). The available data show that lamivudine-resistant HBV has very limited ability to prevent progression of liver disease.

Emtricitabine

Like lamivudine, emtricitabine has potent activity against both HIV and HBV. Although emtricitabine has not been approved by the FDA for the treatment of chronic hepatitis B, HBV DNA levels decreased by 3 log copies/mL in HIV-infected and HIV-uninfected patients treated for 48 weeks [8].  However, resistance to emtricitabine, as with lamivudine, limits this drug’s effectiveness in HIV-HBV coinfected patients. Recently, FDA approved the combination of emtricitabine plus tenofovir  for the treatment of HIV infection, thus coupling two drugs with potent anti-HBV activity.

Entecavir

Entecavir is a nucleoside analogue that is licensed for the treatment of chronic hepatitis B in persons with  and persons without HIV infection. However, it is not active against HIV. In a study of HIV-HBVcoinfected persons receiving lamivudine, a 24-week course of entecavir decreased the HBV DNA load by 3.65 log copies/mL, which is similar to findings for HIV-uninfected persons. To date, no entecavir resistance has been identified in lamivudine-naive patients. The long-term rate of developing entecavir-resistant HBV in HIV-HBVcoinfected persons, many of whom have been treated with lamivudine, is not known.

Adefovir dipivoxil

Adefovir dipivoxil (adefovir/ADV) is a nucleotide analogue that reduces HBV DNA levels an average of 3.5 logs at 48 weeks [9]. Adefovir is FDA-approved for treatment of chronic hepatitis B in persons without HIV infection and is active against lamivudine-resistant HBV. In addition, a total of 35 HBV-HIV coinfected persons received treatment with adefovir for 192 weeks that led to substantial reduction in the HBV DNA load [10].

It is clear from this study and the experience with HIV-uninfected persons that the incidence of clinically evident HBV resistance to adefovir is substantially lower than that for lamivudine [11]. A potential drawback of using adefovir in HIV-HBV-oinfected persons is the theoretical risk of HIV developing cross-resistance to tenofovir, because adefovir is active against HIV at higher doses. “More data are needed to insure that this does not occur,” write the study authors.

Tenofovir DF

Tenofovir is a nucleotide analogue approved by the FDA for treatment of HIV infection. In vitro, tenofovir has activity that is at least equivalent to that of adefovir dipivoxil, perhaps greater. The efficacy of tenofovir appears to be superior to that of adefovir dipivoxil against a triple lamivudine-resistant mutant HBV strain [12], which is found in ~30% of HIV-HBV coinfected individuals [13]. Clinical studies have shown that tenofovir is not inferior to other drugs, including adefovir dipivoxil, approved for the treatment of chronic hepatitis B in HIV-HBVcoinfected persons [14,15].

Thus far, 115 HIV-HBV-coinfected individuals treated with tenofovir have experienced a minimum decrease in the HBV DNA load of 4 log copies/mL during 24-8 weeks of treatment.  One study prospectively followed up 53 individuals infected with lamivudine-resistant HBV [15].  Tenofovir DF was given to 35 of these individuals, and 18 received adefovir dipivoxil. The tenofovir DFtreated group had a more rapid decrease in the HBV DNA load and greater decrease in the hepatitis B e antigen concentration, suggesting a stronger anti-HBV effect of tenofovir.

In addition, multiple retrospective studies presented at research conferences, with the largest following up 107 HIV-HBV-coinfected persons who received tenofovir for a median duration of 10 months [16]. Ninety of these individuals had a detectable HBV DNA level at the start of tenofovir therapy, of whom one-third reached an HBV DNA level of <200 copies/mL.

To date, no significant side effects have been reported in any of the tenofovir studies.  

The Case for Use of Tenofovir in HIV-HBV Coinfection

There are no randomized, controlled trials comparing the possible options, and therefore, strong treatment recommendations cannot be made. Given the widespread use of lamivudine for treatment of HIV infection and the 25% annual incidence of resistance among HBV isolates, the majority of HIV-HBVcoinfected persons taking antiretroviral medications already carry lamivudine-resistant HBV.

For this reason, and the fact that resistance breakthroughs can be clinically significant, many experts recommend alternative anti-HBV medications in HIV-infected persons. Tenofovir and entecavir are both active against lamivudine-resistant HBV, but they have not been compared in HIV-HBV-coinfected persons.

In the opinion of the study authors, “Tenofovir should be strongly considered as treatment for chronic hepatitis B when an adult patient also needs HIV treatment. ^“

“Clearly, the strength of our recommendation for the use of tenofovir DF would be much greater if the drug had been licensed for the treatment of chronic hepatitis B,* but the use of tenofovir DF is easily justified in light of available data.”

“Thus, although tenofovir DF has not been licensed for use for treatment of chronic hepatitis B, we believe that the drug is clinically indicated for treatment of chronic hepatitis B for HIV-infected persons in whom tenofovir DF could also be a component of the antiretroviral regimen.”

“Furthermore, with the commercial availability of tenofovir DFemtricitabine, a single pill that is part of an HIV regimen can be used for hepatitis B treatment, providing two agents with dual activity against HIV and HBV. ^“

Until there are better data to support this recommendation, the authors suggest, “The best approach to the treatment of chronic hepatitis B in HIV-infected persons will require thinking "outside the black box," and in particular, coupling the available data on the treatment of chronic hepatitis B in persons without HIV infection with sound clinical judgment.”

[Editor’s Note: Tenofovir is currently in Phase III testing for the treatment of chronic hepatitis C.]

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09/14/05

References

1.       C L Thio, M S Sulkowski and D L Thomas. Treatment of Chronic Hepatitis B in HIV-Infected Persons: Thinking Outside the Black Box. Clinical Infectious Diseases 41(7): 1035-1040. October 1, 2005.

2.       F W Wit and others. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. Journal of Infectious Diseases 186: 23-31. 2002.

3.       C A Benson and others. Treating opportunistic infections among HIV-infected adults and adolescents. MMWR 54: 311. 2005.

4.       A Alberti and others. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV-coinfected patients. Journal of Hepatology 42: 615-624. 2005.

5.       D K Wong and others. Effect of alfa-interferon treatment in patients with hepatitis B e antigenpositive chronic hepatitis B. Annals of Internal Medicine 119: 312-323. 1993.

6.       P Marcellin and others. Peginterferon alfa-2a (40KDa) (Pegasys) monotherapy is more effective than lamivudine monotherapy in the treatment of HBeAg negative chronic hepatitis B: 72 week results from a phase III, partially double-blind study of Pegasys alone vs. Pegasys plus lamivudine vs. lamivudine [abstract 95]. In: Program and abstracts of the 39th Meeting of the European Association for the Study of Liver Disease (Berlin). Geneva, Switzerland: Keyes International. 2004.

7.       Y Benhamou and others. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virusinfected patients. Hepatology 30:1302-1306. 1999.

8.       J Harris and others. Emtricitabine therapy for hepatitis infection in HIV-1 patients co-infected with hepatitis B: antiviral response and genotypic findings in antiretroviral treatment naive patients [abstract 836]. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (San Francisco). Alexandria, VA: Foundation for Retrovirology and Human Health. 2004.

9.       Y Benhamou and others. Three-year treatment with adefovir dipivoxil in chronic hepatitis B patients with lamivudine-resistant HBV and HIV co-infection results in significant and sustained clinical improvement [abstract 835]. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (San Francisco). Alexandria, VA: Foundation for Retrovirology and Human Health. 2004.

10.    Y Benhamou and others. Long-term treatment with adefovir dipivoxil 10 mg (ADV) in patients with lamivudine-resistant (LAM-R) HBV and HIV co-infection results in significant and sustained clinical improvement [abstract WeOrA1329]. In: Program and abstracts of the 15th International AIDS Conference (Bangkok). Stockholm: International AIDS Society. 2004.

11.    P Angus and others. Resistance to adefovir dipivoxil therapy associated with development of a novel mutation in the HBV polymerase. Gastroenterology 125:292-297. 2003.

12.    O Lada and others. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir. Antiviral Therapy 9:353-363. 2004.

13.    L Cooley and others. Prevalence and characterization of lamivudine-resistant hepatitis B virus mutations in HIV-HBV co-infected individuals. AIDS 17:1649-1657. 2003.

14.    M Peters and others. Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment of hepatitis B virus in subjects who are co-infected with HIV: results of ACTG A5127 [abstract 124]. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections (Boston). Alexandria, VA: Foundation for Retrovirology and Human Health. 2005.

15.    F Van Bommel and others. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 40: 1421-1425.

16.    P Trimoulet and others. Antihepatitis B virus activity of tenofovir disoproxil fumarate in human immunodeficiency virus co-infected subjects [abstract 2467]. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago). Washington, DC: American Society for Microbiology. 2003.

17.    C L Thio and others. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter AIDS Cohort Study (MACS). Lancet 360:1921-1926. 2002.