Discussion

Background

Among HIV-infected persons in the United States, approximately 5 to 10% also have chronic hepatitis B virus (HBV) infection (Figure 1) [1,2]. In persons with hepatitis B and HIV coinfection, HBV-related liver disease progresses more rapidly than in those with HBV monoinfection [3]. In addition, persons coinfected with HIV and HBV have a significant increase in liver-related mortality when compared with those who have HBV monoinfection [4]. Further, HIV-infected patients coinfected with HBV have an increased risk for antiretroviral therapy-related hepatotoxicity [5], particularly when HBV DNA levels exceed 10,000 copies/ml [6]. For all of these reasons, effective treatment of HBV in persons coinfected with HIV is clearly a high priority. The following discussion will address issues related to initial therapy for hepatitis B in persons coinfected with HIV.

Treatment Goals

The long-term goals for patients with HBV and HIV coinfection are the same as in patients with HBV monoinfection: delay development of end-stage liver disease (ESLD), reduce the risk of hepatocellular carcinoma (HCC), and improve survival. Data from patients with HBV monoinfection suggest HBV therapy can achieve these goals, but similar long-term studies in persons coinfected with HIV and HBV have not been done. One retrospective study demonstrated that lamivudine (as part of combination antiretroviral therapy) decreased the risk of liver-related mortality in patients co-infected with HIV and HBV[7], but this study had a median duration of follow-up of only 48 months. The short-term goals when treating HBV in persons coinfected with HIV are similar to treatment goals with HBV monoinfection: suppress HBV DNA, seroconvert to HBeAb positive (in HBeAg-positive patients), and normalize serum alanine aminotransferase (ALT) levels [8]. In addition, coinfected patients who receive treatment for HBV at the same time as they start antiretroviral therapy may decrease their risk for antiretroviral therapy-related hepatotoxicity as well as reducing the risk of developing HBV-related immune reconstitution syndrome [9].

Indications for Initiating Therapy

For individuals coinfected with HIV and HBV, existing treatment guidelines recommend that treatment indications for both HIV and HBV need to be considered in deciding when to initiate HIV or HBV therapy [2,9,10].

Indications to Treat HIV: Current DHHS antiretroviral therapy guidelines (Figure 2) recommend initiating antiretroviral therapy for all HIV-infected persons who have a CD4 count less than 500 cells/mm3 and to consider initiating therapy for those with a CD4 count greater than 500 cells/mm3 [2]. In persons coinfected with HIV and HBV, if antiretroviral treatment for HIV is initiated, the regimen should include medications that also treat HBV, regardless of whether an indication exists to treat HBV. Patients with HIV and HBV coinfection should be advised against self-discontinuation of antiretroviral therapy, since discontinuation of antiviral agents that have HBV activity may cause serious hepatocellular damage as a result of HBV reactivation [2].

Indications to Treat HBV: If a decision is made not to treat HIV, then treatment indications for HBV need to be evaluated (Figure 3) [9,11]. As in the HBV monoinfected patient, treatment is indicated for HBeAg-positive patients who have ALT levels greater than 2 times the upper limit of normal (30 IU/L for men and 19 IU/L for women) and HBV DNA levels greater than 20,000 IU/mL (105 copies per mL). For HBeAg-negative patients, therapy is indicated with ALT levels greater than 2 times the upper limit of normal and HBV DNA levels greater than 2,000 IU/mL (104 copies per mL) [9]. Some experts recommend therapy for HBV even with low levels of HBV DNA (especially in HIV-infected patients), particularly if ALT levels are increased or liver biopsy shows significant histological inflammatory activity and/or fibrosis [8,11]. It is important to remember that patients with HIV-HBV coinfection generally have lower ALT levels and a higher prevalence of cirrhosis than patients with HBV monoinfection [12]. Thus, if a HIV-HBV co-infected patient has a normal ALT level, a liver biopsy should be considered to stage HBV disease, if there are no other compelling reasons for starting antiretroviral therapy.

Antiviral Agents Used to Treat HBV and and Activity Against HIV

Among the antiviral viral agent used to treat hepatitis B, the observed activity of these agents against HIV ranges from strong activity to partial activity to no activity (Figure 4). In general, if therapy is indicated for either HIV or HBV, then treatment should proceed with a combination regimen that will have full activity against both HIV and HBV [13]. Three antiretroviral agents have strong activity against both HIV and HBV: tenofovir (Viread), emtricitabine (Emtriva), and lamivudine (Epivir). Although entecavir (Baraclude) was initially thought to have insignificant activity against HIV-1, investigators have shown entecavir causes a 1 log10 reduction in HIV-1 RNA levels and can select for the lamivudine-resistant HIV polymerase M184V mutation[14,15]. Telbivudine has not been demonstrated to have anti-HIV activity in vitro, but one case report noted HIV RNA decline on telbivudine [16]. The 10 mg dose of adefovir dipivoxil (Hepsera) does not have significant anti-HIV activity, but the known HIV activity of higher-dose adefovir raises the theoretical risk of generating HIV resistance to tenofovir[2,17]. Treatment of hepatitis B with peginterferon or interferon does not cause resistance to any of the HIV antiretroviral medications.

HIV and HBV Therapy-Naïve Patients: Treatment Indicated for HIV

In antiretroviral-naïve patients, all of the first-line DHHS-recommended antiretroviral regimens (Figure 5) also provide treatment for HBV, since they include tenofovir plus emtricitabine (Truvada) as the nucleoside reverse transcriptase inhibitor backbone [2]. Thus, standard first-line therapy for HIV provides three active drugs against HIV and two active drugs against HBV [2]. In HBV-monoinfected patients, tenofovir has generated excellent long-term results [18]. Several studies in HIV-HBV co-infection have demonstrated good efficacy using a tenofovir-based regimen, with similar success as seen in HBV monoinfected patients [19,20,21]. Whether the combination of tenofovir plus emtricitabine (or tenofovir plus lamivudine) is superior to tenofovir alone for the treatment of HBV remains uncertain; this issue has less relevance in an HIV-infected treatment-naïve patient since these patients should receive both tenofovir and emtricitabine as part of the standard regimen to treat HIV. The use of lamivudine (or emtricitabine) as the only active anti-HBV drug should be avoided in HIV-infected patients due to the inferior treatment response when compared with tenofovir (Figure 6 seriesRandomizedTreatment Response) [19] and the unacceptably high rate of HBV lamivudine resistance in HIV-HBV co-infected patients who do not receive a second drug with HBV activity (Figure 7) [22]. If tenofovir cannot be used, then entecavir should be added to the fully suppressive antiretroviral therapy regimen [2]. Other less preferable options to ensure adequate hepatitis B therapy in conjunction with a fully suppressive antiretroviral regimen include the use of peginterferon alfa monotherapy, adefovir in combination with emtricitabine (or lamivudine), or telbivudine. Due to the complexity of this situation, we advise choosing a regimen in consultation with a hepatitis expert.

HIV and HBV Therapy-Naïve Patients: Treatment Indicated for HBV

If HBV treatment is indicated, current guidelines recommend also initiating antiretroviral therapy for the treatment of HIV, regardless of the patient's CD4 cell count or HIV clinical status. The scenario where treatment is indicated for HBV but not for HIV is becoming increasingly uncommon since HIV treatment recommendations have gravitated to earlier initiation of antiretroviral therapy [2,23]. As noted earlier, in persons coinfected with HIV and HBV, treatment initiated for HBV should consist of a regimen that has full activity against both HIV and hepatitis B, even if treatment for HIV is not indicated [2]. The standard first-line recommended DHHS antiretroviral therapy regimens, which include tenofovir and emtricitabine, would provide effective therapy for both hepatitis B and HIV.

Treatment of HIV without Treatment of HBV

In the unusual situation where HIV antiretroviral therapy is indicated, but a decision is made not to initiate therapy for hepatitis B, options exist for treatment of HIV alone. This scenario could arise if significant concerns existed regarding the patient's adherence, with on and off again therapy potentially causing hepatitis flares. If the decision is made to proceed with HIV therapy only, the clinician must carefully select a regimen that does not have significant overlapping anti-hepatitis B activity. Although this type of selection is possible, this approach, in general, is not recommended since any regimen constructed that treats HIV alone without HBV will have to exclude tenofovir, emtricitabine, or lamivudine and thus will not provide a first-line recommended regimen to treat HIV. We advise expert consultation if this situation exists since an unconventional antiretroviral regimen is needed.

Treatment of HBV without Treatment of HIV

In the unusual situation where HBV therapy is indicated, but a decision is made not to initiate antiretroviral therapy for HIV, several options exist for treating hepatitis B alone. In this setting, the clinician must carefully select a regimen that does not have significant overlapping anti-HIV activity. Possible options include the use of peginterferon alfa, telbivudine, adefovir dipivoxil, or telbivudine plus adefovir dipivoxil. Entecavir should not be used in this setting without a fully suppressive antiretroviral therapy regimen, since entecavir has anti-HIV activity and it can select for the HIV mutation M184V, a mutation that results in HIV resistance to lamivudine and emtricitabine [15]. In this setting, telbivudine as a single agent to treat HBV is limited by a moderately high risk of developing drug-resistant HBV, limited data in HIV-HBV co-infected population, and possible activity against HIV [24]. Thus, most experts do not recommend use of telbivudine monotherapy. Although low-dose adefovir does not have significant anti-HIV activity, it is the least potent of the available anti-HBV drugs and thus an inferior option. The combination of telbivudine and adefovir is appealing since it carries the benefit of telbivudine's potency with the assumption that combining adefovir will decrease the rate of developing telbivudine-resistant HBV, but limited data exist with this combination and there is a possibility of anti-HIV activity with telbivudine. Pegylated interferon is effective in HBV monoinfection, but its efficacy in the setting of coinfection is unknown. One retrospective study suggested poorer responses to standard interferon and greater toxicity in coinfected as compared to monoinfected patients [25].

Summary Points

In summary, each of the options has advantages and disadvantages and the decision as to which drug to initiate needs to be individualized to the patient's HBV stage and preference (Figure 8). If the patient is ready to begin HAART, then initiating HAART early is emerging as the preferred option especially in the light of data suggesting that early HAART initiation improves outcomes in HIV monoinfection.

  • The long-term treatment goals are the same for HBV-HIV coinfected patients as for HBV-monoinfection: delay development of end-stage liver disease (ESLD), reduce the risk of hepatocellular carcinoma (HCC), and improve survival.
  • Tenofovir, emtricitabine, and lamivudine have full activity against HIV and HBV.If antiretroviral therapy is indicated for HIV in an HBV-HIV coinfected patient, then the regimen should include tenofovir plus emtricitabine (or lamivudine).
  • Use of emtricitabine or lamivudine as the only HBV-active agent in HAART should be avoided whenever possible given the high rates of HBV resistance that develop in with these medications.
  • If HBV treatment is indicated in an HBV-HIV coinfected patient, then antiretroviral therapy that includes tenofovir plus emtricitabine (or lamivudine) should be started as part of a fully suppressive antiretroviral therapy regimen, regardless of the patient's CD4 cell count or HIV clinical status.
  • In the less common situation where there is a clear indication for treating HBV or HIV alone but reasons for not treating the other infection, then expert consultation is advised.

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    Figure 1. Prevalence of Chronic HBV Infection Among HIV-Infected Persons in the HIV Out-Patient Study, 1996-2007

    Source: Spradling PR, Richardson JT, Buchacz K, Moorman AC, Brooks JT; HIV Outpatient Study (HOPS) Investigators. Prevalence of chronic hepatitis B virus infection among patients in the HIV Outpatient Study, 1996-2007. J Viral Hepat. 2010;17:879-86.


    Figure 1
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    Figure 2. January 2011 DHHS Antiretroviral Therapy Guidelines
Initiating Therapy for HIV in Treatment-Naïve Patients

    Source: Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.


    Figure 2
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    Figure 3. Chronic HBV Infection: AASLD Guidelines for Initiating Therapy

    Source: Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-2.


    Figure 3
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    Figure 4. Antiviral Agents with Activity Against HBV and HIV

    Source: Iser DM, Sasadeusz JJ. Current treatment of HIV/hepatitis B virus coinfection. J Gastroenterol Hepatol. 2008;23:699-706.


    Figure 4
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    Figure 5. January 2011 DHHS Antiretroviral Therapy Guidelines: Preferred Initial Combination Regimens

    Source: Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.


    Figure 5
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    Figure 6: Hepatitis B Therapy in HIV/HBV Coinfected Individuals in Thailand: Study Design. Image 1. Source: Matthews GV, Avihingsanon A, Lewin SR, Amin J, Rerknimitr R, Petcharapirat P et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naive individuals in Thailand. Hepatology. 2008;48:1062-9.
    Figure 6
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    Figure 7. Patients Coinfected with HIV and HBV: Frequency of Lamivudine Resistance with Detectable HBV Viremia

    Source: Matthews GV, Bartholomeusz A, Locarnini S, et al. Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS. 2006; 20:863-70.


    Figure 7
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    Figure 8. HIV and HBV Coinfection: Approach to Treatment
    Figure 8