There are six currently licensed treatments available for the management of HBV infection. These include interferons, nucleoside reverse transcriptase inhibitors (lamivudine, emtricitabine, entecavir and telbivudine) and nucleotide reverse transcriptase inhibitors (tenofovir, tenofovir alafenamide and adefovir).

Interferons

In immunocompetent people, interferon-alfa (alfa-IFN) therapy may result in HBeAg seroconversion and induce a clinical remission in 20-40% of patients with chronic HBV infection.³⁹ Treatment of people with HIV-HBV co-infection is significantly less effective.^40-42 In particular, patients with advanced immunodeficiency usually have poorer responses to therapy.⁴³ It may therefore be reasonable to occasionally consider interferon-based therapy in people with preserved CD4+ T cell counts (> 500/μL) who are not candidates for cART. There are currently no data on pegylated interferon in the setting of co-infection although it would be reasonable to use it given its proven track record in HBV monoinfection and improved pharmacokinetics with once weekly dosing.

Lamivudine / emtricitabine

Lamivudine and emtricitabine are both nucleoside analogue reverse transcriptase inhibitors that suppress both HIV and HBV replication by inhibition of viral RNA-dependent DNA polymerases.^44,45 In HIV-negative people, the reduction in plasma HBV DNA secondary to lamivudine therapy is associated with HBeAg seroconversion, normalisation of liver function and improved histological activity. Efficacy of lamivudine against HBV has also been demonstrated in people with HIV-HBV co-infection.^28,46,47,48 Unfortunately, the long-term effectiveness of lamivudine is diminished by the development of high rates of HBV resistance mutations.⁴⁹ Resistance to lamivudine develops because of mutations in the tyrosine-methionine- aspartate-aspartate (YMDD) motif of the catalytic domain of the HBV polymerase gene. Approximately 20% of patients with HIV-HBV co-infection develop HBV resistance to lamivudine annually, with projected rates of resistance after 4 years of lamivudine therapy of approximately 90%.^50,51 This frequency of lamivudine resistance is higher than that seen in patients with HBV monoinfection.⁵⁰ Prolonged lamivudine therapy has been identified as the major risk factor for the development of drug-resistant HBV. Given that lamivudine, when used as a component of cART, is administered lifelong in patients with co-infection, it is inevitable that HBV monotherapy in this population will result in resistance.⁵⁰ Accordingly, lamivudine or emtricitabine should not be used without a concomitant drug with a high barrier to resistance, such as tenofovir or TAF.

Adefovir dipivoxil

Adefovir dipivoxil is a nucleotide analogue which, at a dose of 10 mg daily, has demonstrated efficacy against both wild-type and lamivudine-resistant HBV. Higher doses of 30 mg or greater have been associated with nephrotoxicity, which has been rarely observed with the 10-mg dose. Adefovir, like alfa-IFN, may also be an alternative option for patients with high CD4+ T cell counts who are not candidates for cART.⁵² It may also be an option for lamivudine-resistant HBV, although better drugs such as tenofovir or TAF should be the drug of choice (see below). Studies to date have been performed on small numbers of patients and the structural similarity of adefovir to tenofovir may theoretically lead to the possibility of HIV cross resistance to tenofovir although this has not yet been reported.⁹

Tenofovir disoproxil

Tenofovir (TDF) is a nucleotide analogue with the ability to inhibit both HIV and HBV DNA polymerases. It has been demonstrated to exert a profound suppression of HBV DNA which is superior to adefovir.⁵³ It also demonstrates activity against viral strains that contain multiple polymerase gene mutations, including common lamivudine-resistant mutations⁵⁴ and has an extremely high barrier to resistance with no signature resistance mutations reported to date.⁵

One small randomised control study has demonstrated its efficacy in patients with HIV-HBV co-infection with superior virological suppression compared to lamivudine.^51,55 Tenofovir is now commonly used as combination therapy in conjunction with lamivudine or emtricitabine for the treatment of HBV in patients with co-infection. In addition, the coformulation of tenofovir and emtricitabine allows convenient single-daily dosing and this combination should be the regimen of choice for the vast majority of people with HIV-HBV co-infection.

Tenofovir alafanemide

Tenofovir alafanemide or TAF is a novel prodrug of Tenfovir with a more targeted effect on lymphocytes and hepatocytes resulting in 91% less systemic exposure compared to TDF. As such, it has been shown to have excellent HIV activity with reduced renal and bone toxicity and has now become the nucleotide backbone of choice for HIV regimens. Like TDF, TAF also has excellent HBV activity which is comparable to TDF but at doses of 25 mg unboosted and 10 mg boosted compared to 300 mg for TDF. Large studies in HBV monoinfection have also demonstrated the comparable efficacy of TAF to TDF.⁵⁶ In addition, switch studies of TAF have shown its efficacy in HIV-HBV coinfection.⁵⁷ Like TDF, TAF has been incorporated into multiple single tablet regimens and is now regarded as the treatment of choice for HIV-HBV coinfection.

Entecavir

Entecavir is a guanosine analogue which has well documented, potent anti-HBV activity both in vitro and clinically and has a high barrier to HBV antiviral resistance.^58-60 Although entecavir was initially reported to have no anti-HIV activity, a recent report of three patients with HIV-HBV co-infection who were treated with entecavir monotherapy demonstrated significant reductions of HIV RNA despite no concomitant HIV therapy. Furthermore, one of these patients was shown to develop an M184V mutation, the signature HIV-resistance mutation for lamivudine.⁶¹ In a larger cohort of 17 patients with HIV-HBV co-infection treated with entecavir monotherapy, a significant reduction in HIV RNA was observed in 13 of them (76%), including treatment-naïve patients. The M184V mutation was also identified in six people including three who were antiretroviral-naïve⁶² Therefore, entecavir should no longer be used as monotherapy for the treatment of HBV in the setting of HIV co-infection.

Occasionally, entecavir needs to be used when issues of tenofovir toxicity (especially renal) arise. In this setting is should be used with fully suppressive cART. Although entecavir has a high barrier to resistance in wild type HBV infection, it has a very low barrier in the setting of pre-existing lamivudine or emtricitabine resistance.⁶³

Telbivudine

There have been no studies to date of telbivudine in HIV-HBV co-infection, however like lamivudine, HBV resistance develops rapidly when telbivudine is used as monotherapy and should therefore not be used in the setting of HIV-HBV co-infection.⁶⁴