Hepatitis B co-infection

Joe Sasadeusz : Victorian Infectious Diseases Service, Royal Melbourne Hospital and Infectious Diseases Unit, The Alfred Hospital, Melbourne VIC

Hepatitis B virus (HBV) infection is an important infection in people with human immunodeficiency virus (HIV) infection because of the influence of HIV on the natural history of HBV infection. Antiviral therapies with activity against both viruses have enabled targeted therapy in people with co-infection without an increase in pill burden.

Epidemiology and pathogenesis

It is estimated that over 400 million people worldwide, or approximately 5% of the global population, have chronic HBV infection. Areas of high endemicity for HBV infection, such as sub-Saharan Africa and Asia, are also most affected by the HIV pandemic.1 HIV and HBV infections occur commonly together because of their shared routes of transmission. The prevalence of chronic HBV infection in people with HIV infection in Australia is approximately 5%.2

HBV is not directly cytopathic, and viral pathogenesis is largely immune mediated. Necroinflammatory changes in liver tissue that characterise chronic HBV infection are a result of cellular immune responses to viral antigens.3 Infection in endemic countries usually occurs very early in life, either through vertical or early horizontal transmission. The disease then passes through four different phases determined by the host immune response. These are the immune tolerant, immune clearance, immune control and immune escape phases and are characterised by varying levels of viral load and necroinflammatory activity.1 HIV infection significantly modifies this natural history as described below. 

Diagnosis

Serology

All people with HIV infection should be screened for HBV infection. Hepatitis B surface antigen (HBsAg) is the classic marker indicative of chronic infection. Although the detection of HBsAg is usually sufficiently sensitive to establish the presence of chronic HBV infection in the normal host, individuals may occasionally be negative for HBsAg, but still have active HBV replication, a phenomenon known as occult infection.4 It is recommended that all people with HIV infection should be tested with a panel of three serological tests to identify their serostatus: HBsAg, Anti-HBV core antigen (antiHBc) and anti-HBV surface antigen (antiHBs). Patients found to be HBsAg positive should also have their e-antigen (HBeAg) status evaluated. People who are HBeAg positive usually have active replication, but some people who are negative for HBeAg and positive for anti-HBe may also have active replication and active liver disease. The failure to synthesise HBeAg is due to the presence of mutations in the precore or core promoter regions. All people who are negative for all markers should be offered vaccination.

HBV DNA

If a person is HBsAg positive or has isolated anti-HBc (without HBsAg or antiHBs) as their only marker of infection, he or she should be evaluated for active HBV replication using a sensitive assay for HBV DNA (also known as HBV viral load). The level of HBV DNA determines whether patients are at risk for transmission, progressive disease and immune reconstitution flares. HBV DNA should ideally be quantified by nucleic acid amplification assays, usually sensitive real time polymerase chain reaction (PCR).

In chronic hepatitis B, robust evidence indicates that the HBV DNA level is strongly associated with the development of the two major clinical complications; cirrhosis and hepatocellular carcinoma.5,6

Disease progression

Effect of HIV on HBV disease progression

HIV co-infection results in considerable modification of the natural history of HBV infection.7-9 Persistent HBV infection is more common in people with HIV infection, with the prevalence of chronic HBV infection estimated at 25%10 compared with a prevalence of 3-5% in HIV-seronegative men who have sex with men. 11,12 Furthermore, during chronic co-infection, the HBV DNA levels are substantially higher than in HIV-seronegative people and rates of seroconversion from HBeAg to anti-HBe are lower.7,13-15 Rarely, seroreversion of infection back to HBsAg positivity may occur despite prior seroconversion to anti-HBs, particularly with advanced immunodeficiency.13

Despite the high levels of HBV replication seen in people with HIV-HBV co-infection, these patients have significantly lower serum alanine aminotransferase (ALT) levels than people with chronic HBV infection alone7,13-15 and liver biopsies usually demonstrate milder necroinflammatory activity.13 Despite this, progression to cirrhosis is more common, indicating accelerated fibrosis.13 Indeed, HIV infection is associated with a 17-fold increase in liver-related mortality compared to HBV monoinfection with the risk being directly related to the degree of immunodeficiency.16 Partly as a result of this, liver disease is now the most common cause of non-AIDS mortality in people with HIV infection.17 This excess mortality is still present despite the use of HBV-active combined antiretroviral therapy (cART).18 The reasons for progression are unclear but may relate to factors such as possible direct effects of HIV on liver fibrosis as well as immune activation due to microbial translocation.

Rarely, in severely immunocompromised patients, HBV may exert direct cytopathic effects that are not immune mediated and result in a unique condition called fibrosing cholestatic hepatitis. This condition is associated with very high levels of HBV DNA and has been described in people with HIV infection.19 The condition has a high mortality rate, although recent treatment approaches have resulted in successful outcomes.

An increased rate of hepatocellular carcinoma has not been described in patients with HIV-HBV co-infection, although this outcome may be related to the high mortality associated with HIV infection before the availability of antiretroviral therapy. It is not yet apparent whether prolonged survival due to cART will result in an increased rate of hepatocellular carcinoma.

Effect of HBV infection on HIV disease progression

In contrast to the effect of HIV on HBV infection, most studies have not detected a significant effect of HBV infection on the clinical course of HIV infection.20,21

Effect of cART on HBV disease

Antiretroviral hepatotoxicity

Severe hepatotoxicity occurs in up to 10% of all patients commenced on cART.22,23 HIV-HBV co-infection is an independent risk factor for the development of cART-related hepatotoxicity.22-24 Although all antiretroviral agents have been associated with abnormal liver function tests, ritonavir, nevirapine and tipranavir25,26 are especially implicated in severe hepatotoxicity22,23 and thus should be used cautiously in the patient with HIV-HBV co-infection. Patients who have co-infection with HBV or hepatitis C virus (HCV) should have their liver function initially checked every 2 weeks after commencing cART. Mild elevations (less than 5 X ULN [upper limit of normal]) can be observed if asymptomatic and usually resolve. More severe elevations or those associated with systemic symptoms should be managed by cART discontinuation.27

Immune restoration disease

In patients with HIV-HBV co-infection, immune restoration following cART has been associated with acute rises in levels of serum aminotransferases known as hepatic flares. They occur in approximately a quarter of patients starting cART and although most cases are asymptomatic and resolve spontaneously, they occasionally result in hepatic decompensation and may even be fatal.28-30 Risk factors include high pretreatment HBV viral loads and alanine aminotransferase (ALT) levels.22,24,28,31 Hepatic flares related to cART have also been reported in other circumstances, including re-activation of HBV infection,28,32 development of lamivudine resistance33 and following withdrawal of lamivudine.34 This highlights the need to test all patients for chronic HBV infection before initiation of cART. Patients with cirrhosis are particularly at risk of hepatic decompensation, and require careful observation after the initiation of cART. The role of corticosteroids in this situation is unproven and cannot be recommended outside of a clinical trial.

Assessment of fibrosis

Fibrosis assessment is an important component of the evaluation of patients with chronic HBV infection. In particular, the detection of cirrhosis is an indication to institute regular hepatocellular carcinoma surveillance and to screen for oesophageal varices.

The traditional and still the gold standard method of assessment of fibrosis is liver biopsy. However, the role of liver biopsy is controversial and the technique is associated with significant rates of complications as well as sampling and interobserver error. Current guidelines base treatment decisions on HBV DNA and ALT levels and do not recommend liver biopsy routinely.35 More recently, a number of non-invasive methods for assessing liver fibrosis have been developed as alternatives to liver biopsy. These methods include serum biomarker algorithms such as aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrotest and Hepascore, as well as scanning techniques such as transient elastography (also known as FibroScan). FibroScan in particular has been validated in HIV-HBV populations and has largely replaced liver biopsy.36

Management

General principles

Sustained suppression of serum HBV DNA to below the level of detection by the most sensitive available assay should be the goal of therapy, and, at present, treatment of HBV in HIV- HBV co-infection is life long. If antiretroviral therapy is required, then two agents with anti-HBV activity should be incorporated into the regimen. Current Australian and US guidelines recommend the consideration of cART in all people with HIV infection regardless of CD4 T-lymphocyte (CD4) cell count in order to reduce the risk of disease progression. This recommendation is especially important in patients with HIV-HBV co-infection regardless of CD4 cell count where liver disease progression is faster and drugs with combined HIV and HBV activity are available. Because emtricitabine (FTC), lamivudine (3TC) and tenofovir (TDF) have activity against both HIV and HBV, if HBV or HIV treatment is needed, antiretroviral therapy should be initiated with the combination of TDF + FTC or TDF + 3TC as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of a fully suppressive antiretroviral regimen.37

If antiretroviral therapy is not used, and HBV therapy is indicated then the treatment chosen should have no anti-HIV activity. Current therapeutic options in this setting are pegylated interferon and adefovir. Of particular note, although entecavir had previously been thought to have no anti-HIV activity, more recent studies have shown that it does and can result in HIV resistance.38 It should therefore not be used without a concomitant fully suppressive cART regimen.

Anti-HBV therapy

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

Interferons

In immunocompetent people, interferon-alfa (alfaIFN) 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 cell counts (> 500 cells/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.

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 alfaIFN, may also be an alternative option for patients with high CD4 cell counts who do not require cART.52 It may also be an option for lamivudine-resistant HBV although better drugs such as tenofovir 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 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.

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.56-58 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.59 In a larger cohort of 17 patients with HIV-HBV co-infection treated with entecavir monotherapy a significant reduction in HIV RNA (defined as > .05 log10) should be converted to copies/mL 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-naïve60 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.61

Telbivudine

There have been no studies to date of telbivudine in HIV-HBV co-infection, however, HBV resistance develops rapidly when telbivudine is used as monotherapy and should therefore not be used in the setting of HIV-HBV co-infection.62

Conclusion

HBV infection in people with HIV infection may result in significant morbidity and mortality. People with HIV-HBV co-infection have higher rates of chronic HBV infection and accelerated hepatic fibrosis and cirrhosis compared with those with HBV infection who do not have HIV. Management of each viral infection is complicated by the presence of the other virus. Sustained suppression of serum HBV DNA to below the level of detection by the most sensitive available assay should be the goal of therapy, and, at present, treatment of HBV in HIV- HBV co-infection is life long with tenofovir–based regimens preferred. Close monitoring is necessary to detect treatment failure or hepatic flares, particularly following initiation of cART. Further studies of newer anti-HBV agents in people with HIV-HBV co-infection are still needed.

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