11.0 Complex situations: Co-infection & Immunosuppression

  • Co-infection with hepatitis B virus (HBV) and human immunodeficiency virus or hepatitis C or D virus results in worse outcomes for patients in terms of all-cause mortality, liver disease and hepatocellular carcinoma.
  • All individuals with chronic hepatitis B should be tested for co-infection following appropriate pre-test discussion.
  • People with ongoing risk factors for co-infection should be offered repeat testing, particularly in the setting of clinical deterioration.
  • The approach to treatment for patients with co-infection is more complex than in the setting of mono-infection, and can be associated with increased risk of adverse outcomes.
  • All patients undergoing significant immune suppression should be tested for HBV infection because viral reactivation and associated flares of hepatitis can occur, and can be fatal.

There are a number of special situations in which the complexity of managing the care of a patient with hepatitis B virus (HBV) infection is increased. Primary care practitioners are optimally placed to recognise and respond to these situations, and to coordinate management and referral to specialist services, to maximise the health and wellbeing of people living with chronic hepatitis B (CHB).

HBV, hepatitis C and D viruses (HCV, HDV) and human immunodeficiency virus (HIV) have shared modes of transmission. The prevalence of co-infections varies widely globally depending of the endemicity of HBV and HDV (see Chapter 1), and the predominant modes of transmission for HIV and HCV. All patients with CHB should be offered testing for the presence of all these co-infections, following appropriate pre-test discussion (1). Each virus affects the natural history of CHB infection, and complicates treatment approaches. The management of co-infection is complex, and usually requires shared care with a specialist physician.

11.2.1 HBV/HIV co-infection Epidemiology

Globally, where CHB prevalence is high (>8%) or intermediate (2–8%), and is most often acquired in early childhood, co-infection in HIV-infected individuals is common, and reflects the background population prevalence. In Australia, which has a low prevalence of both viruses, new HBV infections are most commonly transmitted though parenteral exposure or unprotected sexual contact, and may be transmitted simultaneously with, before or after exposure to HIV (2). An estimated 6% of Australia’s 25,000 HIV-infected individuals (3) are HBV/HIV co-infected (4, 5). Incident HBV infections are more common in HIV-infected individuals and men who have sex with men (MSM) –a population also at increased risk for HIV infection. Recent Australian studies estimate rates around 10 times those of the total population, at about 2 per 1,000 person years (5-8), and highlight the importance of testing, vaccination and (for HIV-infected individuals) boosting vaccination when the titre of antibodies to the hepatitis B surface antigen (anti-HBs) falls below 10 mIU/mL (9) (see Chapter 5). Natural history

Co-infection with HIV has a significant impact on the natural history of CHB. Progression to chronic infection following acute HBV is more common in people with HIV infection than in immune competent adults (5), with the likelihood of failing to clear HBV related to the degree of immunodeficiency (10). High HBV DNA levels and detectable hepatitis B e antigen (HBeAg) are more common in patients with HIV co-infection, and the rate of viral reactivation is also higher, particularly in more immunocompromised patients (11). Occult infection (isolated antibodies to the hepatitis B core antigen [anti-HBc] with detectable HBV DNA) is more common in patients co-infected with HBV and HIV. Anti-HBs-positive patients with a history of resolved HBV infection can undergo reactivation, with reappearance of hepatitis B surface antigen (HBsAg) (reverse seroconversion) and HBV DNA. This is a rare event, but may be more common in the setting of advanced immunodeficiency (12, 13).

Progression to advanced liver disease, such as cirrhosis and hepatocellular carcinoma (HCC), is more rapid, and liver-related mortality is higher, in the setting of HBV and HIV co-infection, despite typically lower alanine aminotransferase (ALT) values and reduced inflammatory activity on biopsy (13). This disparity of less necroinflammatory activity but faster disease progression is not fully understood. In contrast to the significant impact of co-infection on the natural history of HBV, there is little evidence to suggest that the HBV affects progression of HIV infection (13).

With the reduction in mortality related to acquired immune deficiency syndrome (AIDS) and incidence of opportunistic infections since the advent of combined antiretroviral therapy (cART), the burden of liver-related morbidity and mortality has increased (2). HBV infection contributes to liver-related illness either alone or in combination with other factors. Antiretroviral agents can cause liver toxicity, particularly in patients with pre-existing liver disease, such as chronic viral hepatitis (2). Management

The indication for treatment of HBV in the setting of HIV co-infection is similar to that for HBV mono-infection, and the aims are essentially the same (14). If there is indication to start treatment for CHB alone, then treatment with HBV-active cART should be considered, regardless of CD4 level (13). Monotherapy for HBV with any agent (including tenofovir and entecavir) must be avoided, because this can induce HIV-resistance mutations that will make subsequent choice of cART regimens more difficult (2). ALT levels can be low in the presence of significant liver damage; therefore, assessment with FibroScan® or liver biopsy (or both) is important to determine the degree of liver fibrosis. Current treatment of HBV and HIV co-infection usually includes tenofovir in the cART regimen, to allow treatment of both infections. Sole HBV-active agents with a lower barrier to resistance (particularly lamivudine) in a cART regimen are likely to select for HBV resistance (15); therefore, patients should be switched to a regimen that includes tenofovir. Although there is an increased risk of HCC, particularly at lower CD4 counts, routine 6-monthly screening for HBV/HIV co-infected individuals is not currently recommended, and screening for HCC should occur as per guidelines (see Chapter 6) (16).

Immune reconstitution inflammatory syndrome (IRIS) occurs when there is a resurgent immune response to chronic infections in people living with HIV following commencement of cART. HBV flares in the setting of immune reconstitution are more common in patients with a high baseline HBV viral load (13) and low starting CD4 counts (e.g. <200), and can result in significant liver disease and in mortality, particularly in patients with advanced liver disease. However, flares can also lead to HBeAg clearance and sustained suppression of viral replication in some patients. Caution when changing cART regimens in co-infected patients is also necessary, because ceasing HBV-active agents can cause reactivation. Continuation of these antiviral agents should be considered, even if they add little to the patient’s HIV therapy.

11.2.2 HBV/HCV co-infection Epidemiology

HBV/HCV is the most common co-infection in people living with CHB in Australia. HCV infection in Australia is most commonly associated with parenteral exposure, and HBV/HCV co-infected individuals can either be exposed due to this shared mode of transmission or have an independent risk factor for CHB; for example, country of birth, Aboriginal and Torres Strait Islander status or sexual risk (see Chapter 1). About 5% of Australians living with CHB are estimated to be co-infected with HCV. Natural history

In contrast to co-infection with HIV, reduced replication of HBV is common in HCV co-infection, with lower viral loads than in patients with HBV mono-infection, although these may fluctuate over time and should be assessed at regular intervals (14). The suppression of HBV is through the direct interference with replication by HCV (10). As with HIV, occult (HBsAg-negative) CHB is also more common in patients with HCV co-infection, and consideration should be given to testing for the presence of HBV DNA in people living with chronic hepatitis C with isolated anti-HBc on serologic testing (note: this test is not Medicare rebatable in the absence of HBsAg). HBV/HCV co-infection is associated with more severe liver disease, an increased risk of progression to cirrhosis and a higher incidence of HCC (14, 17). A large Australian linkage study showed that those co-infected with HBV and HCV experienced higher mortality rates (liver related and all cause) than those infected with either HBV or HCV alone; patients with co-infection had mortality rates about three times higher than patients with HBV mono-infection (18).

Acute co-infection (usually acquired through injecting drug use) has been associated with an increased incidence of fulminant hepatitis. Management

Patients need to be assessed fully for both viruses and evidence of liver fibrosis. The aim of management of HCV in HBV/HCV co-infection is cure with sustained viral suppression. The aim of treatment of HBV in HBV/HCV co-infection is adequate suppression of the virus and prevention of further liver damage. HCV treatment should be offered to co-infected patients (14) even if HBV infection predominates.

In people co-infected with HBV/HCV and treated for HCV, HBV clearance during treatment with pegylated-interferon (PEG-IFN) and ribavirin is as high as 30%, and can occur during up to 5 years of follow-up, with comparable response rates of treatment for HCV infection (19). Reactivation of previously suppressed HBV replication can occur following successful treatment for HCV, but also during treatment; hence, both viruses need to be monitored at regular intervals. Addition of anti-HBV agents (tenofovir and entecavir) in patients who have an increase in HBV DNA during treatment is recommended. There are no large studies that support the routine addition of an HBV oral antiviral as a standard approach to an HBV/HCV co-infected individual undergoing treatment where HBV replication is suppressed.

11.2.3 HBV/HDV co-infection

HBV, hepatitis B virus; HDV, hepatitis D virus; PCR, polymerase chain reaction

Testing in HBV/HDV co-infection

A positive HDV antibody test should be followed up by HDV RNA PCR testing (such tests are available at a limited number of laboratories; check for availability and charges).

HBV/HDV co-infection requires specialist management because outcomes are worse than mono-infection, and there are special considerations around the treatment approach. Epidemiology

HDV (sometimes called hepatitis delta) relies on HBV infection to replicate. Worldwide, HDV is more common in parts of sub-Saharan Africa, Eastern and Mediterranean Europe, the Amazon Basin and parts of Asia, but can vary within countries and regions (20). HDV prevalence varies widely between populations, but is estimated to affect around 5% of people with HBV infection in Australia (21). As with other co-infections, it can be acquired simultaneously with HBV infection or as a superinfection. In non-endemic countries such as Australia, HBV/HDV infection has been more commonly associated with injecting drug use, although the epidemiology is changing as migration from higher HDV prevalence areas increases and country of birth becomes an increasingly important determinant (21).

HDV/HBV co-infection appears to be rare in Aboriginal and Torres Strait Islander people who do not have other risk factors for infection, based on a recent study from the Northern Territory (22); however, evidence on prevalence among Aboriginal and Torres Strait Islander people in other areas of Australia is lacking. Natural history

HDV is a satellite virus that requires HBV co-infection to synthesise new virions; it therefore cannot infect hepatocytes in the absence of HBV. Similar to the situation of HBV/HCV co-infection, HDV infection usually results in suppression of HBV replication with low or undetectable HBV DNA levels, although this is not uniformly the case (23).

Acute co-infection with HBV/HDV is typically indistinguishable from HBV mono-infection, but has been associated with a higher incidence of fulminant hepatitis. The rate of progression to chronicity is no different from that for HBV infection alone. HDV superinfection in a person with CHB can present as an acute hepatitis flare, and progression to chronic HDV infection is usual. Chronic HBV/HDV co-infection has been associated with more severe liver disease; evidence regarding the influence on HCC incidence is mixed (24). Management

HBV/HDV co-infected patients need to be assessed as usual (see Chapter 6) and the decision for treatment should be made on similar criteria. Initial testing of HDV antibody for all people with CHB should be followed with HDV RNA polymerase chain reaction (PCR) for any patient with a positive result (21); serum HDV RNA results fluctuate, and referral for specialist management is advisable. Antiviral agents for HBV infection are not effective against HDV, but, as is the case in HBV/HCV co-infection, they may be required for the treatment of HBV infection, depending on viral predominance and degree of underlying liver disease (23). Treatment of HBV/HDV co-infection is with a prolonged (1–2 year) course of IFN-alfa, conventional or PEG-IFN (1) although treatment is successful in a minority of patients and relapse following therapy is common (25).

11.2.4 Multiple co-infections

Multiple co-infections with a combination of HBV, HCV, HDV or HIV occur uncommonly and, in the Australian context, are most likely to be associated with a history of injecting drug use.

All patients should be offered testing for the presence of resolved or current HBV infection before immunosuppression (14, 26, 27). This is particularly the case when considering that nearly half of all people living with CHB in Australia are estimated to remain undiagnosed (28). Universal testing for people undergoing cancer chemotherapy or other significant immunosuppression is recommended in Australia’s National Hepatitis B Testing Policy1 (14). Use of ‘biologics’ (drugs that modify the body’s immunological responses, such as rituximab, infliximab and adalimubab) is increasing in the setting of cancer therapy, rheumatology, dermatology and other specialist fields; thus, the primary care provider needs to be aware of the potential impact of CHB infection in diseases where immunosuppression is a treatment modality. Reactivation of CHB is also observed with other immuno-suppressant medications (e.g. steroids and methotrexate) and in the setting of organ transplantation. The short-term use of low-dose steroids in individuals without advanced liver disease is unlikely to cause significant reactivation of the virus.

Primary care providers should be aware of the need for this testing, especially for priority population groups (see Chapter 1) because not all specialist services routinely perform HBV testing for people undergoing immunosuppression (29).

There are two clinical scenarios to consider in the setting of planned immunosuppression after a full panel of HBV testing has been performed (see Chapter 3):

  • an HBsAg-positive individual (CHB)
  • an individual with resolved infection (anti-HBc positive +/– anti-HBs positive >10 mIU/mL) at risk of seroreversion and reactivation in the setting of profound immunosuppression.

The natural history of HBV infection is fundamentally related to the dynamic balance between viral replication and host immune response (see Chapter 4). It is therefore not surprising that immunosuppressive therapy (ongoing, or cyclical, as in the case of cancer chemotherapy) can have a marked impact on chronic HBV infection.

Significant immunosuppression is associated with a reactivation in viral replication and rising HBV DNA. Immunosuppression-associated HBV reactivation and flares have been observed in patients undergoing chemotherapy, organ transplantation, treatment for autoimmune diseases and glucocorticoid therapy. Glucocorticoid therapy both suppresses the host immunity and acts directly on the virus to enhance transcription.

Profound immunosuppression can also cause reactivation of HBV infection in patients with serologically resolved infection or seroreversion (HBsAg negative ⇒ positive in an anti-HBc-positive patient), because patients with this serological pattern have HBV DNA present in hepatocytes. This has particularly been noted in the setting of the treatment of haematological malignancies; for example, CHOP chemotherapy2 plus rituximab in the setting of lymphoma (14, 29).

Reactivation of HBV replication, in either scenario, can be followed by a flare of hepatitis with rising ALT levels. This is particularly noted following the withdrawal of immunosuppressive treatment, commonly over a period of weeks or months, although it can occur after a prolonged delay. The mechanism is similar to flares post pregnancy (see Chapter 10) or in IRIS seen with cART for HIV infection (see above), where the restoration of immune function leads to an increase in the destruction of HBV-infected hepatocytes.

Although many hepatitis flares in the context of immunosuppression are asymptomatic, a full spectrum of presentations is possible, through to liver failure and death. Risk factors for reactivation are shown in Table 11.1 (30). The rate of withdrawal of immunosuppression is an important determinant of the severity of flares. The increased incidence of flares observed in the setting of cancer chemotherapy compared with other immunosuppressive regimens may relate to the cyclical nature of such therapy, with repeated episodes of immune suppression and restoration.

Table 11.1 Risk factors for reactivation
Intensity of immunosuppression or chemotherapy regimen
Specific agents including glucocorticoids and biologics (e.g. rituximab, infliximab and adalimubab)
Longer duration chemotherapy
High baseline HBV DNA
HBeAg positive
Young age
Male gender
Cyclical therapy
Absence of anti-HBs in HBsAg negative anti-HBc positive

anti-HBc, antibodies to hepatitis B c antigen; anti-HBs, antibodies to hepatitis B surface antigen; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen

11.3.1 Management

Presumptive treatment with antiviral therapy has been shown to substantially reduce the incidence of hepatic flares and associated mortality. This prophylaxis should be given to all HBsAg-positive patients before chemotherapy or other immunosuppressive therapy (1, 14). Pre-emptive treatment has been shown to have better outcomes than starting treatment once reactivation has been detected (30).

The choice of antiviral agent depends on the baseline HBV DNA viral load, the intensity and duration of immuno-suppression, and the degree of baseline liver disease. Lamivudine may be considered for limited duration of less intense immunosuppression with little or no baseline HBV replication in a person without advanced fibrosis; otherwise, the treatments of choice are entecavir or tenofovir (see Chapter 7). PEG-IFN is not used in this context.

The approach to patients who are HBsAg negative and anti-HBc positive is less clear, with the risk of reactivation in the setting of profound immunosuppression (e.g. CHOP + rituximab) greater in those who are anti-HBs negative. Current guidelines suggest monitoring with HBV DNA to detect reactivation early (26), although a recent small randomised controlled trial suggested a role for prophylaxis with a significant reduction in reactivation at 0, 5 and 18 months (31).

Special situations of HBV infection, including co-infection and immunosuppression, are potentially associated with worse outcomes, and need coordinated primary and specialist care to prevent unnecessary morbidity and mortality. As patients living with CHB age and are treated with immunosuppressive therapy for cancers and other conditions, primary care needs to be involved in screening and detection of those at risk of reactivation.

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Nicole Allard, Joslin Clinic, Western Region Health Centre, Department of Medicine, University of Melbourne, and WHO Regional Reference Laboratory for Hepatitis B, Victorian Infectious Diseases Reference Laboratory (VIDRL), North Melbourne, VIC

& Benjamin Cowie, Department of Medicine, University of Melbourne, WHO Regional Reference Laboratory for Hepatitis B VIDRL, and Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, VIC

1. Available at http://testingportal.ashm.org.au/hbv

2. Chemotherapy that includes cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone