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 alone,^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 one of the most common causes 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.

A case control study described a higher rate of hepatocellular carcinoma in patients with HIV-HBV co-infection who had a CD4+ T cell counts of < 500/uL, although this was not correlated with the presence of cirrhosis (Clifford et.al. AIDS 2008; 22:2135). Some authorities therefore recommend HCC screening in this setting in addition to other indications for HCC screening, such as cirrhosis.

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 drugs have been associated with abnormal liver function tests, ritonavir, nevirapine and tipranavir^25,26 are especially implicated in severe hepatotoxicity^22,23 and thus should be used cautiously in the patient with HIV-HBV co-infection. Most modern ART regimens, however, use integrase inhibitors where this risk seems to be much lower. 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, known as hepatitis 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 Hepatitis 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 corticosteroid therapy 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 HCC 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