Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV

INTRODUCTION — The worldwide epidemics of hepatitis B and HIV have revealed complicated interactions between these two viruses. Coinfection with HIV has a major impact on the natural history, diagnosis, progression, and morbidity and mortality related to hepatitis B virus (HBV) infection.

The epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients with HIV will be reviewed here. Treatment and prevention as well as issues related to hepatitis C and HIV coinfection are discussed separately. (See "Treatment of chronic hepatitis B in patients with HIV" and "Prevention of hepatitis B virus infection in adults with HIV" and "Treatment of chronic hepatitis C virus infection in the patient with HIV".)

EPIDEMIOLOGY — Hepatitis B virus (HBV) and HIV are often diagnosed in the same patient because they share similar routes of transmission. Chronic HBV affects approximately 8 percent of patients with HIV worldwide [1,2]. However, the rates of HIV/HBV coinfection vary according to geographic region and are highest in sub-Saharan Africa and Asia, where most transmission occurs perinatally and horizontally. In developed countries, laboratory markers of prior HBV infection are more common in men who have sex with men (MSM) and injection drug users [2-4].

DIAGNOSIS OF CHRONIC HBV INFECTION — Patients with HIV should have routine testing for hepatitis B virus (HBV) infection with hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs) [5,6]. A detailed discussion on the diagnosis of HBV infection is found elsewhere and is summarized below. (See "Hepatitis B virus: Screening and diagnosis in adults".)

●Hepatitis B surface antigen – HBsAg is the serologic hallmark of HBV infection and appears in serum 1 to 10 weeks after acute exposure to HBV (figure 1 and table 1). This is followed by detection of IgM and then IgG anti-HBc. Most adult patients clear HBsAg and develop anti-HBs consistent with resolved infection. Persistence of HBsAg for more than six months implies chronic infection, which is associated with the presence of viremia as measured by HBV DNA. Patients with the presence of HBsAg require further laboratory evaluation as described below. (See "Hepatitis B virus: Screening and diagnosis in adults".)

●Hepatitis B e antigen – Hepatitis B e antigen (HBeAg) is a marker of HBV replication and infectivity [7]. The presence of HBeAg is usually associated with high levels of HBV DNA in serum and active liver disease. Seroconversion from HBeAg to anti-HBe is usually associated with declines in serum HBV DNA and remission of liver disease. However, some patients continue to have active liver disease and high levels of HBV DNA in serum after loss of HBeAg (HBeAg-negative chronic hepatitis). The latter patients may have HBV variants that abolish or decrease the production of detectable HBeAg in serum. Thus, it is important for all patients who are HBsAg positive to have testing of HBV DNA regardless of HBeAg status.

●Aminotransferase levels – The alanine aminotransferase (ALT) level is associated with the degree of inflammatory activity and liver injury. Higher levels of aminotransferases tend to be associated with more active liver disease and thus are influential in determining the benefits/risks of treatment [7,8].

●Hepatitis B DNA – Higher HBV DNA levels are associated with increased risk for progression to cirrhosis and hepatocellular carcinoma [9,10]. Thus, HBV DNA is also used when considering treatment.

●Hepatitis D serology – Hepatitis D virus (HDV) is a defective virus that requires HBV to coexist [11]. Patients with HIV and chronic hepatitis B infection should have an assay for anti-HDV at the initial visit or in the context of severe hepatic flares [6]. Those who are anti-HDV positive should be tested for HDV RNA. In chronic HDV infection, markers of HBV replication are usually absent, and the patient is typically HBeAg negative and anti-HBe positive. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection".)

ISOLATED ANTI-HB CORE ANTIBODY — Past exposure to hepatitis B virus (HBV) is suggested by the presence of hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs). However, less than 2 percent of blood donors have anti-HBc in the absence of hepatitis B surface antigen (HBsAg) and anti-HBs. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Isolated anti-HBc'.)

Isolated detection of anti-HBc can occur in three settings:

●During the window period of acute hepatitis B when the anti-HBc is predominantly IgM class

●Many years after recovery from acute hepatitis B when anti-HBs has fallen to undetectable levels

●In the setting of low-level HBV replication with production of small amounts of HBsAg that is cleared by anti-HBs. Immune escape mutants can rarely hamper detection of HBsAg [12]. This condition is also referred to as occult hepatitis B. (See 'Occult HBV' below.)

The clinical significance of this serologic pattern is unclear. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Isolated anti-HBc'.)

Isolated anti-HBc is more common in patients with underlying HIV infection than in the general population [13-15]. However, patients with HIV who are receiving antiretroviral therapy (ART) are less likely to have isolated anti-HBc than those not on ART [15]. By contrast, isolated anti-HBc is more likely to be seen in patients with HIV who are also coinfected with hepatitis C virus (HCV) [14-16]. In a study of 651 patients with HIV who were screened for the presence of anti-HBs and HBsAg, the following results were noted [14,17]:

●Of the 387 subjects who tested negative for both HBsAg and anti-HBs, 142 patients underwent further serologic testing. Sixty (42 percent) had evidence of isolated anti-HBc.

●Among these 60 patients, those coinfected with HCV were much more likely to have isolated anti-HBc than those without HCV (80 versus 16 percent, respectively

The evolution of HBV serologic markers over time has also been evaluated:

●During a five-year period serologic markers for hepatitis B were evaluated in a study of 633 patients with HIV in Taiwan, where the prevalence of HCV coinfection is low [18]. During follow-up, changes in HBV serological markers were demonstrated in one-quarter of the patients. Among the 179 patients with isolated anti-HBc at baseline, 45 percent had persistence of this profile, 41 percent acquired anti-HBs, 10 percent lost anti-HBc, and 4 percent developed HBsAg. Those patients who gained anti-HBs had a significantly greater CD4 T-cell gain in response to ART than those who had persistence of an isolated anti-HBc pattern (223 versus 83 cells/microL after 24 months of ART).

●A subsequent study that evaluated 282 patients with HIV and 40 patients without HIV over a median of 7.5 years found that 71 percent retained an isolated anti-HBc status, 20 percent acquired antibody to hepatitis B surface antigen, and 2 percent acquired hepatitis B surface antigen [19]. In a multivariate analysis, use of potent ART was a significant predictor of anti-HBs acquisition, whereas women with hepatitis C viremia were more likely to retain their isolated anti-HBc status.

The utility of hepatitis B vaccination in patients with isolated core antibody has been studied, and data support that individuals with isolated anti-HBc should be vaccinated against HBV. A more detailed discussion of HBV vaccination in persons living with HIV is found elsewhere. (See "Prevention of hepatitis B virus infection in adults with HIV".)

Occult HBV — Occult HBV infection is defined by the presence of HBV DNA in the serum or liver of individuals with negative test results for HBsAg, but usually anti-HBc (isolated anti-HBc). The mechanisms leading to occult infection are unknown, but may include escape of immune recognition of changes in the S protein, methylation or disruption of key regulatory regions in the HBV genome, or modification of posttranslational mechanisms [20,21].

The clinical impact of occult HBV is unclear, but flares of aminotransferases, advanced fibrosis, and hepatocellular carcinoma have been associated. These patients may also be more likely than persons with anti-HBs to have a flare of HBV when receiving immunosuppressive medication. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'HBsAg-negative'.)

Among patients with isolated anti-HBc, there are conflicting data on the prevalence of occult HBV viremia. Some studies have found a less than 2 percent prevalence of HBV viremia [13,17]. By contrast, in a report in which HBV DNA was sampled repeatedly over time, viremia was detected in 51 of 57 patients in at least one specimen over a mean of 31 months [22]. These disparate findings may be explained in part by transient viremia that is best captured with serial examinations and by variable sensitivity of the HBV DNA assays used in the reported studies. Occult HBV has also been uncommonly described in patients with HIV who are without any serologic markers of HBV infection [23].

PATHOGENESIS

Immunologic factors — The pathogenesis of hepatitis due to hepatitis B virus (HBV) is mainly immune-mediated and not due to cytopathic effects of the virus. Patients who spontaneously recover from HBV infection mount vigorous CD4+ and CD8+ T-cell responses to various HBV epitopes [24,25]. By contrast, patients who develop chronic hepatitis B infection have narrowly focused T-cell responses.

Although recovery from acute hepatitis B is associated with lifelong protective immunity, trace amounts of virus can be detected with sensitive techniques such as polymerase chain reaction. This suggests that residual virus is controlled by cellular and humoral immune responses and that viremia can re-emerge in the setting of immunosuppression. As an example, patients receiving immunosuppressive therapy (eg, chemotherapy or corticosteroids), as well as those with HIV and advanced immunosuppression, can experience reactivation of HBV replication and hepatitis flares [26,27]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Spontaneous serum aminotransferase flares during chronic HBV infection have been attributed to changes in the balance between immunologic responses to HBV and quantitative variations in viremia [28]. As mentioned above, hepatitis is due to immune-mediated mechanisms not direct viral injury. HBV-specific T-cell responses have been detected in peripheral blood preceding HBeAg seroconversion that accompanies the flare.

The factors that spontaneously increase T-cell responses are not well understood. T-cell responses can increase in response to a reduction in HBV DNA induced by HBV antiviral therapy [29].

Virologic factors — Observations of increased HBV replication and lower rates of HBeAg seroconversion in patients with HIV/HBV coinfection, compared to patients with HBV alone, suggest that virologic factors may also contribute to pathogenesis [4].

A novel -1G deletion in the HBV precore and core genes of six HIV/HBV-coinfected patients and three HBV monoinfected patients was identified [30]. This mutation introduced a frameshift that terminated the coding sequence of the HBV core and precore genes; however, HBeAg was still detected due to the continued presence of wild-type virus as a minority member of the quasispecies. The following observations suggest that the -1G deletion may alter disease pathogenesis:

●All patients had high HBV DNA levels that may be related to changes in virulence and replication capacity.

●The protein is truncated at the site of a major CD4 T-cell epitope of the HBV nucleocapsid antigen [31].

HIV AND NATURAL HISTORY OF HBV INFECTION — HIV-related immunosuppression affects the natural history of hepatitis B virus (HBV) infection. Epidemiologic studies suggest the following [4,32-39]:

●HBV DNA levels and reactivation rates are higher in patients with HIV than in subjects with HBV alone; the risk of reactivation may be associated with low CD4 cell counts.

●Reappearance of hepatitis B surface antigen (HBsAg) and HBV viremia has been documented in patients coinfected with HIV and HBV who had serologic markers consistent with resolved HBV infection.

●Patients with HIV have lower rates of spontaneous clearance of HBeAg.

The predisposition of patients with HIV to develop chronic infection after exposure to HBV infection was well illustrated in a hepatitis B vaccine study that includes patients with and without HIV who were not previously infected with HBV [40]. Chronic HBV infection developed in 21 percent of patients with HIV compared with 7 percent of those with HBV alone. This difference could not be explained entirely by more frequent acute HBV infection in the patients with HIV.

In a United States Department of Defense study that evaluated participants with HIV from 1989 to 2008, 20.4 percent of the incident HBV infections became chronic, but the rate of chronicity was higher in the period prior to the introduction of effective antiretroviral therapy (ART) compared with the period after the widespread use of potent ART (1.2 per 100 person-years versus 0.12 per 100 person-years, P <0.001) [41]. In this study, the effect of anti-HBV-specific ART on chronicity was not determined. A subsequent study did evaluate the impact of anti-HBV specific ART and found the proportion of patients with HIV who developed chronic HBV while receiving HBV-active ART at the time of infection was similar to those without HIV (7.7 versus 8.2 percent, respectively); however, among persons with HIV who were not on HBV-active ART, there was a higher proportion who developed chronic HBV (17.5 percent) [42].

The risk of reactivation in the setting of HIV disease was assessed in a retrospective study of 141 HBV-infected patients, 69 of whom had HIV infection [36]. HBeAg seroconversion rates were not affected by the presence of HIV infection. However, among 47 patients who did experience HBeAg seroconversion, reactivation (loss of anti-HBe with reappearance of HBeAg) occurred in eight subjects within two years of follow-up and was significantly associated with HIV infection (5 of 14 HIV-seropositive patients compared with 3 of 33 HIV-seronegative patients).

HIV AND LIVER DISEASE PROGRESSION — Several observational studies from the United States and Europe suggest that patients coinfected with HIV and HBV may have faster rates of fibrosis progression and an increased risk of cirrhosis, end-stage liver disease (ESLD), and hepatocellular carcinoma (HCC) than patients with HBV infection alone [32,36,43-45]. HCC also occurs at an earlier age among patients with HIV compared with patients without HIV [46].

Accumulating data support that HIV antiretroviral therapy (ART) improves liver disease. In a longitudinal study from Nigeria, transient elastography (TE) was used to assess fibrosis in 71 individuals coinfected with HIV and HBV who were started on ART [47]. Regression of ≥1 METAVIR stage occurred in 41 percent after three years of ART and was associated with a baseline CD4 cell count ≥200 cells/microL. Similarly, a cohort study that included 61 patients with HIV and HBV from Zambia found that after one year of ART, there was a significant reduction (based upon TE) in both the proportion of patients with significant fibrosis (45.9 to 21.3 percent) and the proportion with cirrhosis (8.2 to 1.6 percent) [48].

HBV-active ART also decreases the risk for HCC [9,49,50]. In a study of four European cohorts, which included 3625 HIV/HBV-coinfected patients, 72 percent were on a tenofovir-containing ART regimen or were receiving entecavir, and HCC developed in 60 (1.7 percent) with an overall incidence rate of 1.84 per 1000 person-years [51]. The incidence rate was stable in those on tenofovir or entecavir but increased steadily in those not on either drug. In a North American multicohort study of 8354 people with HIV and chronic HBV, the incidence of HCC was 1.8 per 1000 person-years and was significantly reduced with HBV DNA suppression for ≥1 year (adjusted hazard ratio 0.42, 95% CI 0.24-0.73) [52].

There are conflicting data as to whether or not HIV affects the necroinflammatory changes on histopathology [37,53]. Some studies have demonstrated less necroinflammatory changes in patients with concomitant HIV infection, while others have not [35,54,55]. These different findings may be related in part to differences in CD4 counts. Strong epidemiologic data suggest that end-stage liver disease is an important cause of death among patients with coinfection. (See 'Effect of HIV on liver-related mortality' below.)

Hepatitis D virus (HDV) infection may also contribute to faster progression rates in HIV/HBV-coinfected patients. In a case control study of 104 patients in Taiwan with HIV/HBV, 26 of whom also had HDV infection, patients with triple infection had higher rates of hepatitis flares, cirrhosis, hepatic decompensation and death over the eight year period of observation [56]. Treatment of HBV with nucleoside analogs does not reduce the risk of HDV-associated liver injury. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection".)

EFFECT OF HIV ON LIVER-RELATED MORTALITY — HIV/HBV-coinfected patients have an increased risk of liver-related mortality [32,36,43,44]. The magnitude of this effect was evaluated in a cohort of 5293 men who have sex with men (MSM) in which the following findings were noted [43]:

●Liver-related mortality rates were higher in men with HIV and hepatitis B surface antigen (HBsAg) compared with those with only HBsAg (14.2/1000 compared with 0.8/1000).

●In coinfected individuals, the liver-related mortality rate was highest among those with lower nadir CD4 T-cell counts, a finding that has been seen in other studies [36].

●The liver-related mortality rates doubled after the introduction of antiretroviral therapy (ART; 12.3 to 24.7 per 1000 person years). This effect may be related to decreased AIDS-related mortality on ART, which may have unmasked underlying liver-related disease.

EFFECT OF HBV ON HIV PROGRESSION — There remains controversy about whether chronic hepatitis B affects the natural history of HIV.

On one hand, some observations raised concern that hepatitis B virus (HBV) infection was associated with a more accelerated course of HIV progression [57-61]. As an example, one study of 1302 patients with HIV and 262 HIV/HBV-coinfected patients in Nigeria found that high levels of HBV replication were associated with lower CD4 cell counts at the time antiretroviral therapy (ART) was initiated [60]. Another observational study examined 2352 HIV seroconverters including 474 (20 percent) with resolved HBV, 82 (3 percent) with isolated core antibody, and 64 (3 percent) with chronic HBV [61]. This retrospective analysis demonstrated that the risk of AIDS or death was almost twofold higher among those with chronic hepatitis B compared with HIV-monoinfected patients.

However, two longitudinal studies and one retrospective study did not show any impact of HBV coinfection on CD4 depletion, progression to AIDS or AIDS-related mortality [62-64]. Another retrospective study from the Multicenter AIDS Cohort Study found that HBV status did not influence viral suppression or immunologic recovery among those with chronic HBV infection who initiated ART [65].

EFFECT OF HBV ON ALL CAUSE MORTALITY — A meta-analysis performed on data from 12,382 patients with HIV enrolled in 11 studies revealed a significant effect of HIV/HBV coinfection on overall mortality (pooled effect estimate, 1.36; 95% CI 1.12-1.64) [64]. In another study of 2536 individuals with HIV who initiated potent antiretroviral therapy, both chronic and resolved hepatitis B infection were associated with a significantly increased risk for AIDS or death [66].

HBV AND IMMUNE RECONSTITUTION — The terms "immune reconstitution" or "immune reconstitution inflammatory syndrome" (IRIS) describe a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of potent antiretroviral therapy (ART) in individuals with HIV. In patients with HIV/HBV coinfection, interpretation of IRIS is complicated by the concurrent treatment of HBV infection (by using HBV-active ART) and the potential for ART-related direct hepatotoxicity. (See 'HBV and risk of drug-induced hepatotoxicity' below.)

Since HBV is an immunologically mediated disease, immune reconstitution with ART can alter the balance between host-viral interactions and modify the natural history of hepatitis B. Although this shift may temporarily exacerbate liver inflammation, and even cause liver failure, the long-term net effect of treating both infections is positive.

In a prospective study of 36 treatment-naive patients initiating ART, baseline HBV DNA and alanine aminotransferase (ALT) levels were significantly higher in the eight patients who developed hepatic flare (defined as ALT >5 times the upper limit of normal or >200 from baseline) than in those who did not [67]. In a retrospective study of 394 patients initiating ART, 10 of 28 subjects who were coinfected with hepatitis B lost HBeAg in association with a transient hepatitis flare [68]. Immune reconstitution in this scenario is associated with marked clinical benefit since loss of HBeAg is usually associated with declining viremia. HBV seroconversion has occurred after profound improvement in immune responses secondary to ART, even in the absence of effective HBV therapy [69].

CD8+ T-cell responses to HBV antigens that might produce such a change were evaluated in a study of HIV seropositive and HIV-seronegative patients who had markers of resolved HBV infection [70]. HIV infection was associated with a reduction in HBV-specific T-cell responses. The initiation of ART led to restoration of some functionally active T-cell responses. Furthermore, in patients who receive ART containing an agent with activity against HBV, T-cell responsiveness has been associated with reductions in HBV viremia [71].

The improvement in HBV-specific T-cell responses may involve two distinct processes: the reconstitution of responses associated with a reduction in HBV viremia; and the slow restoration of the immune system that occurs with suppression of HIV replication [70]. These in vitro observations may be the underpinning for clinical cases of HBV-related flares of aminotransferases and reactivation syndromes seen after the initiation of ART.

Immune reconstitution in patients with HIV and chronic hepatitis B can lead to liver-related morbidity and mortality. Hepatitis flares secondary to immunologic recovery of HBV-specific T-cells can be life threatening in the patient with little hepatic reserve [72]. The approach to patients who develop IRIS is discussed elsewhere. (See "Monitoring the patient with HIV and chronic hepatitis B virus infection", section on 'Immune reconstitution inflammatory syndrome'.)

HBV AND RISK OF DRUG-INDUCED HEPATOTOXICITY — Both chronic hepatitis C and hepatitis B have been associated with an increased risk of drug-induced liver injury to older antiretroviral therapy (ART) agents [73,74]. The mechanism for the association between chronic viral hepatitis and risk of hepatotoxicity in patients with HIV is unknown.

Drug-induced liver injury in association with chronic viral hepatitis may be related to advanced liver disease and its known association with decreased cytochrome P450 activity, which may lead to increased exposure to protease inhibitors [75]. Even modest declines of cytochrome P450 activity may be important in the face of potent inhibitors, like ritonavir. However, some episodes of elevated aminotransferases may be related to underlying hepatitis B virus (HBV) infection (eg, immune reconstitution syndrome, withdrawal of HBV active ART, breakthrough infection, HBeAg to anti-HBe seroconversion).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV" and "Society guideline links: Diagnosis of hepatitis B".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Hepatitis B virus (HBV) and HIV infections are often diagnosed in the same patient because they share similar routes of transmission. Chronic HBV affects approximately 8 percent of patients with HIV worldwide (See 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of hepatitis due to HBV is mainly immune mediated and not due to cytopathic effects of the virus. Observations of increased HBV replication and lower rates of HBeAg seroconversion in patients with HIV/HBV coinfection, compared with patients with HBV alone, suggest that virologic factors related to HBV may also contribute to pathogenesis. (See 'Pathogenesis' above.)

●Screening and Diagnosis – Patients with HIV should have routine testing for HBV infection including hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs). The diagnosis of chronic hepatitis B in patients with HIV is the same as in patients without HIV. Persistence of HBsAg for more than six months implies chronic infection, which is associated with the presence of viremia, as measured by HBV DNA. (See 'Diagnosis of chronic HBV infection' above.)

●HBV-related outcomes – HIV/HBV-coinfected patients have lower rates of spontaneous HBsAg clearance and higher rates of reactivation. In addition, HIV/HBV-coinfected patients have an increased risk of liver-related mortality compared with patients with HBV infection alone. However, HBV-active ART improves liver disease and decreases the risk for HCC. (See 'Effect of HIV on liver-related mortality' above and 'HIV and natural history of HBV infection' above and 'HIV and liver disease progression' above.)

●Effect of HBV on HIV – There remains controversy about whether chronic hepatitis B affects the natural history of HIV infection. (See 'Effect of HBV on HIV progression' above.)

●Immune reconstitution syndromes – Since HBV is an immunologically mediated disease, immune reconstitution with ART can alter the balance between host-viral interactions and modify the natural history of hepatitis B. Although this shift may temporarily exacerbate liver inflammation, and even cause liver failure, the long-term net effect of treating both infections is positive. In some patients, immune recovery can lead to spontaneous HBsAg clearance. (See 'HBV and immune reconstitution' above.)