Standard screening tests may not detect hidden hepatitis B virus in HIV/HBV-coinfected patients

Study 1

In the first study, Norah Shire, MPH, and colleagues aimed to determine how often occult hepatitis B occurred amongst HIV-positive individuals seen at the University of Cincinnati Infectious Diseases Center in Ohio.

From a database of nearly 4,000 HIV-infected patients, the researchers randomly selected 909 without known HBV infection or non-viral liver disease for further analysis. Stored blood samples were pooled and a real-time polymerase chain reaction (PCR) assay was used to amplify HBV DNA. Samples with detectable HBV DNA were then tested for HBV serological markers using commercially available ELISA tests for anti-HBc, anti-HBs, and HBsAg.

The mean age of the patients was 35 years, 77% were men, and 50% were Caucasian. The mean CD4 cell count was 385 cells/mm³, 62% had detectable HIV viral load, and only 23% were taking antiretroviral regimens, about 60% of which included drugs with anti-HBV activity. About 14% had hepatitis C virus (HCV) infection.

Forty-three patients (4.7%) were found to be positive for HBV DNA. Twelve of these (1.3% of all patients) had occult hepatitis B with no detectable HBsAg. In this group, four tested positive for both HBV surface and core antibodies, two had detectable anti-HBc but not anti-HBs, and five were negative for all HBV blood markers.

Participants with detectable HBsAg had significantly higher HBV DNA titres than those with occult hepatitis B. HBsAg-positive patients also were more likely to have elevated liver enzymes (ALT and/or AST) compared with both occult hepatitis B patients and HIV-monoinfected individuals with undetectable HBV DNA.

Mean CD4 cell counts did not differ significantly among the groups, and the percentages having undetectable HIV viral load were also similar. None of the patients with detectable HBsAg had hepatitis C, compared with about 14% of both occult hepatitis B patients and HBV-negative individuals.

Importantly, none of the participants with occult hepatitis B were taking antiretroviral drugs with anti-HBV activity, such as 3TC (Epivir), emtricitabine (Emtriva), or tenofovir (Viread).

A significant proportion of HIV-positive individuals may have occult hepatitis B virus (HBV) infection that is not identified through standard screening tests, according to two studies published in the March 1^st issue of the Journal of Acquired Immune Deficiency Syndromes.

Occult, or hidden, hepatitis B infection refers to the presence of a low level of HBV genetic material (DNA) in the blood or the liver, without detectable hepatitis B surface antigen (HBsAg).

By contrast, patients with typical chronic hepatitis B have detectable HBsAg, as well as HBV surface and core antibodies (anti-HBs and anti-HBc, respectively). The presence of surface antibodies without surface antigen usually indicates that a person was exposed to HBV in the past but cleared the infection.

Because it is not detectable using standard antigen and antibody blood tests, estimates of the prevalence of occult hepatitis B vary widely.

Study 2

In the second study, Vincent Lo Re, MD, and colleagues conducted a study to determine the prevalence of and risk factors for occult hepatitis B amongst HIV-positive individuals, as well as its clinical significance.

The investigators analysed data from 179 HIV-infected patients with undetectable HBsAg but detectable HBV core antibodies, randomly chosen from a database of 699 study participants at University of Pennsylvania hospitals.

In this study, the mean age was 47 years, 88% were men, and 75% were African-American. One-quarter had CD4 cell counts below 200 cells/mm³ and 40% had HIV viral loads greater than 1,000 copies/mL. Three times as many patients were on antiretroviral regimens as compared with the previous study (73%), of which about 60% contained drugs with anti-HBV activity. About half of the participants (55%) had chronic hepatitis C.

In this group, 17 patients (10%) had detectable HBV DNA using a highly sensitive transcription-mediated amplification assay, signalling occult hepatitis B. Individuals with and without occult HBV were similar with regard to demographic characteristics.

HBV surface antibodies were present in similar proportions of patients with and without occult HBV infection (41% vs 58%, respectively). In a univariate analysis, patients with occult hepatitis B had lower CD4 cell counts, but this was no longer significant after controlling for other factors.

Individuals with HIV viral loads greater than 1,000 copies/mL were almost five times more likely to have occult hepatitis B (adjusted odds ratio [OR] 4.88), whilst those with chronic hepatitis C were less likely (adjusted OR 0.26). In this study, too, use of antiretroviral agents with anti-HBV activity reduced the risk of occult hepatitis B.

In terms of clinical symptoms, patients with occult hepatitis B were slightly less likely to have elevated liver enzymes compared with HBV-uninfected individuals, but this was strongly affected by HCV status. Individuals with occult HBV infection did not have a greater likelihood of significant fibrosis, as determined by the non-invasive AST-to-platelet ratio index (APRI).

The investigators concluded that occult HBV occurred in a “sizable proportion” of HIV-infected patients, adding that it was associated with detectable HIV viral load and the absence of chronic HCV infection.

Implications for patients

Collectively, these studies do little to resolve the uncertainty about the prevalence of occult hepatitis B amongst HIV-positive individuals. Past studies have also produced disparate results, with rates ranging from 0% to 89%, depending on the patient population and the definition of occult hepatitis B.

The recent studies did concur in finding that occult hepatitis B may present with various patterns of serological markers, and is not ruled out by the presence of HBV surface antibodies.

Shire and colleagues said that their results indicate a need for better screening for HBV in “high-risk” populations.

They also recommended that HIV-positive patients who have been vaccinated against HBV should receive regular testing to ensure continued adequate antibody levels.

However, the fact that occult hepatitis B can occur in individuals with no detectable serum markers for HBV and no clinical signs of hepatitis makes it difficult to identify hidden infection using widely available tests. Universal HBV DNA testing is impractical, but it may be useful for individuals with unexplained liver enzyme elevations, even if they have no serological evidence of HBV infection.

Given the lack of liver-related symptoms amongst patients in these studies, further research is needed to clarify the clinical implications of occult hepatitis B in HIV-positive individuals, such as whether it increases the long-term risk of liver cirrhosis or hepatocellular carcinoma. Until then, both studies support the recommendation that HIV/HBV-coinfected patients should include one or more agents with anti-HBV activity in their antiretroviral regimens.