Hepatitis B infection and myeloma in developing countries: therapeutic dilemmas

Hepatitis B virus (HBV) is a major public-health problem [1,2]. Fully 45% of the world's population live in an area where HBV is highly endemic (defined by the World Health Organization [WHO] as > 8% of the population being hepatitis B surface antigen [HBsAg]-positive), and 43% live in areas of intermediate endemicity (defined as 2–7% HBsAg-positive). Only 12% of the world's population live in areas of low endemicity (< 2% HBsAg-positive), including Western Europe and North America, where < 1% of the population are infected [1,2]. The lifetime risk of acquiring HBV infection in areas of high endemicity is over 60%, such that approximately 30% of the world's population, i.e. about 2 billion people, have serological evidence of infection with HBV, and an estimated 350 million of them have chronic HBV infection [1]. HBV is associated with hepatocellular carcinoma (HCC), with a 5–15-fold increased risk in chronic HBV carriers [3]. Worldwide, HCC is the fifth most common cancer and the third leading cause of cancer death worldwide, which is why HBV has been named by the WHO as second only to tobacco as a known human carcinogen [1]. There are multiple ways in which HBV is carcinogenic within the hepatocyte, involving a number of oncogenic viral proteins as well as integration of the viral genome into the host hepatocyte [3]. Epidemiologically, HBV has also been strongly associated with lymphomagenesis, which has been supported by a meta-analysis yielding a pooled odds ratio (OR) consistent with a significant association (OR 2.56; 95% confidence interval 2.24–2.92) [4]. A major conundrum in this association is the uncertainty of the mechanism, since HBV does not enter lymphoid cells. In this way it differs significantly from hepatitis C virus (HCV), which infects and replicates in peripheral blood mononuclear cells [5] and whose relationship to lymphoid maligncies is better documented [6]. For HBV, indirect mechanisms of lymphomagenesis, such as chronic antigenic stimulation, have been hypothesized to be responsible [6].

In the current issue of Leukemia and Lymphoma, Huang et al. [7] report a case–control study showing a high rate of prevalence of HBV infection in Chinese patients with myeloma, which, in this study, was not found in patients with acute myeloid leukemia (AML) in the same population. Hepatitis B is endemic in China and other parts of Asia. In these regions, 8–10% of the adult population are chronically infected. Whether or not HBV infection is causally related to myeloma is a matter of controversy, with conflicting results in various studies, most of which do not show an association [6]. As with lymphomas, the mechanism of “myelomagenesis” is unclear. Of perhaps more importance is the issue of the incidence of complications of HBV infection during and after therapy for myeloma. In Huang's study, evidence of hepatic damage was present in 22.4% of patients prior to therapy and 67.2% following therapy, and was significantly higher for HBV carriers [7]. In this study, treatment consisted of one or more cycles of chemotherapy, containing significant doses of dexamethasone. Liver function abnormalities developed within < 3 cycles for around 70% of the patients and later than the third cycle in the remainder. Current standard medical practice for patients with hematological malignancies who are going to receive chemotherapy recommends testing for HBV exposure, even in the absence of a history of jaundice [8]. Anti-HBVc immunoglobulin G (IgG) is the most sensitive test for this exposure, since this antibody indicates that the patient has been exposed to the virus at some time in the past. While some patients who have been exposed will fail to clear the virus from the blood and will remain HBsAg +, there are patients who may have so-called “occult” infection who are HBsAg negative. Patients who are known to have active HBV, in particular those with abnormal liver function tests, obviously should receive antiviral therapy concurrent with chemotherapy. Even if the HBsAg is negative, if anti-HBVc IgG is positive, the patient should be treated pre-emptively with an antiviral agent to prevent reactivation of HBV [8]. All patients previously infected with HBV are at risk for reactivation following chemotherapy, in particular when receiving protocols containing steroids. The HBV virus contains a glucocorticoid responsive element that facilitates replication, thus amplifying the viral load. Steroid cessation may also induce an HBV flare, particularly upon abrupt withdrawal of treatment. Thus HBV reactivation is a common sequela of chemotherapy, occurring in 21–53% of HBsAg carriers [9]. If left undetected, HBV reactivation may lead to fulminant hepatitis, which carries a grave prognosis despite therapy [8]. Furthermore, even if full recovery is achieved, reactivation may reduce survival because it may require interruption of chemotherapy. Details of risk factors and specific therapies that are associated with reactivation in patients with hematological malignancies have been published [8].

In Huang's study, HBV positivity was defined as HBsAg positivity, which may have identified only some of the patients at risk. Of the 58 HBsAg positive patients, 14 (24%) received effective antiviral therapy. It is not surprising that patients with HBsAg positivity had significantly poorer survival than HBsAg negative patients, since they had, both prior to and following therapy, more abnormalities of liver function [7]. This raises the therapeutic dilemma of the hematologist treating myeloma in a HBV exposed individual: administration of effective anti-myeloma therapy in countries without antiviral therapy due to limited resources may result in serious adverse effects. It is ironic that in Huang's study, patients received costly drugs such as bortezomib and even underwent autologous bone marrow transplant, whereas 75% of the HBsAg positive patients were unable to receive antiviral therapy due to financial constraints [7]. Myeloma is significantly less common in Asia than in the Americas and Europe, although during the past 25 years an almost four-fold incidence of myeloma has occurred in Taiwan (a country inhabited almost exclusively by Chinese) [10]. Public-health programs as well as hematologists–oncologists working in the Far East will have to grapple with the issues raised by these statistics. A vaccine against hepatitis B has been available since 1982. The WHO recommends that all infants should be vaccinated in regions where mother-to-infant spread of HBV is common, that is, in highly endemic areas, and also recommends that children under age 18 be vaccinated [1,2]. Vaccination has proven highly efficacious, but there are social and economic barriers to its implementation [11]. Furthermore, vaccination efforts are aimed at children, and it will take decades until HBV carriership diminishes in the adult population of a given country. In the meantime, in many parts of the world, treating myeloma will raise many problematic therapeutic dilemmas regarding the risks of reactivation of HBV during and following therapy.

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