HBV DOUBLES LYMPHOMA RISK

August 11, 2010 — Patients with hepatitis B (HBV) infection are twice as likely to develop diffuse large B-cell lymphoma or some other subtype of non-Hodgkin's lymphoma (NHL), and over 3 times more likely to develop malignant immunoproliferation than those who are negative for hepatitis B surface antigen (HBsAg).

These are the conclusions of a study published online August 4 in the Lancet Oncology by Eric Engels, MD, from the National Cancer Institute, in Rockville, Maryland, Sun Ha Jee, PhD, from the Graduate School of Public Health, Yonsei University, in Seoul, South Korea, and colleagues.

Dr. Jee told Medscape Medical News that "the most important finding was the increased risk of non-Hodgkin's lymphoma, particularly diffuse large B-cell lymphoma, which is among the most common subtypes of lymphoma. This increased risk was almost double the risk seen in uninfected people and was present over a period ranging up to 14 years."

The researchers used data from the Korean Cancer Prevention Study to determine whether chronic HBV infection was associated with the subsequent development of NHL in 603,585 people.

HBV infection was endemic in South Korea until 1995, when the universal HBV vaccination of neonates was implemented. Before that, about 7% of South Korean adults had detectable plasma concentrations of HBsAg, which is an indication of chronic HBV infection. HBV infection remains common in South Korean adults because of infections acquired in childhood, before the vaccine was available.

The analysis showed that 53,045 study subjects (9%) were positive for HBsAg at baseline. NHL developed subsequently in 133 people who were hepatitis B positive and in 905 who were hepatitis B negative. The NHL incidence was 19.4 per 100 000 person-years in the positive group, and 12.3 per 100 000 person-years in the negative group (hazard ratio [HR], 1·74; 95% confidence interval [CI]. 1.45 - 2.09, adjusted for sex, age at baseline, and enrolment year). NHL risk was consistently higher in the positive group during the 14 years of follow-up.

The researchers also examined the risk for various NHL subtypes. They found an increased risk for diffuse large B-cell lymphoma (HR, 2.01) and for other or unknown subtypes (HR, 1.65).

They also found a nearly 4-fold increased risk for malignant immunoproliferation, a constellation of immune disorders related to NHL (HR, 3.79).

Hepatitis B positivity was not associated with follicular or T-cell NHL, Hodgkin's lymphoma, multiple myeloma, or various leukemias.

Several studies have already established a causal link between hepatitis C (HCV) infection and increased risk for NHL, but studies on hepatitis B and NHL have so far been small. The link to NHL for both HBV and HCV is thought to involve chronic immune stimulation in the setting of sustained liver infection. Sustained immune activation can lead lymphocytes to develop DNA mutations that promote their proliferation and progression to NHL.

Association Does Not Prove HBV Causes NHL

Dr. Jee emphasized that association is not causality.

"Additional case–control and cohort studies are needed to replicate our findings in other populations and to evaluate further whether other lymphoma subtypes are associated with hepatitis B infection. It is also important to determine whether hepatitis B treatment reduces the risk of developing non-Hodgkin's lymphoma, and to determine whether treatment for hepatitis B can lead to remission of lymphoma in the people who have already developed the cancer," he said.

The authors note that "for HCV-infected patients with low-grade NHL (especially marginal zone lymphomas), HCV treatment seems effective for hematological remission. Thus, we speculate that treatment directed at HBV in similar low-grade NHL might lead to a clinical response and remove the need for chemotherapy."

Implications for Treating NHL Patients

This study has immediate clinical implications, however.

"In countries such as South Korea, where hepatitis B virus infection is common, physicians should routinely screen patients with non-Hodgkin's lymphoma and other hematologic malignancies for this infection, because chemotherapy can lead to severe liver damage in the absence of specific prophylaxis," Dr. Jee said.

In an accompanying editorial, Sook-Hyang Jeong, MD, from Seoul National University in South Korea, warned against assuming that HBV vaccination will prevent NHL.

"Although the study had some limitations, such as absence of HCV and HIV data and lack of information about replication status of HBV or severity of liver disease, it presented reliable evidence for an important role of HBV infection in lymphomagenesis. If the association is causal, might the globally increasing implementation of universal HBV vaccination and increasing use of antiviral drugs for treatment of chronic HBV-related liver disease reduce development of NHL? Engels and colleagues commented that the causal association is small in magnitude, and that HBV infection would account for only a few NHL cases. Thus, those efforts would be expected to have a limited effect on NHL incidence," Dr. Jeong writes.

Dr. Jeong also points out that although there is some evidence suggesting that antiviral therapy for HCV in low-grade NHL might have produced hematological remission, "similar results from antiviral therapy for HBV have not been reported." Dr. Jeong said that "[lymphomagenesis] mechanisms involving HBV seem to differ from those involving HCV."

Dr. Jee and Dr. Jeong have disclosed no relevant financial relationships.

Lancet Oncol. Published online August 4, 2010. Abstract, Abstract