Preventing Infection-Associated Cancer: From Bench to Hillside
Authors: J. J. Goedert
Journal: JNCI Journal of the National Cancer Institute (2005)

Identifying, characterizing, and interrupting the primary cause of a disease is far more effective than diagnosing and treating the disease itself. As the saying goes, “ An ounce of prevention is worth a pound of cure. ” Together, laboratory and epidemiologic research efforts have identifi ed several viruses and one bacterium as human carcinogens. Research on hepatitis B virus (HBV) and its association with hepatocellular carcinoma (HCC) exemplifi es the historical accomplishments, current progress, and challenges remaining for cancer prevention once the cause is known. In 1965, Blumberg et al. ( 1 ) reported the initial detection of the “ Australia antigen, ” which was found in serum from an Australian aborigine and is now known as hepatitis B virus surface antigen (HBsAg). During the 1970s, chronic carriage of HBsAg was closely tied to HBV infection during infancy ( 2 ) , and HBsAg was detected in a large fraction of patients with HCC ( 3 ) . In seminal studies, Beasley and colleagues ( 4 ) found that HCC mortality was 223-fold higher for Taiwanese men who were HBsAgseropositive than for those who were HBsAg-seronegative and that perinatal transmission of HBV could be prevented by administering hepatitis B immune globulin to neonates and an HBV vaccine to infants ( 5 ) . These fi ndings motivated the initiation of Taiwan’s population-wide HBV screening and vaccination program ( 6 ) . During the fi rst 20 years of this ongoing program, there have been marked reductions in chronic carriage of HBsAg, HCC incidence, and liver cancer mortality among children in Taiwan ( 7 , 8 ) . Comparisons of the similarities and differences between HBV and another virus that acts as a human carcinogen, human immunodefi ciency virus (HIV), elucidate pathogenic mechanisms and potential control measures. For example, the level of viral DNA in the blood, also known as virus load, refl ects the rate of viral replication as well as the inadequacy of the host immune response to the infection. HIV load is the major determinant of progression to acquired immunodefi ciency syndrome (AIDS), and the parallel may be true for HBV load and progression to HCC. Although the hepatitis B “ e ” antigen (HBeAg) is the classical measure of HBV load in blood and a strong indicator of HCC risk ( 9 ) , quantifi cation of HBV DNA in serum is more sensitive, specifi c, and precise. In this issue of the Journal, Yu et al. ( 10 ) report the results of a prospective study of HCC diagnosed during a median followup of 6.7 years in a cohort of HBsAg-seropositive Taiwanese men aged 30 years or older. The authors found that compared with men whose baseline plasma HBV load was low or undetectable, men who had a plasma HBV load of 10 4.2 – 5.9 copies/ mL (15 000 to 800 000 copies/mL) had a twofold higher risk of HCC and men who had a very high HBV load (i.e., more than 10 5.9 copies/mL) had a sevenfold higher risk of HCC. HBV load was positively associated with HCC risk among men who were HBeAg-negative. This was not true among men who were HBeAg-positive, but no comparison group could be defi ned for those with HBeAg positivity because they all had a high or very high HBV load ( 10 ) . In addition to perinatal acquisition of infection and virus load for those with chronic infection, heterogeneity within the viral genome may affect the likelihood that HBV infection will lead to cirrhosis, end-stage liver disease, or HCC. For example, some HBV genotypes, which differ from one another by at least 8% across the viral genome, appear to be associated with differences in the risk of liver disease. Chu et al. ( 11 ) found all eight HBV genotypes (A through H) among patients at 17 tertiary referral centers in the United States, with a preponderance of type A (35%), type B (22%), type C (31%), and type D (10%). HBV genotypes B and C were highly prevalent among patients who were born in Asia (prevalences of 38% and 51%, respectively) ( 11 ) . Patients infected with HBV genotype B appeared to have less hepatic disease than those infected with other HBV genotypes, but confounding by birth in Asia (refl ecting the high likelihood that HBV infection had been acquired perinatally) and by other risk factors was not evaluated ( 11 ) . In East Asia, HBeAg positivity, severe hepatic infl ammation and fi brosis, and HCC are more frequently associated with HBV genotype C than HBV genotype B ( 12 ) . Yu et al. ( 10 ) now provide strong evidence that HBV genotypes matter: their prospective data revealed that the risk of HCC was increased approximately fi vefold among men infected with HBV genotype C compared with other genotypes (almost all type B). HBV load was higher with HBV genotype C than with HBV genotype B, and the risk of HCC was additive: men who had both HBV genotype C and a very high HBV viral load had a 26-fold higher risk of HCC than those with other genotypes and low or undetectable viral loads ( 10 ) . Studies in other populations with different genotype distributions are needed to validate these associations and clarify whether they apply elsewhere. HBV genotypes may or may not affect patient responses to or complications from the three medications — interferon alpha, lamivudine, and adefovir dipivoxil — that are approved by the U.S. Food and Drug Administration for use against chronic HBV infection ( 12 ) . The latter two drugs are nucleoside analogues that reduce HBV replication by inhibiting the viral RNA-dependent DNA polymerase and by introducing errors in the HBV genome. Although such treatment cannot eradicate HBV from cells that are already infected, inhibiting viral replication reduces ongoing infl ammation and necrosis in the liver and facilitates the host immune response. In one study ( 13 ) , treatment of patients with chronic hepatitis B and advanced liver disease with lamivudine alone for 30 months reduced HCC incidence and liver disease progression by 50%, despite incomplete suppression of HBV DNA replication, the development of resistance mutations, and virologic breakthrough. Perhaps widespread use of lamivudine in clinical practice will alter the incidence of HCC, similar to what was seen with the incidence