Correspondence to: James J. Goedert, MD, Viral Epidemiology Branch, National Cancer Institute, 6120 Executive Blvd., Rm. 8012, Rockville, MD 20892 (e-mail: goedertj{at}mail.nih.gov).
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 identified several viruses and one bacterium as human carcinogens. Research on hepatitis B virus (HBV) and its association with hepatocellular carcinoma (HCC) exemplifies 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 HBsAg-seropositive 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 findings motivated the initiation of Taiwan's population-wide HBV screening and vaccination program (6). During the first 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 immunodeficiency virus (HIV), elucidate pathogenic mechanisms and potential control measures. For example, the level of viral DNA in the blood, also known as virus load, reflects 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 immunodeficiency 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), quantification of HBV DNA in serum is more sensitive, specific, 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 follow-up 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 104.25.9 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 105.9 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 defined 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 (reflecting the high likelihood that HBV infection have been acquired perinatally) and by other risk factors was not evaluated (11). In East Asia, HBeAg positivity, severe hepatic inflammation and fibrosis, 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 fivefold 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 medicationsinterferon alpha, lamivudine, and adefovir dipivoxilthat 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 inflammation 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 of AIDS when zidovudine was introduced against HIV (14). The prospects for secondary prevention of HCC are likely to improve as clinical trials of new agents and combinations are completed (15).
Despite advances in pharmacology, virology, and epidemiology, challenges to reducing HCC incidence and mortality abound. Worldwide in 2002, primary cancer of the liver, most of which was HBV-associated HCC, was the third leading cause of cancer mortality among men and the fifth leading cause of cancer mortality among women (16). Given that most of the 360 million people living with chronic HBV infection are in resource-poor countries (17), surgical resection or ablation of HCC has the potential to reduce mortality only for a select few. Antiviral therapies may have a measurable impact on HCC mortality but will make the care of patients with chronic HBV infection even more complex and costly than it already is if years of treatment are required (18). The slow, but sure, approach to reducing liver cancer mortality over the next 50 years is primary prevention of HCC by universal HBV vaccination, particularly of infants in the remote hillside, grassland, forest, and riverbank communities of Africa, Asia, and South America, where HCC mortality is 20-fold higher than it is in the United States (16). HBV vaccination is safe, effective against all genotypes, increasingly affordable, and of paramount importance for controlling this lethal infectious carcinogen (19). Victory in the war on cancer that was declared in 1971 by President Richard Nixon through the National Cancer Act will require an expensive, global battle against HBV and other infectious causes of cancer that will need to be sustained for decades (20).
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