esophagitis severity by comparing it with the HD scale andpointing out that scale’s imperfections. How well does it do that?

Certainly, standardizing the endoscopic appearance ofvarious grades of esophagitis helps to establish a picture that isunderstandable to all gastroenterologists. A scale is also im-portant in evaluating the response to therapy. As pointed out bythe authors, the LA system has already proven reliable (1, 2).However, a problem with grading systems is that, althoughthere is an effort to quantify the extent and size of the injury,grading represents a gestalt that is both experience, and ob-server-based. This is demonstrated by the fact that both intra-and interobserver reliability is less for trainees than for expertsfor both scales. When one considers the small number ofevaluators, particularly when it appears the trainees weretrained by the experts, one is left wondering how this scalewould stand up in a community setting. This is not addressed.

A grading system seems to be most problematic whenestablishing a grade 2 or 3 esophagitis. The authors point tothis as a major difficulty in using the HD scale. They doclearly establish that the LA classification may be better fordistinguishing mild from severe esophagitis.

The other problem is that there are so many grading schemesit is difficult to compare results between studies. Establishingone scale would be key. In addition, the two scales used in thisstudy fail to look at the added factors of the “MUSE” (3)system (metaplasia, ulcer, stricture, erosions), i.e., metaplasiaand stricture. These items are currently irreversible and arecrucial in management of patients.

The proponents of the “MUSE” system point to this as aclassification that looks at all aspects—evaluation, treat-ment, risk of bleeding or malignancy, and the need for longterm surveillance. Even this system fails to address whetherthat stricture is caused by reversible (inflammation, spasm)versus irreversible change (fibrosis).

It seems apparent from this article that the LA system is“good” for evaluating clinical severity of esophagitis andresponse to therapy. It is a scale that is clearly for esoph-agitis and not for all endoscopic abnormalities seen in gas-troesophageal refux disease.

Ultimately the scale that is adopted must be easy to use forcommunity as well as academically based gastroenterologists.This question is not answered and needs to be addressed.Finally, to fully evaluate esophagitis, perhaps a two-componentscale analogous to inflammation and fibrosis on liver biopsy isneeded. A scale that looks at both the macroscopic and micro-scopic picture could also be simple to use and be more inclu-sive in helping to evaluate the whole spectrum of gastroesoph-ageal reflux disease both clinically and therapeutically, notlimiting itself to only esophagitis.

Lucy Harris, M.D.Weill Medical College of Cornell University

New York, New York

Phillip Katz, M.D., F.A.C.G.Graduate Hospital

Philadelphia, Pennsylvania

REFERENCES

1. Kahrilas PJ, Falk GW, Johnson DA, et al. Esomeprazole im-proves healing and symptom resolution as compared with ome-prazaole in reflux oesaphagitis patients: A randomized con-trolled trial. The Esomeprazole Study Investigators. AlimentPharmacol Ther 2000;14:1249–58.

2. Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety ofesomeprazole compared with omeprazole in GERD patientswith erosive esophagitis: A randomized controlled trial. Am JGastroenterol 2001;96:656–65.

3. Armstrong D. Endoscopic evaluation of gastroesophageal re-flux disease. Yale J Biol Med 1999;72:93–100.

How Much Hepatitis B Is Too Much?Chu CJ, Hussain M, Lok AS.Quantitative Serum HBV DNA Levels During Different StagesOf Chronic Hepatitis B InfectionHepatology 2002;36:1408–15.

ABSTRACTThe goals of this study were to determine whether there isa threshold hepatitis B virus (HBV) DNA value associatedwith spontaneous or antiviral therapy–related hepatitis B eantigen (HBeAg) clearance, and to determine whether thereis an HBV DNA value that can be used to differentiateinactive carriers from patients with HBeAg-negativechronic hepatitis B infection. The authors measured HBVDNA with a polymerase chain reaction (PCR) based assayin sequential samples of 165 Chinese patients with differentstages of chronic HBV infection. They found that 89% ofpatients who remained HBeAg positive had HBV DNAlevels that were persistently � 105 copies/ml. There was amean decrease of 3 log10 in patients who lost the HBeAg,but at the time of seroconversion, 51% had levels � 105

copies/ml. Among HBeAg negative patients, the HBV DNAlevels were significantly lower compared with HBeAg-pos-itive patients. Using a threshold of 105 copies/ml in e-antigen–negative patients to differentiate active from inac-tive carriers missed 30%–45% of patients with activehepatitis, depending on how often the testing was repeated.Serial determinations were more accurate than single-pointmeasurement in detecting active patients.

The authors concluded that serum HBV DNA levels �105 exclude all inactive carriers. HBV DNA levels decreasesignificantly in patients with HBeAg loss, but there is not aset threshold associated with HBeAg clearance. AmongHBeAg-negative patients, the levels of HBV DNA fluctuatesignificantly, and a single cut-off value cannot be used todifferentiate active hepatitis from inactive carriers. (Am JGastroenterol 2003;98:1436–1437. © 2003 by Am. Coll. ofGastroenterology)

COMMENT

In chronic HBV infection, the HBV genome becomes inte-grated with the host cell. This is one of the reasons that the

1436 World Literature Review AJG – Vol. 98, No. 6, 2003

virologic endpoints in the treatment of hepatitis B infectiondiffer from those of hepatitis C infection. Whereas the goalin treating hepatitis C infection is to lose detectable virusfrom serum, this goal is seldom achieved, and often notnecessary, when treating hepatitis B infection. As long asthe patient remains HBsAg positive, it is likely that detect-able virus will be circulating, but this is not always associ-ated with active hepatitis and disease progression.

In the past, HBV DNA was measured using less sensitivehybridization assays with lower limits of detection, between105 and 106 copies/ml. Once the viremic level droppedbelow this threshold, the test was reported as negative, andwe all felt confident that the patient either had responded totherapy or was in an inactive stage. Advances in molecularbiology–based techniques (1) have now allowed widespreadaccess to PCR-based HBV DNA quantitation with very highsensitivity, and as result, the less-sensitive hybridizationassays have either been phased out or updated to reflect ahigher sensitivity. Suddenly, many of the patients previ-ously thought to be inactive carriers or responders to anti-viral therapy have positive results detecting viremia withPCR-based assays. This has caused a lot of confusionamong clinicians, prompting many to ask, “How muchhepatitis B virus is too much?”

In an effort to clarify these issues, the National Institutesof Health workshop on the management of hepatitis Binfection proposed that HBV DNA levels � 105 copies/mlbe used to differentiate active infection from inactive car-riers (2). This recommendation was based, in part, on stud-ies using single-point determination of HBV DNA, whichfound that results generally exceed 105 copies/ml and couldbe as high as 1010 copies/ml in patients with active disease(3, 4). Prior studies, however, have not done serial deter-minations in patients and have not always differentiatedbetween wild-strain and e-antigen–negative active hepatitispatients. Because there is little data on what level of HBVDNA is associated with progressive liver damage, there isno consensus as to the level of serum HBV DNA at whichtreatment is indicated.

The article by Chu et al reviewed here takes us one stepcloser to correctly interpreting HBV DNA results. Theirfindings suggest to me that we probably should not make adecision regarding treatment based solely on the viral quan-titation result; rather, we need to integrate the serologic,histologic, and biochemical parameters of each patient be-fore deciding whether treatment is needed. Nevertheless,some important general guidelines can be extracted fromthis informative article.

1. A patient with an HBV DNA level � 105 copies/ml is notan inactive carrier and should be strongly considered acandidate for therapy, regardless of the e-antigen status.

2. Among patients with e-antigen–negative chronic hepati-tis B infection, using a level of 105 copies/ml wouldexclude 30%–45% of patients with active disease andneed for therapy. In this group of patients, a threshold of

104 copies/ml would increase the sensitivity for activepatients. Because levels of HBV DNA fluctuate more inHBeAg-negative patients, serial measurements over timeis a more sensitive way of finding active patients; thosewith levels � 104 copies/ml at any occasion should beconsidered possible therapy candidates.

3. Among inactive carriers, HBV DNA remains detectablein most, but levels tend to be stable over a 5-year follow-up; none had levels � 105 copies/ml, and 93% had levelspersistently under 104 copies/ml.

4. Once antiviral therapy is initiated, there is no magic viralthreshold under which HBeAg seroconversion is likely;however, once seroconversion occurs, a significant de-crease in viral load becomes evident.

Much more data is needed to fully understand the naturalhistory of hepatitis B infection and its relation to viral loadand viral kinetics. The reproducibility and comparability ofthe available PCR assays should also be explored. TheWorld Health Organization has established an internationalstandard for universal standardization of HBV DNA quan-tification units and an HBV DNA international unit has beendefined (5); it is hoped that most laboratories will adopt thisstandard. Virologic data similar to that presented by Chu etal is needed for non-Asian patients; it is possible that sig-nificant differences may emerge. Until these and other ques-tions are answered, in most patients, histologic examinationof the liver biopsy is still the best way of assessing theseverity of chronic hepatitis B, establishing prognosis, andguiding the decision to treat. Deciding which hepatitis Bpatients need antiviral therapy continues to be art rather thanpure science.

Jorge L. Herrera, M.D.Division of Gastroenterology

University of South Alabama College of MedicineMobile, Alabama

REFERENCES

1. Pawlotsky JM. Molecular diagnosis of viral hepatitis. Gastro-enterology 2002;122:1554–68.

2. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitisB 2000: Summary of a workshop. Gastroenterology 2001;120:1828–53.

3. Nobong U, Gusdal A, Horal P, Lindh M. Levels of viraemia insubjects with serologic markers of past or chronic hepatitis Binfection. Scand J Infect Dis 2000;32:249–52.

4. Niitsuma H, Ishii M, Miuta M, et al. Low level hepatitis Bviremia detected by polymerase chain reaction accompanies theabsence of HBe antigenemia and hepatitis in hepatitis B viruscarriers. Am J Gastroenterol 1997;92:119–23.

5. Saldanha J, Gerlich W, Lelie N, et al. An international collab-orative study to establish a World Health Organization interna-tional standard for hepatitis B virus DNA nucleic acid ampli-fication techniques. Vox Sang 2001;80:63–71.

1437AJG – June, 2003 World Literature Review