美国肝病协会抗乙肝防治指南英文原版.docx

1、美国肝病协会抗乙肝防治指南英文原版55th Annual Meeting of the American Association for the Study of Liver DiseasesViral Liver Disease CME October 29, 2004 - November 2, 2004, Boston, Massachusetts Developments in the Management of Hepatitis BIntroductionHepatitis B virus (HBV) is a major healthcare problem around the

2、 world. It is estimated that 350-400 million people are chronically infected.1,2 Patients with chronic hepatitis B are at increased risk for progression to cirrhosis and end-stage liver disease and for the development of hepatocellular carcinoma (HCC), including patients who are asymptomatic. Interf

3、eron has been used to treat hepatitis B since the mid-1980s . The efficacy of pegylated interferon is now being actively investigated. The development and availability of nucleoside and nucleotide analogues has greatly altered the management of patients with chronic hepatitis B. Unfortunately, the i

4、ncreased use of these drugs, particularly when used as monotherapy, has produced mutations that confer viral resistance, much as what was seen in the management of HIV. Investigators have sought to define these mutations and to examine the role of combination therapy to improve virologic response an

5、d reduce viral resistance.Hepatitis B and the Risk of Developing HCCIt is known that patients with chronic hepatitis B who are hepatitis B e antigen (HBeAg)-positive are at greatest risk for both the progression of liver disease and the development of HCC.3 What this implies, but what hasnt been cle

6、arly shown, is that the HBV viral load also correlates with disease progression and the risk of HCC. Chen and colleagues4 looked at this issue in their 10-year, prospective cohort study of 3464 patients found to be hepatitis B surface antigen (HBsAg)-positive at screening between 1992 and 1993. Ten

7、years later, 2354 of these patients had either sufficient baseline serum samples or adequate follow-up information to allow them to be included in a mortality analysis; 1681 patients had both sufficient baseline serum samples and were willing to undergo rescreening with physical examination, laborat

8、ory tests, and liver ultrasound. All of the patients were placed in 1 of 3 viral load categories on the basis of their viral loads at the time of entry: undetected ( 1.6 x 103 copies/mL), low titer (/= 1.6 x 103 copies/mL), and high titer (/= 105 copies/mL). Liver disease was characterized as normal

9、, mild, moderate, or severe on the basis of adapted Dionysos criteria. HCC was diagnosed by the presence of a 2-cm mass on ultrasound and an alpha-fetoprotein level 400 ng/mL.The patients in the high-titer virus group at entry were found to be at a statistically significant greater risk for mortalit

10、y from progressive liver disease or HCC than patients with low or undetectable viral loads. Although it did not reach statistical significance, low viral load also appeared to be associated with an increased risk of mortality from progressive liver disease or HCC when compared with patients with an

11、undetectable viral load.This study has potentially significant implications for the management of patients with chronic hepatitis B. There is controversy regarding whether patients in the immunotolerant stage of HBV infection (patients with high levels of HBV DNA, normal aminotransferases, and littl

12、e to no necroinflammatory activity on liver biopsy) should be treated. This study by Chen and colleagues4 provides additional weight to the argument that perhaps these patients would benefit from being treated and highlights the need for a trial to be designed to look at this specific question. The

13、end points of such a study, the progression of liver disease and the development of HCC, would take many years to assess and will require the enrollment of large numbers of patients. In addition, the study would need to use multiple anti-HBV agents to prevent the development of viral resistance. Hop

14、efully, studies, such as this one by Chen and colleagues,4 will provide the impetus for such future investigation.Prevention of Hepatitis BThe use of passive and active immunity to reduce the risk of vertical transmission of hepatitis B is well accepted in clinical practice.5 Hepatitis B immunoglobu

15、lin (HBIg), given at the time of birth in combination with 3 doses of the recombinant hepatitis B vaccine given over the first 6 months of life, has proven to be as much as 95% effective in preventing vertical transmission.6 However, the risk of vertical transmission of hepatitis B increases as the

16、mothers viral load increases. In one series of mothers with high viral loads (defined as HBV DNA /= 1.2 x 109 copies/mL), this risk was as high as 28%.7 It stands to reason that if the mothers viral load could be reduced at the time of birth, the risk of vertical transmission could also be reduced.

17、This is exactly what Xu and colleagues8 examined with a well-structured, multicenter, randomized, double-blind, placebo-controlled study carried out at centers in China and the Philippines.Mothers chronically infected with hepatitis B (HBsAg-positive) and with high HBV viral loads (defined as a seru

18、m HBV DNA 1000 mEq/mL) were enrolled. One hundred fourteen mothers completed the study; 56 mothers received lamivudine, 100 mg a day, beginning at the 32nd week of gestation and continuing until 4 weeks post partum. The control group of mothers (n = 59) received placebo. All of the infants received

19、standard prophylaxis (HBIg within 24 hours of birth and vaccination with the recombinant HBV vaccine; 3 injections over the first 6 months of life). The primary end point of the study was HBsAg positivity in the infants at 1 year. Secondary end points were hepatitis B surface antibody (HBsAb) positi

20、vity and HBV DNA positivity in the infants at 1 year.Not surprisingly, the mothers treated with lamivudine were more likely (98%) to have a reduction in their viral loads to 1000 mEq/mL than the controls (31%). This reduction in viral load translated into improved outcomes for the infants of mothers

21、 receiving lamivudine. They had a lower likelihood of being HBsAg-positive at 1 year of age (18% vs 39%; P = .014) or to be viremic (20% vs 46%; P = .003). Infants also had a greater chance of being HBsAb-positive at 1 year of age (84% vs 61%; P = .008). There was no difference seen in adverse event

22、s between the treatment and control groups in either the mothers or the infants.Although this study had some issues with patient dropout, it nonetheless strongly suggests that the use of lamivudine in the third trimester of pregnancy in mothers with high HBV viral loads is effective in reducing the

23、risk of vertical transmission beyond what can be achieved with passive and active immunization. In addition, this therapy is safe for both the mother and the infant. While we await additional trials, lamivudine* should be considered for use in the third trimester in those mothers infected with chron

24、ic hepatitis B at greatest risk for passing the infection on to their infants - ie, those with high viral loads.New and Old Therapies for Hepatitis BEntecavir, a carbocyclic analogue of 2-deoxyguanosine, is a potent and selective inhibitor of HBV polymerase. Rosmawati and colleagues9 reported the re

25、sults of a phase 3 trial comparing entecavir, .5 mg a day, with lamivudine, 100 mg a day, for 48 weeks in patients with HBeAg-positive chronic hepatitis B. The investigators chose to pay particular attention to those patients with low-baseline alanine aminotransferase (ALT) levels, defined as 2.6 ti

26、mes the upper limit of normal. The reason for this focus was a previously completed phase 2 trial that suggested that entecavir may be as effective in patients with low-baseline ALT as in those with more elevated ALT. This was of interest because patients with normal or near-normal ALT levels at bas

27、eline respond less well to interferon or lamivudine than do patients with elevated ALT. The investigators did not explain why the threshold value of 2.6 times the upper limit of normal was chosen for this particular analysis. The results showed that in those patients with a baseline ALT 2.6 times th

28、e upper limit of normal, entecavir produced a mean log reduction in the HBV DNA of 6.79 at 48 weeks compared with a 4.85 log reduction for lamivudine (P /= 2.6 times the upper limit of normal, entecavir produced a mean log reduction in the HBV DNA of 7.18 at 48 weeks compared with a 6.15 log reducti

29、on for lamivudine (P .0001). Entecavir was much more likely to suppress the HBV DNA to 400 copies/mL by polymerase chain reaction at week 48. No data were provided on HBeAg loss or seroconversion.In a phase 1/2 clinical trial, clevudine, an L-nucleoside, was shown to have potent anti-HBV activity ov

30、er a 12-week period. Lee and colleagues10 examined the safety and antiviral activity of clevudine, 30 mg a day, in 21 patients with HBeAg-positive chronic hepatitis B over 24 weeks at 7 sites in South Korea. The results shown in Table 1 suggest that clevudine has excellent anti-HBV activity with inc

31、reased benefit at 24 weeks compared with 12 weeks. There was no viral breakthrough reported.Table 1. Viral Suppression and Normalization of ALTEnd PointWeek 12Week 24Log reduction in HBV DNA4.054.64HBV DNA 4700 copies/mL59%82%HBV DNA 400 copies/mL24%59%Normalization of ALT47%76%HBeAg loss12%24%ALT =

32、 alanine aminotransferase; HBeAg = hepatitis B e antigenMarcellin and colleagues11 reported the 144-week data in a long-term study of adefovir, 10 mg a day, in patients with HBeAg-positive chronic hepatitis B. Eighty-four patients were followed through the 144 weeks. These patients enjoyed increasing rates of HBeAg seroconversion (12% at 48 weeks, 29% at 96 weeks, and 43% at 144 weeks), HBV DNA suppression defined as 1000 copies/mL (28% at 48 weeks, 45% at 96 weeks, and 56% at 144 w