55th Annual Meeting of the American Association for the Study of Liver Diseases
Viral Liver Disease CME
October 29, 2004 - November 2, 2004, Boston, Massachusetts
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Developments in the Management of Hepatitis B
Disclosures
Daniel Pratt, MD
Introduction
Hepatitis B virus (HBV) is a major healthcare problem around the 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. Interferon has been used to treat hepatitis B since the mid-1980s with limited results. 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 increased 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 and reduce viral resistance.
This report reviews some of the most clinically interesting HBV-related research presented during this year's meeting of the American Association for the Study of Liver Diseases.
Hepatitis B and the Risk of Developing HCC
It 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 hasn't been clearly shown, is that the HBV viral load also correlates with disease progression and the risk of HCC. Chen and colleagues[4] 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 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, laboratory 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 (< 105 copies/mL but >/= 1.6 x 103 copies/mL), and high titer (>/= 105 copies/mL). Liver disease was characterized as normal, 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 mortality 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 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 little to no necroinflammatory activity on liver biopsy) should be treated. This study by Chen and colleagues[4] 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 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. Hopefully, studies, such as this one by Chen and colleagues,[4] will provide the impetus for such future investigation.
Prevention of Hepatitis B
The 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 immunoglobulin (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 mother's 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 mother's viral load could be reduced at the time of birth, the risk of vertical transmission could also be reduced. This is exactly what Xu and colleagues[8] 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 serum 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 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) positivity 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 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 events 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 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 chronic 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 B
Entecavir, a carbocyclic analogue of 2'-deoxyguanosine, is a potent and selective inhibitor of HBV polymerase. Rosmawati and colleagues[9] reported the results 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 times 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 baseline 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 the 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 < .0001). In those patients with a baseline ALT of >/= 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 reduction 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 over a 12-week period. Lee and colleagues[10] 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 increased benefit at 24 weeks compared with 12 weeks. There was no viral breakthrough reported.
Table 1. Viral Suppression and Normalization of ALT
End Point / Week 12 / Week 24Log reduction in HBV DNA / 4.05 / 4.64
HBV DNA < 4700 copies/mL / 59% / 82%
HBV DNA < 400 copies/mL / 24% / 59%
Normalization of ALT / 47% / 76%
HBeAg loss / 12% / 24%
ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen
Marcellin and colleagues[11] 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 weeks), and normalization of ALT.
Other important findings included the low resistance rate at 144 weeks (3.1%) and the absence of any renal dysfunction in patients followed through the 144 weeks. This study shows that adefovir can be used safely for an extended period of time with increasing efficacy. The most desired end point of any treatment for HBeAg-positive chronic hepatitis B is e-antigen seroconversion. Treatment with any noninterferon therapy should be continued until this occurs. This study shows that although the rate of seroconversion at 48 weeks is only 12%, the rate increases over time at a rate of 12% to 15% per year of therapy. It is conceivable that all of the treated patients might eventually achieve seroconversion, assuming that resistance has not developed. This is further support for the use of multidrug regimens to prevent resistance while awaiting the development of seroconversion.
Combination Therapies for Chronic Hepatitis B
Up until this point, combination therapies for HBV have not been shown to improve virologic response. Specific therapies that have been examined include lamivudine + LdT (telbivudine) and adefovir + lamivudine. However, in a study presented during this year's meeting, Lau and colleagues[12] evaluated the efficacy of adefovir + emtricitabine. Thirty treatment-naive, HBeAg-positive patients with serum ALT > 1.3 times the upper limit of normal were randomized to either adefovir (10 mg a day) plus emtricitabine (200 mg a day) or adefovir (10 mg a day) plus placebo for 48 weeks. Combination therapy produced a median log10 reduction of 3.14 vs 2.16 for adefovir alone (P = .004) at 24 weeks and 3.48 vs 2.22 (P = .036) at 48 weeks. There was no difference in HBeAg seroconversion between the groups. Larger studies will be required to determine whether there is a difference in seroconversion. This was the first time that a combination therapy regimen showed improved virologic response over monotherapy. It is important to keep in mind that the primary benefit of combination therapy will likely not be an improved virologic response, but rather a decreased rate of viral resistance.
There were a number of studies looking at the combination of pegylated interferon* and lamivudine. Piratvisuth and colleagues[13] reported the results from a study comparing pegylated interferon alfa-2a, 180 mcg/week, plus lamivudine, 100 mg/day (n = 179), with pegylated interferon plus placebo (n = 177), and lamivudine alone (n = 181) in HBeAg-negative chronic hepatitis B. All groups received 48 weeks of treatment and were followed for an additional 24 weeks. The results are shown in Table 2.
Table 2. Pegylated Interferon Alfa-2a ± Lamivudine vs Lamivudine Alone in HBeAg-Negative Chronic Hepatitis B
Week 72 / Peg IFN +Placebo / Peg IFN +
LAM / LAM / P Value (Peg IFN vs LAM/
Peg IFN + LAM vs LAM)
ALT normalization / 59% / 60% / 44% / .004/.003
HBV DNA < 20,000 copies/mL / 43% / 44% / 29% / .007/.003
HBsAg loss / 4.00% / 2.80% / 0% / .007
HBsAg seroconversion / 3% / 2% / 0% / .029
ALT = alanine aminotransferase; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; Peg IFN = pegylated interferon; LAM = lamivudine; HBsAg = hepatitis B surface antigen
Patients receiving pegylated interferon alfa-2a, with or without lamivudine, had statistically better results for each of the measured end points than those receiving lamivudine alone. The investigators also noted that the use of pegylated interferon alfa-2a, with or without lamivudine, had on-therapy ALT elevations and that there was a significant association between a marked on-therapy elevation of the ALT (defined as an ALT level > 10 times the upper limit of normal) and a sustained ALT normalization. These ALT elevations were not associated with serious safety issues in the majority of patients -- no patients experienced hepatic decompensation and no patient was withdrawn from therapy. These data suggest that pegylated interferon alfa-2a has efficacy in patients with HBeAg-negative chronic hepatitis B and that the addition of lamivudine adds little benefit. No resistance data were provided to indicate whether the combination therapy protected against the development of lamivudine resistance.
The same study group examined predictors of response in these patients (HBeAg-negative chronic hepatitis B).[14] They found that a low-baseline HBV DNA and a high-baseline ALT level were predictive of response -- the exact positive predictors described in patients with HBeAg-positive chronic hepatitis. It was also found that patients with genotype D disease did better with the combination of pegylated interferon alfa-2a and lamivudine than with pegylated interferon alfa-2a alone -- a finding not seen with genotypes B or C. However, the investigators cautioned that the small numbers of subjects involved (with genotype D) make it necessary to confirm these data.
Lau and colleagues[15] compared the efficacy of pegylated interferon alfa-2a 180 mcg/week plus lamivudine 100 mg/day (n = 271); pegylated interferon alfa-2a (180 mcg/week) + placebo (n = 271); and lamivudine 100 mg/day (n = 272), in patients with HBeAg-positive chronic hepatitis B. The duration of therapy was 48 weeks with a 24-week follow-up. The results are shown in Table 3.
Table 3. Pegylated Interferon Alfa-2a ± Lamivudine vs Lamivudine in HBeAg-Positive Chronic Hepatitis B
End Points / Peg-IFN +LAM / Peg-IFN +
Placebo / LAM / P Value (Peg-IFN + LAM vs LAM/
Peg-IFN vs LAM)
ALT normalization / 39% / 41% / 28% / .006/.002
HBV DNA <
100,000 copies/mL / 34% / 32% / 22% / .003/.012
HBeAg seroconversion / 27% / 32% / 19% / .023/< .001
ALT = alanine aminotransferase; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; Peg-IFN = pegylated interferon; LAM = lamivudine
The use of pegylated interferon for 48 weeks provided excellent results in this group of HBeAg-positive chronic hepatitis B patients, and was well tolerated. The 48-week duration is longer than the 16- to 24-week duration typically used with standard interferon alfa-2a and -2b. Lamivudine added no additional benefit. No resistance data were provided.
Janssen and colleagues[16] studied the combination of pegylated interferon alfa-2b (100 mcg/week for 32 weeks, then 50 mcg/week for 20 weeks) in combination with lamivudine 100 mg/day (n = 130) or placebo (n = 136) in HBeAg-positive chronic hepatitis B. Patients were followed for an additional 26 weeks of treatment. Seven percent of patients treated with pegylated interferon, with or without lamivudine, were HBsAg-negative at the end of follow-up. Patients with genotype A disease were most likely to have HBsAg loss (14%), whereas those who were genotype D were least likely to achieve HBsAg loss (2%). None of the patients, including those with viral genotype D, seemed to derive any benefit from the combination of pegylated interferon and ribavirin. No resistance data were provided.
On the basis of these studies, pegylated interferon looks promising in both HBeAg-positive and HBeAg-negative chronic hepatitis B, particularly for those patients with low-baseline HBV DNA and high-baseline ALT levels. The optimal duration of treatment appears to be at least 1 year, particularly in the HBeAg-negative patients. Lamivudine appears to add no benefit, except perhaps in the subset of patients with genotype D disease -- but this finding will require confirmation.
Drug Resistance in Hepatitis B
HBV resistance to lamivudine occurs at a rate of 15% to 20% per year of use. There are 4 well-described, major mutational patterns that confer resistance: L180M + M240V (seen in about 60% of patients), V173L + L180M + M204V, M204I, and L180M + M204I.[17] All of these patterns include either M240V or M204I, the mutations that affect the YMDD site. All confer high levels of resistance to lamivudine.