Overlap Lam Treatment in Patients With CHB Receiving Adefovir
Overlap Lam Treatment in Patients With CHB Receiving Adefovir
Adefovir dipivoxil is effective against lamivudine-resistant hepatitis B virus (HBV) strains. Whether short-term overlap lamivudine is beneficial remains unknown, particularly in patients with decompensated chronic hepatitis B. We enrolled 30 patients who underwent 48-week adefovir treatment (10 mg daily) for exacerbation of hepatitis B, associated with lamivudine-resistant mutants. Nineteen (63.3%) patients had baseline evidence of hepatic decompensation. Lamivudine was combined for ≤1 month in eight (group I), 2-5 months in 10 (group II) and ≥6 months in 12 (group III). We analysed their serial alanine aninotransferase (ALT) levels, Child-Pugh (CP) score, serum viral load and lamivudine-resistant strains. We found that serum ALT became normalized in 20 (66.7%) and HBV-DNA decreased to ≤100 copies/mL in eight (26.7%) at the end of the 48-week treatment. The log(10) reduction of serum HBV-DNA was significantly smaller in group I patients compared with group II and III patients at week 24 and 48 of treatment [median (range): 3.0 (1.5-5.6) vs 4.5 (1.5-7.4), P = 0.032; and 3.4 (0.9-4.7) vs 5.2 (2.2-7.7), P = 0.008 respectively]. In contrast, the virologic responses at the end of the 48-week therapy were similar between group II and III patients. The improvement in serum ALT and CP score at week 48 was similar irrespective of baseline decompensation, liver cirrhosis and the duration of overlap lamivudine therapy. Our findings suggested that an overlap of lamivudine for ≥2 months might lead to better virological but not biochemical outcomes in patients receiving adefovir for lamivudine-resistance HBV. As our sample size was small and the study was not randomly controlled, further studies are needed.
Hepatitis B virus (HBV) infection can cause a wide spectrum of liver diseases, such as fulminant or acute hepatitis, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The number of individuals infected with this virus has been estimated to be as high as 350 million and the annual mortality associated with persistent HBV infection is about 1.2 million worldwide. Thus, in addition to global hepatitis B vaccination, effective treatment of chronic hepatitis B to prevent progression into end-stage liver diseases and hepatocellular carcinoma is needed.
Three drugs have been approved for the treatment of chronic hepatitis B so far: interferon (IFN) alpha, lamivudine and adefovir dipivoxil. IFN has been used to treat chronic hepatitis B for more than one decade and the virologic response is durable in about 90% of patients. However, only around one-third of patients achieve sustained response and adverse effects are common. Lamivudine is well tolerated and effective in patients with hepatitis B e antigen (HBeAg)-positive or -negative chronic hepatitis B. However, drug-resistant mutations within the tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif of HBV polymerase gene develop in approximately 65% of patients after 5 years of treatment, and in contrast to IFN virologic response to lamivudine treatment, may not be durable. Adefovir dipivoxil is a new nucleotide analogue that has recently been shown to have potent anti-HBV activity similar to that of lamivudine. Serum HBV-DNA levels can be reduced and improvement in liver histology and serum alanine aminotransferase (ALT) levels is also achieved. Most importantly, it has also been shown to be effective in patients with lamivudine-resistant HBV. In addition, only <2% of patients developed viral resistance after 96 weeks of therapy. Nevertheless, several issues remain to be addressed. Peter et al.'s study suggested that the biochemical and virologic responses were comparable between adefovir in combination with lamivudine and adefovir monotherapy in patients with lamivudine-resistant HBV. However, exacerbation of hepatitis was more commonly encountered in those receiving adefovir alone. Thus, an overlap of a 2-3-month combination was recommended recently to minimize the risk of exacerbations during transition. It has to be noted that the recommendation was not based on solid evidence. Furthermore, in Peter et al.'s report, all patients had well-compensated liver disease at enrollment. It remained unknown whether the development of hepatitis exacerbation had any impact on the clinical outcome if the patients already had evidence of decompensated chronic hepatitis B at baseline, and whether overlapping lamivudine therapy after starting adefovir treatment could decrease such a risk. Moreover, the clinical significance and dynamics of lamivudine-resistant YMDD mutants under adefovir therapy remain largely unknown.
To address these issues, we enrolled 30 patients with chronic hepatitis B who developed hepatitis after the emergence of lamivudine-resistant viral mutants and were given add-on adefovir dipivoxil (on compassionate grounds). Decompensated chronic hepatitis B was documented at enrollment (n = 19) or in the past (n = 11). They underwent overlapped lamivudine treatment at different periods. We analysed their serial serum ALT level, Child-Pugh (CP) score, serum hepatitis B viral load and YMDD status before and during the 48-week adefovir therapy, and aimed to clarify the influence of combining lamivudine treatment on the clinical and virologic outcomes in these patients.
Adefovir dipivoxil is effective against lamivudine-resistant hepatitis B virus (HBV) strains. Whether short-term overlap lamivudine is beneficial remains unknown, particularly in patients with decompensated chronic hepatitis B. We enrolled 30 patients who underwent 48-week adefovir treatment (10 mg daily) for exacerbation of hepatitis B, associated with lamivudine-resistant mutants. Nineteen (63.3%) patients had baseline evidence of hepatic decompensation. Lamivudine was combined for ≤1 month in eight (group I), 2-5 months in 10 (group II) and ≥6 months in 12 (group III). We analysed their serial alanine aninotransferase (ALT) levels, Child-Pugh (CP) score, serum viral load and lamivudine-resistant strains. We found that serum ALT became normalized in 20 (66.7%) and HBV-DNA decreased to ≤100 copies/mL in eight (26.7%) at the end of the 48-week treatment. The log(10) reduction of serum HBV-DNA was significantly smaller in group I patients compared with group II and III patients at week 24 and 48 of treatment [median (range): 3.0 (1.5-5.6) vs 4.5 (1.5-7.4), P = 0.032; and 3.4 (0.9-4.7) vs 5.2 (2.2-7.7), P = 0.008 respectively]. In contrast, the virologic responses at the end of the 48-week therapy were similar between group II and III patients. The improvement in serum ALT and CP score at week 48 was similar irrespective of baseline decompensation, liver cirrhosis and the duration of overlap lamivudine therapy. Our findings suggested that an overlap of lamivudine for ≥2 months might lead to better virological but not biochemical outcomes in patients receiving adefovir for lamivudine-resistance HBV. As our sample size was small and the study was not randomly controlled, further studies are needed.
Hepatitis B virus (HBV) infection can cause a wide spectrum of liver diseases, such as fulminant or acute hepatitis, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The number of individuals infected with this virus has been estimated to be as high as 350 million and the annual mortality associated with persistent HBV infection is about 1.2 million worldwide. Thus, in addition to global hepatitis B vaccination, effective treatment of chronic hepatitis B to prevent progression into end-stage liver diseases and hepatocellular carcinoma is needed.
Three drugs have been approved for the treatment of chronic hepatitis B so far: interferon (IFN) alpha, lamivudine and adefovir dipivoxil. IFN has been used to treat chronic hepatitis B for more than one decade and the virologic response is durable in about 90% of patients. However, only around one-third of patients achieve sustained response and adverse effects are common. Lamivudine is well tolerated and effective in patients with hepatitis B e antigen (HBeAg)-positive or -negative chronic hepatitis B. However, drug-resistant mutations within the tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif of HBV polymerase gene develop in approximately 65% of patients after 5 years of treatment, and in contrast to IFN virologic response to lamivudine treatment, may not be durable. Adefovir dipivoxil is a new nucleotide analogue that has recently been shown to have potent anti-HBV activity similar to that of lamivudine. Serum HBV-DNA levels can be reduced and improvement in liver histology and serum alanine aminotransferase (ALT) levels is also achieved. Most importantly, it has also been shown to be effective in patients with lamivudine-resistant HBV. In addition, only <2% of patients developed viral resistance after 96 weeks of therapy. Nevertheless, several issues remain to be addressed. Peter et al.'s study suggested that the biochemical and virologic responses were comparable between adefovir in combination with lamivudine and adefovir monotherapy in patients with lamivudine-resistant HBV. However, exacerbation of hepatitis was more commonly encountered in those receiving adefovir alone. Thus, an overlap of a 2-3-month combination was recommended recently to minimize the risk of exacerbations during transition. It has to be noted that the recommendation was not based on solid evidence. Furthermore, in Peter et al.'s report, all patients had well-compensated liver disease at enrollment. It remained unknown whether the development of hepatitis exacerbation had any impact on the clinical outcome if the patients already had evidence of decompensated chronic hepatitis B at baseline, and whether overlapping lamivudine therapy after starting adefovir treatment could decrease such a risk. Moreover, the clinical significance and dynamics of lamivudine-resistant YMDD mutants under adefovir therapy remain largely unknown.
To address these issues, we enrolled 30 patients with chronic hepatitis B who developed hepatitis after the emergence of lamivudine-resistant viral mutants and were given add-on adefovir dipivoxil (on compassionate grounds). Decompensated chronic hepatitis B was documented at enrollment (n = 19) or in the past (n = 11). They underwent overlapped lamivudine treatment at different periods. We analysed their serial serum ALT level, Child-Pugh (CP) score, serum hepatitis B viral load and YMDD status before and during the 48-week adefovir therapy, and aimed to clarify the influence of combining lamivudine treatment on the clinical and virologic outcomes in these patients.
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