Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy

Abstract

Treatment of hepatitis B virus (HBV) with lamivudine is effective in suppressing virus replication and results in reduced inflammatory activity. However, the emergence of lamivudine-resistant mutant virus, with amino acid substitution in the YMDD motif of DNA polymerase, has been reported. We report the emergence and takeover of YMDD mutant and re-takeover by wild type during and after long-term lamivudine therapy. YMDD mutants were detected in five patients who showed DNA breakthrough (HBV DNA becoming detectable after a period of DNA negativity), which occurred after 9 to 14 months of lamivudine therapy. Four of five mutants had amino acid sequence YIDD, and the remaining mutant had YVDD. Patients with high HBV-DNA titer and/or hepatitis B e antigen tended to develop breakthrough (P ‫؍‬ .038). Using a sensitive and specific polymerase chain reaction (PCR)-based method developed in this study, the emergence of YMDD mutants was detected 1 to 4 months before DNA breakthrough, but not detected in any of the pretreatment sera. The mutants were predominant at breakthrough, but were replaced by wild-type virus 3 to 4 months after cessation of therapy in the two patients who discontinued therapy. One of these patients had a relapse of hepatitis. Mutant continued to replicate in the remaining three patients who continued to receive treatment, and relapse occurred in only one of these patients. Our results suggest that the replication of YMDD mutant viruses is less than wild type and is re-overtaken by wild type after cessation of therapy. Re-administration of lamivudine, possibly combined with other antiviral therapy, might be useful in some patients experiencing hepatitis with lamivudine-resistant variants. (HEPATOLOGY 1998;27: 1711-1716.)is a potent inhibitor of RNA-dependent DNA polymerase of hepatitis B virus (HBV), as well as human immunodeficiency virus (HIV) reverse transcriptase. [1][2][3][4][5][6][7][8][9][10] The in vivo antiviral activity of lamivudine has been reported in animal studies as well as in humans. [11][12][13][14][15][16][17][18][19][20][21][22] However, the emergence of lamivudineresistant HBV strains was initially noticed in patients who received orthotopic liver transplantation and immunosuppressive therapy. [23][24][25][26][27][28] Such resistant viruses show a characteristic mutation of the 550th amino acid methionine in the YMDD motif of DNA polymerase to isoleucine (YIDD mutant) or valine (YVDD mutant). Honkoop et al. 29 recently showed the emergence of such mutant viruses in 5 of 14 (36%) immunocompetent patients who were treated with lamivudine over 26 weeks. However, in a larger placebo-controlled study in 358 Asian patients with HBV infection treated for 52 weeks, the rate of detection of lamivudine-resistant variants by polymerase chain reaction (PCR) was 19 of 134 (14%) in patients treated with 100 mg daily. 30 To our knowledge, there is no report that describes the presence of mutant viruses in the serum before administration of lamivudine. The low incidence and late emergence of YM...

Infection of Human Hepatocyte Chimeric Mouse With Genetically Engineered Hepatitis B Virus *

“…Our model is especially useful for the study of the biology and drug susceptibility of such mutants, because almost all such drug resistances are based on only one or two point mutation(s). 29,31 In conclusion, the mouse model presented in this study is very useful for the study of HBV biology and evaluating of anti-HBV drugs. Furthermore, many applications of this model are expected because we can easily create, manipulate, and modify the model compared with other models.…”

“…Lamivudine is a potent anti-HBV drug that reduces the virus and induces clinical remission and histological improvement. [26][27][28] Emergence of drug-resistant HBV mutants against this drug as well as other anti-viral drugs is a serious problem in the treatment of HBV, [29][30][31] as has been seen in the therapy of human immunodeficiency virus infection. Our model is especially useful for the study of the biology and drug susceptibility of such mutants, because almost all such drug resistances are based on only one or two point mutation(s).…”

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

“…This study design reflects the real-world situation in which lamivudine treatment is often stopped when resistance emerges. Because the replicative capacity of lamivudine-resistant virus may be less than that of wild-type virus, the reemergence of wild-type virus (and archiving of mutant virus) after cessation of lamivudine could be anticipated [19,27]. Although the detection of lamivudine-resistant virus at baseline was not a requirement for randomization, 42% of randomized patients had HBV DNA polymerase mutations at baseline.…”

Pretreatment and on-treatment predictors of viral breakthrough in lamivudine therapy for chronic hepatitis B

“…Unfortunately prolonged LAM treatment is associated with increasing risk of drug resistance, which may be cross-reactive. Emergence of antiviral resistance may lead to viral and biochemical breakthrough and sometimes hepatitis flare-up and rapid decompensation [5,6]. A high incidence of viral breakthrough (VBT) that results from viral resistance is a major disadvantage of prolonged LAM therapy for CHB [7].…”