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Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China.

Gu L, Han Y, Li Y, Zhu T, Song X, Huang Y, Yang F, Guan S, Xie J, Gohda J, Hosoya N, Kawana-Tachikawa A, Liu W, Gao GF, Iwamoto A, Li T, Ishida T - PLoS ONE (2015)

Bottom Line: HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups.By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group.Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level.

View Article: PubMed Central - PubMed

Affiliation: China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China; Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

ABSTRACT
In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15-20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV.

No MeSH data available.


Related in: MedlinePlus

Changes in HBV DNA loads during ART in patients who exhibited insufficient suppression of HBV DNA loads.The case numbers 1–10 represent the 10 patients in whom HBV DNA loads were insufficiently suppressed. Mutations related to 3TC resistance were detected in samples collected from No.1–No.8 but not No.9 and No.10. The open circles indicate the time points at which the mutations were detected, and the mutated amino acids and their sequence numbers are listed above these circles.
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pone.0134539.g002: Changes in HBV DNA loads during ART in patients who exhibited insufficient suppression of HBV DNA loads.The case numbers 1–10 represent the 10 patients in whom HBV DNA loads were insufficiently suppressed. Mutations related to 3TC resistance were detected in samples collected from No.1–No.8 but not No.9 and No.10. The open circles indicate the time points at which the mutations were detected, and the mutated amino acids and their sequence numbers are listed above these circles.

Mentions: Intriguingly, HBV breakthrough or insufficient suppression of HBV DNA load was observed in 10 patients of the ART-3TC group after 96-week treatment, and in 8 of these patients, mutations associated with 3TC resistance were detected (Table 2, Fig 2 and S3 Fig). In the patients harboring these mutants, DNA loads at baseline were significantly higher than those in the remaining patients (P < 0.05; Fig 3). However, with regard to the emergence rate of 3TC-resistance mutations, we detected no significant differences between genotypes B and C (S1 Fig). In this study, 16 patients (32%) were HBeAg-positive, and the HBV DNA load of these patients was significantly higher than that of HBeAg-negative patients (P < 0.0001; S4 Fig). In both cases, the HBV DNA load was markedly reduced after ART with or without the inclusion of TDF (S4 Fig). However, in the patient group in which the 3TC mutants emerged, both ART-3TC and ART-3TC/TDF did not effectively suppress HBV DNA loads (S4 Fig). Furthermore, in the HBeAg-positive patients, ART-3TC suppressed HBV DNA loads significantly more weakly than did ART-3TC/TDF (P < 0.0001; S4 Fig). Recent clinical studies on chronic hepatitis B have revealed that high HBV DNA loads are correlated with HBeAg positivity, which plays a crucial role in the progression of hepatitis [20, 33–35]. Thus, our data also strongly suggest that HBV DNA loads must be measured and, if possible, HBeAg tests must be conducted in order to check for and avoid the emergence of 3TC-resistant HBV. We could not analyze a large number of patients for whom a TDF-based regimen has been used, because treatments that include TDF have only recently become available for HIV patients in China. However, we used Stata 11.0 software and calculated the statistical power based on previous data obtained in the case of HIV-HBV coinfection, and our results showed that the statistical power here reached 0.90. This indicates that the number of patients included in our analysis yielded statistically significant data.


Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China.

Gu L, Han Y, Li Y, Zhu T, Song X, Huang Y, Yang F, Guan S, Xie J, Gohda J, Hosoya N, Kawana-Tachikawa A, Liu W, Gao GF, Iwamoto A, Li T, Ishida T - PLoS ONE (2015)

Changes in HBV DNA loads during ART in patients who exhibited insufficient suppression of HBV DNA loads.The case numbers 1–10 represent the 10 patients in whom HBV DNA loads were insufficiently suppressed. Mutations related to 3TC resistance were detected in samples collected from No.1–No.8 but not No.9 and No.10. The open circles indicate the time points at which the mutations were detected, and the mutated amino acids and their sequence numbers are listed above these circles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543549&req=5

pone.0134539.g002: Changes in HBV DNA loads during ART in patients who exhibited insufficient suppression of HBV DNA loads.The case numbers 1–10 represent the 10 patients in whom HBV DNA loads were insufficiently suppressed. Mutations related to 3TC resistance were detected in samples collected from No.1–No.8 but not No.9 and No.10. The open circles indicate the time points at which the mutations were detected, and the mutated amino acids and their sequence numbers are listed above these circles.
Mentions: Intriguingly, HBV breakthrough or insufficient suppression of HBV DNA load was observed in 10 patients of the ART-3TC group after 96-week treatment, and in 8 of these patients, mutations associated with 3TC resistance were detected (Table 2, Fig 2 and S3 Fig). In the patients harboring these mutants, DNA loads at baseline were significantly higher than those in the remaining patients (P < 0.05; Fig 3). However, with regard to the emergence rate of 3TC-resistance mutations, we detected no significant differences between genotypes B and C (S1 Fig). In this study, 16 patients (32%) were HBeAg-positive, and the HBV DNA load of these patients was significantly higher than that of HBeAg-negative patients (P < 0.0001; S4 Fig). In both cases, the HBV DNA load was markedly reduced after ART with or without the inclusion of TDF (S4 Fig). However, in the patient group in which the 3TC mutants emerged, both ART-3TC and ART-3TC/TDF did not effectively suppress HBV DNA loads (S4 Fig). Furthermore, in the HBeAg-positive patients, ART-3TC suppressed HBV DNA loads significantly more weakly than did ART-3TC/TDF (P < 0.0001; S4 Fig). Recent clinical studies on chronic hepatitis B have revealed that high HBV DNA loads are correlated with HBeAg positivity, which plays a crucial role in the progression of hepatitis [20, 33–35]. Thus, our data also strongly suggest that HBV DNA loads must be measured and, if possible, HBeAg tests must be conducted in order to check for and avoid the emergence of 3TC-resistant HBV. We could not analyze a large number of patients for whom a TDF-based regimen has been used, because treatments that include TDF have only recently become available for HIV patients in China. However, we used Stata 11.0 software and calculated the statistical power based on previous data obtained in the case of HIV-HBV coinfection, and our results showed that the statistical power here reached 0.90. This indicates that the number of patients included in our analysis yielded statistically significant data.

Bottom Line: HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups.By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group.Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level.

View Article: PubMed Central - PubMed

Affiliation: China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China; Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

ABSTRACT
In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15-20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV.

No MeSH data available.


Related in: MedlinePlus