Lamivudine microbiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
Microbiology
Antiviral Activity
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values (50% effective concentrations) were in the range of 0.003 to 15 µM (1 μM = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 µM (range: 0.200 to 2.007 µM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 µM (1.37 to 3.68 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003 to 0.120 μM in peripheral blood mononuclear cells. Ribavirin (50 μM) decreased the anti-HIV-1 activity of lamivudine by 3.5 fold in MT-4 cells. In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios exhibited synergistic antiretroviral activity. Please see the full prescribing information for EPIVIR-HBV for information regarding the inhibitory activity of lamivudine against HBV.
Resistance
Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine to either isoleucine or valine (M184V/I).
HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from subjects. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In subjects receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most subjects became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.
Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include: rtL80I and rtA181T. Similar HBV mutants have been reported in HIV-1-infected subjects who received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus [see Warnings and Precautions (5.2)].
Cross-Resistance
Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI) and zalcitabine (ddC). In some subjects treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged.
Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Subjects With Virologic Failure: Trial EPV20001: Fifty-three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma HIV-1 RNA level 400 copies/mL) by Week 48. Twenty-eight subjects were randomized to the lamivudine once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma HIV-1 RNA levels of subjects in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 copies/mL and 4.6 log10 copies/mL, respectively.
Genotypic analysis of on‑therapy isolates from 22 subjects identified as virologic failures in the lamivudine once-daily group showed that isolates from 0/22 subjects contained treatment-emergent amino acid substitutions associated with zidovudine resistance (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E), isolates from 10/22 subjects contained treatment-emergent amino acid substitutions associated with efavirenz resistance (L100I, K101E, K103N, V108I, or Y181C), and isolates from 8/22 subjects contained a treatment-emergent lamivudine resistance-associated substitution (M184I or M184V).
Genotypic analysis of on-therapy isolates from subjects (n = 22) in the lamivudine twice-daily treatment group showed that isolates from 1/22 subjects contained treatment-emergent zidovudine resistance substitutions, isolates from 7/22 contained treatment-emergent efavirenz resistance substitutions, and isolates from 5/22 contained treatment-emergent lamivudine resistance substitutions.
Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine once daily showed that isolates from 12/13 subjects were susceptible to zidovudine; isolates from 8/13 subjects exhibited a 25- to 295-fold decrease in susceptibility to efavirenz, and isolates from 7/13 subjects showed an 85- to 299-fold decrease in susceptibility to lamivudine.
Phenotypic analysis of baseline-matched on-therapy HIV-1 isolates from subjects (n = 13) receiving lamivudine twice daily showed that isolates from all 13 subjects were susceptible to zidovudine; isolates from 3/13 subjects exhibited a 21- to 342-fold decrease in susceptibility to efavirenz, and isolates from 4/13 subjects exhibited a 29- to 159-fold decrease in susceptibility to lamivudine.
Trial EPV40001: Fifty subjects received zidovudine 300 mg twice daily plus abacavir 300 mg twice daily plus lamivudine 300 mg once daily and 50 subjects received zidovudine 300 mg plus abacavir 300 mg plus lamivudine 150 mg all twice-daily. The median baseline plasma HIV-1 RNA levels for subjectsin the 2 groups were 4.79 log10 copies/mL and 4.83 log10 copies/mL, respectively. Fourteen of 50 subjects in the lamivudine once-daily treatment group and 9 of 50 subjects in the lamivudine twice-daily group were identified as virologic failures.
Genotypic analysis of on-therapy HIV-1 isolates from subjects (n = 9) in the lamivudine once-daily treatment group showed that isolates from 6 subjects had an abacavir and/or lamivudine resistance-associated substitution M184V alone. On-therapy isolates from subjects (n = 6) receiving lamivudine twice daily showed that isolates from 2 subjects had M184V alone, and isolates from 2 subjects harbored the M184V substitution in combination with zidovudine resistance-associated amino acid substitutions.
Phenotypic analysis of on-therapy isolates from subjects (n = 6) receiving lamivudine once daily showed that HIV-1 isolates from 4 subjects exhibited a 32- to 53-fold decrease in susceptibility to lamivudine. HIV-1 isolates from these 6 subjects were susceptible to zidovudine.
Phenotypic analysis of on-therapy isolates from subjects (n = 4) receiving lamivudine twice daily showed that HIV-1 isolates from 1 subject exhibited a 45-fold decrease in susceptibility to lamivudine and a 4.5-fold decrease in susceptibility to zidovudine.[1]
References
- ↑ "EPIVIR (LAMIVUDINE) TABLET, FILM COATED EPIVIR (LAMIVUDINE) SOLUTION [VIIV HEALTHCARE COMPANY]". Retrieved 9 January 2014.
Adapted from the FDA Package Insert.