After M184V, Continue the 3TC
After M184V, Continue the 3TC
Patients with the M184V mutation who continued 3TC alone, instead of stopping all treatment, had virologic and clinical benefits, and no new resistance mutations were observed.
Patients receiving 3TC-containing regimens who have detectable viremia rapidly select for the M184V mutation. Although this mutation confers high-level in vitro resistance to 3TC, it has also been shown to reduce viral replication capacity, leading researchers to speculate that 3TC might still be beneficial in patients with the mutation. To evaluate this possibility, investigators randomized 60 patients who were receiving 3TC-containing regimens and harboring the M184 mutation to either stop all antiretroviral medications or continue 3TC alone. Eligible patients had CD4 counts >500 cells/mm and viral loads >1000 copies/mL. Important exclusion criteria included chronic hepatitis B virus infection and a history of HIV-related thrombocytopenia. The primary study endpoint was the occurrence of immunologic or clinical failure, with the former defined as a CD4 count <350 cells/mm. Results are based on 58 evaluable patients, 29 in each group.
At 48 weeks, 69% of the treatment-interruption group and 41%of the 3TC-alone group had discontinued the study because of immunologic or clinical failure. The treatment-interruption group also had a significantly higher mean increase in viral load, a finding that was consistent with corresponding differences in replication capacity at week 48. No new genotypic mutations were selected by 3TC alone. Response to subsequent therapy, measured by the proportion of patients achieving viral loads <50 copies/mL, was higher with 3TC alone than with treatment interruption (75% vs. 42%).
The apparent paradox between high-level in vitro resistance and the continued benefit of 3TC-containing (and presumably FTC-containing) regimens was first observed in monotherapy studies. As the authors note, this paradox might be due to the effect of the M184V mutation on replication capacity, the continued antiviral effects of 3TC, or both. Regardless of the mechanism, the collective data clearly show that with their low toxicity profiles, 3TC and FTC should in most cases be continued in salvage regimens, the M184V mutation notwithstanding. The attractiveness of this strategy is enhanced by the absence of new resistance mutations with 3TC alone and by the paucity of new NRTIs in development, as highlighted by the recent discontinuation of dD4FC (Reverset) development.
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Patients with the M184V mutation who continued 3TC alone, instead of stopping all treatment, had virologic and clinical benefits, and no new resistance mutations were observed.
Summary
Patients receiving 3TC-containing regimens who have detectable viremia rapidly select for the M184V mutation. Although this mutation confers high-level in vitro resistance to 3TC, it has also been shown to reduce viral replication capacity, leading researchers to speculate that 3TC might still be beneficial in patients with the mutation. To evaluate this possibility, investigators randomized 60 patients who were receiving 3TC-containing regimens and harboring the M184 mutation to either stop all antiretroviral medications or continue 3TC alone. Eligible patients had CD4 counts >500 cells/mm and viral loads >1000 copies/mL. Important exclusion criteria included chronic hepatitis B virus infection and a history of HIV-related thrombocytopenia. The primary study endpoint was the occurrence of immunologic or clinical failure, with the former defined as a CD4 count <350 cells/mm. Results are based on 58 evaluable patients, 29 in each group.
At 48 weeks, 69% of the treatment-interruption group and 41%of the 3TC-alone group had discontinued the study because of immunologic or clinical failure. The treatment-interruption group also had a significantly higher mean increase in viral load, a finding that was consistent with corresponding differences in replication capacity at week 48. No new genotypic mutations were selected by 3TC alone. Response to subsequent therapy, measured by the proportion of patients achieving viral loads <50 copies/mL, was higher with 3TC alone than with treatment interruption (75% vs. 42%).
Comment
The apparent paradox between high-level in vitro resistance and the continued benefit of 3TC-containing (and presumably FTC-containing) regimens was first observed in monotherapy studies. As the authors note, this paradox might be due to the effect of the M184V mutation on replication capacity, the continued antiviral effects of 3TC, or both. Regardless of the mechanism, the collective data clearly show that with their low toxicity profiles, 3TC and FTC should in most cases be continued in salvage regimens, the M184V mutation notwithstanding. The attractiveness of this strategy is enhanced by the absence of new resistance mutations with 3TC alone and by the paucity of new NRTIs in development, as highlighted by the recent discontinuation of dD4FC (Reverset) development.
Source
Castagna A et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: A randomized pilot study (E-184V study). AIDS 2006 Apr 4; 20:795-803.
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Source...