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LB10 Virologic and Immunologic Evaluation of Structured Treatment Interruptions (STI) in Patients Experiencing Long-term Virologic Failure. S. G. DEEKS*, T. WRIN, R. HOH, J. TROIANO, T. LIEGLER, M. HAYDEN, C. PETROPOULOS, N. HELLMANN, J. BARBOUR, R. M. GRANT, J. M. McCUNE, M. HELLERSTEIN. Univ. of California, San Francisco; ViroLogic, South San Francisco, CA; and Gladstone Inst. of Virology and Immunology, San Francisco, CA. Background: We performed a prospective study of treatment interruptions among patients experiencing virologic failure of protease inhibitor (PI) based therapy. Methodology: Eligible patients had virologic failure on a PI for > 12 months and a viral load (VL) > 2500 copies RNA/mL. Phenotypic resistance, VL and T-cell levels were measured weekly for 12 weeks, and then every 4 weeks. Replicative fitness was measured using a recombinant virus, single cycle replication assay (see abstract 233). T-cell turnover was measured at baseline and week 12 (deuterated glucose method). Results: 18 patients stopped therapy (baseline CD4 245 cells/mm; VL 4.6 log; median decrease in PI susceptibility: 56 fold). Interrupting therapy for 12 weeks was associated with a median CD4 decrease of 94 cells/mm and a VL increase of 0.82 log. Virus in 16 of 18 patients reverted to a PI-susceptible phenotype (mean time to reversion 8.5 weeks; range 2-15). In a multivariate Cox model, greater PI resistance and lower reductions in VL below pre-therapy baseline were associated with delayed reversion (p=0.04 and p=0.003 respectively). Nucleoside analogue resistance persisted, often at much reduced levels, after reversion to a fully PI susceptible virus in 7 patients. Replicative fitness (relative to a wild-type virus) increased from a median 22.3% to 67.1% (p=0.004). Resistant virus identical to baseline was cultured from PBMCs 12 to 36 weeks after therapy discontinuation in 4 of 8 patients showing phenotypic reversion. At baseline, CD4 fractional replacement rate (k) was low (median 0.011/d) compared to untreated controls (0.032/d, p=0.002), suggesting prolonged T-cell half-life among virologic failures. Discontinuing therapy was associated with either decreased T-cell half-life or decreased CD4 production. Conclusion: These data suggest that antiretroviral therapy is associated with continued immunologic and virologic benefit, despite high level resistance. This benefit may reflect, in part, the maintenance of a less fit virus. The safety and efficacy of STIs as a therapeutic strategy remains to be determined. Key Words: |
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