Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid

Objectives: To delineate and compare the nature and frequency of mutations known to confer resistance to HIV-1 nucleoside reverse transcriptase inhibi tors in the cerebrospinal fluid (CSF) and blood compartments. Methods: Fifty-three paired CSF and plasma specimens had been prospectively collected and stored from 49 HIV-1 infected patients. These were tested us ing a commercially available line probe assay which allows the simultaneous detection of wild-type and drug selected variants conferring resistance to one or more drugs: zidovudine, didanosine, zalcitabine and lamivudine. Results: Of the 53 (58%) paired samples, 31 could be amplified by nested PC R. The current assay's limitation for use with CSF is highlighted as 91% of blood samples amplified compared with 60% of CSF samples showing the assay s inability to amplify viral loads below 1000 copies/ml. Of the 31 patients 21 (68%) had identical resistance patterns in the CSF and plasma; the othe r 10 (32%) patients had a resistance profile in the CSF that was different from that in their plasma. Of these, three samples demonstrated amino acid changes associated with high level zidovudine resistance in the CSF but the blood sample remained genotypically sensitive. Nine samples demonstrated r esistance in blood but remained wild-type in the CSF. Resistant genotypes w ere detected in CSF for all nucleosides except didanosine. Conclusions: Differences in the positions and frequencies of wild-type and drug selected variants in specimens derived from the CSF and blood compartm ents were detected in a significant number of patients; this argues for the independent development of drug resistance in the CNS in some patients. Th ese findings may have important implications in guiding antiretroviral ther apy in HIV-1 infection. (C) 2000 Lippincott Williams & Wilkins.