Intermittent administration of high-dose stavudine to nucleoside-experienced individuals infected with HIV-1.
To explore a novel method to use nucleosides in heavily treated patients, 4-week cycles of high-dosage (280 mg/d) stavudine were given to 11 asymptomatic patients who had previously received an average of 6 years of nucleoside reverse transcriptase inhibitors (NRTIs). The stavudine dose was targeted to produce a calculated steady-state concentration of 1.5 microM (336 ng/mL). Participants received stavudine for the first 4 weeks, after which it was discontinued for 4 weeks. Additional 4-week drug cycles were given if plasma HIV-1 RNA levels increased to at least 75% of baseline values. The 11 subjects received 38 cycles (average, 3.5 cycles per subject) during the 44-week study. Stavudine was well tolerated. Considering all data, there was a median 0.65 log(10) reduction in viral load as well as a median increase in CD4 cell count of 110/mm3 at the end of the cycles. However, plasma viremia increased and CD4 cell counts decreased between cycles. Viral load and CD4 cell responses were similar for up to 4 successive cycles. This suggested that increasing viral resistance was not a problem, as reflected by the acquisition of only one new nucleoside reverse transcriptase mutation among the participants. Significant relationships between stavudine exposure and changes in plasma HIV RNA levels were observed. A similar approach might be considered using a more potent regimen for patients in whom resistance to nucleosides is a major reason for therapeutic failure.
Acosta
Edward P
EP
Department of Clinical Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Balfour
Henry H
HH
D000328:Adult; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D018119:Stavudine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D012367:RNA, Viral; D018119:Stavudine; D054303:HIV Reverse Transcriptase