Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers.
This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.
Mathé
G
G
Institut de Cancérologie et d'Immunologie & Hôpital Suisse de Paris, Issy-les-Moulineaux, France.
Morette
C
C
Hallard
M
M
Blanquet
D
D
D000386:AIDS-Related Complex / Q000188:drug therapy* / Q000276:immunology; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004334:Drug Administration Schedule; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D004611:Ellipticines / Q000627:therapeutic use; D005500:Follow-Up Studies; D005622:Friend murine leukemia virus / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification* / Q000502:physiology; D006801:Humans; D051379:Mice; D012192:Retroviridae Infections / Q000188:drug therapy; D014412:Tumor Virus Infections / Q000188:drug therapy
D019380:Anti-HIV Agents; D004611:Ellipticines; C053305:N(2),N(6)-dimethyl-9-hydroxyellipticinium