COMBINATIONS OF 3 OR 4 HIV-1 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-relate d complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original n otions: a) it is not the number of the virostatics applied to each pat ient at any phase which determines their effect: it is the number of a ffected virus targets which determines the effect. Thus, the so called ''tritherapies'', imposed by the ''AIDS Command'' to thousands of pat ients selected at random, to be compared to the same number of subject s receiving only ''bi'' or ''monotherapies'', might be beginning to fa ce failure because they attack only two targets: retro-transcriptase a nd HIV, protease. Having discovered, owing to our experimental screeni ng, original HIV, virostatics, acriflavine (ACF) and several elliptici ne analogues among which we have used methyl-hydroxy-ellipticine (MHE) , we are able to attack two virus targets unaffected by classical viro statics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentall y combined these two agents with AZT, which inhibits retro-transcripta se, 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 tar gets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five pa tients out of five who received the combinations of four virostatics c hosen 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 delectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostat ics and as HIV, resistances may happen as soon as 12 weeks of treatmen t, the combinations have been, in our study, applied in shorter (3 wee k) sequences, differing from each other due to drug rotation; c) neith er toxicity nor resistance occurred; d) curiously, the CD4 numbers, ev en when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limita tion can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappea r without treatment change. Our thesis proposes the possibility that t his CD4 restoration handicap may be due to a possible latent GVH due t o a micro-allo-chimerism, which we could demonstrate in two of seven c arefully studied patients.