AIDS THERAPY WITH 2, 3 OR 4 AGENT COMBINATIONS, APPLIED IN SHORT SEQUENCES, DIFFERING FROM EACH OTHER BY DRUG ROTATION .1. FIRST OF 2 PARTS- A PHASE-I TRIAL EQUIVALENT, CONCERNING 5 VIROSTATICS - AZT, DDI, DDC, ACRIFLAVINE AND AN ELLIPTICINE ANALOG

We have individually treated ten AIDS patients whose CD4 numbers were inferior to 200/mm(3), with the five following HIV1 virostatics: a) az ido-deoxythymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (dd C), which affect the same viral target, retrotranscriptase, by acrifla vine (ACF) and methyl-hydroxy-ellipticine (MHE) which we have discover ed to be strong virostatics in vivo, in mice, against Friend's virus, and in man, against AZT resistant HIV1. We have shown that their combi nations with AZT, hitting three viral targets, reduces in mice, the bl ood Friends virus load below detectable level. Due to the short doubli ng time of HIV1, AIDS therapy must be continuous, and to allow the bes t tolerance, the five virostatic combinations were applied in short, t hree-week sequences, each differing as much as possible from the forme r and from the following one, due to drug rotation [1], Among the ten patients, a) three received the two-drug combinations for 15 to 30 mon ths, followed by the three-drug combinations, by three received the th ree-drug combinations from the beginning, c) four received the four-dr ug combinations also from the beginning, two having less than 10 CD4/m m(3) at Initiation of treatment, and two having more than 100. The tol erance was remarkable: the only side-effect being macrocytosis. The ap plication of the two-drug combination sequences maintained stable CD4 levels in two subjects whose viral load (the evaluation of which bad b ecame available) was, at the end of this period, of 4,486 and 39,238 R NA copies. The third subject who had received, an intensive UV irradia tion for a psoriasis, presented an irreversible decrease in his CD4 co unt and a high viral load (1,352,495 RNA copies/mL) at the end of the two-drug period, Fifteen to 25 months after the shift to the three-dru g combinations, the viral load decreased. from 39,328 to 13,291 in one of the non-UV irradiated subjects, and from 1,352,495 to 314,387 in t he irradiated one. No subject had an increase in CD4 number. In the th ree patients having initially received the three-drug combinations, a very strong decrease of viral load was registered after periods of obs ervation varying from 77 to 40 months, while the CD4 counts increased moderately in two subjects, and noticeably in the third (from 126 to 2 66), Out of the four subjects initially treated with four-drug combina tions, the two with less than 10 CD4/mm(3) had a moderate decrease in viral load in about three months, and the CD4 increased from 9 to 34/m m(3) in one. But the two subjects, because of opportunistic infections and psychological reasons, abandoned their treatments. In the two sub jects who had more than 100 CD4/mm(2) at initiation of the four-drug c ombination treatment, the viral load decreased to undetectable levels after four months: but their CD4 counts, after some oscillations, had very moderately increased at the end of the observation period (respec tively, from 200 to 222 and from 129 to 134). In practice, these resul ts suggest the interest of conducting phase II or III studies of AIDS treatment protocols, starring with the four-drug combination model. an d attempting to maintain the effect with the three-drug combination on e. As for theoretical considerations, one must underline the contrast between the remarkable reduction of the viral load and the usually mod erate increase of the CD4 counts, The study but nut the trial has been interrupted, due to the unavailability of three antiproteases, saquin avir, ritonavir and indinavir, which are now introduced in the same ty pe of combinations, one by one, in replacement of one of the studied a gents as shown in figure 1. The effect of increasing the total number of virostatics from five to eight will be published in the second part of this article series.