Susan Erickson-Vitanen and colleagues from Dupont Pharmaceuticals have been working on a series of PIs that are substituted sulfonamide compounds; data concerning these compounds were presented at the 8^th Conference on Retroviruses and Opportunistic Infections (8^th CROI). Two of these, DPC-681 and DPC-684, were shown to be active in nM range against wild-type and neurotropic isolates of HIV-1 as well as non-clade B isolates (abstract 11) [1]. Both drugs were active against viruses containing the D30N substitution. Five-fold or less of a drop in activity was noted against viruses containing 3-5 resistance-associated mutations in the protease gene. In contrast, viruses that displayed 13- to 190-fold reduced sensitivity to currently approved PIs showed only a 3- to 6-fold loss in susceptibility to DPC-681 and DPC-684. Both compounds were able to maintain good plasma levels and are now being evaluated in phase I studies.

John Erickson of Tibotec also reported on a new series of PIs (e.g., TMC126) that have activity in the nM range (abstract 12) [2]. These drugs select for a different series of mutations than conventional PIs and do so more slowly than currently available drugs. They are also active against other drug-resistant variants of HIV, including PI-resistant viruses.

Rudy Pauwels and colleagues from Tibotec reported on TMC120, a novel NNRTI that is active against viruses containing the K103N, Y181C, or G190 A/S mutations in culture (abstract 13 and 304) [3,4]. When given to patients twice daily for 7 days, decreases in viral load of approximately 1.5 logs were reported in patients who initially had viral loads of approximately 40,000 copies/mL. TMC120 was administered at doses of 50 mg or 100 mg bid. Patients were continued on triple-drug therapy after the initial period of monotherapy with TMC120 (see related article by Brian Conway).

Joseph Eron and colleagues presented data on T-1249, a peptide fusion inhibitor, which has a non-overlapping resistance profile with T-20 (abstract 14) [5]. The drug was given by subcutaneous injection as monotherapy in a dose-ranging study. The drug was well-tolerated and yielded dose-dependent effects in terms of reductions in viral load. The pharmacokinetics of this compound were encouraging and support once-daily dosing.

The new BMS PI, BNS-232632, was assessed in a phase II trial (abstract 15) [6]. The drug was well tolerated in combination with d4T/ddI, and led to viral load reductions to below 50 copies/mL in a high proportion of subjects. This drug can be given once daily.

C. Van Der Horst of the University of North Carolina reported equivalence of results when FTC was given once daily vs. 3TC bid in patients who also received d4T plus either nevirapine or efavirenz (abstract 18) [7]. Their conclusion was that FTC is effective once daily. However, it is likely that 3TC can also be effective on a once-daily basis.

L. Dunkle of Achillion Pharmaceuticals presented data on ACH-126,443 (b-L-Fd4C), a novel L-nucleoside with potent anti-HIV and anti-HBV activity (abstract 303) [8]. This drug has a half-life in excess of 24 hr, is 10 times more potent than 3TC, and appears to be non-toxic in animals. The IC₅₀ against wild-type HIV and almost all drug-resistant viruses, except 184V mutants, was 1-3 mM; the IC₅₀ against 184V-containing viruses was 1-4 mM.

The group of E. Kodama of Kyoto University in Japan reported on a series of 4'-substituted nucleosides that suppressed a wide array of NRTI and NNRTI-resistant viruses (abstract 305) [9].

Finally, Z. Gu et al of Biochem Pharma presented pre-clinical data on a novel nucleoside analog, BCH-10618, ((-)2'deoxy-3'-oxa-4'-thiocytidine) (abstract 472) [10]. The resistance profile of this drug is excellent in regard to both laboratory and clinical isolates that are resistant to all other nucleoside drugs. BCH-10618 was also found to select for BCH-10618-resistant virus only slowly.

Related Article:
NNRTI Resistance Update: Using the Old Ones, Looking Toward the New
(Brian Conway, March 12, 2001)

References