Preclinical and early clinical data on new NRTI, NNRTI, integrase inhibitors, co-receptor inhibitors and novel entry inhibitors were presented in one oral and one poster session at the 9th Conference on Retroviruses and Opportunistic Infections. Each of the agents discussed below has potential utility in patients harboring HIV with resistance to currently available drugs, although demonstrations of clinical safety and efficacy are pending.

Co-receptor antagonists and entry inhibitors
Phase 1/2 data on SCH-C, a CCR5 antagonist, were presented by Reynes et al [1]. Administration of SCH-C was shown to result in an approximate 0.5 log₁₀ reduction in viral load in a limited number of subjects over 10 days. Additional in vitro data were presented by Xu et al, who demonstrated that SCH-C caused elevated ß-chemokine expression and CCR5 receptor expression in tissue culture [2]. The significance of these findings is unclear, although the latter effect would appear to be paradoxical in a CCR5 antagonist.

A CXCR4 antagonist termed AMD-3100 was also shown to cause viral load reductions of 0.8 log₁₀ over 11 days [3]. In about half of the subjects studied (n=19), a loss of CXCR4-tropic viruses was noted in the case of individuals who possessed either dual tropic or mixed tropic (X4+R5) infections. In a separate study, the authors failed to demonstrate antiviral potency with this drug [4].

The novel entry inhibitor BMS-806, an antagonist of CD4-gp 120 interactions, was addressed in two oral abstract presentations by Lin et al [5,6]. This compound, which is still in pre-clinical development, was active against multiple subtypes of HIV-1 with EC₅₀ values in the 60 nM range. Selection for resistance in culture revealed mutations in gp41 and within the CD4-binding domain of gp120, establishing proof of principle. BMS-806 was effective at even lower concentrations (2-4 nM) in fusion assays and was effective against viruses displaying CXCR4 and CCR5 tropism in both lymphocytes and monocytes. The significance of the resistance-conferring mutations was confirmed in site-specific mutagenesis experiments as well as in assays that demonstrated reduced levels of binding of BMS-806 to viruses containing the aforementioned mutations [5].

Integrase inhibitors
This topic was addressed in a study by Yoshinaga et al involving a compound termed S-1360 [7]. S-1360 was shown to be effective, with an IC₅₀ of 20 nM, against multiple isolates of HIV-1. Selection for resistance was demonstrated, and the relevance of identified mutations was confirmed by site-directed mutagenesis. Very little information was available with respect to possible cross-resistance with integrase inhibitors previously identified by investigators at Merck.

NNRTI
Two groups presented 7-day clinical data demonstrating the potent anti-HIV activity of TMC 125, in spite of a requirement for high pill burden [8,9]. This compound was found to possess activity against viruses containing mutations associated with resistance to other NNRTI in tissue culture, and was found to reduce viral load in patients who had failed NNRTI-containing regimens.

A third study identified a number of substituted 2-quinolone compounds that possess NNRTI activity, although further work will be needed to generate substances of potential clinical utility [10].

Nucleosides and nucleotides
Bethell et al identified a very promising heterosubstituted nucleoside analog termed BCH-13520, which was determined to possess activity against multiple HIV subtypes, as well as viruses containing mutations conferring resistance to other NRTI [11]. The IC50 of BCH-13520 was in the 0.2 µM range and the compound showed only low toxicity in tissue culture. Some level of resistance was noted in regard to viruses containing either position 69 inserts in RT or the Q151M mutation. Selection for resistance yielded a number of mutations, including V75I, K65R, M16I, K103R and G196R, but the levels of resistance observed were low (2-4 fold).

In a different study, a novel cytosine analog, DPC-817, was studied [12]. Although this compound is now being evaluated in a phase 1/2 clinical trial, results are not yet available. Finally, Lee et al presented preclinical data on GS7340, a pro-drug of tenofovir. GS7340 was found to possess potent activity against both HIV and HBV [13].

References

J. Reynes, R. Rouzier, T. Kanouni, V. Baillat, B. Baroudy, A. Keung, C. Hogan, M. Markowitz, M. Laughlin. SCH C: Safety and Antiviral Effects of a CCR5 Receptor Antagonist in HIV-1- Infected Subjects. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 1.
S. Xu, L. Wojcik, J. Strizki. Antagonism of the CCR5 Receptor by SCH-C Leads to Elevated beta-Chemokine Levels and Receptor Expression in Chronically Treated PBMC Cultures. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 398.
D. Schols, S. Claes, E. De Clercq, C. Hendrix, G. Bridger, G. Calandra, G. Henson, S. Fransen, W. Huang, J. M. Whitcomb, C. J. Petropoulos for the AMD-3100 HIV Study Group. AMD-3100, a CXCR4 Antagonist, Reduced HIV Viral Load and X4 Virus Levels in Humans. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 2.
C. Hendrix, A. C. Collier, M. Lederman, R. Pollard, S. Brown, M. Glesby, C. Flexner, G. Bridger, K. Badel, R. MacFarland, G. Henson, G. Calandra for the AMD-3100 HIV Study Group. AMD-3100 CXCR4 Receptor Blocker Fails to Reduce HIV Viral Load by > 1 Log following 10-Day Continuous Infusion. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 391.
P-F. Lin, B. Robinson, Y-F. Gong, K. Ricarrdi, Q. Guo, C. Deminie, R. Rose, T. Wang, N. Meanwell, Z. Yang, H. Wang, T. Zhang, R. Colonno. Identification and Characterization of a Novel Inhibitor of HIV-1 Entry - I: Virology and Resistance. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 9.
P-F. Lin, K. Guo, R. Fridell, H-T. Ho, G. Yamanaka, and R. Colonno. Identification and Characterization of a Novel Inhibitor of HIV-1 Entry - II: Mechanism of Action. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 10.
T. Yoshinaga, A. Sato, T. Fujishita, and T. Fujiwara. S-1360: in Vitro Activity of a New HIV-1 Integrase Inhibitor in Clinical Development. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 8.
B. Gazzard, A. Pozniak, K. Arasteh, S. Staszewski, W. Rozenbaum, P. Yeni, G. van't Klooster, K. De Dier, M. Peeters, M. P. de Béthune, N. Graham, R. Pauwels. TMC125, A Next-Generation NNRTI, Demonstrates High Potency After 7 Days Therapy in Treatment-Experienced HIV-1-Infected Individuals with Phenotypic NNRTI Resistance. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 4.
S. Sankatsing, G. Weverling, G. van't Klooster, J. Prins, J. Lange. TMC125 Monotherapy for 1 Week Results in a Similar Initial Rate of Decline of HIV-1 RNA as Therapy with a 5-Drug Regimen. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 5.
G. Freeman, A. Hopkins, C. Andrews III, G. Lowell, S. Gonzales, J. Cowan, L. Schaller, G. Koszalka, R. Hazen, L. Boone, R. Ferris, K. Creech, G. Roberts, S. Short, K. Weaver, J. Milton, D. Stuart, D. Stammers, J. Chan. 2-Quinolone Derivatives as Potential HIV NNRTI Agents. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 389.
R. C. Bethell, B. Allard, J. M. De Muys, Z. Gu1, N. Guyen-Ba, C. Ren, M. A. Wainberg, P. McKenna, D. L. Taylor. BCH-13520, a New Heterosubstituted Nucleoside Analogue, Is an Effective Inhibitor of Drug-Resistant HIV-1. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 386.
S. Erickson-Viitanen, R. F. Schinazi, J. Mellors, R. Geleziunas, G. Trainor, J. T. Wu, K. Gallagher, R. Klabe, M. Otto, M. Pierce, D. E. Martin. DPC 817: A Cytidine Nucleoside Analog with Activity against AZT- and 3TC-Resistant Viral Variants. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 385.
W. Lee, G. He, A. Mulato, W. Delaney, E. Eisenberg, T. Cihlar, S. Xiong, M. D. Miller, S. Gill, R. Shibata, C. Gibbs. In Vivo and in Vitro Characterization of GS 7340, an Isopropylalaninyl Phenyl Ester Prodrug of Tenofovir; Selective Intracellular Activation of GS 7340 Leads to Preferential Distribution in Lymphatic Tissues. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 384.