SPECIAL REPORT
Fusion inhibitors intercept virus at cell entry point
Researchers at the 8th Conference on Retroviruses and Opportunistic Infections, held in February 2001 in Chicago, presented a variety of studies on the use of fusion inhibitors as possible HIV treatment. This new class of drugs is expected to fight HIV at its entry point into a cell and has the potential of being a well-tolerated and potent treatment that could be used in combination with antiretroviral medications.
Here is a brief summary of some of the fusion inhibitor research presented:
• A 36-amino-acid synthetic peptide called T-20 demonstrated the greatest plasma drug exposure in a cohort receiving subcutaneous doses of 60 mg/m2 when compared with two lower-dose intravenous cohorts. Also, people receiving the subcutaneous dose achieved 12-hour troughs above the target level of 1,000 ng/mL.1
• Fusion inhibitors T-20 and T-1249, currently in Phase III and Phase I/II clinical trials, respectively, target a structural transition in the viral envelope glycoprotein gp41 required for membrane fusion and virus entry. This study found that virus coreceptor usage does not modulate sensitivity to the fusion inhibitors investigated, despite recent reports suggesting such a result.2
• Separate research involving fusion inhibitors T-20 and T-649 found that sensitivity to both of the synthetic peptides is strongly influenced by coreceptor specificity defined by the V3 loop of gp120.3
• A combination of CCR5 and CXCR4 inhibitors completely blocked infection with CCR5 HIV-1 infection, while each inhibitor alone was only partially effective in blocking CCR5 or CXCR4 HIV-1 infection. The research suggests that combinations of the inhibitors may prevent coreceptor switch variants and provide increased safety.4
• One abstract built upon previous research showing that double- and triple-drug cocktails of attachment inhibitors, coreceptor inhibitors, and fusion inhibitors potently and synergistically block HIV-1 entry over a wide range of experimental conditions in vitro. Investigators found that the data suggested a model in which the drugs act cooperatively to delay the recruitment of a critical number of fusion-active HIV-1 envelope glycoproteins to the site of the fusion pore.5
• A Phase II trial assessing various doses of T-20 used in combination with a protease inhibitor regimen found that patients who were failing therapy with at least one PI and who were naive to non-nucleoside reverse transcriptase inhibitors fared better with the addition of T-20 to their antiretroviral regimens. T-20 was well-tolerated and provided additional virologic and immunologic activity in addition to that provided by the oral antiretroviral regimen alone.6
• A pediatric study of T-20 indicated that short-term subcutaneous administration of T-20 is safe and well-tolerated in children, and the compound rapidly suppresses HIV.7
• Based on a promoter single nucleotide polymorphism (59029) differences in CCR5 expression on monocytes correlate with genotype (59029 G/G = low; G/A = medium; A/A = high CCR5 expression on monocytes). There’s a logical increase in viral propagation of R5 viruses in cells that have higher levels of CCR5 expression.8
References
1. Kosel B, Church J, Cunningham C, et al. Pharmacokinetics (PK) of selected doses of T-20, a fusion inhibitor, in HIV-1-infected children. Abstract 726 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
2. Greenberg ML, McDanal CB, Stanfield-Oakley SA, et al. Virus sensitivity to T-20 and T-1249 is independent of coreceptor usage. Abstract 473 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
3. Derdyn CA, Decker JM, Sfakianos JN, et al. Sensitivity of HIV-1 to the fusion inhibitors T-20 and T-649 is modulated by coreceptor specificity and involves distinct regions of gp41. Abstract 475 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
4. Picchio G, Sabbe R, Neal M, et al. Coreceptor trap therapy: Combination of CCR5 and CDCR4 inhibitors blocks human immunodeficiency virus type I infection in vivo. Abstract 311 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
5. Nagashima K, Rosenfield S, Thompson D, et al. Mechanisms of synergy between HIV-1 attachment, coreceptor and fusion inhibitors. Abstract 310 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
6. Lalezari J, Drucker J, Demasi R, et al. A controlled phase II trial assessing three doses of T-20 in combination with Abacavir, Amprenavir, low dose Ritonavir and Efavirenz in non-nucleoside naive protease inhibitor experienced HIV-1 infected adults. Abstract LB5 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
7. Church J, Cunningham C, Palumbo P, et al. Safety and antiviral activity of chronic subcutaneous administration of T-20 in HIV-1-infected children. Abstract 681 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
8. Salkowitz JR, Zimmerman PA, Meyerson HJ, et al. CCR5 promoter and open reading frame polymorphisms affect in vitro susceptibility to infection with X4-tropic HIV-1. Abstract 46 presented at the 8th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 4-8, 2001.
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