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Covering All the Bases: Targeting HIV-1 Integrase
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[Editorial]
"...it is possible that......new antiretroviral targets (integrase inhibitors, CCR5 antagonists, maturation inhibitors) and new agents in existing classes (TMC 125)....will change our treatment paradigms as radically as the first efficacy trials of HAART in the mid-1990s altered the face of HIV treatment in the developed world."
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 43(5) 15 December 2006 pp 507-508
Wong, Joseph K MD*; Lampiris, Harry MD*
From the *Medical Service, Veterans Affairs Medical Center, San Francisco, CA; and Department of Medicine, University of California San Francisco, San Francisco, CA.
In this issue of JAIDS, Markowitz et al1 report another milestone for HIV therapeutics, the safety and short-term virologic efficacy data for MK-0518 (Merck & Co., Inc., West Point, PA). This represents the first published human data on the in vivo efficacy and tolerability of an antiretroviral drug directed at the last of the 3 HIV-1-encoded enzymes critical for completion of the viral life cycle, the HIV integrase. This short-term monotherapy study suggests that MK-0518 has extremely impressive in vivo antiviral potency that, despite necessary caveats about cross-study comparisons, matches or exceeds the most potent compounds now in use. As a new class of antiretroviral compound, it promises to have strong activity against all existing drug-resistant HIV-1.
A requirement for high-level HIV production after infecting a susceptible cell is the integration of the reverse-transcribed HIV viral DNA into the host chromosome, a 2-step process mediated by the HIV integrase. Integrase catalyzes a preparatory step that excises 2 nucleotides from 1 strand at both ends of the HIV DNA and a final strand-transfer step that inserts the viral DNA into exposed regions of cellular DNA. This 2nd step of the integration process is targeted by MK-0518 and related compounds that were shown earlier to have potent antiviral activity in vitro2 and in animal models.3
MK-0518 is a structural analogue of a class of compounds with a distinct di-keto acid moiety that confers a range of different inhibitory potencies. It is metabolized by hepatic glucuronidation and has no effect on CYP3A4. Although the prototype L-733,988 and L-708,906 compounds exhibited 50% inhibitory concentration (IC50) of 80 nM and 150 nM against wild-type HIV,2 MK-0518 has an IC95 of 33 nM.
In the present phase of the study, 35 drug-naive patients were randomized to 1 of 4 doses of MK-0518 (600, 400, 200, and 100 mg) or to placebo taken orally twice daily. Pharmokinetic studies showed mean trough levels exceeding the IC95 at all doses. At the doses used, adverse effects were mild and were reported no more frequently in patients receiving MK-0518 than for patients receiving placebo.
Markowitz et al1 used frequent viral load assessments during 10 days of monotherapy to investigate the in vivo antiviral potency of MK-0518. The first-phase slope of decay of HIV RNA after administration of antiviral therapy provides a measure of the effectiveness of inhibition of HIV-1 replication.4,5 Using this metric, the decay, resulting in approximately a 2-log reduction in plasma viral load after 10 days of treatment at all 4 doses, equaled or exceeded those reported with all existing antiviral compounds studied in this way and compares favorably to some multidrug combinations.5-7 Impressively, the recently presented phase II data comparing 2 nucleosides with efavirenz versus 2 nucleosides plus MK-0518 showed significantly more rapid reductions in HIV RNA in the MK-0518 arm than in the efavirenz arm at several time points.8 Furthermore, although the long-term efficacy of MK-0518 remains to be determined, this and another ongoing, phase-2 study indicates sustained virologic activity after 16 to 24 weeks of therapy for both drug-naive and -experienced patients with multidrug-resistant HIV-1.8,9
How this agent and this class of antiviral compounds will fit into the anti-HIV armamentarium remains to be seen. Features like the genetic barrier to the development of drug resistance, whether resistance impairs virus replication capacity or fitness, synergism with other antivirals, the pharmacodynamic predictors of virologic efficacy, the pharmacokinetic interactions with other available antiretroviral agents and other drugs, and long-term tolerability and toxicity will all impact the clinical value of MK-0518. An important question for the future is how effective this drug will be against non-B subtype HIV-1. As the first in class of drugs against a new target, it should be a welcome addition for treatment of patients infected with multidrug-resistant virus. Because a large number of new antiretroviral targets (integrase inhibitors, CCR5 antagonists, maturation inhibitors) and new agents in existing classes (TMC 125) are in advanced clinical development, much research must be done to determine the optimum utilization of combination therapy with these new agents in highly treatment-experienced patients. It is possible that these new developments will change our treatment paradigms as radically as the first efficacy trials of HAART in the mid-1990s altered the face of HIV treatment in the developed world.
REFERENCES
1. Markowitz M, Morales-Ramirez JO, Nguyen B-Y, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006;43:509-515.
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2. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration inhibit HIV-1 replication in cells. Science. 2000;287:646-650.
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3. Hazuda DJ, Young SD, Guare JP, et al. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science. 2004;305:528-532.
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4. Ho DD, Neumann AU, Perelson AS, et al Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373:123-126.
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5. Louie M, Hogan C, Di Mascio M, et al. Determining the efficacy of highly active antiretroviral therapy. J Infect Dis. 2003;187:896-900.
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6. Kilby JM, Lalezari JP, Eron JJ, et al. The safety, plasma pharmacokinetcs, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Research and Human Retroviruses. 2002;18:685-693.
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7. Louie M, Hogan C, Hurley A, et al. Determining the antiviral activity of tenofovir disoproxil fumarate in treatment-naive chronically HIV-1 infected individuals. AIDS. 2003;17:1151-1156.
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8. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. XVI, International AIDS Conference. Toronto, Canada, Aug 13-18, 2006.
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9. Grinsztejn B, Nguyen B-Y, Katlama C, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistance virus. 13th Conference on Retroviruses and Opportunistic Infections 2006, Denver, CO.
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