Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1994 Apr;38(4):656–661. doi: 10.1128/aac.38.4.656

Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro.

T Mazzulli 1, S Rusconi 1, D P Merrill 1, R T D'Aquila 1, M Moonis 1, T C Chou 1, M S Hirsch 1
PMCID: PMC284521  PMID: 8031028

Abstract

We compared the in vitro efficacies of two-, three-, and four-drug combinations given continuously or in alternating regimens against a clinical isolate of human immunodeficiency virus type 1. In H9 cells and peripheral blood mononuclear cells, at the drug concentrations used in this study, there was greater suppression of human immunodeficiency virus type 1 infection as the number of drugs in the regimen was increased from one to four simultaneously administered agents. Although alternating drug regimens were effective, they were not better than continuous administration of either single drugs or combinations of agents and were less effective than giving all drugs of an alternating regimen simultaneously.

Full text

PDF
656

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berglund O., Engman K., Ehrnst A., Andersson J., Lidman K., Akerlund B., Sönnerborg A., Strannegård O. Combined treatment of symptomatic human immunodeficiency virus type 1 infection with native interferon-alpha and zidovudine. J Infect Dis. 1991 Apr;163(4):710–715. doi: 10.1093/infdis/163.4.710. [DOI] [PubMed] [Google Scholar]
  2. Campbell T. B., Young R. K., Eron J. J., D'Aquila R. T., Tarpley W. G., Kuritzkes D. R. Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine. J Infect Dis. 1993 Aug;168(2):318–326. doi: 10.1093/infdis/168.2.318. [DOI] [PubMed] [Google Scholar]
  3. Chou T. C. On the determination of availability of ligand binding sites in steady-state systems. J Theor Biol. 1977 Mar 21;65(2):345–356. doi: 10.1016/0022-5193(77)90329-0. [DOI] [PubMed] [Google Scholar]
  4. Chou T. C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. doi: 10.1016/0065-2571(84)90007-4. [DOI] [PubMed] [Google Scholar]
  5. Chow Y. K., Hirsch M. S., Merrill D. P., Bechtel L. J., Eron J. J., Kaplan J. C., D'Aquila R. T. Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature. 1993 Feb 18;361(6413):650–654. doi: 10.1038/361650a0. [DOI] [PubMed] [Google Scholar]
  6. Davey R. T., Jr, Davey V. J., Metcalf J. A., Zurlo J. J., Kovacs J. A., Falloon J., Polis M. A., Zunich K. M., Masur H., Lane H. C. A phase I/II trial of zidovudine, interferon-alpha, and granulocyte-macrophage colony-stimulating factor in the treatment of human immunodeficiency virus type 1 infection. J Infect Dis. 1991 Jul;164(1):43–52. doi: 10.1093/infdis/164.1.43. [DOI] [PubMed] [Google Scholar]
  7. Dueweke T. J., Poppe S. M., Romero D. L., Swaney S. M., So A. G., Downey K. M., Althaus I. W., Reusser F., Busso M., Resnick L. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother. 1993 May;37(5):1127–1131. doi: 10.1128/aac.37.5.1127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Eron J. J., Chow Y. K., Caliendo A. M., Videler J., Devore K. M., Cooley T. P., Liebman H. A., Kaplan J. C., Hirsch M. S., D'Aquila R. T. pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo. Antimicrob Agents Chemother. 1993 Jul;37(7):1480–1487. doi: 10.1128/aac.37.7.1480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eron J. J., Gorczyca P., Kaplan J. C., D'Aquila R. T. Susceptibility testing by polymerase chain reaction DNA quantitation: a method to measure drug resistance of human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3241–3245. doi: 10.1073/pnas.89.8.3241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eron J. J., Jr, Johnson V. A., Merrill D. P., Chou T. C., Hirsch M. S. Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro. Antimicrob Agents Chemother. 1992 Jul;36(7):1559–1562. doi: 10.1128/aac.36.7.1559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fitzgibbon J. E., Howell R. M., Haberzettl C. A., Sperber S. J., Gocke D. J., Dubin D. T. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother. 1992 Jan;36(1):153–157. doi: 10.1128/aac.36.1.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gao W. Y., Shirasaka T., Johns D. G., Broder S., Mitsuya H. Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J Clin Invest. 1993 May;91(5):2326–2333. doi: 10.1172/JCI116463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hartshorn K. L., Vogt M. W., Chou T. C., Blumberg R. S., Byington R., Schooley R. T., Hirsch M. S. Synergistic inhibition of human immunodeficiency virus in vitro by azidothymidine and recombinant alpha A interferon. Antimicrob Agents Chemother. 1987 Feb;31(2):168–172. doi: 10.1128/aac.31.2.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jacobsen M. A., van der Horst C., Causey D. M., Dehlinger M., Hafner R., Mills J. In vivo additive antiretroviral effect of combined zidovudine and foscarnet therapy for human immunodeficiency virus infection (ACTG Protocol 053). J Infect Dis. 1991 Jun;163(6):1219–1222. doi: 10.1093/infdis/163.6.1219. [DOI] [PubMed] [Google Scholar]
  15. Johnson V. A., Barlow M. A., Merrill D. P., Chou T. C., Hirsch M. S. Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A. J Infect Dis. 1990 Jun;161(6):1059–1067. doi: 10.1093/infdis/161.6.1059. [DOI] [PubMed] [Google Scholar]
  16. Johnson V. A., Merrill D. P., Chou T. C., Hirsch M. S. Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro. J Infect Dis. 1992 Nov;166(5):1143–1146. doi: 10.1093/infdis/166.5.1143. [DOI] [PubMed] [Google Scholar]
  17. Johnson V. A., Merrill D. P., Videler J. A., Chou T. C., Byington R. E., Eron J. J., D'Aquila R. T., Hirsch M. S. Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis. 1991 Oct;164(4):646–655. doi: 10.1093/infdis/164.4.646. [DOI] [PubMed] [Google Scholar]
  18. Larder B. A. 3'-Azido-3'-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 1992 Dec;36(12):2664–2669. doi: 10.1128/aac.36.12.2664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Larder B. A., Coates K. E., Kemp S. D. Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture. J Virol. 1991 Oct;65(10):5232–5236. doi: 10.1128/jvi.65.10.5232-5236.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  21. McLeod G. X., Hammer S. M. Zidovudine: five years later. Ann Intern Med. 1992 Sep 15;117(6):487–501. doi: 10.7326/0003-4819-117-6-487. [DOI] [PubMed] [Google Scholar]
  22. McLeod G. X., McGrath J. M., Ladd E. A., Hammer S. M. Didanosine and zidovudine resistance patterns in clinical isolates of human immunodeficiency virus type 1 as determined by a replication endpoint concentration assay. Antimicrob Agents Chemother. 1992 May;36(5):920–925. doi: 10.1128/aac.36.5.920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Meng T. C., Fischl M. A., Boota A. M., Spector S. A., Bennett D., Bassiakos Y., Lai S. H., Wright B., Richman D. D. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study. Ann Intern Med. 1992 Jan 1;116(1):13–20. doi: 10.7326/0003-4819-116-1-13. [DOI] [PubMed] [Google Scholar]
  24. Perno C. F., Yarchoan R., Balzarini J., Bergamini A., Milanese G., Pauwels R., De Clercq E., Rocchi G., Calio R. Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages. Antiviral Res. 1992 Apr;17(4):289–304. doi: 10.1016/0166-3542(92)90024-y. [DOI] [PubMed] [Google Scholar]
  25. Skowron G., Bozzette S. A., Lim L., Pettinelli C. B., Schaumburg H. H., Arezzo J., Fischl M. A., Powderly W. G., Gocke D. J., Richman D. D. Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex. Ann Intern Med. 1993 Mar 1;118(5):321–330. doi: 10.7326/0003-4819-118-5-199303010-00001. [DOI] [PubMed] [Google Scholar]
  26. Smith M. S., Brian E. L., Pagano J. S. Resumption of virus production after human immunodeficiency virus infection of T lymphocytes in the presence of azidothymidine. J Virol. 1987 Dec;61(12):3769–3773. doi: 10.1128/jvi.61.12.3769-3773.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sommadossi J. P. Nucleoside analogs: similarities and differences. Clin Infect Dis. 1993 Feb;16 (Suppl 1):S7–15. doi: 10.1093/clinids/16.supplement_1.s7. [DOI] [PubMed] [Google Scholar]
  28. Spector S. A., Ripley D., Hsia K. Human immunodeficiency virus inhibition is prolonged by 3'-azido-3'-deoxythymidine alternating with 2',3'-dideoxycytidine compared with 3'-azido-3'-deoxythymidine alone. Antimicrob Agents Chemother. 1989 Jun;33(6):920–923. doi: 10.1128/aac.33.6.920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. St Clair M. H., Martin J. L., Tudor-Williams G., Bach M. C., Vavro C. L., King D. M., Kellam P., Kemp S. D., Larder B. A. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 Sep 27;253(5027):1557–1559. doi: 10.1126/science.1716788. [DOI] [PubMed] [Google Scholar]
  30. Yarchoan R., Lietzau J. A., Nguyen B. Y., Brawley O. W., Pluda J. M., Saville M. W., Wyvill K. M., Steinberg S. M., Agbaria R., Mitsuya H. A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. J Infect Dis. 1994 Jan;169(1):9–17. doi: 10.1093/infdis/169.1.9. [DOI] [PubMed] [Google Scholar]
  31. Yarchoan R., Perno C. F., Thomas R. V., Klecker R. W., Allain J. P., Wills R. J., McAtee N., Fischl M. A., Dubinsky R., McNeely M. C. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet. 1988 Jan 16;1(8577):76–81. doi: 10.1016/s0140-6736(88)90283-8. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES