Current problems and the future of antiretroviral drug trials

Science

Volumn 276, Issue 5312, 1997, Pages 548-550

  Lange, Joep M A ^a,b  

^a UNIVERSITY OF AMSTERDAM   (Netherlands)

^b BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIRETROVIRUS AGENT; CD4 ANTIGEN; LAMIVUDINE; PROTEINASE INHIBITOR; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; TRANSACTIVATOR PROTEIN;

CLINICAL RESEARCH; CLINICAL TRIAL; DRUG RESEARCH; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; PRIORITY JOURNAL; REVIEW; TREATMENT OUTCOME; VIRUS INHIBITION;

ACQUIRED IMMUNODEFICIENCY SYNDROME; ANTI-HIV AGENTS; CONTROLLED CLINICAL TRIALS; DRUG ADMINISTRATION SCHEDULE; DRUG INDUSTRY; DRUG RESISTANCE, MICROBIAL; DRUG THERAPY, COMBINATION; HIV; HIV INFECTIONS; HUMANS; VIRAL LOAD; VIRUS REPLICATION;

EID: 0030948565     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.276.5312.548     Document Type: Review

References (42)

1. X. Wei et al., Nature 373, 117 (1995); D. D. Ho et al., ibid., p. 123; J. M. Coffin, Science 267, 483 (1995); A. S. Perelson, A. U. Neumann, M. Markowitz, J. M. Leonard, D. D. Ho, ibid. 271, 1582 (1996).
2. X. Wei et al., Nature 373, 117 (1995); D. D. Ho et al., ibid., p. 123; J. M. Coffin, Science 267, 483 (1995); A. S. Perelson, A. U. Neumann, M. Markowitz, J. M. Leonard, D. D. Ho, ibid. 271, 1582 (1996).
3. X. Wei et al., Nature 373, 117 (1995); D. D. Ho et al., ibid., p. 123; J. M. Coffin, Science 267, 483 (1995); A. S. Perelson, A. U. Neumann, M. Markowitz, J. M. Leonard, D. D. Ho, ibid. 271, 1582 (1996).
4. X. Wei et al., Nature 373, 117 (1995); D. D. Ho et al., ibid., p. 123; J. M. Coffin, Science 267, 483 (1995); A. S. Perelson, A. U. Neumann, M. Markowitz, J. M. Leonard, D. D. Ho, ibid. 271, 1582 (1996).
5. D. D. Richman, Science 272, 1886 (1996); W. A. O'Brien et al., N. Engl. J. Med. 334, 426 (1996); J. W. Mellors et al., Science 272, 1167 (1996).
6. D. D. Richman, Science 272, 1886 (1996); W. A. O'Brien et al., N. Engl. J. Med. 334, 426 (1996); J. W. Mellors et al., Science 272, 1167 (1996).
7. D. D. Richman, Science 272, 1886 (1996); W. A. O'Brien et al., N. Engl. J. Med. 334, 426 (1996); J. W. Mellors et al., Science 272, 1167 (1996).
8. J. M. A. Lange and D. D. Richman, Antiviral Ther. 1, 69 (1996).
9. E. A. Emini, 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract L1) [Infectious Diseases Society of America (IDSA) Foundation for Retrovirology and Human Health, Alexandria, VA, 1996].
10. D. D. Richman and J. M. A. Lange, Antiviral Ther. 1, 208 (1996).
11. C. A. B. Boucher and B. A. Larder, Viral Variation and Therapeutic Strategies in HIV Infection (MediTech Media, London, 1994); J. H. Condra et al., Nature 374, 569 (1995).
12. C. A. B. Boucher and B. A. Larder, Viral Variation and Therapeutic Strategies in HIV Infection (MediTech Media, London, 1994); J. H. Condra et al., Nature 374, 569 (1995).
13. D. Rey et al., Antiviral Ther. 1 (suppl. 1), 24 (1996).
14. R. T. Schooley, AIDS 10 (suppl. 2), S1 (1996).
15. E. S. Daar, X. L. Li, T. Moudgil, D. D. Ho, Proc. Natl. Acad. Sci. U.S.A. 87, 6574 (1990); J. P. Moore, J. A. McKeating, Y. Huang, A. Ashkenazi, D. D. Ho, J. Virol. 66, 235 (1992).
16. E. S. Daar, X. L. Li, T. Moudgil, D. D. Ho, Proc. Natl. Acad. Sci. U.S.A. 87, 6574 (1990); J. P. Moore, J. A. McKeating, Y. Huang, A. Ashkenazi, D. D. Ho, J. Virol. 66, 235 (1992).
17. D. L. Georges, M.-C. Hsu, E. Connell, S. Tam, M. M. Lederman, 2nd National Conference on Human Retroviruses and Related Infections, Washington, DC, 29 January to 2 February 1995 (abstract 480) (American Society for Microbiology, Washington, DC, 1995).
18. M. Bryant et al., Antimicrob. Agents Chemother. 39, 2229 (1995).
19. D. J. Manion, D. P. Merrill, M. S. Hirsch, 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, 22 to 26 January 1997 (abstract 11) (IDSA Foundation for Retrovirology and Human Health, Alexandria, VA, 1997).
20. B. Cameron et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract LB6a).
21. F. Ryan, The Forgotten Plague: How the Battle Against Tuberculosis Was Won and Lost (Little-Brown, Boston, MA, 1992).
22. R. Schuurman et al., J. Infect. Dis. 171, 1431 (1995).
23. D. D. Richman et al., J. Virol. 68, 1660 (1994).
24. R. Yarchoan et al., J. Infect. Dis. 169, 9 (1994); M. D. de Jong et al., ibid., p. 1346.
25. R. Yarchoan et al., J. Infect. Dis. 169, 9 (1994); M. D. de Jong et al., ibid., p. 1346.
26. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
27. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); M. W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
28. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
29. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
30. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
31. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
32. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
33. R. M. Gulick et al., XIth International Conference on AIDS, Vancouver, 7 to 12 July 1996 (abstract Th.B.931) (Transcontinental Printing, Vancouver, Canada, 1996); W. Meyers et al., ibid. (abstract Mo.B.294); D. Mathez et al., ibid. (abstract Mo.B.175); M. Markowitz et al., ibid. (abstract Th.B.933); A. S. Perelson, P. Essunger, M. Markowitz, D. D. Ho, ibid. (abstract Th.B.930); A.G. Saimot et al., ibid. (abstract Mo.B.1332); D. Mathez, C. Winter, J. Leibowitch, ibid. (abstract Tu.B.2115); F. Massari et al., 3rd Conference on Retroviruses and Opportunistic Infections, Washington, DC, 28 January to 1 February 1996 (abstract 200).
34. For instance, the comparison between zalcitabine (ddC) and zidovudine (ZDV) in antiretroviral-naive patients (ACTG 114), showing inferiority of ddC to ZDV, to my knowledge still has not been published many years after completion of the trial. I am not sure, however, whether the blame for such delayed reporting always lies with the pharmaceutical company concerned. It may also lie with the investigators or medical journals concerned, who may not be very eager to publish "nonsexy" study results.
35. M. Gisslén, G. Norkrans, B. Svennerholm, L. Hagberg, J. Infect. Dis. 175, 434 (1997); N. Foudraine et al., 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, 22 to 26 January 1997 (abstract LB5).
36. M. Gisslén, G. Norkrans, B. Svennerholm, L. Hagberg, J. Infect. Dis. 175, 434 (1997); N. Foudraine et al., 4th Conference on Retroviruses and Opportunistic Infections, Washington, DC, 22 to 26 January 1997 (abstract LB5).
37. H. C. Lane, Fourth International Workshop on HIV Drug Resistance, Sardinia, 6 to 9 July 1995 (abstract 1) (Workshop Secretariat, Wellcome Research Laboratories).
38. J. A. Kovacs et al., N. Engl. J. Med. 335, 1350 (1996).
39. J. M. A. Lange and D. D. Richman, Antiviral Ther. 1, 126 (1996).
40. Not more than 1% of HIV-infected participants in the Amsterdam Cohort Studies on HIV Infection and AIDS have experienced no deterioration of immune status during 10 years of follow-up (R. Keet, personal communication).
41. M. M. Kitahata, T. D. Koepsell, R. A. Deyo, N. Engl. J. Med. 334, 701 (1996).
42. This article is based on the presentation "Tribulations of Trials: Where Do We Go From Here?," which I gave on 25 January 1997 at the 4th Conference on Retroviruses and Opportunistic Infections, in Washington, DC. I thank R. T. Schooley and D. D. Richman for stimulating me to formulate my thoughts on this subject; I am very much indebted to them. I also thank G. J. Weverling and R. van Leeuwen for help.