Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Introduction Gavin X. McLeod & Scott M. Hammer To cite this article: Gavin X. McLeod & Scott M. Hammer (1992) Introduction, Hospital Practice, 27:sup2, 3-4, DOI: 10.1080/21548331.1992.11705594 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705594
Published online: 17 May 2016.
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Date: 02 July 2016, At: 22:48
Introduction
Downloaded by [Monash University Library] at 22:48 02 July 2016
GAVIN X. McLEOD
and
SCOTT M. HAMMER
Harvard University
Since the onset of the acquired immunodeficiency syndrome pandemic in 1981, scientists and physicians have made substantial progress in the understanding and treatment of this still fatal disease. For the first six years after AIDS was described, no antiretroviral therapies were generally available for patients infected With the human immunodeficiency virus (HIV) typ~ l. After the discovery of the in vivo antiretroviral effect of zidovudine (AZT, azidothymidine) in 1985, 1 clinical trials of this agent were begun. Within two years, a multicenter double-blind placebo-controlled trial2 demonstrated AZT's efficacy in prolonging the lives of patients With AIDS and AIDS-related complex (ARC). AZT was then quickly approved by the Food and Drug Administration in 1987 as the first licensed antiretroviral agent. Although efficacious, AZT had substantial toxicity-primarily hematologic-which often necessitated discontinuance of therapy. 3.4 Coincident with the early evaluation of AZT, the AIDS Clinical Trials Group (ACTG) was established by the National Institute of Allergy and Infectious Diseases to provide a national organization to coordinate and perform clinical studies of the treatment of HIV-infected patients. Subsequent landmark ACTG studies have defined treatment guidelines With respect to AZT in HIV-infected patients. For example, the benefits oflower-dose therapy have been clarified. In the initial trial2 that demonstrated the agent's efficacy, AZT was given at a dosage of 1,500 mglday. ACTG 0025 showed that 600 mglday (folloWing four weeks of 1,200 mglday) had the same antiretroviral effect as the higher dosage but was associated with a statistically significant increase in survival and a decrease in toxicity. ACTG 0166 and 019 7 were designed to evaluate earlier AZT therapy. ACTG 016, which compared AZT and placebo in patients with early ARC and CD4lymphocyte counts above 200 cells/mm 3, revealed a significant decrease in the development of AIDS and severe ARC in AZT-treated patients. ACTG 019 analyzed the benefit of two differentAZT dosages, 500 mglday and 1,500 mglday, in the treatment of asymptomatic HIV-infected patients. Results showed a significant decrease in progression to AIDS and advanced ARC in both AZT-treat-
ed groups compared With the placebo group. Furthermore, the 500 mglday group did as well as those treated with 1,500 mglday, and they experienced significantly less toxicity. As a result of these studies, a State-of-the-Art Conference convened by the National Institutes of Health in 1990 recommended AZT for all HIV-infected persons With CD4 counts less than 500 cells/mm3.s The benefit of AZT in HIV-infected individuals has also been shown in epidemiologic studies. The Zidovudine Epidemiology Study Group, 9 a multicenter prospective study of 866 patients With AIDS or ARC, found thatAZTsignificantlyprolongedsurvival. Other epidemiologic studies 10·11 have shown that median survival of patients With AIDS and a diagnosis of Pneumocystis cartnit pneumonia increased from 11 to 13 months withoutAZT treatment to 21 to 25 months with treatment. Another study 12 found fewer new cases of AIDS than expected in three cities because of early AZT treatment of HIV-infected homosexual and bisexual men. A Veterans Affairs Cooperative Study 13 has led to controversy over the exact time to initiate AZT therapy in patients With early HIV infection, that is, CD4 counts between 200 and 500 cells/mm3. This study found a decrease in the progression to AIDS in patients given early rather than later therapy when their CD4 count fell below 200 cells/mm3. However, improved survival was not apparent for the early therapy group. In contrast, the Multicenter AIDS Cohort Study14 recently reported a survival benefit from AZT in patients with CD4 counts less than 350 cells/mm3. Although AZT has proved useful, several factors limit its utility. As noted and described in this supplement, AZT toxicities are substantial. Furthermore, AIDS patients who have been takingAZT for more than six months may exhibit signs of clinical deterioration. This decline may be due in part to the development of resistance to AZT, as shown by a
Dr. Mcleod is Clinical and Research Fellow, Harvard Medical School and Division of Infectious Diseases, New England Deaconess Hospital, Boston. Dr. Hammer is Associate Professor of Medicine, Harvard Medical School, and Director, Research Virology Laboratory, New England Deaconess Hospital.
3
Downloaded by [Monash University Library] at 22:48 02 July 2016
number ofinvestigators. 15• 18 While correlations between resistance and clinical outcome are still being studied, the limited efficacy of AZT and the discovery of resistant isolates have prompted development of newer antiretroViral agents. Didanosine (ddl, dideoxyinosine) became the second antiretroviral agent to be licensed when it was approved by the FDA in 1991. Although studies have not yet demonstrated improved survival with this agent, ddl has been shown to increase CD4 counts and to decrease HN p24 antigen levels in patients with advanced HN infection who are intolerant to AZT or in whom therapy has failed. 19•21 More recently, a preliminary analysis ofthe yet unpublishedACTG trial116B/ 117 showed that ddl at 500 mg/day may be more beneficial than AZT in patients with advanced HN infection who have re-
ceived at least 16 weeks of AZT therapy. The third major dideoxynucleoside to date, zalcitabine (ddC, dideoxycytidine), was only recently approved by the FDA for use in combination with AZT in patients with advanced infection. Clinical trial data22 accrued thus far suggest that ddC monotherapy is less efficacious than AZT, but ddC may prove particularly valuable in combination therapy. As the AIDS pandemic enters its second decade, treatment of HN becomes more complex as well as more effective. The primary care physician must keep abreast of the rapidly evolving field of antiretroViral therapy. This supplement will detail experience with the nucleoside analogues as monotherapy, the current status and promise of combination therapy, and the toxicities of these agents. D
References 1. Mitsuya H et al: 3'-Azido-3'-deoxythym!dine (BW A509U): An antiViral agent that inhibits the infectivi· ty and cytopathic effect of human T-lymphotroplc virus type Ill/lymphadenopathy-associated virus in vitro. Proc NatlAcad Sci USA82: 7096, 1985 2. Fischl MA et al: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. NEnglJMed317:185, 1987 3. Richman DD et al: The toxicity of azidothymidine (AZTJ in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. Ibid, p 192 4. Groopman JE: Zidovudine intolerance. Rev Infect Dis 12(Suppl5):500, 1990 5. Fischl MA et al: A randomized controlled trial of areduced daily dose of zidovudine in patients with the acquired Immunodeficiency syndrome. N Engl J Med 323: 1009, 1990 6. Fischl MA et al: The safety and efficacy of zidovudlne (AZTJ In the treatment of subjects with mildly symptomatic HIV infection: A double-blind. placebo-controlled trial. Ann Intern Med 112:727, 1990 7. Volberding PA et al: Zidovudine in asymptomatic human immunodeficiency virus infection. N Engl J Med322:941, 1990 8. State-of-the-Art Conference on Azidothymidine Therapy for Early HIV Infection. Am J Med 89: 335, 1990 9. Moore RD et al: Long-term safety and efficacy of zidovudlne In patients with advanced human immunodeficiency disease. Arch Intern Med 151 : 981, 1991 10. Creagh-Kirk T et al: Survival experience among patients with AIDS receiving zidovudine. JAMA 260:3009,1988 11. Moore RD et al: Zidovudine and the natural history of the acquired immunodeficiency syndrome. N EnglJMed324:1412,1991 12. Gail MH et al: Therapy may explain recent deficits In
4
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
AIDS incidence. J Acquir Immune Defic Syndr 3:296, 1990 Hamilton JD et al: A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency Virus infection: Results of the Veterans Affairs Cooperative Study. N Engl J Med326:437, 1992 Graham NMH et al: The effects on survival of early treatment of human immunodeficiency Virus infection. N Engl J Med 326: 1037, 1992 Larder BA et al: HIV with reduced sensitivity to zidovudine (AZTJ isolated during prolonged therapy. Science 243 : 1731, 1989 Rooke et al: Isolation of drug-resistant isolates of HIV-1 from patients on long-term zidovudlne therapy.AIDS3:411. 1989 McLeod GX et al: 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 36: 920, 1992 Boucher CAB et al: Ordered appearance of zidovudine resistance mutations during treatment of 18 human Immunodeficiency Virus-positive subjects. J InfectD!s 165:105, 1992 Lambert JS et al: 2',3'-Dideoxylnosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: A phase I trial. N EnglJMed322:1333.1990 CooleyTP etal: Once-daily administration of2',3'dideoxylnosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Ibid, p 1340 Connolly KJ et al: Phase I study of 2' ,3'-dideoxytnosine (ddl) administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine. Am J Med 91 : 4 71, 1991 Salgo MP: Letter to physicians. Hoffmann-La Roche Inc, 1/13/92
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Introduction Gavin X. McLeod & Scott M. Hammer To cite this article: Gavin X. McLeod & Scott M. Hammer (1992) Introduction, Hospital Practice, 27:sup2, 3-4, DOI: 10.1080/21548331.1992.11705594 To link to this article: http://dx.doi.org/10.1080/21548331.1992.11705594
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Monash University Library]
Date: 02 July 2016, At: 22:48
Introduction
Downloaded by [Monash University Library] at 22:48 02 July 2016
GAVIN X. McLEOD
and
SCOTT M. HAMMER
Harvard University
Since the onset of the acquired immunodeficiency syndrome pandemic in 1981, scientists and physicians have made substantial progress in the understanding and treatment of this still fatal disease. For the first six years after AIDS was described, no antiretroviral therapies were generally available for patients infected With the human immunodeficiency virus (HIV) typ~ l. After the discovery of the in vivo antiretroviral effect of zidovudine (AZT, azidothymidine) in 1985, 1 clinical trials of this agent were begun. Within two years, a multicenter double-blind placebo-controlled trial2 demonstrated AZT's efficacy in prolonging the lives of patients With AIDS and AIDS-related complex (ARC). AZT was then quickly approved by the Food and Drug Administration in 1987 as the first licensed antiretroviral agent. Although efficacious, AZT had substantial toxicity-primarily hematologic-which often necessitated discontinuance of therapy. 3.4 Coincident with the early evaluation of AZT, the AIDS Clinical Trials Group (ACTG) was established by the National Institute of Allergy and Infectious Diseases to provide a national organization to coordinate and perform clinical studies of the treatment of HIV-infected patients. Subsequent landmark ACTG studies have defined treatment guidelines With respect to AZT in HIV-infected patients. For example, the benefits oflower-dose therapy have been clarified. In the initial trial2 that demonstrated the agent's efficacy, AZT was given at a dosage of 1,500 mglday. ACTG 0025 showed that 600 mglday (folloWing four weeks of 1,200 mglday) had the same antiretroviral effect as the higher dosage but was associated with a statistically significant increase in survival and a decrease in toxicity. ACTG 0166 and 019 7 were designed to evaluate earlier AZT therapy. ACTG 016, which compared AZT and placebo in patients with early ARC and CD4lymphocyte counts above 200 cells/mm 3, revealed a significant decrease in the development of AIDS and severe ARC in AZT-treated patients. ACTG 019 analyzed the benefit of two differentAZT dosages, 500 mglday and 1,500 mglday, in the treatment of asymptomatic HIV-infected patients. Results showed a significant decrease in progression to AIDS and advanced ARC in both AZT-treat-
ed groups compared With the placebo group. Furthermore, the 500 mglday group did as well as those treated with 1,500 mglday, and they experienced significantly less toxicity. As a result of these studies, a State-of-the-Art Conference convened by the National Institutes of Health in 1990 recommended AZT for all HIV-infected persons With CD4 counts less than 500 cells/mm3.s The benefit of AZT in HIV-infected individuals has also been shown in epidemiologic studies. The Zidovudine Epidemiology Study Group, 9 a multicenter prospective study of 866 patients With AIDS or ARC, found thatAZTsignificantlyprolongedsurvival. Other epidemiologic studies 10·11 have shown that median survival of patients With AIDS and a diagnosis of Pneumocystis cartnit pneumonia increased from 11 to 13 months withoutAZT treatment to 21 to 25 months with treatment. Another study 12 found fewer new cases of AIDS than expected in three cities because of early AZT treatment of HIV-infected homosexual and bisexual men. A Veterans Affairs Cooperative Study 13 has led to controversy over the exact time to initiate AZT therapy in patients With early HIV infection, that is, CD4 counts between 200 and 500 cells/mm3. This study found a decrease in the progression to AIDS in patients given early rather than later therapy when their CD4 count fell below 200 cells/mm3. However, improved survival was not apparent for the early therapy group. In contrast, the Multicenter AIDS Cohort Study14 recently reported a survival benefit from AZT in patients with CD4 counts less than 350 cells/mm3. Although AZT has proved useful, several factors limit its utility. As noted and described in this supplement, AZT toxicities are substantial. Furthermore, AIDS patients who have been takingAZT for more than six months may exhibit signs of clinical deterioration. This decline may be due in part to the development of resistance to AZT, as shown by a
Dr. Mcleod is Clinical and Research Fellow, Harvard Medical School and Division of Infectious Diseases, New England Deaconess Hospital, Boston. Dr. Hammer is Associate Professor of Medicine, Harvard Medical School, and Director, Research Virology Laboratory, New England Deaconess Hospital.
3
Downloaded by [Monash University Library] at 22:48 02 July 2016
number ofinvestigators. 15• 18 While correlations between resistance and clinical outcome are still being studied, the limited efficacy of AZT and the discovery of resistant isolates have prompted development of newer antiretroViral agents. Didanosine (ddl, dideoxyinosine) became the second antiretroviral agent to be licensed when it was approved by the FDA in 1991. Although studies have not yet demonstrated improved survival with this agent, ddl has been shown to increase CD4 counts and to decrease HN p24 antigen levels in patients with advanced HN infection who are intolerant to AZT or in whom therapy has failed. 19•21 More recently, a preliminary analysis ofthe yet unpublishedACTG trial116B/ 117 showed that ddl at 500 mg/day may be more beneficial than AZT in patients with advanced HN infection who have re-
ceived at least 16 weeks of AZT therapy. The third major dideoxynucleoside to date, zalcitabine (ddC, dideoxycytidine), was only recently approved by the FDA for use in combination with AZT in patients with advanced infection. Clinical trial data22 accrued thus far suggest that ddC monotherapy is less efficacious than AZT, but ddC may prove particularly valuable in combination therapy. As the AIDS pandemic enters its second decade, treatment of HN becomes more complex as well as more effective. The primary care physician must keep abreast of the rapidly evolving field of antiretroViral therapy. This supplement will detail experience with the nucleoside analogues as monotherapy, the current status and promise of combination therapy, and the toxicities of these agents. D
References 1. Mitsuya H et al: 3'-Azido-3'-deoxythym!dine (BW A509U): An antiViral agent that inhibits the infectivi· ty and cytopathic effect of human T-lymphotroplc virus type Ill/lymphadenopathy-associated virus in vitro. Proc NatlAcad Sci USA82: 7096, 1985 2. Fischl MA et al: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. NEnglJMed317:185, 1987 3. Richman DD et al: The toxicity of azidothymidine (AZTJ in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. Ibid, p 192 4. Groopman JE: Zidovudine intolerance. Rev Infect Dis 12(Suppl5):500, 1990 5. Fischl MA et al: A randomized controlled trial of areduced daily dose of zidovudine in patients with the acquired Immunodeficiency syndrome. N Engl J Med 323: 1009, 1990 6. Fischl MA et al: The safety and efficacy of zidovudlne (AZTJ In the treatment of subjects with mildly symptomatic HIV infection: A double-blind. placebo-controlled trial. Ann Intern Med 112:727, 1990 7. Volberding PA et al: Zidovudine in asymptomatic human immunodeficiency virus infection. N Engl J Med322:941, 1990 8. State-of-the-Art Conference on Azidothymidine Therapy for Early HIV Infection. Am J Med 89: 335, 1990 9. Moore RD et al: Long-term safety and efficacy of zidovudlne In patients with advanced human immunodeficiency disease. Arch Intern Med 151 : 981, 1991 10. Creagh-Kirk T et al: Survival experience among patients with AIDS receiving zidovudine. JAMA 260:3009,1988 11. Moore RD et al: Zidovudine and the natural history of the acquired immunodeficiency syndrome. N EnglJMed324:1412,1991 12. Gail MH et al: Therapy may explain recent deficits In
4
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
AIDS incidence. J Acquir Immune Defic Syndr 3:296, 1990 Hamilton JD et al: A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency Virus infection: Results of the Veterans Affairs Cooperative Study. N Engl J Med326:437, 1992 Graham NMH et al: The effects on survival of early treatment of human immunodeficiency Virus infection. N Engl J Med 326: 1037, 1992 Larder BA et al: HIV with reduced sensitivity to zidovudine (AZTJ isolated during prolonged therapy. Science 243 : 1731, 1989 Rooke et al: Isolation of drug-resistant isolates of HIV-1 from patients on long-term zidovudlne therapy.AIDS3:411. 1989 McLeod GX et al: 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 36: 920, 1992 Boucher CAB et al: Ordered appearance of zidovudine resistance mutations during treatment of 18 human Immunodeficiency Virus-positive subjects. J InfectD!s 165:105, 1992 Lambert JS et al: 2',3'-Dideoxylnosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: A phase I trial. N EnglJMed322:1333.1990 CooleyTP etal: Once-daily administration of2',3'dideoxylnosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Ibid, p 1340 Connolly KJ et al: Phase I study of 2' ,3'-dideoxytnosine (ddl) administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine. Am J Med 91 : 4 71, 1991 Salgo MP: Letter to physicians. Hoffmann-La Roche Inc, 1/13/92
