Salvage Therapy for Zidovudine-Intolerant HIV-Infected Patients with Alternating and Intermittent Regimens of Zidovudine and Dideoxycytidine SAMUELA. BOZZEITE,M.D., DOUGLASD. RICHMAN,M.D. San Diego, ca/ifornia
ntiretroviral therapy with nucleoside analogues is A a cornerstone of current acquired immunodeficiency syndrome (AIDS) treatment [l]. Unfortu-
Zidovudine (AZT) prolongs life in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex but often causes dose-limiting bone marrow suppression in this population. This has prompted a search for salvage therapies for use in persons who cannot tolerate continuous AZT treatment. One approach involves alternating administration of AZT and 2’,3’dideoxycytidine. 2’,3’-Dideoxycytidine is a potent inhibitor of human immunodeficiency virus in vitro and in uivo. Although it does not cause clinically significant bone marrow suppression, its usefulness at high continuous doses is limited by the occurrence of painful peripheral neuropathy. Because the toxicities of these nucleosides are non-overlapping, intermittent or alternating schedules may limit the toxicity of each agent while extending active antiretroviral therapy in these patients. In an ongoing study, patients have been randomly assigned to weekly intermittent, weekly alternating, and monthly alternating regimens of AZT and 2’, 3’-dideoxycytidine. The study will determine the best-tolerated regimen and provide insights into the use of toxic nucleoside analogues in persons with advanced human immunodeficiency virus disease.
I
nately, the period of useful therapy with drugs currently known to possess activity against the human immunodeficiency virus (HIV) in patients is often limited. The first limitation is due to the development of dose-limiting toxicities [2]. In the case of zidovudine (AZT), the occurrence of hematologic toxicity often becomes dose-limiting in persons with AIDS or AIDSrelated complex [3]. In the case of dideoxycytidine (ddC), peripheral neuropathy often becomes doselimiting during high-dose continuous therapy [41. A second potential limitation is the development of HIV strains resistant to AZT during treatment. This has, as yet, only been shown to have significance in vitro but may have clinical significance as well and may occur with other nucleoside analogues [5]. Persons with advanced HIV disease are more likely to develop both toxicity and resistance because of their high burden of morbidity and virus [6,7].
CLINICALASPECTSOF AZT THERAPY
I
From the Division of Infectious Diseases, University of California, San Diego, and the Departments of Pathology and Medicine, University of Caldornia, San Diego and the San Diego Veterans Administration Medical Center, San Diego, California. This work was supported by the AIDS Clinical Trials Group of the National Institute of Allergy and infectious Diseases. Requests for reprints should be addressed to Samuel A. Bozzette, M.D., University of California, San Diego Medical Center, H208, 225 Dickinson Street, San Diego, California 92103..
58-24s
May 21, 1990
The American Journal of Medicine
AZT has been demonstrated to prolong life in persons with advanced HIV disease and to decrease the risk of progression in persons with early HIV disease [1,8,91. Persons receiving AZT frequently experience dose-limiting hematologic toxicity, particularly in advanced disease when the marrow is often already abnormal [lo]. Over the course of one year, up to 40 percent of patients with advanced disease who start therapy with 1,200 mg per day of AZT will suffer doselimiting hematologic intolerance [ll]. However, hematologic toxicity occurs in less than 6 percent of those with asymptomatic disease administered this same dose [12]. The antiretroviral effect of nucleoside analogues is reflected by reductions in the amount of HIV p24 core protein present in serum [13,14]. In patients with detectable HIV p24 in serum at baseline, the majority of the decrease in p24 occurs in the first weeks of AZT therapy. However, the hematologic toxicity of AZT, which is characterized by both macrocytic anemia and granulocytopenia, is generally not seen until four to six weeks of therapy [21. The accompanying abnormalities in the marrow include megaloblastic change and depletion of both red blood cell and white blood cell precursors [15]. The clinical response to cessation of AZT therapy is generally prompt improvement of cytopenias. The distinctive morphologic changes that accompany AZT toxicity generally resolve in the bone marrow within one month of cessation of therapy (MA Fischl, personal communication). Several approaches to increasing the therapeutic index of AZT are possible. Attempts to reduce macro-
Volume 88 (suppl 55)
SYMPOSIUM
ON ddC / BOZZETTE and RICHMAN
3EGIMENS lonthly Alternating (low-dose ddC) lonthly Alternating (high-dose ddC) Meekly Alternating (low-dose ddC) Meekly Alternating (high-dose ddC) Veekly
Intermittent (AZT)
Meekly Intermittent (high-dose ddC)
2
Figure 1. AIDS Clinical Trials Group protocol 050: study regimens of alternating and intermittent doses of AZT and ddC.
3
4
5
6
7
B
:I
cytic anemia by supplementation with vitamin B1a have failed (J McCutchan, personal communication). Some investigators are exploring the use of continuous low-dose therapy at 300 mg per day [Xl. This may reduce toxicity but the impact of this dose on drug activity and the emergence of resistant strains is as yet uncertain. A second approach is to use repeated short courses of standard-dose therapy. This would provide optimal therapy during the periods of treatment and possibly spare the bone marrow by either allowing recovery between courses or reducing the dose per unit time to below a threshold for toxicity. CLINICAL ASPECTS OF ddC THERAPY ddC is a very potent inhibitor of HIV in vitro and in phase I human testing [4,1’71. In a phase I dose-ranging trial, an antiviral response as measured by change in HIV p24 was observed at all tested doses, but was more vigorous at the highest tested doses, which were 0.03 and 0.06 mg/kg every four hours 141. The highest doses were also associated with greater incidence and severity of toxicity. An acute syndrome of clinical toxicity consisting of oral ulcers and/or rash was not dose-limiting in any case. However, doselimiting peripheral neuropathy occurred commonly at the higher doses tested [4]. The neuropathy was a distal, symmetric, primarily sensory polyneuropathy characterized by aching, burning, or lancinating pain. Motor dysfunction was less common and generally limited to loss of the Achilles reflex. Morphologic abnormalities in the sural nerve were not seen and electromyographic change was generally limited to loss of the “H” wave. After
cessation of therapy, some coasting or increase in symptomatology was commonly observed with later improvement being the rule (HH Schaumburg, personal communication). MULTIDRUG APPROACHES TO SALVAGE THERAPY IN AIDS Although clinically non-overlapping, the primary dose-limiting toxicities of AZT and ddC are both related to dosing intensity and perhaps to total doses, as well as to stage of disease. The latter factor may be a marker for the presence of pre-existing damage to target organs of toxicity. The toxicities attributable to both agents regress after interruption or discontinuation of dosing. It follows that the rest periods provided by intermittent therapy may improve tolerance for these drugs by decreasing the total exposure to the agent over time andlor by allowing recovery from subclinical damage. Intermittent therapy may provide acceptable antiHIV coverage, especially as a salvage regimen for persons intolerant to continuous therapy. However, the nonoverlapping toxicities of AZT and ddC may allow persons to receive continuous anti-HIV therapy by alternating drugs. The optimal duration of therapy cycles in an alternating regimen is unclear. A weekly alternating AZTI ddC regimen has been piloted at the National Cancer Institute with comparatively little hematologic or neurologic toxicity. However, the weekly rest periods may not be sufficient to prevent neurologic or hematologic toxicity in patients with very advanced HIV disease. Monthly rest periods may allow more complete
May 21, 1990
The American Journal of Medicine
Volume 88 (suppi 5B)
5525s
SYMPOSIUMON ddC/ BOZZEllE and RICHMAN TABLE I AIDS Clinical Trials Group Protocol 050 Entry Criteria * Must have received 2 4 weeks of AZf for advanced HIV infection (former label criterion] Recovery from hematologic intolerance to AIT at 5 600 mgiday. Hematologic intolerance defined as: -Hemoglobin < 9 g/d1or -Transfusion of > 4 units of red blood cells every 6 weeks or -Granulocytes < 900 cells/mm3 * No symptoms of peripheral neuropathy; some signs allowed * No neurotoxic drugs allowed l
recovery of subclinical neurologic damage and minimize clinical neurotoxicity, but may lead to unacceptably frequent hematologic toxicity since persons with prior AZT toxicity may not be able to tolerate a month of continuous AZT therapy. AIDS Clinical Trials Group protocol 050 is being conducted by the ddC study group (University of Minnesota, University of Miami, Robert Wood Johnson School of Medicine, St Luke’s-Roosevelt Hospital Center, Harvard University, Tulane University, University of Southern California, Stanford University, Northwestern University, Washington University, George Washington University, and University of California, San Diego) of the.National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. The study is designed to evaluate potentially useful intermittent salvage regimens for patients with advanced HIV disease who have recovered from hematologic intolerance to AZT. Participants are randomly assigned to weekly intermittent, weekly alternating, and monthly alternating regimens. All AZT dosing was initially at 1,000 mg per day and ddC dosing was at 0.01 mg/kg every four hours or 0.03 mgikg every four hours. The entry criteria and six treatment arms are illustrated in Table I and Figure 1. The primary analysis will determine which of the salvage regimens gives the lowest risk of dose-limiting toxicity over time. The risk of toxicity at a given total dose will be determined for each regimen. Finally, the risk factors for the development of doselimiting toxicity will be examined. Surrogate markers of activity such as CD4+ lymphocyte count and HIV p24 will also be examined. Preliminary analyses are consistent with the theoretical constructs outlined earlier. In all groups, a somewhat lower risk of dose-limiting toxicity seems to be associated with lower drug doses and earlier stage of disease. Longer rest periods may be associated with a lower risk of ddC-associated neurotoxicity, whereas shorter exposure periods may be associated with less AZT-associated hematologic toxicity. An
56-26s
May 21, 1990
The American Journal of Medicine
unacceptably high risk of neurotoxicity has been observed in persons with pre-existing signs of peripheral nerve dysfunction, even when the abnormalities were asymptomatic. This observation is consistent with knowledge regarding the risk for other forms of toxic neuropathy and serves as a caution to physicians and patients as neurotoxic deoxynucleosides become more widely available. It is hoped that the completion and analysis of this work will lead to clinically useful salvage therapies. In any case, examination of the patient- and dose-related risks for neurotoxicity in this study will yield additional valuable lessons for the development and use of ddC as well as other neurotoxic nucleosides such as 2’,3’-dideoxyinosine and 2’,3’-dideoxy-2’,3’-didehydrothymidine. REFERENCES 1. Frschl MA, Richman DD, Grieco MH, et a/: The efficacy of azidothymidine (AZT) in the treatment of patrents wrth AIDS and AIDS-related complex. A double-blind, placebocontrolled trial. N Engi J Med 1987; 317: 185-191. 2. Richman DD. Fischl MA, Grieco MH, et at The toxicrty of azidothymrdrne (ATT) rn the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebocontrolled trial. N Engl J Med 1987; 317: 192-197. 3. Richman DD, Andrews J, and the ATT Collaborative Working Group. Results of continued monitoring of participants in the placebo-controlled trial of zidovudine for serious human immunodeficrency virus infection. Am J Med 1988; 85 (suppl 2A): 208-213. 4. Merigan TC, Skowron G, Bozzette S, et al: Circulating p24 antigen levels and responses to dideoxycytidine in human immunodefrcrency virus (HIV) infectrons: a phase I and II study. Ann Intern Med 1989; 110: 189-194. 5. Larder BA, Darby G, Richman DD: HIV with reduced sensitirty to zidovudine (ATT) Isolated during prolonged therapy. Science 1989; 243: 1731-1734. 6. Ho DD, Moudgil T, Alam M, et al: Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med 1989; 321: 1621-1625. 7. Coombs RW, Collier AC, Allarn JP et af Plasma viremia in human immunodeficrency virus infection, N Engl J Med 1989; 321: 1626-1631. 8. Yarchoan R, Klecker RW, Wernhold KJ, et at Administration of 3’.azido3’.deoxythymrdine, an inhibitor of HTLV-IIIILAV replication, to patrents with AIDS or AIDS-related complex, Lancet 1986; I: 575-580. 9. Yarchoan R, Berg G, Brouwers P, ei at Response of human immunodeficiency-virus associated neurological disease to 3’.azido-3’.deoxythymidine. Lancet 1987; I: 132-135. 10. Crea&Kirk T, Doi P, Andrews E, et at Survival experience among patients with AIDS receiving zidovudine: follow-up of patients rn a compassionate plea program. JAMA 1988; 260: 3009-3015. 11. Fischl MA, Richman DD, Causey DM, et al: Prolonged zidovudine therapy in patrents with AIDS and advanced AIDS-related complex. JAMA 1989; 262: 2405-2410. 12. Volberdrng PA, Lagakos SU, Koch MA, eta/: Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CDCpositive cells per cubrc millimeter. N Engl J Med 1990; 322: 941-949. 13. Chaisson RE,Aliain JP, Leutner M, et a/: Significant changes in HIV antigen level in the serum of patrents treated with ATT (letter). N Engl J Med 1986; 315: 1610-1611. 14. Jackson GG, Paul DA, Falk LA, et al: Human immunodeficiency virus antigenemia rn AIDS and the effect of treatment with zidovudine. Ann Intern Med 1988; 108: 175-180. 15. Bozzette S, Fleck A, Stayboldt C, et at Hematologic toxicity of AZT (abstr). Presented at UCLA Symposia Conference on Human Retroviruses, Cancer, and AIDS: approaches to prevention and therapy, Keystone, Colorado, p. 303, March 19&7. 16. Collier A>Coombs R, Bozzette SA, et a/:Virologic and clinrcal response to combination zidovudine (AZT) and acyclovir (ACV) in AIDS-related complex (ARC) (abstr 30). In: Program and abstracts of the 29th International Conference on Antimicrobial Agents and Chemotherapy, Houston: American Society for Microbiology, 1989. 17. Yarchoan R, Perno CF, Thomas RV, et al: Phase I studies of 2’,3’-drdeoxycyirdine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (UT) Lancet 1988; I: 76-81.
Volume 88 (suppl 5B)
ntiretroviral therapy with nucleoside analogues is A a cornerstone of current acquired immunodeficiency syndrome (AIDS) treatment [l]. Unfortu-
Zidovudine (AZT) prolongs life in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex but often causes dose-limiting bone marrow suppression in this population. This has prompted a search for salvage therapies for use in persons who cannot tolerate continuous AZT treatment. One approach involves alternating administration of AZT and 2’,3’dideoxycytidine. 2’,3’-Dideoxycytidine is a potent inhibitor of human immunodeficiency virus in vitro and in uivo. Although it does not cause clinically significant bone marrow suppression, its usefulness at high continuous doses is limited by the occurrence of painful peripheral neuropathy. Because the toxicities of these nucleosides are non-overlapping, intermittent or alternating schedules may limit the toxicity of each agent while extending active antiretroviral therapy in these patients. In an ongoing study, patients have been randomly assigned to weekly intermittent, weekly alternating, and monthly alternating regimens of AZT and 2’, 3’-dideoxycytidine. The study will determine the best-tolerated regimen and provide insights into the use of toxic nucleoside analogues in persons with advanced human immunodeficiency virus disease.
I
nately, the period of useful therapy with drugs currently known to possess activity against the human immunodeficiency virus (HIV) in patients is often limited. The first limitation is due to the development of dose-limiting toxicities [2]. In the case of zidovudine (AZT), the occurrence of hematologic toxicity often becomes dose-limiting in persons with AIDS or AIDSrelated complex [3]. In the case of dideoxycytidine (ddC), peripheral neuropathy often becomes doselimiting during high-dose continuous therapy [41. A second potential limitation is the development of HIV strains resistant to AZT during treatment. This has, as yet, only been shown to have significance in vitro but may have clinical significance as well and may occur with other nucleoside analogues [5]. Persons with advanced HIV disease are more likely to develop both toxicity and resistance because of their high burden of morbidity and virus [6,7].
CLINICALASPECTSOF AZT THERAPY
I
From the Division of Infectious Diseases, University of California, San Diego, and the Departments of Pathology and Medicine, University of Caldornia, San Diego and the San Diego Veterans Administration Medical Center, San Diego, California. This work was supported by the AIDS Clinical Trials Group of the National Institute of Allergy and infectious Diseases. Requests for reprints should be addressed to Samuel A. Bozzette, M.D., University of California, San Diego Medical Center, H208, 225 Dickinson Street, San Diego, California 92103..
58-24s
May 21, 1990
The American Journal of Medicine
AZT has been demonstrated to prolong life in persons with advanced HIV disease and to decrease the risk of progression in persons with early HIV disease [1,8,91. Persons receiving AZT frequently experience dose-limiting hematologic toxicity, particularly in advanced disease when the marrow is often already abnormal [lo]. Over the course of one year, up to 40 percent of patients with advanced disease who start therapy with 1,200 mg per day of AZT will suffer doselimiting hematologic intolerance [ll]. However, hematologic toxicity occurs in less than 6 percent of those with asymptomatic disease administered this same dose [12]. The antiretroviral effect of nucleoside analogues is reflected by reductions in the amount of HIV p24 core protein present in serum [13,14]. In patients with detectable HIV p24 in serum at baseline, the majority of the decrease in p24 occurs in the first weeks of AZT therapy. However, the hematologic toxicity of AZT, which is characterized by both macrocytic anemia and granulocytopenia, is generally not seen until four to six weeks of therapy [21. The accompanying abnormalities in the marrow include megaloblastic change and depletion of both red blood cell and white blood cell precursors [15]. The clinical response to cessation of AZT therapy is generally prompt improvement of cytopenias. The distinctive morphologic changes that accompany AZT toxicity generally resolve in the bone marrow within one month of cessation of therapy (MA Fischl, personal communication). Several approaches to increasing the therapeutic index of AZT are possible. Attempts to reduce macro-
Volume 88 (suppl 55)
SYMPOSIUM
ON ddC / BOZZETTE and RICHMAN
3EGIMENS lonthly Alternating (low-dose ddC) lonthly Alternating (high-dose ddC) Meekly Alternating (low-dose ddC) Meekly Alternating (high-dose ddC) Veekly
Intermittent (AZT)
Meekly Intermittent (high-dose ddC)
2
Figure 1. AIDS Clinical Trials Group protocol 050: study regimens of alternating and intermittent doses of AZT and ddC.
3
4
5
6
7
B
:I
cytic anemia by supplementation with vitamin B1a have failed (J McCutchan, personal communication). Some investigators are exploring the use of continuous low-dose therapy at 300 mg per day [Xl. This may reduce toxicity but the impact of this dose on drug activity and the emergence of resistant strains is as yet uncertain. A second approach is to use repeated short courses of standard-dose therapy. This would provide optimal therapy during the periods of treatment and possibly spare the bone marrow by either allowing recovery between courses or reducing the dose per unit time to below a threshold for toxicity. CLINICAL ASPECTS OF ddC THERAPY ddC is a very potent inhibitor of HIV in vitro and in phase I human testing [4,1’71. In a phase I dose-ranging trial, an antiviral response as measured by change in HIV p24 was observed at all tested doses, but was more vigorous at the highest tested doses, which were 0.03 and 0.06 mg/kg every four hours 141. The highest doses were also associated with greater incidence and severity of toxicity. An acute syndrome of clinical toxicity consisting of oral ulcers and/or rash was not dose-limiting in any case. However, doselimiting peripheral neuropathy occurred commonly at the higher doses tested [4]. The neuropathy was a distal, symmetric, primarily sensory polyneuropathy characterized by aching, burning, or lancinating pain. Motor dysfunction was less common and generally limited to loss of the Achilles reflex. Morphologic abnormalities in the sural nerve were not seen and electromyographic change was generally limited to loss of the “H” wave. After
cessation of therapy, some coasting or increase in symptomatology was commonly observed with later improvement being the rule (HH Schaumburg, personal communication). MULTIDRUG APPROACHES TO SALVAGE THERAPY IN AIDS Although clinically non-overlapping, the primary dose-limiting toxicities of AZT and ddC are both related to dosing intensity and perhaps to total doses, as well as to stage of disease. The latter factor may be a marker for the presence of pre-existing damage to target organs of toxicity. The toxicities attributable to both agents regress after interruption or discontinuation of dosing. It follows that the rest periods provided by intermittent therapy may improve tolerance for these drugs by decreasing the total exposure to the agent over time andlor by allowing recovery from subclinical damage. Intermittent therapy may provide acceptable antiHIV coverage, especially as a salvage regimen for persons intolerant to continuous therapy. However, the nonoverlapping toxicities of AZT and ddC may allow persons to receive continuous anti-HIV therapy by alternating drugs. The optimal duration of therapy cycles in an alternating regimen is unclear. A weekly alternating AZTI ddC regimen has been piloted at the National Cancer Institute with comparatively little hematologic or neurologic toxicity. However, the weekly rest periods may not be sufficient to prevent neurologic or hematologic toxicity in patients with very advanced HIV disease. Monthly rest periods may allow more complete
May 21, 1990
The American Journal of Medicine
Volume 88 (suppi 5B)
5525s
SYMPOSIUMON ddC/ BOZZEllE and RICHMAN TABLE I AIDS Clinical Trials Group Protocol 050 Entry Criteria * Must have received 2 4 weeks of AZf for advanced HIV infection (former label criterion] Recovery from hematologic intolerance to AIT at 5 600 mgiday. Hematologic intolerance defined as: -Hemoglobin < 9 g/d1or -Transfusion of > 4 units of red blood cells every 6 weeks or -Granulocytes < 900 cells/mm3 * No symptoms of peripheral neuropathy; some signs allowed * No neurotoxic drugs allowed l
recovery of subclinical neurologic damage and minimize clinical neurotoxicity, but may lead to unacceptably frequent hematologic toxicity since persons with prior AZT toxicity may not be able to tolerate a month of continuous AZT therapy. AIDS Clinical Trials Group protocol 050 is being conducted by the ddC study group (University of Minnesota, University of Miami, Robert Wood Johnson School of Medicine, St Luke’s-Roosevelt Hospital Center, Harvard University, Tulane University, University of Southern California, Stanford University, Northwestern University, Washington University, George Washington University, and University of California, San Diego) of the.National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. The study is designed to evaluate potentially useful intermittent salvage regimens for patients with advanced HIV disease who have recovered from hematologic intolerance to AZT. Participants are randomly assigned to weekly intermittent, weekly alternating, and monthly alternating regimens. All AZT dosing was initially at 1,000 mg per day and ddC dosing was at 0.01 mg/kg every four hours or 0.03 mgikg every four hours. The entry criteria and six treatment arms are illustrated in Table I and Figure 1. The primary analysis will determine which of the salvage regimens gives the lowest risk of dose-limiting toxicity over time. The risk of toxicity at a given total dose will be determined for each regimen. Finally, the risk factors for the development of doselimiting toxicity will be examined. Surrogate markers of activity such as CD4+ lymphocyte count and HIV p24 will also be examined. Preliminary analyses are consistent with the theoretical constructs outlined earlier. In all groups, a somewhat lower risk of dose-limiting toxicity seems to be associated with lower drug doses and earlier stage of disease. Longer rest periods may be associated with a lower risk of ddC-associated neurotoxicity, whereas shorter exposure periods may be associated with less AZT-associated hematologic toxicity. An
56-26s
May 21, 1990
The American Journal of Medicine
unacceptably high risk of neurotoxicity has been observed in persons with pre-existing signs of peripheral nerve dysfunction, even when the abnormalities were asymptomatic. This observation is consistent with knowledge regarding the risk for other forms of toxic neuropathy and serves as a caution to physicians and patients as neurotoxic deoxynucleosides become more widely available. It is hoped that the completion and analysis of this work will lead to clinically useful salvage therapies. In any case, examination of the patient- and dose-related risks for neurotoxicity in this study will yield additional valuable lessons for the development and use of ddC as well as other neurotoxic nucleosides such as 2’,3’-dideoxyinosine and 2’,3’-dideoxy-2’,3’-didehydrothymidine. REFERENCES 1. Frschl MA, Richman DD, Grieco MH, et a/: The efficacy of azidothymidine (AZT) in the treatment of patrents wrth AIDS and AIDS-related complex. A double-blind, placebocontrolled trial. N Engi J Med 1987; 317: 185-191. 2. Richman DD. Fischl MA, Grieco MH, et at The toxicrty of azidothymrdrne (ATT) rn the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebocontrolled trial. N Engl J Med 1987; 317: 192-197. 3. Richman DD, Andrews J, and the ATT Collaborative Working Group. Results of continued monitoring of participants in the placebo-controlled trial of zidovudine for serious human immunodeficrency virus infection. Am J Med 1988; 85 (suppl 2A): 208-213. 4. Merigan TC, Skowron G, Bozzette S, et al: Circulating p24 antigen levels and responses to dideoxycytidine in human immunodefrcrency virus (HIV) infectrons: a phase I and II study. Ann Intern Med 1989; 110: 189-194. 5. Larder BA, Darby G, Richman DD: HIV with reduced sensitirty to zidovudine (ATT) Isolated during prolonged therapy. Science 1989; 243: 1731-1734. 6. Ho DD, Moudgil T, Alam M, et al: Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med 1989; 321: 1621-1625. 7. Coombs RW, Collier AC, Allarn JP et af Plasma viremia in human immunodeficrency virus infection, N Engl J Med 1989; 321: 1626-1631. 8. Yarchoan R, Klecker RW, Wernhold KJ, et at Administration of 3’.azido3’.deoxythymrdine, an inhibitor of HTLV-IIIILAV replication, to patrents with AIDS or AIDS-related complex, Lancet 1986; I: 575-580. 9. Yarchoan R, Berg G, Brouwers P, ei at Response of human immunodeficiency-virus associated neurological disease to 3’.azido-3’.deoxythymidine. Lancet 1987; I: 132-135. 10. Crea&Kirk T, Doi P, Andrews E, et at Survival experience among patients with AIDS receiving zidovudine: follow-up of patients rn a compassionate plea program. JAMA 1988; 260: 3009-3015. 11. Fischl MA, Richman DD, Causey DM, et al: Prolonged zidovudine therapy in patrents with AIDS and advanced AIDS-related complex. JAMA 1989; 262: 2405-2410. 12. Volberdrng PA, Lagakos SU, Koch MA, eta/: Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CDCpositive cells per cubrc millimeter. N Engl J Med 1990; 322: 941-949. 13. Chaisson RE,Aliain JP, Leutner M, et a/: Significant changes in HIV antigen level in the serum of patrents treated with ATT (letter). N Engl J Med 1986; 315: 1610-1611. 14. Jackson GG, Paul DA, Falk LA, et al: Human immunodeficiency virus antigenemia rn AIDS and the effect of treatment with zidovudine. Ann Intern Med 1988; 108: 175-180. 15. Bozzette S, Fleck A, Stayboldt C, et at Hematologic toxicity of AZT (abstr). Presented at UCLA Symposia Conference on Human Retroviruses, Cancer, and AIDS: approaches to prevention and therapy, Keystone, Colorado, p. 303, March 19&7. 16. Collier A>Coombs R, Bozzette SA, et a/:Virologic and clinrcal response to combination zidovudine (AZT) and acyclovir (ACV) in AIDS-related complex (ARC) (abstr 30). In: Program and abstracts of the 29th International Conference on Antimicrobial Agents and Chemotherapy, Houston: American Society for Microbiology, 1989. 17. Yarchoan R, Perno CF, Thomas RV, et al: Phase I studies of 2’,3’-drdeoxycyirdine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (UT) Lancet 1988; I: 76-81.
Volume 88 (suppl 5B)
