Original Article
A Controlled Trial of Early versus Late Treatment with Zidovudine in Symptomatic Human Immunodeficiency Virus Infection
N Engl J Med 1992; 326:437-443February 13, 1992
- Abstract
- Abstract
Background.
Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established.
Methods.
We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2×109 and 0.5×109 cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2×109 per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed.
Results.
During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2×109 per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash.
Conclusions.
In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects. (N Engl J Med 1992;326:437–43.)
Media in This Article
Figure 1
Estimated Kaplan–Meier Distribution of Time to Death, According to Study Group.Figure 2
Estimated Kaplan–Meier Distribution of Time to a Diagnosis of AIDS, According to Study Group.Article Activity
- Article
PLACEBO-controlled trials have demonstrated that zidovudine reduces morbidity and mortality when administered to patients with human immunodeficiency virus (HIV) infection late in the course of their infection,1 and that this drug also reduces morbidity when administered to symptomatic2 or asymptomatic patients3 earlier in the course of infection. The best time to initiate zidovudine therapy remains unknown, however.4
We conducted a four-year, multicenter, randomized, double-blind trial to evaluate when to administer zidovudine. Specifically, we wanted to determine the long-term clinical benefits and liabilities of earlier as compared with later therapy in symptomatic patients with HIV infection whose CD4+ counts were between 0.2×109 and 0.5×109 cells per liter (200 to 500 per cubic millimeter).
Methods
Patient Population
Patients were selected from seven participating medical centers. To be eligible for the study, they had to have proved HIV infection (as determined by enzyme-linked immunosorbent assay and Western blot test), a peripheral-blood CD4+ lymphocyte concentration of 0.2×109 to 0.5×109 per liter (200 to 500 per cubic millimeter) as determined by two measurements performed at least two weeks apart, and symptoms or signs of HIV infection. Required symptoms and signs included a history or the presence of thrush, oral hairy leukoplakia, herpes zoster, unintentional weight loss of ≥10 percent of body weight, unexplained persistent diarrhea, fever (temperature, ≥38°C [100.5°F]), night sweats, fatigue, dermatitis, or lymphadenopathy.
Patients were excluded if they had the acquired immunodeficiency syndrome (AIDS) as defined by the Centers for Disease Control (CDC),5 had received antiretroviral chemotherapy, or had any of the following abnormal laboratory values: a creatinine level of more than 177 μmol per liter (2.0 mg per deciliter), hemoglobin level of less than 5.9 mmol per liter (9.5 g per deciliter), white-cell count below 2.0×109 per liter (2000 per cubic millimeter), or granulocyte count below 1.0×109 per liter (1000 per cubic millimeter). Patients with unstable disease (defined as active infection or hospitalization within the previous two weeks) and those who were considered unreliable were also excluded.
The protocol and consent forms were approved by the Human 0ights Committee of the Cooperative Studies Program and by the investigational review board at each participating hospital. All the patients gave written informed consent.
Study Design and Treatment Regimens
At enrollment, we stratified patients according to their mean CD4+ cell concentration (stratum 1, 0.200×109 to 0.299×109 cells per liter [200 to 299 per cubic millimeter]; and stratum 2, 0.300×109 to 0.500×109 cells per liter [300 to 500 per cubic millimeter]) and randomly assigned them to one of two treatments using a permuted-blocks scheme6: zidovudine for the entire study period (early therapy) or placebo followed by zidovudine when the patient's CD4+ concentration fell to less than 0.2×109 per liter (200 per cubic millimeter) or when AIDS developed (late therapy). Patients received 250 mg of zidovudine or matching placebo by mouth every four hours (1500 mg per day), a dosage chosen to equal that administered in the initial phase II trial.1 Patients from both treatment arms who reached a clinical or immunologic end point were switched from blinded therapy to open-label zidovudine therapy at the same dosage (1500 mg per day).
Adverse effects were evaluated according to criteria established by the Eastern Cooperative Oncology Group.7 When an adverse effect occurred, the study medication was limited to every eight hours (750 mg per day) or stopped, depending on the type and severity of the reaction. When symptoms resolved or laboratory measures improved according to predefined criteria, the study medication was resumed at either the original or the reduced dosage. Additional information on the protocol for adverse effects is available elsewhere.* If the adverse effect did not resolve, the study medication was discontinued.
*See NAPS document no. 04933 for 16 pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada, add postage of $4.50 ($1.75 for microfiche postage). There is a $15 invoicing charge for all orders filled before payment.
Modification of the Protocol
In June 1989, after the publication of new guidelines by the CDC, the protocol was revised to allow prophylaxis against Pneumocystis carinii pneumonia.8
In August 1989, the AIDS Clinical Trials Group announced the termination of its placebo-controlled studies on zidovudine in symptomatic2 and asymptomatic3 HIV infection. On the basis of those studies, the Antiviral Advisory Committee of the Food and Drug Administration recommended that zidovudine therapy be initiated for all patients with symptomatic or asymptomatic HIV infection whose CD4+ concentrations were below 0.5×109 per liter (500 per cubic millimeter). Our data-monitoring board and its external advisors decided to continue our trial, to inform in writing each study patient of the findings and recommendations of the AIDS Clinical Trials Group and the FDA, and to obtain additional informed consent. Patients who did not wish to continue receiving blinded therapy were offered open-label zidovudine.
Criteria for Response
Death and progression to AIDS5 were the clinical end points of this study. Our definition of dementia was based on suggested criteria for and staging of the AIDS dementia complex.9 , 10 AIDS-related death was defined as death associated with a current AIDS-defining condition. Death with HIV progression was defined as death preceded by AIDS or an HIV-associated illness (e.g., pneumococcal bacteremia and meningitis), increased symptoms, or a decrease in the CD4+ concentration to less than 0.2×109 per liter (200 per cubic millimeter). The immunologic end point of the study was a decrease in the CD4+ concentration to less than 0.2×109 per liter (200 per cubic millimeter) on two successive measurements performed six or more weeks apart.
Evaluation and Follow-up
Both before and during the study, all the patients were carefully evaluated according to a strict protocol to rule out the presence of an AIDS-defining illness. Additional information on the protocol for screening for AIDS is available elsewhere.* After randomization and the initiation of the blinded study medication, the patients were seen at least monthly for a detailed history, physical examination, and laboratory evaluations. Lymphocyte subgroups and serum p24 antigen levels were measured at months 1, 2, and 4 and at four-month intervals thereafter. Plasma zidovudine concentrations were measured bimonthly at random times within four hours after dosing.
Data Management
Data collected at participating sites were sent to the study cochairman's office and to the Cooperative Studies Program Coordinating Center for review. Data were keyed in twice for verification and checked routinely for outliers and erroneous values. The study cochairman reviewed the information on all clinical end points (clinical data, pathological and radiologic materials, and the results of laboratory studies) and referred relevant objective data to independent blinded outside consultants.
Special Laboratory Studies
Lymphocyte phenotyping by flow cytometry was performed on peripheral-blood mononuclear cells prepared on a Ficoll–Hypaque gradient or by the whole-blood lysis technique with monoclonal reagents (Becton Dickinson, Mountainside, Calif.).
Serum p24 antigen was measured at a central reference laboratory with an antigen-capture enzyme-linked immunosorbent assay kit (Dupont, Wilmington, Del.; lower limit of sensitivity, 10 pg per milliliter). Plasma zidovudine concentrations were measured at a central reference laboratory by previously described methods.11
Statistical Analysis
The comparability of the treatment groups was assessed by a chi-square test or Fisher's exact test for discrete variables and by Student's t-test or the Wilcoxon rank-sum test for continuous variables.12 Time to toxicity, clinical end points, and immunologic end points were estimated with Kaplan–Meier and proportional-hazards regression methods. Stratified log-rank tests and proportional-hazards models were used to compare treatment groups and to estimate relative risks and confidence intervals, with adjustment for the stratification according to CD4+ cell concentration.13 Qualitative interactions were tested with the method developed by Gail and Simon.14 During the study, our data-monitoring board used a modified O'Brien—Fleming boundary to adjust for repeated looks at the data.15 Here, however, we report classic confidence intervals because they provide a useful summary of the evidence and the amount of information on treatment effect. Throughout, we report the relative risks comparing late treatment with early treatment. Test statistics for comparisons of major end points were regarded as significant if the P value was ≤0.05; test statistics for all other end points or subgroups were considered significant at a P level of 0.01. All primary analyses were performed on an intention-to-treat basis, and all P values are two-tailed.
Results
Base-Line Characteristics
A total of 338 patients were randomly assigned to either early therapy (170 patients) or late therapy (168 patients) from January 1987 to January 1990. This number included 11 patients (4 in the early-therapy group and 7 in the late-therapy group) who did not meet the eligibility criteria in minor ways. The exclusion of these 11 patients does not alter the conclusions of the study.
The patients were on average 40 years old. They were predominantly male and non-Hispanic white. Sixty-three percent reported homosexual or bisexual contacts without intravenous drug use, 16 percent reported intravenous drug use, 9 percent were homosexual or bisexual and used intravenous drugs, and 12 percent reported other risk factors. They had an average of three symptoms, a Karnofsky score of 89, and a CD4+ concentration of 0.355×109 per liter (355 per cubic millimeter). Nineteen percent of them had p24 antigenemia. There were no statistically significant imbalances between the treatment groups in the distribution of important covariates (Table 1Table 1
Base-Line Characteristics of the Study Patients.*).Follow-up and Compliance
The overall mean follow-up periods for the early-therapy and late-therapy groups were 27.2 and 28.2 months, respectively. For blinded therapy, the periods were 14.8 and 13.9 months, respectively (P = 0.32). Fifteen patients (nine in the early-therapy group and six in the late-therapy group) were lost to follow-up.
In the early-therapy group, 79 patients switched to open-label zidovudine, 52 because of the protocol and 27 by choice. The 27 who switched by choice did so a mean of 9.6 months before the end of the study, when their median CD4+ count was 0.317×109 per liter (317 per cubic millimeter). In the late-therapy group, 121 patients switched to open-label therapy, 82 because of the protocol and 39 by choice. The 39 who switched by choice did so a mean of 10.2 months before the end of the study, when their median CD4+ count was 0.304×109 per liter (304 per cubic millimeter).
Of the patients eligible for prophylaxis against P. carinii pneumonia, 98 percent of the early-therapy group (46 of 47) received it, as compared with 90 percent of the late-therapy group (54 of 60, P = 0.14).
The groups were equally compliant. Sixty-eight and 72 percent of the scheduled visits were made in the early-therapy and late-therapy groups, respectively; pill counts were 94 and 95 percent of expected; and 90 and 92 percent of the plasma zidovudine concentrations were appropriate. During blinded treatment, the early-therapy group had a mean increase of 13.35 f1 in mean corpuscular volume, as compared with an increase of 0.086 f1 in the group treated later. During open-label treatment, the mean corpuscular volume was on average 14.3 f1 above base line.
Clinical End Points
There were 43 deaths, 23 in the early-therapy group and 20 in the late-therapy group (P = 0.48; relative risk for late vs. early therapy, 0.81; 95 percent confidence interval, 0.44 to 1.59) (Table 2Table 2
Major Clinical End Points.). Most patients who died had evidence of HIV progression even when death was not attributed to AIDS. Only four patients died without evidence of HIV progression; all were in the early-therapy group. The causes were suicide, murder, congestive heart failure, and large-cell undifferentiated carcinoma. AIDS preceded 13 of the 23 deaths in the early-therapy group and all 20 deaths in the late-therapy group. Thus, all 10 of the deaths that were not preceded by or associated with an AIDS-defining event occurred in the early-therapy group. There was a trend toward earlier non-AIDS-related death in the early-therapy group, which was balanced by earlier AIDS-related deaths in the late-therapy group. Nineteen of the deaths in each group were preceded by at least one CD4+ count of less than 0.2×109 per liter (200 per cubic millimeter). The respective survival rates at one, two, and three years were 97, 93, and 77 percent for early therapy and 98, 95, and 83 percent for late therapy (Fig. 1Figure 1Estimated Kaplan–Meier Distribution of Time to Death, According to Study Group.).The early-therapy group had 28 patients who progressed to AIDS, whereas the late-therapy group had 48 (P = 0.02; relative risk, 1.75; 95 percent confidence interval, 1.1 to 2.8) (Table 2). Thirty-nine percent (11 of 28) of those treated early and 31 percent (15 of 48) of those treated later had P. carinii pneumonia as their first AIDS-defining condition. The proportion of patients in the early-therapy group who progressed to AIDS and had at least one subsequent AIDS-defining condition was 57 percent (16 of 28), as compared with 42 percent (20 of 48) in the late-therapy group (P = 0.19). The respective percentages free of AIDS at one, two, and three years were 93, 84, and 82 percent for early therapy and 91, 79, and 65 percent for late therapy (Fig. 2Figure 2
Estimated Kaplan–Meier Distribution of Time to a Diagnosis of AIDS, According to Study Group.).Of the 28 patients in the early-therapy group who progressed to AIDS, 13 (46 percent) subsequently died, as compared with 20 (42 percent) of the 48 patients in the late-therapy group who progressed to AIDS. The median time from the diagnosis of AIDS to death was 16 months in the early-therapy group and 19 months in the late-therapy group (P = 0.87).
A CD4+ concentration of less than 0.2×109 per liter (200 per cubic millimeter) preceded the AIDS-defining events in 17 patients (61 percent) in the early-therapy group and in 35 patients (73 percent) in the late-therapy group. A CD4+ count was obtained within four months before or two weeks after a diagnosis of P. carinii pneumonia in 21 of 26 patients (81 percent). In 19 (90 percent) of these patients, the CD4+ concentration was less than 0.2×109 per liter (200 per cubic millimeter).
Proportional-hazards models of the outcomes showed that base-line age and CD4+ count were significantly related to survival, but that Karnofsky score, p24 antigen positivity, symptom count, and medical center were not. By the same models, all these variables were significantly related to progression to AIDS. These effects were independent of treatment.
Clinical End Points within Subgroups
A higher proportion of patients in stratum 1 than in stratum 2 died (24 percent vs. 9 percent), and a higher proportion progressed to AIDS (31 percent vs. 19 percent). Although no treatment difference was significant within strata, the trends for each end point were similar to the overall results (Table 3Table 3
Major Clinical End Points, According to Subgroup.).Patients who were positive for p24 antigen at entry were more likely to die or progress to AIDS (18 percent and 33 percent, respectively) than patients who were negative for the antigen (10 percent and 19 percent). Although most treatment comparisons within these subgroups showed no significant differences, early treatment of patients who were negative for p24 antigen delayed the onset of AIDS (Table 3).
Intravenous drug use did not appear to be a major factor in explaining the effects observed. Early therapy significantly delayed progression to AIDS in patients who did not use intravenous drugs, but no other comparisons produced significant results (Table 3).
The racial and ethnic groups appeared to respond differently to the timing of zidovudine therapy. Fewer minority (black and Hispanic) patients died in the late-therapy group (two deaths) than in the early-therapy group (nine deaths), but the difference was not significant. Among non-Hispanic white patients, early therapy significantly delayed the onset of AIDS but had no effect on survival (Table 3). Minority patients were much more likely than white patients to be intravenous drug users (40 percent vs. 10 percent, respectively). Adjusting the time-to-failure analyses within racial and ethnic groups for intravenous drug use, however, had little impact on either the treatment effect or any possible effect of race or ethnic group.
The only subgroup analysis planned in advance was a comparison within strata. The results of tests for qualitative interaction with treatment were not significant for either death or progression to AIDS in any subgroup.
Immunologic and Virologic Results
As compared with late therapy, early therapy prolonged the time before CD4+ concentrations fell below 0.2×l09 per liter (200 per cubic millimeter) and were sustained at that level (P = 0.01). Changes in CD4+ counts from base-line values showed clear differences between treatment groups over time (Fig. 3Figure 3
Mean (±SE) Changes from Base Line in CD4+ Counts (Panel A) and Serum p24 Antigen Concentrations (Panel B).A). At 4, 12, and 20 months, respectively, the mean changes from base line were +0.0115, +0.0003, and —0.0355×109 cells per liter (+11.5, +0.3, and —35.5 per cubic millimeter) in the early-therapy group, but —0.0086, —0.0487, and —0.0836×109 cells per liter (—8.6, —48.7, and —83.6 per cubic millimeter) in the late-therapy group.At base line, 19.6 percent of the 321 patients tested (95 percent of the total group of 338) were positive for serum p24 antigen. Of these, a higher proportion had converted to seronegative at four months in the early-therapy group than in the late-therapy group (15 of 19 vs. 6 of 17 [79 percent vs. 35 percent]), but the difference was not sustained thereafter (Fig. 3B).
Toxicity of Study Drugs
Leukopenia occurred in 82 percent of the patients receiving early therapy and 77 percent of those receiving late therapy; 20 percent and 16 percent, respectively, had anemia. Fourteen percent and 10 percent, respectively, had severe leukopenia (white-cell count, <2.0×l09 per liter [2000 per cubic millimeter]; neutrophil count, <1.0×l09 per liter [1000 per cubic millimeter]); and 5 percent and 2 percent had severe anemia requiring transfusion. Nausea (or vomiting) and diarrhea occurred more frequently in the early-therapy group than in the late-therapy group (40 percent vs. 23 percent, respectively; P<0.01). Skin rashes were more common in the late-therapy group (58 percent) than in the early-therapy group (47 percent, P = 0.03). The proportions of patients with hemorrhage, fever, infection, peripheral neuropathy, genitourinary symptoms, or symptoms or signs of heart, lung, or liver disease did not differ significantly between the treatment groups.
The dosage of blinded study medication was reduced because of adverse reactions in 64 of the patients assigned to zidovudine (early therapy) and in 29 of those assigned to placebo (late therapy) (P<0.001). In 11 of these patients in the early-therapy group and in 2 of those in the late-therapy group, the medication was eventually discontinued (P<0.01). During blinded therapy, one or more transfusions (range of units per patient, 2 to 46) were required in 14 patients, 12 in the early-therapy group and 2 in the late-therapy group (P<0.01). After patients switched to open-label therapy, 2 additional patients in the early-therapy group and 14 in the late-therapy group required transfusions.
Discussion
The goal of our study was to compare the initiation of zidovudine therapy early in the course of HIV infection, when patients are symptomatic but have CD4+ counts between 0.2×109 and 0.5×109 per liter (200 and 500 per cubic millimeter), with initiation later on, when the CD4+ count is below 0.2×109 per liter (200 per cubic millimeter) or AIDS has developed. After more than two years of follow-up, we found no difference in survival between the two treatment groups. We can exclude any large survival benefit for the early-therapy regimen used in this study, since the confidence intervals indicate that early therapy could provide no more than 1.6 times the benefit of late therapy, but that late therapy could be as much as 2 times more beneficial than early therapy. Excluding data on patients who died without HIV progression did not alter the overall conclusion that there is no survival advantage for either treatment regimen. We believe this conclusion to be generalizable, because our patients were representative of those in our large hospital system and similar to those seen in other public facilities.
In the patients who received early treatment we found a significant reduction in progression to AIDS, a finding that complements those of the placebo-controlled studies conducted by the AIDS Clinical Trials Group in symptomatic2 and asymptomatic3 patients. In our study this benefit appeared to be greater in patients with CD4+ counts below 0.3×109 per liter (300 per cubic millimeter), in those who had no detectable serum p24 antigen at entry, in those who had not used intravenous drugs, and in non-Hispanic whites.
Early zidovudine therapy slowed the progression to AIDS but did not improve overall survival in our trial. Once AIDS developed in patients receiving early therapy, more of them tended to have multiple AIDS diagnoses, a slightly higher proportion died, and the median survival time was slightly shorter than in similar patients who received late therapy. The time to AIDS-related death or other death was similar in both groups. The 18-month median overall survival after an AIDS-defining diagnosis was similar to that seen in another large series.16 Furthermore, it must be recognized that we compared earlier with later zidovudine therapy according to a protocol designed so that no patient would continue to receive placebo throughout the follow-up period.
The CD4+ count was consistently higher in the early-therapy group throughout follow-up. This resulted in a significant difference between groups in the proportion of patients who were switched to open-label zidovudine and a sustained difference in the mean CD4+ count through 18 months.
We used a higher dosage of zidovudine than the FDA currently recommends for patients like ours; however, most published randomized studies have had one arm with a dosage similar to ours.1 2 3 , 17 The results of some of these studies have been used to suggest that the benefits of low and high doses are equivalent and that low doses are preferable because they are less toxic.3 , 17 If this is true, our results should be applicable to low-dose therapy if they are not confounded by excess toxicity. Toxic reactions did occur in our patients. They were less frequent, however, than those reported in the study by Richman et al., in which patients received the same dosage as our patients but had more advanced disease.18 Also, our study included a protocol for lowering the dosage; the number of patients in whom the drug was actually discontinued was small, however. It therefore seems unlikely that adverse effects related to dosage could compromise the conclusions of our study.
The different trends in treatment response that we noted among racial and ethnic groups were the result of unplanned subgroup analyses. The results of unplanned analyses must be regarded with caution and skepticism and do not warrant differential treatment of minority patients. At most, we believe, the results should be used to generate hypotheses for future testing.
Our data raise anew the debate over the best time to initiate zidovudine treatment in patients with symptomatic HIV infection and CD4+ counts higher than 0.2×109 per liter (200 per cubic millimeter). On the basis of our data and the reports of Fischl et al.2 and Volberding et al.,3 we believe that early zidovudine therapy is an option that warrants consideration in symptomatic or asymptomatic patients with CD4+ counts of less than 0.5×109 per liter (500 per cubic millimeter), because initiating therapy at that point clearly delays AIDS-defining events. On the other hand, the long-term effects of zidovudine on the quality of life, cumulative drug toxicity, the development of drug resistance, and the cost of therapy have not been fully clarified. Thus, because of the uncertainty about long-term effects and because no survival benefit has been observed, we also believe that one may consider delaying the initiation of zidovudine therapy in patients whose condition is stable and whose CD4+ counts are between 0.2×109 and 0.5×109 per liter (200 and 500 per cubic millimeter).
Supported by the Cooperative Studies Program of the Medical Research Service, Department of Veterans Affairs, Central Office, Washington, D.C., and the U.S. Army Medical Research and Development Command.
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Presented in part at the annual meetings of the American Federation for Clinical Research, Seattle, May 3—6, 1991, and the Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 29—October 2, 1991.
*The other members of the study group are listed in the appendix.
We are indebted to the Burroughs Wellcome Company for its donation of the drug and matching placebo for this study.
Source Information
From the Department of Veterans Affairs Medical Centers in Baltimore (G.L.D., M.J.E.), Durham, N.C. (J.D.H.), Houston (C.J.L., N.P.W.), Los Angeles (W.L.G., W.A.O.), Miami (G.M.D., N.G.K.), New York (M.S.S., G.R.D., S.B.Z.-P.), San Francisco (P.C.J.), and Washington, D.C. (F.M.G., A.M.L.); the Veterans Affairs Coordinating Centers in West Haven, Conn. (P.M.H.) and Albuquerque, N.M. (P.L.D.); Duke University, Durham, N.C. (K.J.W.); and the Walter Reed Army Hospital, Washington, D.C. (C.A.H., C.N.O.). Address reprint requests to Dr. Hamilton at the Veterans Affairs Medical Center, 508 Fulton St., Durham, NC 27705.
Appendix
The other members of the Veterans Affairs Cooperative Study Group on AIDS Treatment were as follows:
Houston Veterans Affairs Medical Center (VAMC): M. Griffin, K. Harper, D. Musher, A. Peacock, R. Rossen, J. Thomas, and J. Wilson; Los Angeles VAMC: V. Allsup, C. Austin, E. Crawford, R. Endow, S. Finegold, J. Fleischman, M. Oliver, D. Reeves, and C. Silbar; Miami VAMC: R. Greenman, J. Meagher, J. Mix, R. Mendez, G. Paperwalla, and M. Smith; New York VAMC: E. Bailey, W. El-Sadr, V. Gianakakos, N. Haren, and J. O'Leary; San Francisco VAMC: A. Cotleur, G. Gilliland, R. Jalbert, M. Marovich, and J.L. Ziegler; Walter Reed Army Hospital, Washington, D.C.: D. Bille, C. Ebersole, E. Greenberg, B. Ovadia, and J. Romeo; Washington, D.C., VAMC: P. Ackerson, P. Kramer, M. Krol, M. Majewski, J. Scott, M. Smith, and M. Wholey; West Haven, Conn., Cooperative Studies Program Coordinating Center: D. Collins, M. Antonelli, A. Cross, A. DeRosa, T. Economou, M. Edgington, P. Ferrucci, L. Franklin, and S. Marcinauskis; Durham, N.C., VAMC, Cochairman's Office: B. Cox, D. Noviki, P. Spivey, and N. Williams; Duke University Virology Center: C. Compton, T. Drummond, A. Langlois, T. Matthews, T. Rudoll, and C. van der Horst; University of Maryland Pharmacology Laboratory: M. Rosen and H. Standiford; Albuquerque, N.M., Cooperative Studies Program Pharmacy Coordinating Center: M. Sather, C. Haakenson, S. Simpson, L. Richards, R. Felter, and R. Jaurequi; Consultants: R. Price, R. Vollmer, and W. Van Gorp; Data Monitoring Board: M. Gail (chair), J.G. Bartlett, P. Feorino, R. Redfield, R. Roberts, and A. Rubenstein; Human Rights Committee: J. Messore, J. Evans, B. Kathe, V. Marenna, J. Niederman, and W. Pritchett; and Advisory Panel: D. DeMets, E. Diaz, W. Pritchett, N. Spritz, and R. Wenzel.
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Citing Articles
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