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1 Placebo-Controlled Trial to Evaluate Zidovudine in Treatment of Human Immunodeficiency Virus Infection in Asymptomatic Patients With Hemophilia By Thomas C. Merigan, David A. Amato, James Balsley, Maureen Power, William A. Price, Sharon Benoit, Angela Perez-Michael, Alan Brownstein, Amy Simon Kramer, Doreen Brettler, Louis Aledort, Margaret V. Ragni, W. Abe Andes, Joan C. Gill, Jonathan Goldsmith, Sally Stabler, Natalie Sanders, George Gjerset, Jeanne Lusher, and the NHF-ACTG 0 Study Group One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 11 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 00 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 1). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 ECAUSE ZIDOVUDINE (ZDV) prevented death B and opportunistic infections in patients with advanced acquired immunodeficiency syndrome (AIDS)- related complex (ARC) and AIDS, the National Institute of Allergy and Infectious Diseases AIDS Clinical Trial Group (ACTG) undertook a study of its efficacy in treating earlier stages of human immunodeficiency (HIV) infection. From the Center for AIDS Research, Stanford University School of Medicine, Stanford, CA; Harvard School of Public Health, Boston, MA; the National Institute of Allergy and Infectious Disease AIDS Program, Bethesda, MD; Research Triangle Institute, Research Triangle, NC; the National Hemophilia Foundation (NHF), New York, ht Medical Center of Central Massachusetts-Memorial, Wooster, MA; Mount Sinai Medical Center, New York, Nu; University of Pittsburgh, Pittsbqh, PA; Tulane University School of Medicine, New Orleans, LA; Great Lakes Hemophilia Foundation, Milwaukee, WI; University of Nebraska Medical Center, Omaha; Huntington Hospital Hemophilia Center, Pasadena, CA; and University of Washington, Seattle, WA. Submitted March 5, 1991; accepted April 18, Supported by NIAID Grant No. AI-8278 to the NHF, the Research Triangle Institute, the participating ACTUS, and Grant No. AI-9500 to the statistical center at Harvard. Address reprint requests to Thomas C. Merigan, MD, Center for AIDS Research, Stanford University Medical Center, Rm S-15 Grant Building Stanford, CA The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked advertisement in accordance with I8 U.S.C. section 17 solely to indicate this fact by The American Society of Hematology. OOo-971/91 j780-oo21$.00/0 patients aged more than 0 years who were receiving treatment. In this subgroup, there was a similar trend (1 1 v ). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P =.02) among the older patients. The pretreatment distribution of CD counts for the placebo and ZDV groups were similar, but patients aged more than 0 years had significantly (P <.09) fewer CD cells than patients aged less than 0 years. A beneficial ZDV effect is also supported by a trend toward higher CD counts (a 8-cell increase in the ZDV group at 2 weeks as compared with a four-cell increase in the placebo group) and a significant (P =.0) difference in weight gain in the ZDV patients aged more than 0 years (8 pounds) as compared with the older placebo patients (aged more than 0 years) (2 pounds) at week 2. The findings in the asymptomatic hemophilic patients aged more than 0 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients. o 1991 by The American Society of Hematology. Because the pathogenesis of HIV infection in hemophilic patients might be different from that in other populations: we believed it important to evaluate treatment of asymptomatic HIV-infected individuals in this population. The original ACTG centers were located in areas of the highest population density of infected individuals, primarily homosexual males, inner-city intravenous (IV) drug abusers, or their consorts. Because hemophilia occurs uniformly throughout the population of the United States, these patients do not necessarily live close to ACTG centers. To obtain significant participation of the hemophilic population, the NIAID contracted with the National Hemophilia Foundation, a national advocacy group, to organize a nationwide group of centers to study the impact of early treatment with ZDV on the progression of HIV infection. An existing network of federally funded comprehensive hemophilic treatment centers was used. Ten regional centers were identified to work with the National Hemophilia Foundation, the outlying hemophilia centers, and the ACTG. Because of logistic difficulties inherent in the involvement of so many centers, the study started later than ACTG protocol 019, the nonhemophilic protocol for similar early treatment of HIV infection with ZDV. The primary endpoints of the hemophilia study were clinical progression of HIV infection, immune markers such as CD lymphocyte counts, weight change, and frequency of adverse reactions. We recognized that there was a preexisting high prevalence of posttransfusion hepatic disease in this population that could alter the pharmacokinetics of ZDV, its efficacy, and its side effects. Accordingly, a preliminary study of this dosage of ZDV was completed in hemophilic patients to insure that no interference with 900 Blood, Vol78, No (August 15). 1991: pp

2 ZIDOVUDINE IN TREATMENT OF HIV INFECTION 90 1 coagulation mechanisms, required clotting factor therapy, or major toxicity would be produced by the drug: MATERIALS AND METHODS Recruitment and entry cnteria. Patients were enrolled on an outpatient basis at hemophilia treatment centers (HTC) and treated at selected AIDS Clinical Trial Units (ACTU). Patients had to have well-established factor VI11 or IX deficiency, other coagulopathies (eg, factor V deficiency), or von Willebrand s disease, and had to have HIV antibody confirmed by Western blot. All patients were aged 12 years or older, and written consent of the parents or guardians was obtained for patients aged less than 18 years. Men and women were eligible; persons of reproductive potential were urged to practice adequate birth control. Subjects with progressive generalized lymphadenopathy as defined by the Centers for Disease Control (CDC) were not excluded. Patients had to have a Karnofsky performance of at least 90 unless performance was impaired by orthopedic complications of hemophilia, in which case a Karnofsky status as low as 0 was allowed. Patients had to have a CD cell count less than or equal to 500 cells/pl before randomization, a granulocyte count greater than 1,000 cells/pl, a platelet count greater than 75,000 cells/pl, a hematocrit greater than 0%, a serum creatinine level less than 1.5 times the upper limit of normal, and an alanine aminotransferase (ALT) level less than 10 times the upper limit of normal. Subjects with preexisting symptomatic HIV disease (except those with lymphadenopathy alone) and those with previous medication use or illness that suggested limited tolerance to ZDV were excluded from study. All patients signed a statement of informed consent approved by their local institutional review board. Eligible patients were randomized to therapy with orally administered ZDV at a dosage of 00 mg every hours while awake (5 doses per day) or to a placebo control arm. The ZDV dose was modified to 200 mg every hours when patients were awake (5 doses per day) in adolescent patients whose body surface area was less than 1.75 mz at the time of enrollment. Randomization and follow-up. Randomization occurred during evaluation at the ACTU, and therapy was started within 72 hours of randomization. Patients were assigned to the treatment or placebo arms on the basis of two stratification variables: CD cells less than 0OipL versus 00 to 500/pL and age 12 to 20 years versus age greater than 20 years. The randomization process used permeated blocks with dynamic balancing by institution to ensure that the difference between the numbers assigned to each treatment group in an ACTU did not exceed four. The treatment assignments were double blinded. Patients were examined weekly at their local HTC for the first 8 weeks, every other week for the next 8 weeks, and then every weeks thereafter. Patients were examined at the ACTU clinic twice yearly. Uniform toxicity management and criteria for monitoring disease progression were used. The accrual target plan was 58 patients to be entered into the study, with interim analyses of the data presented to the ACTG Data and Safety Monitoring Board (DSMB). The study was opened on February 25, In August 1989, the results of the first full interim analysis of patients in ACTG protocol 019 with initial T counts less than 500, which provided clear evidence of the beneficial effects of ZVD for this population, were made public. Because of the strong evidence that ZVD is beneficial in a similar population of patients, it was no longer considered ethical for patients on protocol 0 to continue to be treated with a placebo. At this time, entry of new patients to this study ceased; all patients in both treatment groups were crossed-over to ZDV therapy at a dose of 500 mg/d. At that time, 19 patients had been accrued. Follow-up on all patients continued, but only the data for patients up to the time they were crossed over to ZVD at 500 mg/d are included in this analysis because this represents the purest comparison of the treatment groups. The distributions of time to a critical event were estimated using the method of Kaplan and Meier. Comparisons between these distributions for the treatment groups were made using the log-rank test in an intent-to-treat analysis. Change from baseline in CD count and in weight was analyzed using two-sample t tests. Because of the comparison of ZDV with a placebo arm, all Pvalues are one-sided unless otherwise stated. The study was designed to have at least a 90% chance of detecting a reduction in the 2-year failure rate from 25% for placebo to 17% for ZDV, using a one-sided test and a 5% significance level. To achieve this goal, 58 patients (29 per arm) were to be entered and years of additional follow-up after the last patient was entered was required. Because accrual was terminated early and because follow-up time was necessarily shortened, the chance of detecting an effect of this magnitude was reduced to 20%. The chance of detecting a much larger reduction in the 2-year failure rate from 25% to 5% was only 8%. Spouse study. Spouses (steady sexual partners) of the patients on study were contacted by the hemophilia center staff, and of them agreed to be followed for possible HIV infection. This separate substudy involved its own consent form, serologic studies for HIV infection eveq months, and questionnaires regarding sexual activity. This survey was a unique opportunity to perform a blinded, prospective study of HIV seroconversion in a population whose sexual partners were HIV-positive and were randomly allocated to receive ZDV or placebo. The sexual partners underwent follow-up enzyme-linked immunosorbent assay (ELISA) testing at the time the corresponding patient left the study. In addition, all sexual partners were asked to return for follow-up ELISA testing at the time the study was unblinded. RESULTS The distributions of selected baseline characteristics of the study subjects are shown in Table 1. Ninety-one percent of entered patients were white, 2% had CD counts of less than 200 cells/pl, and 89% had hemophilia A. The median age was 1 years. The two treatment groups were well balanced with respect to distributions of baseline characteristics. Furthermore, there was no significant difference in these pretreatment factors according to age except that CD levels were significantly lower in the older patients (median 2 v 5, P <.09). Use of monoclonal antibody (MoAb)-purified factor VI11 concentrates, factor VIII, factor IX, and cryoprecipitates also were similar in the various groups. Table 2 shows the overall outcome of therapy for patients in the study. The voluntary withdrawal rate was 1% and was not different in ZDV and placebo groups. This rate is comparable to those observed in other studies of HIVinfected patients. The Pneumocystis prophylaxis regimen (aerosolized pentamidine) was used equivalently in both populations. Owing to the early termination of the study, as explained in the Materials and Methods section, the average number of months on study was 9.; this was not different between placebo and ZDV recipients. There were no differences in follow-up between the two groups as demonstrated by Kaplan-Meier plots in patients who were aged more than or less than 0 years of age (data not shown).

3 ~~ 902 MERIGAN ET AL Table 1. Selected Pretreatment Characteristics All Patients Age s0y Age > 0 y Characteristics Placebo ZDV Placebo ZDV Placebo ZDV Race White 17 Black 9 Other 7 1 a Median age (y) 0. CD Count < > a Median 28 Type of clotting disorder Hemophilia A 12 Hemophilia B 19 Other 2 1 a SGOT (x above ULM) 1.0 Monoclonal factor concentrate use Yes 7 No a Median quantity of Factor Vlll (U/mo),500 Factor IX (U/mo),500 Cryoprecipitate (bags/mo) 1 a ,000, ,500,00 15 a a I + Pi a I a ,000,000,500,000,500,500,500 2, ,000 5,00 0. a ,000 2,70 18 Table summcrizes the toxicities of the patients, including reported symptoms. As expected, the ZDV had more granulocyte toxicities as well as multiple hematologic toxicities (17% v nonr;, P <.mol). The notable symptomatic differences between ZDV and placebo recipients included asthenia (P =.05), malaise (P =.08), and nausea (P <.WOl). These complaints, as well as hematopoietic toxicities, were generally similar in the groups aged more than 0 years ahd less than 0 years (data not shown). In addition, the difference between the meau hemoglobin decrease iq the ZDV group aged more than 0 years as compared with placebo patients in the same group was Table 2. Overall Outcome for Patients on Study Status of All Patients Who Entered Study Placebo ZDV Patients on treatment at end of controlled trial phase Patients who died on study 1 Patients off treatment at end during con- trolled trial phase because of 21 ia 9 Clinical endpoint* Toxicity Voluntary withdrawal Average time (mo) on Pneumocystis prophylaxis (no. of patients) (12) (8) (20) Average time on study (mol *Development of AIDS or advanced AIDS-related complex. nearly statistically significant (P =.05) (data not shown). No special problems with hepatic dysfunction were observed despite the high incidence of underlying liver disease. Table summarizes the efficacy parameters in the study for all patients, as well as those aged less than or equal to 0 years and those aged more than 0 years. Thirty years was a convenient dividing line for separating older patients from younger patients because half of the patients were aged more than 0 years. By combining all disease progression landmarks in the study, including single ARC symptoms, the usefulness of ZDV was suggested. That the observed differences are not statistically significant (P =.19) is not surprising because of the small size of the study group and the short follow-up period. Neither were the differences significant by Kaplan-Meier analysis (P =.8) (Fig 1A). There was little evidence in the group aged 0 years or less for a ZDV effect. Indeed, there were more serious events in the ZDV group than in the placebo group, but the difference was not significant (P =.ll to.25). The only statistically significant changes observed occurred in patients aged more than 0 years. This group was analyzed separately because of recent epidemiologic analyses showing more rapid disease progression in this subgroup.8 In this group, ZDV treatment was associated with lower mortality and lesser progression to AIDS (P =.02). This difference was not affected by inclusion of events defined by time of onset of advanced ARC. Older patients had a poorer initial

4 ZIDOVUDINE IN TREATMENT OF HIV INFECTION 90 Table. Summary of Toxicities and Symptoms ously in the ACTG 019 study.' Figure 1B shows the Regimen Kaplan-Meier distribution of event-free intervals, related Placebo ZDV to our most statistically significant difference: failure to die or to progress to AIDS in the group aged more than 0 years when ZDV and placebo recipients were compared. The overall CD counts did not show a statistically 9 (5) 2 (2) 7 (8).09 significant difference between the placebo and ZDV groups, Type of --- Laboratory Toxicity n(%) n(%) n(%) PValue' Hematologic toxicities Hemoglobin < 8 g/dl Granulocytes <75O/kL 1 (8) O(0) 1 (17) <.0001 although at week 12 the older ZDV recipient group showed Platelets <5O,OOO/~L 5 () () 1 (1).7 Any a cell increase of 7lipL on the average. At week 2, the of the above 2 (1) () 2o (22),ool Multiple hematologic toxicities (2) 0 (0) ().05 ZDV group, as a whole, showed an increase in CD cell Hepatic Toxicitiest counts that was of borderline significance as compared with SGOT > 10 x upper limit (2) () O(0).12 the placebo group (P =.l) (most likely because of the SGPT > 10 x upper limit 7 () () ().71 incomplete sampling). At 2 weeks in the weight gain Alkaline phosphatase >5 x analysis, ZDV group as a whole had a 5-pound increase on upper limit 1 (1) O(0) 1 (1).8 the average as compared with start of therapy; older Bilirubin >5 x upper limit 1 (1) 1 (1) 0 (0) 1.0 patients had a weight gain averaging 8 pounds. The actual Any of the above 10 (5) 5 (5) 5 (5) 1.0 Multiple hepatic toxicities (2) () 0 (0).25 Symptoms* Anorexia (2) 0 (0) ().ll weight gain became significantly greater in the older placebo recipients at this time (P <.0) (Table 5). Apparently, compliance with treatment in this study was Asthenia (2) 0 (0) ().05 adequate, as shown by an analysis of the mean corpuscular Diarrhea () () () 1.0 volume (MCV) levels in drug and placebo recipients. The Dizziness 2 (1) l(1) l(1) 1.0 mean MCV values increased in the ZDV-treated group for Fever (2) l(1) 2 (2).1 the first 20 weeks and then stabilized at a higher level Headache 12 () () 8 (9).17 (averaging 105 to 110 fl) for the next 5 weeks. On the Insomnia 2(1) O(0) 2(2).2 other hand, placebo recipients showed no such increase Malaise I I () () 8 ('I.08 and were stable at a lower level (averaging 8 to 89 fl). This Myalgia l(1) 0 (0) 1 (1).8 result is similar to ACTG 019.' Nausea 1 (7) O(0) 1 (1) <.0001 Forty-two sexual partners of hemophilic patients en- Pain in abdomen 5 () () 2 (2) 1.00 rolled in the ACTG protocol 0 were recruited to partici- Rash l(1) 0 (0) l(1).8 Sample size pate in a study of their seroconversion. Forty-one of the enrolled subjects were female partners of male hemo- *From x2 test or Fisher's exact test. philics; one male sexual partner of a woman with von tupper limit refers to the upper limit of the normal range. Willebrand's disease was also enrolled. Forty-three percent Severe symtoms making patient unable to perform daily activity (grade and ). and 57% of enrolled subjects were sexual partners of patients randomized to receive ZDV and placebo, respectively. Baseline HIV ELISA testing was reported for 1 of prognosis7 as reflected by their lower CD levels On study the enrolled sexual partners; all were seronegative at entry. enro11ment, and the effect Of ZDV appears to be neater in this patient subgroup* Thus, even a group size Of 89 patients allowed demonstration of the beneficial effects of ZDV. The starting CD levels in the five patients who reached major endpoints in the group aged more than 0 years appear to be well distributed in the starting populations of that group. In all, the ACTG 0 data are compatible with the experience in asymptomatic patients reported previ- Twentyfive sexual partners had follow-up ELISA testing at the end of the controlled trial and remained seronegative. The mean time to follow-up ELISA testing was 9 months. DISCUSSION The results of this study are not clearly conclusive as to the usefulness of early ZDV treatment because of the Table. Summary of Efficacy Measures All Patients Age 5 0 y Age > 0 y Regimen Regimen Regimen Characteristic Pooled (n) Placebo ZDV PValue* Pooled (n) Placebo ZDV PValue+ Pooled (n) Placebo ZDV P Value* Death I. 1 0 I AIDS, death ,015 AIDS, advanced ARC, death I AIDS, advanced ARC, single ARC, death ,08 AIDS, advanced ARC, early ARC, single ARC, death Sample size Abbreviations: Advanced ARC, advanced AIDS-related complex; single ARC, single symptom of AIDS-related complex. *From long-rank test.

5 90 MERIGAN ET AL 2 I a DISTRIBUTION OF EVENT FREE INTERVALS 1 z E I 0.0! I I I I I I I I I a U a /B ::: MONTHS IN STUDY MONTHS IN STUDY Fig 1. (A) Kaplan-Meier plot of death, onset of AIDS, or ARC diagnosis or a single ARC symptom for the entire study group. Log rank test: P =.8. (B) Kaplan-Meier plot of occurrence of death or diagnosis of AlDSfor patients aged more than 0 years. Regimen: (-) placebo; (----) ZDV. partial (0%) accrual of the target population and the early termination of the study for ethical reasons. In contrast to results in younger patients, results in patients aged more than 0 years, who initially usually had lower CD cells, ZDV appears to have decreased the incidence of death and progression to AIDS. Therefore, these results support the findings of protocol 019' to the extent that could be expected owing to the short follow-up of the numbers of patients studied. Considering the side effects observed in the 1,500-mg arm in protocol 019, neither is it surprising that there was a higher rate of hematologic toxicity and nausea among ZDV recipients in this trial. Because ZDV is glycosylated in the liver, we were concerned that the preexisting hepatic disease would influence either the toxicity or efficacy of this therapy; however, this did not appear to be true. There were no differences in characteristics between the placebo and the ZDV groups at entry that would explain the apparent diminished disease progress in the older patients who received ZDV. The analyses of CD counts data unfortunately are limited by some missing values because patients had to be followed at many different hemophilia centers and ACTU sites. The trends toward higher CD counts in the treated group, including those who were older, are of interest, as is the increased weight gain in the older ZDV-treated patients. These trends, however, could be influenced by potential differences in the dropout rate in the two arms. Because weight gain also was not consistently documented, the patients in the drug arm may have preferentially dropped out because of weight loss due to nausea. If so, the Table 5. Change in CD Counts and Body Weight Related to Therapy All Patients s0y >0y Parameter Placebo ZDV PValue Placebo ZDV PValue Placebo ZDV PValue _ ~ ~ _ CD count Week 0 Median n Week 12 Median n Week 2 Median n Week 52 Median n Weight Week 0 Median NS n Week 2 Median NS n

6 ZIDOVUDINE IN TREATMENT OF HIV INFECTION 905 Table. Comparative Results of ZDV Therapy in Controlled Trials No. of Average Months Trial Patients of Therapy Results (Pvalues) Stage of Disease ~~~ ~ ACTG 019' 1,8 1.1 AIDS, advanced ARC (both ZVD doses.002) Asymptomatic T <500 ACTG 0 (present study) 19 9 Y2 J. t*, AIDS (> 0-y strata,.015) Asymptomatic T < 500 ACTG 01' t*, AIDS, advanced ARC (.002) Early ARC BW phase 11' 282 %.1 t* (.001) AIDS, advanced ARC *Dagger denotes death. estimation of the true mean percentage weight gain would not be representative because patients with negative changes would not be represented. Thus, the surrogate marker results for disease progression from this study were disappointing. Table summarizes all ZDV controlled trials that have been reported. It is of methodologic interest that in patients who are studied early in disease death is an unlikely endpoint, even if substantial numbers of patients are studied, as in ACTG 019. Although conclusions regarding usefulness of therapy are less definitive without a demonstrated difference in survival, death will probably not be used as the primary endpoint in future trials. For more efficient analysis of trials, we must determine which of the minor symptoms, surrogate markers, or signs of disease progression with which the action of drugs in this infection can be compared are most reliable. We hope that ongoing clinical trial efforts together with analyses of studies such as ours will clarify this issue. Owing to the early termination of accrual and the limited duration of follow-up, this study had little sensitivity to detect moderate or even fairly large effects of ZDV. If the study could have been completed as planned, with three times as many patients and adequate follow-up, we might have been able to identify beneficial effects of ZDV, both overall and for the subgroup of patients aged less than 0 years. Further study of the usefulness of these doses of ZDV in younger asymptomatic hemophilic patients appears prudent. Finally, in the spousal study, our ability to demonstrate a useful effect of ZDV in prevention of transmission is not surprising considering the short follow-up and the small numbers of patients entered in the study. It is also consistent with previous studies, indicating that seroconversion of partners occurs infrequently." Results of this study clearly support the conclusions of ACTG 019 and suggest that in future trial designs pooling certain data or conducting studies in certain subpopulations may yield drug efficacy information with fewer patients. This may be important as we begin to study more and more methods and comparisons with active drug controls in these and other HIV-infected populations. An important benefit from this study is that through their enrollment in this study 1% of all persons with hemophilia in the United States, their comprehensive care centers, and their national advocacy group have become more knowledgeable about AIDS treatment trials. This has led to the increased involvement of hemophilia investigators in the national ACTG meetings and their sponsorship of and involvement in ACTG protocol 1, a phase 1-2 study of combination antiretrovirals. Integrating these institutions and their patients more readily into other existing or new ACTG trials while retaining their social support network and optimum medical care should now be possible. ACKNOWLEDGMENT This study would not have been possible without the involvement of many physicians, nurses, and pharmacists who care for hemophilic patients throughout the United States. We are grateful to them and to others, including Dr Thomas Peterman and Kathleen Patishall for help in the original protocol design and Ranny Dafni for help in data analysis. The NHF-ACTG 0 Study Group includes: National Hemophilia Foundation: Richard Atwood, MPH, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC; Karen Bloodgood, RN, University of North Carolina, Chapel Hill, NC; Marianne Casicino, RN, Hemophilia Center of Western Pennsylvania, Pittsburgh, PA; Joann Deutsche, RN, BSN, Rehabilitation Institute of Chicago, Chicago, IL; Patricia Forand, RN, Worchester Memorial Hospital, Worchester, MA; David Green, MD, PhD, Rehabilitation Institute of Chicago, Chicago, IL; Ralph A. Guppa, MD, Childt m 's Hospital Medical Center, Cincinnati, OH; Wahid Hanna, MD, University of Tennessee Medical Center, Knoxville, TN, William E. Hathaway, MD, University of Colorado Health Sciences Center, Denver, CO; Edward J. Hershgold, MD, University of Utah Medical, Salt Lake City, UT; Naomi Israel, RN, George Washington University Medical Center, Washington, DC; Kimberly Jackson, RN, Huntington Hospital Hemophilia Center and Orthopaedic Hospital Hemophilic Center, Pasadena, CA, Christina Johnson, MD, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC; James Keyes, Puget Sound Blood Center, Seattle, WA; E. W. Louvrian, MD, Oregon Health Science University, Portland OR; Rita Lovely, RN, University of Nebraska, Omaha, NE; Jeannia MacFarland, RN, University of Tennessee Medical Center, Knoxville, TN, Barbara Miller, RN, BSN, Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, Margot L. Nelson, MSN, University of Minnesota, Minneapolis, MN; John P. Olson, MD, Mary M. Gooley Hemophilia Center, Rochester, Ny, Nan E. Rausch, MD, Albany Medical Center, Albany, Ny; Brenda Riske, RN, University of Colorado Health Sciences Center, Denver, CO; Esther Rose, MD, Mount Sinai Medical Center, New York, Ny, Karen Sachse, RN, George Washington University Medical Center, Washington, DC; Parvin Saidi, MD, UMDNJ Robert Wood Johnson Medical School, New Brunswick, NJ; Stephanie Seremetis, MD, Mount Sinai Medical Center, New York, NY; Amy Shapiro, MD, Indiana Comprehensive Hemophilia Center, Indianapolis, I N Sandor S. Shapiro, MD, Cardeza Foundation Hemophilia Center, Philadelphia, PA; Betty Song, RN, Puget Sound Blood Center, Seattle, WA, Stephen Spector, MD, University of California, San Diego, San Diego, CA; John Sprandio, MD, Cardeza Foundation Hemophilia Center, Philadelphia, PA, Patricia Timmons, RN, Great Lakes Hemophilia Foundation, Milwaukee, WI; Gilbert C. White, MD, University of North Carolina, Chapel Hill, NC; The ACTG 0 Study Group consists of Michael T. Brady, MD, Division of Infectious Diseases, Depart-

7 90 MERIGAN ET AL ment of Pediatrics, Ohio State University College of Medicine, Columbus, OH; Lynda Costanzo, RN, BS, George Washington University Hemophilia Comprehensive Care Center, Washington, DC, M. Elaine Eyster, MD, Pennsylvania State University School of Medicine, Hershey, PA; Kenneth H. Fife, MD, PhD, Indiana University School of Medicine, Indianapolis, IN, David J. Gocke, MD, Robert Wood Johnson Medical School, New Brunswick, NJ; JoeAnn Goldsmith, MD, Northwestern University Medical School, Chicago, Illinois; Ralph A. Gruppo, MD, University of Cincinnati Childrens Hospital, Research Foundation, Cincinnati, OH; Monto Ho, MD, Department of Infectious Diseases & Microbiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, Michael M. Lederman, MD, Case Western Reserve University School of Medicine, Cleveland, OH; Kenneth McIntosh, MD, Children s Hospital, Boston, MA, Professor of Pediatrics, Harvard Medical School, Boston, MA, Margot L. Nelson, RN, MSN, University of Minnesota, Minneapolis, MN; Richard C. Reichman, MD, Department of Medicine, School of Medicine and Dentistry, Rochester, NY; Douglas Richman, MD, Department of Pathology and Medicine, University of California at San Diego Medical Center, Veterans Administration Medical Center, La Jolla, CA; Henry S. Sacks, PhD, MD, Mount Sinai Medical Center, New York, NY; Charles van der Horst, MD, Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, and Karen Vedrenne, BSN, Louisiana Comprehensive Hemophilia, New Orleans, LA. 1. Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, Balfour HH, Reichman RC, Bartlett JA, Hirsch MS, Murphy RL, Harday WD, Soeiro R, Fischl MA, Bartlett JF, Merigan TC, Hyslop NE, Richman DD, Valentine FT, Corey L, and the Aids Clinical Trials Group of the National Allergy and Infectious Diseases: Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD-positive cells per cubic millimeter. N Engl J Med 22:91, Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberdine PA, Laskin 01, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D, and the AZT Collaborative Working Group: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 17:185,1987. Eyster M, Gail MH, Ballard JO, Al-Mondhiry H, Goedert JJ: Natural history of human immunodeficiency virus infections in hemophiliacs: Effects of T-cell subsets, platelet counts, and age. Ann Intern Med 1071,1987. Morse GD, Portmore A, Olson J, Taylor C, Plank C, Reichman RC Multiple-dose pharmacokinetics of oral zidovudine in hemophilia patients with human immunodeficiency virus infection. Antimicrob Agents Chemother, Zelem M: The randomization and stratification of patients to clinical trials. J Chron Dis 27:5, 197 REFERENCES. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 5:57, Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Can Chemother Rep 50:1, Goddert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC, Drummond JE, Vaidya K, Eyster E, Ragni HV, Lederman MM, Cohen AR, Bray GL, Rosenberg PS, Freidman RM, Hilgartner MW, Blattner WA, Droner B, Gail MH: A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 21:111, Fischl MA, Parker CB, Pettinelli C, Wolfson M, Hirsch MS, Collier AC, Causey D, Ho M, Richman DD, Fuchs E, Merigan TC, Reichman RC, Gold J, Steigbigel N, Leoung GS, Rasheed S, Tsiatis A, and the AIDS Clinical Trials Group of the National Allergy and Infectious Diseases: The efficacy and safety of a lower daily dose of zidovudine in the treatment of patients with AIDS: A randomized controlled trial. N Engl J Med 2:1011, Ragni MV, Kingsley LA, Nimorwicz P, Mann DL, Gupta P, Rinaldo CR Heterosexual HIV transmission: Lack of relation to serum P2 antigens, T number, clinical diagnosis, or duration of HIV exposure. J AIDS 2557,1989