Special Article
Zidovudine and the Natural History of the Acquired Immunodeficiency Syndrome
N Engl J Med 1991; 324:1412-1416May 16, 1991
- Abstract
- Abstract
Background and Methods.
We sought to describe the trends in survival from 1983 to 1989 among persons with the acquired immunodeficiency syndrome (AIDS) and to examine the relative effects on the natural history of AIDS of zidovudine use and demographic and clinical characteristics. This longitudinal, observational, population-based study used data from the Maryland Human Immunodeficiency Virus Information System, a data base that links information from the Maryland AIDS Registry with data on public and private health care claims, vital statistics, and hospital, long-term care, and ambulatory care records.
Results.
The median survival after diagnosis among persons with AIDS (n = 1028) was 140 days longer for those given their diagnoses between 1987 and 1989 than for those given their diagnoses between 1983 and 1985 (450 vs. 310 days). Among the 714 persons in whom AIDS was diagnosed after April 1987 (when zidovudine became available), two-year survival was greater among men than women (P<0.03), among persons less than 45 years old than among older persons (P<0.001), among non-Hispanic whites than among minorities (P<0.001), and among persons whose category of human immunodeficiency virus transmission was homosexual contact than among those with heterosexual, transfusion-related, or less common modes of transmission (P<0.02). In all the analyses the groups with the longer survival were more likely to have received zidovudine. The median survival among those who received zidovudine was 770 days, as compared with 190 days among those who never received the drug (P<0.001). By proportional-hazards analysis, zidovudine therapy was the factor most strongly associated with improved survival.
Conclusions.
For Maryland residents with AIDS there has been an improvement in survival since 1987. Zidovudine therapy and perhaps other aspects of care associated with it have contributed substantially to the improved survival. (N Engl J Med 1991; 324:1412–6.)
Media in This Article
Figure 1
Product-Limit Estimates of the Probability of Survival Stratified According to Receipt of Zidovudine.Table 1
Kaplan–Meier Estimates of the Probability of Survival after a Diagnosis of AIDS.Article Activity
- Article
SURVIVAL after a diagnosis of the acquired immunodeficiency syndrome (AIDS) is influenced by a number of factors. Early studies of persons given a diagnosis of AIDS before antiretroviral therapy became available suggested that age, the AIDS-defining diagnosis, and possibly sex and race influenced survival. These studies found little or no evidence of a secular trend toward improved survival.1 , 2 Therapy with zidovudine (formerly azidothymidine, or AZT) was subsequently shown in clinical trials to prolong survival.3 , 4 Recent studies of persons with AIDS, all of whom received zidovudine, indicate that survival is further influenced by characteristics such as functional status, hemoglobin concentration, and CD4+ lymphocyte count, as well as the length of time between the diagnosis of AIDS and the beginning of therapy with zidovudine.5 6 7 Two recent studies suggest that the incidence of AIDS has declined and the survival of persons given a diagnosis of AIDS has improved since the middle of 1987.8 , 9 Several explanations for the decrease in the incidence of AIDS and the improvement in survival have been proposed, including changes in the surveillance definition of AIDS in 1987, reporting delays, and changes in therapy for human immunodeficiency virus (HIV) disease, particularly the introduction of zidovudine in the spring of 1987.
This study was undertaken to describe survival trends among patients in whom AIDS was diagnosed in Maryland and to determine how survival is modified by demographic and clinical characteristics, particularly therapy with zidovudine. This study uses data from the Maryland Human Immunodeficiency Virus Information System, an automated, person-based, longitudinal system linking epidemiologic information, vital statistics, data on inpatient and community-based services, and information from public and private insurance claims.
Methods
The Human Immunodeficiency Virus Information System was established in 1987 by the Center for AIDS Services Planning and Development of the Maryland Department of Health and Mental Hygiene to assess the volume, nature, and cost of health care services associated with HIV disease and related disorders.10 , 11 Patients become a part of this data base when reported by their physicians to the department as having AIDS as defined by the Centers for Disease Control (CDC) or when identified as having AIDS through active, ongoing surveillance of clinical laboratories, hospitals, and insurance-claims files managed by the state. In addition to using case reports and the surveillance of claims files, the department identifies persons with AIDS by means of a net of ICD-9-CM (International Classification of Diseases, 9lh Revision, Clinical Modification) codes developed and matched with diagnostic data maintained in various automated secondary data sets that feed into the Human Immunodeficiency Virus Information System. When a discharge or claim record captured by the diagnostic net identifies a case that has not been reported, the case is investigated by surveillance staff using standard guidelines for the investigation of infectious disease. New cases identified by this method are subsequently added to the information system. The HIV Registry is the base file for the Human Immunodeficiency Virus Information System and includes items required for reports to the CDC as well as elements collected for state epidemiologic purposes. Each of the four data modules —vital records, health insurance claims, institutional systems, and community-based systems — is made up of secondary data sets, each containing information relevant to that module. Cases within each module are matched according to name, sex, race, date of birth, and social security number to the HIV Registry. Cases with unknown dates of death are investigated through a search of the National Death Index of the National Center for Health Statistics. Strict confidentiality is maintained in all parts of the data base.
The analyses presented in this paper are based on data from Maryland residents who were 17 years of age or older; had CDC-defined AIDS; were enrolled in the Maryland Medical Assistance Program (Medicaid), Maryland Pharmacy Assistance, Maryland Blue Cross and Blue Shield, or Maryland AIDS Drug Assistance Program; or had received zidovudine through the Johns Hopkins University AIDS Clinical Trials Unit (ACTU). Analyses of temporal survival trends were based on data from 1028 persons given a diagnosis of AIDS from January 1983 through June 1989, with follow-up through June 1990. All analyses assessing the effect of zidovudine therapy were based on data from the 714 persons who received diagnoses between April 1987 and June 1989. April 1987 was chosen because in that month zidovudine was licensed for use and became widely available. Treatment with zidovudine was ascertained through claims submitted for the receipt of the drug and through administrative records. Persons with at least one claim for zidovudine were coded as having received the drug, and the date zidovudine was first dispensed was determined.
The data were analyzed by chi-square test, product-limit survival analyses, and Cox proportional-hazards regression analysis. All survival analyses measured survival as the number of days from the diagnosis of AIDS to death. Twenty-six persons with a posthumous diagnosis of AIDS were coded as having a zero survival time. Since patients may not have received zidovudine when AIDS was first diagnosed, a standard Kaplan–Meier product-limit comparison of those who never received zidovudine with those who received it might be biased in favor of those who received zidovudine. This potential bias was addressed in two ways: first, by estimating the survival function only for persons who began receiving zidovudine when AIDS was diagnosed; and second, by a lefttruncated product-limit method, which adjusts survival estimates for the time between diagnosis and the start of therapy (the truncation time) and allows data on all persons to be included.12 Similarly, a left-truncated proportional-hazards analysis was used to examine the relative hazard associated with zidovudine use and other variables.
Results
Survival estimates stratified according to the year of the AIDS-defining diagnosis are shown in Table 1Table 1
Kaplan–Meier Estimates of the Probability of Survival after a Diagnosis of AIDS.. Median survival increased significantly from 310 days for persons given diagnoses between 1983 and 1985 to 450 days for those given diagnoses between 1987 and 1989.Additional analyses were conducted involving only the 714 persons in whom AIDS was diagnosed between April 1987 and June 1989. The median, six-month, one-year, and two-year probabilities of survival are shown in Table 2Table 2
Kaplan–Meier Estimates of the Probability of Survival after a Diagnosis of AIDS Received between April 1987 and June 1989., with stratification according to sex, race and ethnic group, principal mode of HIV transmission, age group, and AIDS-defining diagnosis. Significant differences were found with regard to sex, with men surviving longer than women (P<0.03), race and ethnic group, with non-Hispanic whites surviving longer than minorities (P<0.001), and age, with those under 45 years old surviving longer than older persons (P<0.001). Homosexual men survived longer than those who acquired HIV infection through heterosexual contact, transfusion, or other less common modes (P<0.02). Those with an AIDS-defining diagnosis of Pneumocystis carinii pneumonia or Kaposi's sarcoma had a one-year (P<0.01) but not a two-year survival advantage over those whose AIDS-defining diagnosis was another opportunistic condition.Of the 714 members of the cohort given their diagnosis after April 1987, 352 (49 percent) received zidovudine (Table 3Table 3
Characteristics of Persons Who Were Given a Diagnosis of AIDS between April 1987 and June 1989, According to Whether They Received Zidovudine Therapy.). Zidovudine was received by 53 percent of the men but only 33 percent of the women (P<0.001), by 63 percent of non-Hispanic whites but only 43 percent of the minority persons (P<0.001), and by 56 percent of those 30 or younger but only 41 percent of those 45 or older (P<0.02). Zidovudine was more commonly received by homosexual men (59 percent) than by those who acquired HIV through heterosexual contact, transfusion, or other less common modes (49 percent), and it was least likely to be received by intravenous drug users (38 percent). Persons whose AIDS-defining diagnosis was Kaposi's sarcoma were most likely to receive zidovudine (60 percent), then those with a diagnosis of P. carinii pneumonia (53 percent), and finally those with other AIDS-defining diagnoses (42 percent).We performed both standard Kaplan–Meier product-limit analysis and a left-truncated product-limit survival analysis stratifying according to receipt of zidovudine therapy (Fig. 1Figure 1
Product-Limit Estimates of the Probability of Survival Stratified According to Receipt of Zidovudine.). Only the 56 persons (16 percent) who first received zidovudine at the time of the diagnosis of AIDS were included in the standard analysis. A left-truncated estimate involving all persons who received zidovudine was similar to the standard estimate. Median survival was 770 days among persons who received zidovudine, as compared with 190 days among those who never received the drug, and the survival advantage extended to two years after the diagnosis of AIDS (P<0.001 by log-rank test).There were 229 non-Hispanic whites. Minority persons included 472 blacks (97.3 percent), 12 Hispanics (2.5 percent), and 1 Asian (0.2 percent). Comparing non-Hispanic whites who did not receive zidovudine with those who did, we found that the one-year probability of survival increased from 0.37 (95 percent confidence interval, 0.27 to 0.47) to 0.77 (95 percent confidence interval, 0.67 to 0.87), and the two-year probability increased from 0.26 (95 percent confidence interval, 0.16 to 0.36) to 0.56 (95 percent confidence interval, 0.46 to 0.66) (P<0.001 by logrank test). Similarly, the one-year probability of survival for minority persons increased from 0.32 (95 percent confidence interval, 0.26 to 0.38) to 0.70 (95 percent confidence interval, 0.60 to 0.79), and the two-year probability increased from 0.19 (95 percent confidence interval, 0.14 to 0.24) to 0.47 (95 percent confidence interval, 0.39 to 0.55) (P<0.001 by logrank test).
A left-truncated proportional-hazards analysis was used to assess the relative chance of survival associated with zidovudine therapy after simultaneous adjustment for the other factors (Table 4Table 4
Cox Proportional-Hazards Analysis of the Adjusted Effect of Zidovudine Therapy and Clinical and Demographic Characteristics on Survival in Persons Given a Diagnosis of AIDS between April 1987 and June 1989.). With adjustment, zidovudine use was significantly associated with longer survival (relative hazard = 0.62; 95 percent confidence interval, 0.49 to 0.79). Minority race or ethnic group was associated with poorer survival (P<0.05), but the interaction between race or ethnic group and zidovudine use was not significant. Interactions between an age ≥45 and the year of the diagnosis of AIDS after 1987 were also not significant (data not shown).Finally, it is notable that the survival distribution of the cohort given a diagnosis of AIDS in 1986 was more like the distributions of the cohorts given a diagnosis in 1987 to 1989 than like those of the cohorts given a diagnosis in 1983 to 1985. Zidovudine was received by 4 percent of those in whom AIDS was diagnosed in 1983 to 1985, by 25 percent of those in whom AIDS was diagnosed in 1986, and by 49 percent of those in whom it was diagnosed in 1987 or later. The survival distribution of the persons given a diagnosis in 1986 who did not receive zidovudine was found to be almost identical to the survival distribution of those given a diagnosis in 1983 to 1985, whereas the survival distribution of those given a diagnosis in 1986 who received zidovudine was almost identical to the distributions of the later cohorts.
Discussion
This study was conducted to determine whether an improvement in survival over time among persons with AIDS could be demonstrated in Maryland, where a substantial and growing number of persons representing a broad mix of racial and ethnic groups, sexes, ages, and modes of transmission are infected with HIV. Using data from a comprehensive, longitudinal statewide information system, we found that survival improved most among patients given a diagnosis of AIDS in 1987 through 1989, as compared with those given a diagnosis in previous years. Homosexual men, non-Hispanic whites, young persons, and persons with an AIDS-defining diagnosis of Kaposi's sarcoma or P. carinii pneumonia survived longest among all those in whom AIDS was diagnosed in April 1987 or after. These subgroups were also the most likely to receive zidovudine therapy, the predominant factor affecting survival after multivariate adjustment.
Before the advent of antiretroviral therapy, studies found a relatively short median survival (11 to 13 months) among patients with AIDS, without trends of improvement over time.1 , 2 A more recent study found fewer reported new cases of AIDS than expected according to projections that used the back-calculation method to predict incidence among homosexual and bisexual men in three U.S. cities, although not among intravenous drug users.8 Statistical modeling suggested that AIDS therapy available since 1987 was the most likely explanation. In another study, survival among more than 4300 patients with AIDS in San Francisco was found to have improved in 1986 and 1987 as compared with previous years, primarily among patients in whom P. carinii pneumonia was diagnosed.9 For most of the study population the use of zidovudine was unknown, but in a small subset of 172 patients (<1 percent) documented to have received the drug, median survival was 21 months, similar to the median survival of 25 months in the persons who received zidovudine in our study. National AIDS surveillance data also demonstrate a temporal improvement in survival among persons whose initial diagnosis is P. carinii pneumonia,12 though the effect of antiretroviral therapy cannot be assessed.
By using a statewide data base that incorporates information from pharmacy claims and clinical trials, we were able to measure rather than estimate the use of antiretroviral therapy. Zidovudine is a relatively expensive drug that is unlikely to be purchased out of pocket. Given the high percentage of those with AIDS in this population who received coverage through Medicaid or Blue Cross and Blue Shield, and given our knowledge of the sources of zidovudine in Maryland, it is unlikely that more than a minimal amount of zidovudine use was not identified. The data indicate that the effect of zidovudine therapy may be even greater than previously estimated and suggest that we would have found an even larger difference in survival trends if more persons with AIDS had received zidovudine. In those not receiving zidovudine, median survival was less than one year — a figure comparable to estimates of survival in patients with AIDS before antiretroviral therapy. Because insurance status defined this cohort, the persons whose data we analyzed probably had similar access to medical care, as determined by the ability to pay. It is therefore notable that a large number of persons with AIDS (more than 50 percent) did not receive zidovudine therapy, despite its availability. These data do not address the reasons for the demographic disparities in zidovudine use. They do, however, indicate that race and ethnic group, sex, age, and possibly risk category can identify those who may benefit from targeting strategies to improve the receipt of medical care for HIV infection. In regard to race and ethnic group, our data indicate that minorities (predominantly blacks) have a shorter survival time than non-Hispanic whites but that medical care, including the use of zidovudine, contributes to improved survival similarly among blacks and whites.
Several comments should be made in regard to interpreting our results. First, we did not assess the effect of the 1987 revised CDC surveillance definition of AIDS on overall survival in our study population. The revision could have biased the survival distributions in that more persons are now given a diagnosis of AIDS at an earlier stage of HIV disease, resulting in longer survival after diagnosis. However, as suggested in the study by Lemp et al., the effect of the change in definition probably altered median survival by only 20 days.9 Second, zidovudine therapy is likely to be a marker for access to other AIDS treatment, including other drug therapies as well as various types of home and community-based supportive care. For example, aerosolized pentamidine therapy, which may improve survival,13 , 14 was not included in our analysis because reliable information on its use was not available for the entire cohort. Third, our data are not designed to address certain clinical prognostic factors, such as degree of immunologic impairment. Several key prognostic factors were known, however, including AIDS-defining diagnosis, date of progression to AIDS, and principal risk category for HIV transmission. Another advantage is that the Human Immunodeficiency Virus Information System relies not only on reports of patients to the HIV Registry, but also on an intensive surveillance system. This serves to minimize bias from delays in reporting cases of AIDS. Many persons with AIDS "spend down" to a lower socioeconomic status, but the Human Immunodeficiency Virus Information System maintains longitudinal information on these people because of its access to data from the state or private and public insurers. Although relatively few persons with AIDS leave the state,15 care received outside Maryland is also recorded.
In summary, our analysis shows an improvement in survival over time among persons with AIDS in Maryland that coincides with the availability of antiretroviral therapy. Our data suggest that zidovudine (and perhaps other aspects of care associated with zidovudine therapy) has made a sizable difference in survival for persons with AIDS living in Maryland. The challenge now appears to be to increase the use of that therapy in all segments of the population infected with HIV.
We are indebted to Mei-Cheng Wang, Ph.D., Department of Biostatistics, Johns Hopkins University School of Hygiene and Public Health, for her valuable assistance in designing and conducting survival analyses; and to Joseph Bareta, Nancy Adler, and Nancy Allen for their contributions to the development of the Human Immunodeficiency Virus Information System.
Source Information
From the Johns Hopkins University School of Medicine (R.D.M., R.E.C.); the Department of Health and Mental Hygiene, AIDS Administration (J.H., B.W.S.); and the Drug Policy Center, School of Pharmacy, University of Maryland at Baltimore (J.H.); all in Baltimore. Address reprint requests to Dr. Moore at Johns Hopkins Hospital, 1830 E. Monument St., Rm. 8059, Baltimore, MD 21205.
Dr. Moore is a Burroughs Wellcome Scholar in Pharmacoepidemiology. The Maryland Human Immunodeficiency Virus Information System is supported by the Agency for Health Care Policy and Research (grant HS06185–01), Burroughs Wellcome Company, the Food and Drug Administration (contract 223–89–3603), the Centers for Disease Control (cooperative agreement U6Z/CCU301930–02), the Health Care Financing Administration (grant 18-C-99552), the National Institute of Allergy and Infectious Diseases (contract 5U01 AI27668), and the state of Maryland. The views expressed in this paper are not necessarily those of these agencies or the Maryland Department of Health and Mental Hygiene.
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