Acquired immunodeficiency syndrome (AIDS)-defining opportunistic illnesses (OIs) are the major cause of morbidity and mortality among persons infected with human immunodeficiency virus (HIV). As a result of new treatments that reduce mortality for persons with AIDS, the number of persons living with AIDS is increasing, and the incidence of AIDS is decreasing. In 1997, an estimated 271,245 persons were living with AIDS in the United States and thus were at high risk for OIs. In 1997, an estimated 21,909 HIV-infected persons died with AIDS, nearly all as a result of OIs.
Aggregate data and trends for 1992-1997 were examined to determine a) the frequencies at which OIs occurred first; b) the incidence of OIs; c) the percentage of persons among those who have died who had had a given OI during their course of AIDS, and d) the frequency of prescriptions for antiretroviral therapy and prophylaxis for Pneumocystis carinii pneumonia (PCP) and for Mycobacterium avium complex disease (MAC).
Data were analyzed from the Adult/Adolescent Spectrum of HIV Disease (ASD) sentinel surveillance project, a prospective medical record review of HIV-infected persons aged greater than or equal to 13 years conducted in 11 U.S. cities. ASD data were standardized to national AIDS surveillance data for 1992-1997 by age; race; sex; country of birth; year of AIDS diagnosis; HIV exposure mode; and for incidence calculations, by CD4+ T-lymphocyte distribution.
The incidence declined significantly for each of 15 of the 26 specific AIDS-defining OIs (p<0.05). PCP was the most common AIDS-defining OI to occur first (PCP was the first OI to occur for 36% of HIV-infected persons), the most common incident AIDS-defining OI (274 cases per 1000 person-years), and the most common AIDS-defining OI to have occurred during the course of AIDS (53% of persons who died with AIDS had PCP diagnosed at some time during their course of AIDS). Of persons with CD4+ T-lymphocyte counts <500 cells/uL, the number with prescriptions for triple combination therapy increased from zero in 1992 to 40% in 1997, and 80% of persons had a prescription for any antiretroviral therapy in 1997. Of persons with CD4+ T-lymphocyte counts <200 cells/uL, the percentage with prescriptions for PCP prophylaxis remained stable from 1992 through 1997 (range: 75% to 80%). Of persons with CD4+ T-lymphocyte counts <50 cells/uL, the percentage with prescriptions for MAC prophylaxis increased from 9% in 1992 to 44% in 1997.
The incidences of many OIs are decreasing primarily because of advances in HIV-related therapy. However, OIs are still occurring, especially when patients access care late during the course of disease. Even after accessing care, persons may develop OIs because of lack of prescription for prophylaxis, antiretroviral drug resistance, or poor adherence to therapy. During 1992-1997, most patients in need of PCP prophylaxis received a prescription for it; however, even in 1997, most patients in need of MAC prophylaxis did not receive a prescription for it.
These surveillance data are used by persons involved with developing guidelines for preventing OIs to determine the importance of and trends in OIs and preventive therapy. CDC is developing population-based approaches for surveillance of HIV disease progression, OIs, and therapies with the goal of making these data available in more geographic areas to help assess public health and health-care programs.
Acquired immunodeficiency syndrome (AIDS)-defining opportunistic illnesses (OIs) are the major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. As a result of new treatments that improve outcomes for HIV-infected persons, the prevalence of AIDS is increasing (1). In 1997, an estimated 271,245 persons were living with AIDS in the United States and thus were at high risk for OIs (1). In 1997, an estimated 21,909 HIV-infected persons died with AIDS, nearly all from OIs.
The incidence of major OIs (2-4) and the percentage of HIV-infected persons with various OIs during a specified period have been documented (5). However, few studies have reported the occurrence of each AIDS-defining OI during the course of AIDS (6,7). Such analyses are helpful for determining the preventive medications and treatments needed for HIV-infected persons. In addition, examination of the frequencies and trends in the AIDS-defining OIs first to occur can assist in determining the first severe and potentially preventable life-threatening event encountered by HIV-infected persons. To determine the frequencies and trends in the OIs first to occur, the incidence of OIs, and the OIs that occurred during the course of AIDS, data were analyzed from the CDC-sponsored Adult/Adolescent Spectrum of HIV Disease (ASD) sentinel surveillance project.
ASD was implemented by CDC in collaboration with state and local health departments to monitor the spectrum and frequency of HIV-associated illnesses. Data collection started in 1990. The methods for ASD have been described previously (8). At selected sites in Denver, Colo.; Los Angeles, Calif.; Atlanta, Ga.; New Orleans, La.; Detroit, Mich.; New York, N.Y.; Dallas, Houston, and San Antonio, Tex.; Seattle, Wash.; and Bayamon, Puerto Rico, HIV-infected persons aged greater than or equal to 13 years are identified at their first health-care encounter in an ASD clinic, regardless of the stage of their HIV infection. Approximately 100 medical facilities that provide inpatient and/or outpatient care for HIV-infected patients were included in this analysis. The facilities comprised public (73%) and private (27%) institutions.
All HIV-infected persons who attend participating clinics are eligible for enrollment. To prevent oversampling of certain groups relative to the national population with AIDS, sampling of patients for inclusion is conducted at some sites: 50% of African American males in Atlanta since January 1994; 25%-50% of white males in Dallas, San Antonio, and selected sites in Seattle since 1990-1991; no white males (except injecting-drug users [IDUs]) at some Los Angeles sites since 1992; 40%-50% of all men at Detroit sites since 1993; and 16%-50% of white males at some New York City sites since January 1995.
Information is collected about demographic characteristics, mode of HIV exposure, and any previous occurrences of conditions listed in the 1993 AIDS surveillance case definition (9). ASD data are reported to CDC without personal identifying information. During successive 6month follow-up intervals, medical records are reviewed for illnesses, AIDS-defining conditions, prescriptions, laboratory tests (including CD4+ T-lymphocyte tests), and use of medical care. The CDC hierarchical classification is used for HIV exposure mode (1). OIs were defined by using the clinical AIDS conditions in the 1993 AIDS surveillance case definition (9). Definitive and presumptive diagnoses were combined for this analysis. Cytomegalovirus (CMV) retinitis was analyzed separately from other CMV disease. For ASD, lost to follow-up was defined as unable to locate a patient for greater than or equal to 18 months; during 1992-1997, 15.5% of ASD participants were lost to follow-up. . . .
From January 1992 through December 1997, AIDS-defining OIs were diagnosed in 12,982 HIV-infected persons. Of these, 10,658 (82%) were males, and 2,324 (18%) were females. The percentage of males with an AIDS-defining OI for whom a given OI occurred first ranged from zero (for chronic isosporiasis) to 35.7% (for PCP) (Table 1 [redacted]). Similarly, the percentage of women with an AIDS-defining OI for whom a given OI occurred first ranged from zero (for chronic isosporiasis, Burkitts lymphoma, and recurrent Salmonella septicemia) to 33.7% (for PCP) (Table 2 [redacted]).
The frequency at which AIDS-defining OIs occurred first varied by sex. For example, for males, the OIs more likely to occur first were Kaposi sarcoma (KS), extrapulmonary cryptococcosis, and CMV disease (Table 1). For females, the OIs more likely to occur first were esophageal candidiasis, recurrent pneumonia, pulmonary tuberculosis (TB), and chronic herpes simplex (Table 2). However, among IDUs, pulmonary TB was more likely to occur first among males than among females.
The frequency at which AIDS-defining OIs occurred first also varied by HIV exposure mode (Table 1 and Table 2). The OIs that occurred first more frequently among men who have sex with men (MSM) were KS, CMV retinitis, CMV disease, and chronic cryptosporidiosis. However, the OIs that occurred first more frequently among both male IDUs and males exposed to HIV through heterosexual contact were pulmonary TB, extrapulmonary TB, recurrent pneumonia, toxoplasmosis of the brain, and disseminated histoplasmosis. In addition, chronic herpes simplex and disseminated coccidioidomycosis occurred first more frequently among men exposed to HIV through heterosexual contact. There were few statistically significant differences in the frequency at which OIs occurred first between female IDUs and females exposed to HIV through heterosexual contact. However, toxoplasmosis of the brain occurred first more frequently among females exposed to HIV through heterosexual contact, and immunoblastic lymphoma occurred first more frequently among female IDUs (values in Table 2 are rounded).
During 1992-1997, the frequency at which OIs occurred first increased for five OIs and decreased for five OIs (Table 3) [Table 3 omitted]. The frequency at which PCP occurred first remained constant during this period, and the frequency at which esophageal candidiasis occurred first increased.
Overall, 22,558 HIV-infected persons (17,404 [77%] males and 5,154 [23%] females) were followed 35,933 person-years; 6,113 persons had incident OIs. The incidence of AIDS-defining OIs varied by sex. Overall, the incidences of KS, CMV disease, and extrapulmonary cryptococcosis were higher in males than in females (Tables 4 and 5) [Tables 4 and 5 omitted]; however, among IDUs and persons exposed to HIV through heterosexual contact, the incidence of CMV disease was higher in females than in males. Overall, the incidences of pulmonary TB, chronic herpes simplex disease, and extrapulmonary TB were higher in females than in males. However, among IDUs, the incidence of extrapulmonary TB was higher in males than in females.
The incidence of AIDS-defining OIs also varied by HIV exposure mode (Tables 4 and 5) [Tables 4 and 5 omitted]. The incidences of MAC, CMV retinitis, KS, CMV disease, and chronic cryptosporidiosis were higher for MSM than for other male groups. However, the incidences of PCP, recurrent pneumonia, toxoplasmosis of the brain, pulmonary TB, and extrapulmonary TB were higher for male IDUs and males exposed to HIV through heterosexual contact (except PCP) than for MSM. The incidences of any OI (combined) and of esophageal candidiasis were higher for female IDUs than females exposed to HIV through heterosexual contact. The incidence of CMV retinitis was higher for females with a heterosexual HIV exposure risk than for female IDUs.
During 1992-1997, the incidence decreased significantly for any AIDS-defining OI (combined) and for 15 of the 26 specific AIDS-defining OIs (p<0.05) (Table 6) [Table 6 omitted]. Even for many OIs without statistically significant declines over all years, incidences declined in 1997. For example, in 1997, incidences declined for esophageal candidiasis, recurrent pneumonia, progressive multifocal leukoencepalopathy, immunoblastic lymphoma, primary brain lymphoma, and disseminated histoplasmosis. No significant increases in incidence occurred during 1992-1997. In general, the largest decreases in incidence occurred during the most recent years.
During 1992-1997, a total of 10,353 HIV-infected persons observed in the ASD project died with AIDS. Of these, 8,811 (85%) were males, and 1,542 (15%) were females. Overall, the percentages of males who ever had a given OI during the course of AIDS ranged from 0.1% (for chronic isosporiasis) to 52.8% (for PCP) (Table 7 [redacted]). Overall, the percentages of females who ever had a given OI during the course of AIDS ranged from zero (for Burkitts lymphoma and chronic isosporiasis) to 52.2% (for PCP) (Table 8 [redacted]). OIs diagnosed more frequently among males than among females were KS, CMV retinitis, CMV disease, extrapulmonary cryptococcosis, and toxoplasmosis of the brain (Table 7 and Table 8). However, for IDUs, CMV disease was diagnosed more frequently among females than among males. Overall, OIs diagnosed more frequently among females than among males were esophageal candidiasis, pulmonary TB, and chronic herpes simplex. However, for IDUs and persons exposed to HIV through heterosexual contact, pulmonary TB was diagnosed more frequently among males than among females.
The frequency of OIs during the course of AIDS also varied by sex and HIV exposure mode. For example, MAC, KS, CMV retinitis, CMV disease, and chronic cryptosporidiosis were diagnosed more frequently among MSM than among other groups of men (Table 7). However, male IDUs had pulmonary TB and extrapulmonary TB diagnosed more frequently than other groups of men. There were few significant differences in the frequency of OIs during the course of AIDS among women (Table 8). However, pulmonary TB was diagnosed more frequently among female IDUs, and CMV retinitis was diagnosed more frequently among females exposed to HIV through heterosexual contact.
For many AIDS-defining OIs, the annual percentage of persons with specific OIs during the course of AIDS remained constant during 1992-1997 (Table 9 [redacted]). However, the percentage decreased for persons who ever had PCP, toxoplasmosis of the brain, extrapulmonary TB, disseminated non-MAC Mycobacterium, and pulmonary candidiasis, and the percentage increased for persons who ever had wasting syndrome, recurrent pneumonia, or pulmonary TB. The median number of unique AIDS-defining OIs per person during the course of AIDS was two (25th percentile, one unique AIDS-defining OI; 75th percentile, three unique AIDS-defining OIs) (range: 1-10 unique AIDS-defining OIs).
From 1992 through 1997, among persons with CD4+ T-lymphocyte counts <500 cells/uL, prescription of dual combination therapy increased from 22% to 32%, and prescription of triple combination therapy increased from zero to 40% (Figure 1) [all figures omitted]. During this period, prescription of monotherapy decreased from 58% to 7% (Figure 1). Among persons with CD4+ T-lymphocyte counts <200 cells/uL, prescriptions to prevent PCP remained relatively stable (75%-80%), but the percentage of persons receiving TMP-SMZ increased from 1992 through 1995 (from 57% to 64%) (Figure 2). Although prescriptions to prevent MAC increased each year during 1993-1997 among persons with CD4+ T-lymphocyte counts <50 cells/uL (Figure 3), most (56%) of these severely immunosuppressed HIV-infected persons still had not had this medication prescribed in 1997.
During 1992-1997, PCP was the most common AIDS-defining OI to occur first (36%), the most common incident AIDS-defining OI, and the most common AIDS-defining OI to have occurred among persons who had died with AIDS. The incidence of PCP decreased, and the percentage of persons who ever had PCP during the course of AIDS decreased. However, previous analyses in ASD during this period indicated that PCP remained the most common OI to occur first because of a) delays in diagnosis of HIV infection and in access to care for some groups, b) occurrence despite use of prophylaxis at low CD4+ T-lymphocyte counts, and c) probable lack of compliance with prophylaxis (14). Previous analyses in ASD also have indicated that up to 50% of PCP cases occur in persons who have not been tested for HIV or who have not accessed care (14). In the current analysis, the percentage of PCP that ever occurred among persons who had died with AIDS was substantially lower (53% during 1992-1997 and 43% in 1997) than that found in 1990 and before (67%) (6). The recommendations for PCP prophylaxis were promulgated in 1989 (15) and probably account for much of the decline in the incidence of PCP. The percentage of persons with prescriptions for TMP-SMZ increased from 57% in 1992 to 64% in 1995 and remained relatively stable thereafter (Figure 2). TMP-SMZ is easy to administer and is effective at preventing PCP (16). Since late 1995, triple combination antiretroviral therapy probably has had a substantial impact on PCP (and other OIs) by slowing the progression of HIV disease. Other studies indicate a substantial reduction from January 1994 through June 1997 in the incidence of PCP and other OIs associated with an increase in combination therapy (including protease inhibitors) (17). However, PCP still occurs, particularly among persons who were tested late for HIV or who failed to access care (18-21).
In addition, the incidence of toxoplasmic encephalitis decreased, and the percentage of persons who had toxoplasmic encephalitis diagnosed during the course of AIDS decreased. These decreases are probably a result of PCP prophylaxis with TMP-SMZ, a medication that also prevents toxoplasmic encephalitis (22-24). The frequency at which toxoplasmosis occurred first has remained relatively stable over time. Reasons for this lack of decline may be similar to the reasons for the lack of decline in the frequency at which PCP occurred first (i.e., late HIV testing and failure to access care). Prophylaxis for toxoplasmic encephalitis was recommended in 1995 for adults and adolescents seropositive for Toxoplasma and with CD4+ T-lymphocyte counts <100 cells/uL (25).
During 1992-1997, both the frequency at which MAC occurred first and the incidence of MAC decreased, but the percentage of persons who had MAC diagnosed during the course of AIDS remained stable. MAC prophylaxis and antiretroviral therapy probably have contributed to the decline in the incidence of MAC, but occurrence at low CD4+ T-lymphocyte counts (despite prescription of prophylaxis) and poor compliance with therapy may result in eventual development of MAC in some persons. MAC prophylaxis was first recommended in 1993 for adults and adolescents with CD4+ T-lymphocyte counts <75 cells/uL (26); the recommendations were updated in 1997 to limit use in adults and adolescents to those with CD4+ T-lymphocyte counts <50 cells/uL (27).
The findings that the rates of esophageal candidiasis and chronic herpes simplex were higher for females than for males have been noted previously (28-31). Higher rates of esophageal candidiasis may occur in women because of vaginal colonization with Candida (29). Higher rates of herpes simplex may occur in women because the disease is more common in female IDUs than in male IDUs (32). Researchers have suggested that the exchange of sex or money for drugs may be more common among female than among male IDUs, resulting in a higher rate of sexually transmitted diseases (including herpes simplex virus infection) among women (33,34).
In addition, rates of TB were higher for females than for males. Injecting-drug use has been associated with TB among persons with AIDS (35-37). Because a greater proportion of women than men are IDUs, women are more likely to have TB. However, among IDUs only, the rates of TB generally were higher for males than for females.
Rates of KS, CMV disease, and CMV retinitis were higher for males than for females. These diseases are associated with sexual transmission, and a larger proportion of men than women have sexual HIV risks. However, the higher rate of CMV disease among female IDUs than male IDUs may be associated with the practice of exchange of sex for money or drugs.
The findings in this report are subject to at least four limitations associated with the ASD data. First, ASD data may not be complete because illnesses in general are not always diagnosed and, even when diagnosed, are not always recorded in the medical chart. However, because AIDS-defining OIs are serious medical conditions, they usually are recorded in the chart. Second, because ASD does not represent the entire population of persons in the United States with HIV infection and AIDS, these findings may not be generalizable to the entire U.S. population. The frequency of some OIs (e.g., TB and coccidioidomycosis) varies by region. However, ASD has a large patient population enrolled from a diverse group of clinics and hospitals nationwide. Third, medications recorded in ASD are those prescribed any time during each 6-month data abstraction interval, regardless of the duration of treatment. The reasons for prescribing medications are not recorded, and adherence to therapy is not assessed. Fourth, ASD may exclude diagnoses that occur outside the enrolled hospitals and clinics. However, whenever possible, hospital and clinic staff attempt to obtain medical records from other facilities to help ensure optimal patient care.
Many persons are enrolled in ASD when their first OI occurs, and they may not have medical care before their first major illness. As a result, preventable OIs occur in ASD patients at a higher frequency than in populations in which most patients obtain care early during the course of HIV disease. One previous study in ASD indicated that, for IDUs, incidences have not decreased as frequently or for as many OIs as for MSM (35).
Persons at risk for HIV infection must receive HIV testing and access medical care before onset of advanced immunosuppression. This enables administration of chemoprophylaxis to prevent OIs, vaccinations to prevent illnesses (e.g., pneumococcal disease), and antiretroviral treatment to prevent progression and the serious manifestations of HIV-related disease. In addition, the progression of HIV infection to AIDS should be monitored. Antiretroviral drug resistance and poor adherence to medications can substantially increase the rate of disease progression. Surveillance for severe HIV-related illnesses will continue to be essential in determining how well HIV-related morbidity is being prevented.
The authors gratefully acknowledge the administrative assistance of Scott B. McCombs, MPH, and data management of Pei-Chun Wan, MS, with the Adult and Adolescent Spectrum of HIV Disease surveillance project.
The Adult and Adolescent Spectrum of HIV Disease investigators are Melanie Thompson, MD, Julia Gable, MS, and William McCarthy, PhD, AIDS Research Consortium of Atlanta, Atlanta; Sylvia Odem, MPH, and Sharon Melville, MD, Texas Department of Health, Austin; Arthur Davidson, MD, David L. Cohn, MD, and Cornelius Rietmeijer, MD, Denver Department of Health and Hospitals, Denver; Linda L. Wotring, PhD, MPH, and Eve D. Mokotoff, MPH, Michigan Department of Community Health, Detroit; Wes McNeely, MS, and Kaye Reynolds, Houston Department of Health and Human Services, Houston; Frank Sorvillo, PhD, and Dorothy Masters, Los Angeles County Department of Health Services, Los Angeles; Susan Troxler, MPH, and Anne Morse, Louisiana Office of Public Health, New Orleans; Judy Sackoff, PhD, and Jeffrey McFarland, MD, The City of New York Department of Health, New York City; Jose Otero, MPH, Robert Hunter, MD, and Maria de los Angeles Gomez, PhD, University Central del Caribe, Bayamon, and Sandra Miranda, MPH, Puerto Rico Department of Health, San Juan; and Susan Buskin, PhD, and Sharon G. Hopkins, DVM, Seattle-King County Department of Public Health, Seattle.
MMWR. 1999;48(suppl 2):1-22. 4 tables, 3 figures, and 37 references omitted.
Jones JL, Hanson DL, Dworkin MS, Alderton DL, Fleming PL, Kaplan JE, Ward J. Surveillance for AIDS-Defining Opportunistic Illnesses, 1992–1997. Arch Dermatol. 1999;135(8):897-902. doi:10-1001/pubs.Arch Dermatol.-ISSN-0003-987x-135-8-dmm0899