12.04.2021

Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection

Demographic Characteristics

Our analyses include data on 1255 HIV-1-infected persons with at least one CD4+ cell count below 100 per cubic millimeter who were among the more than 3500 HIV-infected patients seen as part of the HIV Outpatient Study during the period of analysis (January 1994 through June 1997). About 80 percent were 30 to 49 years of age, and the age distribution did not shift during the period of analysis. We observed nonsignificant trends toward increasing numbers of blacks, Hispanics, and women (making up 20 percent, 9 percent, and 12 percent, respectively, of the total by June 1997) and decreasing proportions of men who reported same-sex sexual activity (accounting for 65 percent of those seen by June 1997). The proportion of patients who reported injection-drug use (about 14 percent) did not change significantly over time.

The proportion of persons whose initial CD4+ cell count at study entry was less than 50 per cubic millimeter decreased slightly (it was 55 percent in 1994, 51 percent in 1995, 44 percent in 1996, and 42 percent in 1997). The proportion of patients whose most recent CD4+ cell count was less than 50 per cubic millimeter diminished significantly (from 67 percent in 1994 to 57 percent in 1995, 43 percent in 1996, and 29 percent in 1997).

Use of Antiretroviral Agents

During the study, the pattern of antiretroviral therapy changed dramatically among patients with CD4+ cell counts below 100 per cubic millimeter. The proportion of patients for whom any antiretroviral therapy was prescribed increased, from 72 percent of patients in 1994 to 95 percent by June 1997, with marked increases in the prescription of combination regimens (from 25 percent in 1994 to 94 percent by June 1997). The most dramatic increases were in the rate of use of regimens containing protease inhibitors, from 2 percent in mid-1995 to 82 percent by June 1997. The use of combinations incorporating protease inhibitors differed little according to patients’ demographic characteristics, although the study sites varied widely in their rates of use of protease inhibitors. In the first quarter of 1996, site-specific rates of protease-inhibitor use ranged from 6 percent to 71 percent; by the second quarter of 1997, the rates ranged from 40 percent to 95 percent. Publicly funded clinics were slower to use protease inhibitors; however, the proportional increases in use were similar among all sites.

Mortality

Table 1. Table 1. Mortality among Patients with CD41 T-Lymphocyte Counts of Fewer than 100 per Cubic Millimeter, According to Type of Antiretroviral Therapy and Calendar Quarter, 1994 through June 1997. Figure 1. Figure 1. Mortality and Frequency of Use of Combination Antiretroviral Therapy Including a Protease Inhibitor among HIV-Infected Patients with Fewer than 100 CD4+ Cells per Cubic Millimeter, According to Calendar Quarter, from January 1994 through June 1997.

Mortality declined markedly in 1996 and early 1997, after remaining constant during 1994 and 1995. Death rates decreased from 29.4 per 100 person-years in 1995 to 16.7 per 100 person-years in 1996 and to 8.8 per 100 by the second quarter of 1997 (Table 1 and Figure 1).

Patterns of reduction in death rates among men and women, white and nonwhite persons, and persons <40 or above 40 years of age were similar and declined in the same way during the 14 quarters of observation. Although mortality decreased proportionally among injection-drug users, they had consistently higher mortality rates than patients who did not report a history of injection-drug use. Although mortality and morbidity differed among the study sites, declines in both rates were noted at all clinics. The rate of use of prophylaxis against opportunistic infections was consistent during the 42 months of observation: the proportion of patients receiving prophylaxis against M. avium complex ranged from 46 percent to 55 percent; the rate of prophylaxis against P. carinii ranged from 92 to 94 percent. Death rates among persons receiving these types of chemoprophylaxis were evaluated; the patterns of decreasing mortality were similar to those in the study group as a whole.

Death rates are shown according to antiretroviral-therapy category in Table 1. Death rates declined in virtually every quarter, correlating inversely with the intensity of the antiretroviral therapy prescribed (Figure 1), and declined most dramatically during the last six quarters covered by the analysis (Table 1).

Differences among the patients in sex, age, race or ethnic group, or risk category did not explain the observed temporal trend in mortality or morbidity when these factors were included in the preliminary failure-rate model. The inclusion of the use of chemoprophylaxis against opportunistic infections in the model also did not explain the trend; however, both the initial CD4+ cell count and the study site were significant (P<0.01) and were therefore retained in the model.

Table 2. Table 2. Relative Risk of Death and Morbidity among Patients with CD41 T-Lymphocyte Counts of Fewer than 100 per Cubic Millimeter, According to Type of Antiretroviral Therapy.

When the effect of treatment was included in the failure-rate model used to evaluate mortality, the effect of the calendar quarter of observation was not significant (P = 0.49). The interaction of treatment with quarter was also not significant (P>0.34). Comparisons of mortality in different antiretroviral-therapy categories within this model (Table 2) revealed that for each increase in the intensity of antiretroviral therapy, there was a significant additional benefit in terms of lower mortality. Notably, mortality among patients receiving combination regimens that did not include protease inhibitors was 1.5 times that among patients receiving combination regimens that included a protease inhibitor.

Table 3. Table 3. Mortality and Rates of Prescription of Protease Inhibitors among Patients with CD41 T-Lymphocyte Counts of Fewer Than 100 per Cubic Millimeter, According to Calendar Quarter, 1994 through June 1997.

Mortality rates are shown according to patients’ primary source of payment for medical services in Table 3. The patients whose care was funded under the Ryan White Care Act prescription programs and those who paid for their own care together made up about 10 percent of the total population and had mortality rates similar to those for patients who were receiving Medicare. Although mortality declined overall among patients covered by Medicaid and those who were privately insured, the death rates for patients insured by Medicaid were higher than the rates in the overall study population in all but two quarters. In 1995, mortality among those covered by Medicaid was 46.9 per 100 person-years; among those with private insurance, it was 24.4 per 100 person-years (data not shown). Patients with private insurance were consistently more likely to receive a protease inhibitor than were patients in any other payer group, although the use of protease inhibitors increased markedly for both privately insured patients and those whose care was publicly funded. The vast majority of patients in all payer groups were prescribed protease inhibitors by the second quarter of 1997. The difference in mortality between patients with private insurance and those covered by public funding narrowed in later quarters; by the second quarter of 1997, mortality among those with private insurance had fallen to 7.7 per 100 person-years; for those covered by Medicaid, mortality was 9.2 per 100 person-years.

In a preliminary failure-rate model with the study center, CD4+ cell count, and payment category as independent covariates, mortality differed significantly (P = 0.02) according to payment category. However, when the type of antiretroviral therapy was added to this model, the effect of the payment category was not significant (P = 0.09), suggesting that differences in mortality among payment groups were accounted for by different patterns of treatment.

A subgroup analysis of mortality among patients with a CD4+ cell count below 50 per cubic millimeter mirrored previous findings; there was a decline in mortality from 39.1 per 100 person-years in the first quarter of 1994 to 10.7 per 100 person-years by the second quarter of 1997. Again, decreases in mortality correlated temporally with the increased use of combination antiretroviral regimens, especially those containing protease inhibitors.

Morbidity

Figure 2. Figure 2. Rates of Cytomegalovirus Infection, Pneumocystis carinii Pneumonia, and Mycobacterium avium Complex Disease among HIV-Infected Patients with Fewer Than 100 CD4+ Cells per Cubic Millimeter, According to Calendar Quarter, from January 1994 through June 1997.

For the 1255 patients we studied, the incidence of serious opportunistic infections declined markedly in 1996 and early 1997 (Figure 2). The incidence of any AIDS-defining diagnosis decreased from approximately 50 per 100 person-years in 1994 and 1995 to 28.6 per 100 person-years in 1996; during the last two quarters of 1996, this rate fell to 13.3 per 100 person-years, where it remained during the first two quarters of 1997. To simplify the analysis, we focused on three serious common infections: P. carinii pneumonia, M. avium complex disease, and cytomegalovirus retinitis. In 1994 the incidence of these three opportunistic infections was 21.9 per 100 person-years; by the second quarter of 1997, it was 3.7 per 100 person-years (Figure 2). None of the independent demographic variables had a significant effect on the incidence of infection in the failure-rate model, either in the group as a whole or in the various antiretroviral-therapy categories; however, chemoprophylaxis against M. avium complex did have a significant effect (P = 0.001).

The final model for morbidity included the study center, category of antiretroviral therapy, initial CD4+ cell count, and the use of chemoprophylaxis against M. avium complex. The effect of time on morbidity was nonsignificant (P = 0.13) when the first 12 quarters of the observation period were analyzed; apparent temporal trends were explained by changes in antiretroviral-therapy categories. However, when data from the last two quarters of 1997 were included, there appeared to be a confounding effect between the quarter (time) and the type of antiretroviral therapy when both were entered into the model simultaneously; as a result, the effect of time appeared to be significant and the treatment regimen appeared less so. Comparisons in which patients were stratified according to the antiretroviral regimen were problematic because few patients remained in the no-therapy or monotherapy groups and because there were too few opportunistic events in these groups for meaningful comparisons of morbidity among treatment groups. Hence, the fact that time appears to have a significant effect in the later quarters is a reflection of the dramatic redistribution of patients to more aggressive antiretroviral-treatment categories and a consequently lower number of infections. After the strong correlation between these measures had been demonstrated, the calendar quarter was removed from the model, and as expected, the observed benefit was linked to antiretroviral therapy.

The most marked reductions in the overall incidence of opportunistic infections occurred during the last five quarters of analysis and paralleled increases in the frequency of use of protease inhibitors. The number of patients receiving protease inhibitors tripled from the first to the fourth quarter of 1996, and 84 percent of all patients with fewer than 100 CD4+ cells per cubic millimeter received protease inhibitors by the second quarter of 1997.

Comparisons of the incidence of any one of the three major opportunistic infections among the antiretroviral-therapy categories in the failure-rate model produced findings consistent with the data on mortality (Table 2); with increases in the intensity of antiretroviral regimens, stepwise reductions in morbidity were noted.

The routine use of measurements of viral load in the participating clinics increased during the period of analysis; by June 1997, at least one such determination had been recorded for 85 percent of patients. Viral-load measurements, which were calculated as the mean of the median values for each patient within each antiretroviral-therapy category, were inversely related to the intensity of therapy. The group mean for those receiving no therapy, expressed as the log of the number of copies of HIV RNA per milliliter of blood, was 4.10; the corresponding values were 3.66 for those receiving monotherapy, 3.43 for those receiving combination antiretroviral therapy without a protease inhibitor, and 2.97 for those receiving combination regimens that included a protease inhibitor.

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