Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease

The introduction of combination antiretroviral therapy for HIV infection revolutionized treatment of AIDS and HIV disease. Such treatment, which usually includes two nucleoside analogue inhibitors of HIV reverse transcriptase and at least one HIV protease inhibitor or non-nucleoside inhibitor of HIV reverse transcriptase, is called highly active antiretroviral therapy (HAART). Early cohort and registry-based studies showed a lower incidence of AIDS and decreased rates of AIDS-related mortality after the introduction of HAART in late 1995 in the United States (1-3), France (4), Australia (5), Germany (6), and Switzerland (7). However, ecologic studiesthose that measured use of HAART and mortality in groups rather than in individual patientsmay be subject to confounding by calendar period changes in other unmeasured variables. In addition, many studies that directly measured the effects of HAART on survival of patients with AIDS did not provide specific evidence of such effects in the patients with the most advanced cases (8-10), with the exception of small cohorts of patients with cytomegalovirus (CMV) retinitis (11) and progressive multifocal leukoencephalopathy (12). We therefore studied the effect of HAART in a large multicenter trial of blood transfusion in patients with advanced HIV disease who were also anemic, an indicator of poor prognosis (13, 14). Because the study spanned the period before and after the introduction of HAART, we could directly assess the effect of HAART status on subsequent death or opportunistic events. In addition, because our person-year analysis was controlled for calendar time, our estimates of the magnitude of the effect of HAART on mortality and morbidity are less likely to be confounded by changes in patient mix or medical practice compared with previously published studies. Methods Patients and Study Design The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus nonleukoreduced red blood cell transfusion in HIV-infected patients who required a first transfusion for anemia. Details of the study design have been published elsewhere (15, 16). In brief, we enrolled patients who were HIV seropositive, were CMV seropositive or had a history of documented CMV disease, had an expected survival of at least 1 month, and required red blood cell transfusion for anemia. Data on clinical end points and prescribed medications were obtained by interview and medical record review at baseline and every 3 months thereafter. Ophthalmologic examinations to detect CMV retinitis were done at baseline and every 6 months thereafter. In patients who did not return for follow-up visits, vital status was ascertained by review of the medical record, a search for a death certificate, and tracing by using public databases. Of 528 patients, 58 were excluded before death or end of the study, including 29 for whom no follow-up information on opportunistic events was available and 3 for whom follow-up for death but not for opportunistic events was complete. The CD4+ lymphocyte count and plasma HIV RNA level were measured by using frozen blood specimens at the central study laboratory, as described elsewhere (15). The study protocol was approved by the institutional review boards of the 11 participating medical centers, and informed consent was obtained from all participants. Definitions of HAART and End Points The VATS did not dictate the choice of antiretroviral therapy for enrolled patients, except that prescription of new antiretroviral drugs was discouraged during the 2 weeks after the first two transfusion episodes. Highly active antiretroviral therapy was defined as prescription of at least three antiretroviral medications with activity against HIV, at least one of which was an HIV protease inhibitor or a non-nucleoside HIV reverse transcriptase inhibitor. Medication history collected at each quarterly visit included the names and start and stop dates of any HIV antiretroviral medications taken since the previous visit or in the 30 days before entry into the study. Patients taking no HIV antiretroviral medications and those taking HIV antiretroviral medications that did not fulfill our definition of HAART were classified as before HAART until the day that they began HAART. Once a patient initiated HAART, all of his or her subsequent follow-up time remained designated as after HAART even if they discontinued HAART, to approximate an intention-to-treat analysis. We made this conservative decision to avoid overestimating the effect of HAART, which would occur if patients who stopped HAART because of intolerance subsequently contributed outcomes to the before HAART person-years. Adherence to prescribed medications was not measured. End points of the current study were death, opportunistic events, and recurrent transfusions. Opportunistic events were defined a priori and confirmed by expert reviewers; they included clinical diagnoses corresponding to the Centers for Disease Control and Prevention's AIDS-defining conditions (17), with some modifications. Presumptive diagnoses of central nervous system toxoplasmosis were allowed according to the Centers for Disease Control and Prevention's definition. For CMV retinitis, progression of disease requiring initiation of or a change in anti-CMV medication counted as a clinical event. For analysis, end points were grouped as follows: CMV opportunistic events; non-CMV opportunistic events; all opportunistic events; death; and any end point, including death and all opportunistic events. We analyzed recurrent red blood cell transfusion (that is, occurring after the enrollment transfusion event) as a separate end point. Statistical Analysis We used a person-years approach to analyze event rates. The denominator for these rates was not the individual patient but was person-years of observation time, defined as study follow-up time for each patient classified as before or after initiation of HAART and summed over all patients. For example, patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively. Observation time for a patient extended from the date of study entry to death or the end of follow-up. Because some patients had no follow-up information for opportunistic events and a few had less follow-up for opportunistic events than for mortality, the total observation time for opportunistic events was shorter than that for overall survival. Events were assigned to the time period during which they occurred, and incidence was reported as the number of events per person-year of observation time. A single patient could contribute multiple events (except for the mortality analysis) to the same or to different time periods. The association between HAART use and incidence rates was expressed as a rate ratio. Confidence intervals and P values were calculated from a Poisson regression model using generalized estimating equations with exchangeable correlation structure to adjust for correlated observations across time within the same patient (18, 19). All P values are two sided. Because the use of HAART increased dramatically over the 4 years of the study, the comparison of post-HAART and pre-HAART data is confounded with calendar time. In addition, the mixture of HIV risk groups, prevalence of prophylaxis against opportunistic infections, diagnostic testing accuracy, and physician experience may have changed over time. To evaluate and control for these and other calendar time effects, each patient's observation time was further categorized as four 1-year calendar time periods, starting in July 1995. Similarly, a patient's time since entering the study was divided into five study time periods (0 to 6, 7 to 12, 13 to 18, 19 to 24, or >24 months from randomization). The Poisson regression generalized estimating equations method was then used to calculate the rate ratios associated with CD4 T-cell count, plasma HIV RNA level, calendar time, and time on study and to adjust the comparisons of post-HAART and pre-HAART data for these covariates, both in pairs and combined with patient characteristics. Results Participants The VATS enrolled patients with anemia and HIV infection who received a first red blood cell transfusion between August 1995 and July 1998. Patients were followed until death or their last scheduled quarterly visit before 30 June 1999. Of 531 patients enrolled in VATS, we excluded 3 patients for whom no data on medication were available; thus, the sample for analysis in this study was 528 patients. Table 1 shows the baseline characteristics of the study sample. Most patients were 30 to 49 years of age and male, and equal proportions of patients were of white and nonwhite ethnicity. Half of the patients were men who reported sex with other men as their only HIV risk factor; 19% each were injection drug users or sexually active heterosexuals without other risk factors for HIV; and 12% had multiple or other risk factors. At baseline, the median CD4+ lymphocyte count was 0.015 109 cells/L, and 69% of patients had a CD4+ lymphocyte count less than 0.050 109 cells/L. The median HIV RNA level was 4.8 log10 copies/mL, and only 8% of patients had plasma levels of HIV RNA levels less than 200 copies/mL. Table 1. Baseline Characteristics of 528 Patients in the Viral Activation Transfusion Study At baseline, most patients had previously taken antiretroviral medication; more than half had taken such medication for 12 months or longer. The proportion of patients taking prophylaxis or treatment of Pneumocystis carinii pneumonia and Mycobacterium avium complex infection decreased from 95% and 49%, respectively, in 19951996 to 82% and 44% in 19