1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
2 Northwestern University Medical School and Howard Brown Health Center, Chicago, IL.
3 School of Public Health, University of California Los Angeles, Los Angeles, CA.
4 Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
5 Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
Received for publication March 26, 2002; accepted for publication November 6, 2002.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
cohort studies; epidemiologic methods; HIV
Abbreviations: Abbreviations: AIDS, acquired immunodeficiency syndrome; CI, confidence interval; D <200, deferred treatment group of men whose CD4+ counts were <200 cells/µl; D <350, deferred treatment group of men whose CD4+ counts were 200349 cells/µl; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Benefits of delayed treatment include reserving the limited number of available drugs until later in the course of HIV disease, reducing adverse effects and the expense of treatment, and minimizing the development of viral drug resistance (6). One of the primary arguments for early treatment is that it may delay progression to AIDS (8). Early treatment has also been postulated to preserve immune function that cannot later be reconstituted and to reduce the risk of viral transmission (9, 10).
The research and clinical communities have discussed the design and conduct of randomized clinical trials to determine the appropriate stage of HIV infection at which to initiate HAART (11). One such trial would randomize asymptomatic persons whose CD4+ counts are 350499 cells to either immediate or deferred treatment arms and monitor the incidence of AIDS and death. The principal strength of such a trial would be to minimize the effect of subjective factors related to treatment decisions. The major limitation would be the lengthy follow-up, during which therapeutics would likely change and comparability would be compromised. In addition, participants might not adhere to the original treatment if changes in practice occurred in the community. Thus, at the end of follow-up, differences in AIDS risk might not be due to the timing of treatment but rather to treatment choices.
The goal of this analysis was to simulate such a trial by using data collected in an ongoing cohort study. Advantages of this setting include the comparability of treatments, given that HAART was initiated during the same calendar period for all participants, as well as improved efficiency since questions may be answered with existing data. An important limitation is the lack of randomization in treatment assignment. Another potential problem is lead time bias.
In screening, lead time is the additional survival time associated with the detection of disease early in its natural history, that is, during the asymptomatic stage. In our context, lead time is the additional survival time prior to initiating therapy among those who start HAART at a later disease stage, that is, the time required for that person to progress from the early stage (i.e., a high CD4+ count) to the later stage (i.e., a low CD4+ count), at which time therapy is then initiated. Acknowledgment of lead time is essential when comparing survival times for persons at different disease stages. For example, a person initiating HAART with a CD4+ count of 150 cells/µl may appear to develop AIDS more quickly compared with a person initiating HAART with a CD4+ count of 450 cells/µl. However, the former person initiated HAART at a later disease stage, and the time it took to reach 150 cells/µl from 450 cells/µl must be considered. Accounting for lead time also permits observation of events that may occur during this progression from early to later disease stages. These concepts are illustrated in figure 1.
|
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Study participants returned every 6 months for visits that included an extensive interview about behavioral practices, medical history, and health care utilization; a physical examination; and a psychosocial self-assessment (1416). In addition, participants provided blood specimens for storage in local/national repositories and for concomitant laboratory analyses including standardized flow cytometry (17, 18) and plasma HIV RNA determinations using the Roche Amplicor assay (19). Men who had AIDS as well as men whose CD4+ counts were <200 cells/µl were contacted at least every 3 months to obtain information on recent clinical events, confirmed by medical record review. Reports by proxy contacts and passive surveillance were also used to determine vital status. Study questionnaires are available at the following Internet Web site: www.statepi.jhsph.edu/macs/macs.html.
Use of antiretroviral therapy
At each visit, participants were asked for names of the antiretroviral medications used since their previous visit. This information was used to identify men who initiated HAART between July 1, 1995, and January 1, 2000. The definition of HAART (20) was guided by the US Department of Health and Human Services/Kaiser Family Foundation Panel guidelines (6) and the International AIDS SocietyUSA Panel (7). The date of HAART initiation was the midpoint between the first visit at which a person reported HAART and the preceding visit.
Outcome
The outcome for this analysis was clinical AIDS, defined by the opportunistic infections and malignancies identified by the Centers for Disease Control and Prevention 1993 criteria (21). Asymptomatic men whose CD4+ counts were <200 cells/µl were not considered to have AIDS. All AIDS-defining events occurring prior to July 1, 2000, were included.
Nested cohort study design
Our objective was to mimic a clinical trial in which AIDS-free persons with CD4+ counts of 350499 cells/µl would be randomly assigned to either immediate (defined as starting HAART when CD4+ counts were 350499 cells/µl) or one of two deferred treatment groups: those starting HAART when counts were <200 cells/µl and 200349 cells/µl. Our study population consisted of HIV-infected men who had a CD4+ count of 350499 cells/µl while AIDS free and who later reported use of HAART. Only visits after July 1, 1990, were included to account for prognostic changes due to historical events, for example, use of combination medications, prophylaxis for opportunistic infections, and diagnostic practices.
Based on his CD4+ count preceding HAART initiation (defined as the average of the CD4+ counts measured at the two semiannual visits immediately prior to HAART initiation), each participant was assigned to one of three categories (350499 cells/µl, 200349 cells/µl, and <200 cells/µl), as illustrated in figure 2. The first group corresponds to the immediate treatment arm in a clinical trial, whereas the second and third groups correspond to deferred treatment arms. Hereafter in this paper, the groups are referred to as the immediate group, the deferred group <350 (D <350), and the deferred group <200 (D <200).
|
Alternatively, one could select the first or last visit when a persons CD4+ count was 350499 cells/µl. This would overestimate or underestimate lead time, respectively, because in a clinical trial, participants would have had CD4+ counts of 350499 cells/µl for varying (and unknown) lengths of time when the trial was initiated.
Statistical methods
We compared groups at the index visit for prior use of antiretroviral therapy, demographic characteristics, and markers of disease stage. Wilcoxon tests were used to compare groups for differences in continuous variables, and chi-square tests were used to assess the significance of differences in discrete variables.
We conducted a time-to-event analysis to determine whether treatment deferrals were associated with a decreased probability of remaining AIDS free (22). Men who developed AIDS before July 1, 2000, contributed time from the index visit to the date of diagnosis; those who developed AIDS after July 1, 2000, were censored at this date. Men who withdrew from the study before July 1, 1999, were censored at the time of withdrawal; men followed after this date were administratively censored at July 1, 2000.
Time from the index visit to AIDS by treatment group was depicted graphically by using Kaplan-Meier survival analysis. Cox proportional hazards models were used to assess the effect of treatment timing on progression to AIDS.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The groups did not differ significantly (p < 0.05) by race, CD4+ count, or HIV RNA levels, although the D <200 group had slightly higher HIV RNA values at the index visit (table 1). In addition, the rate of decline in CD4+ count prior to index (approximately 30 cells/year overall) was similar across groups (p = 0.77). The groups differed in the proportion reporting prior antiretroviral therapy, however. Specifically, 46.5 percent of the D <200 group and 59.2 percent of the D <350 group reported prior antiretroviral therapy compared with 73.9 percent of the immediate group. The observed differences are explained by the studys design; the index visits for persons in the immediate group occurred in the late 1990s compared with the early 1990s for the deferred groups. The design also explains why men in the deferred groups were younger (age 39.3 and 40.4 years, respectively) than those in the immediate group (age 42.6 years) and why the deferred groups had less seropositive time on study prior to index, since the date of the first HIV seropositive visit was similar across groups. From the direction of these differences (i.e., more experience with antiretroviral therapy and older age), and because these factors were prognostic in the pre-HAART era, the immediate group may be expected to subsequently progress more rapidly.
|
The components of the initial HAART regimens reported did not differ significantly across treatment groups and represented those used by the overall Multicenter AIDS Cohort Study population (20). In addition, the treatment groups did not differ in the proportion of men reporting more than three drugs in their initial HAART regimen (data not shown). Slightly more of the immediate group initiated HAART with a protease inhibitor-sparing regimen, not surprising given that more of them started HAART after July 1997.
Figure 3 depicts AIDS-free time according to treatment group. A total of 103 cases of AIDS occurred in the three groups. As shown, 28 men (21.5 percent) in the D <350 group and 64 men (50.4 percent) in the D <200 group developed AIDS following the index visit. Of these, 60.7 percent (17 of 28) and 75.0 percent (48 of 64), respectively, developed AIDS prior to HAART initiation. Since 71 percent of the AIDS cases in the deferred groups occurred prior to HAART initiation, these men would not be affected by the use of HAART (i.e., drug classes, number of antiretroviral therapies, or treatment adherence). Compared with the immediate group, the relative hazards of AIDS were 1.05 (95 percent confidence interval (CI): 0.52, 2.13) for men in the D <350 group and 2.68 (95 percent CI: 1.40, 5.14) for those in the D <200 group.
|
To investigate a possible threshold between 200 and 349 cells/µl at which the risk of AIDS increased, we examined those men in the D <350 group whose CD4+ counts were above and below 275 cells/µl, given that the median CD4+ count at HAART initiation was 270 cells/µl. Compared with the immediate group, the 67 men who deferred HAART to a CD4+ count of <275 cells/µl had an increased, but nonsignificant risk of AIDS (relative hazard = 1.40, p = 0.385), whereas the relative hazard of AIDS for those 63 men who deferred HAART to a CD4+ count of 275 cells/µl was 0.69 (p = 0.411), suggesting a potential threshold below 300 cells/µl.
The D <350 group was composed of men whose index visit spanned the period 19901995. Since all persons had similar CD4+ counts when HAART was initiated (200349 cells/µl) and similar CD4+ counts at the index visit (350499 cells/µl), those whose index visits occurred earlier progressed more slowly prior to HAART. When we stratified the D <350 group according to index visit date (median, approximately January 1993), the relative hazards for those whose index visits occurred before and after January 1993 were 1.18 (95 percent CI: 0.49, 2.83) and 1.06 (95 percent CI: 0.48, 2.32), respectively, compared with the immediate group. These similar relative hazards suggest that the difference in AIDS progression prior to HAART did not account for the lack of difference between the D <350 group overall and the immediate group.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Using data collected by the Multicenter AIDS Cohort Study, we found that the risk of AIDS did not differ between those delaying treatment until their CD4+ counts were 200349 cells/µl and those who initiated treatment with CD4+ counts of >350 cells/µl. Men who delayed treatment until they had <200 CD4+ cells/µl had a significantly worse prognosis. These results do not suggest compelling risks associated with delaying HAART initiation until CD4+ counts are 200350 cells/µl. Furthermore, the lack of an increased risk of AIDS among those who initiated treatment with CD4+ counts of 275349 cells/µl suggests a potential threshold for HAART initiation in the neighborhood of 275 cells/µl. Other benefits and risks of early versus late treatment will require additional studies.
Limitations of this analysis are the lack of randomization to group, a relatively extended period before treatment onset after reaching initiation thresholds, and potentially different underlying progression in the three groups (table 2). We investigated each of these limitations and discuss their implications below.
|
Second, one must evaluate and adjust for imbalances among treatment groups with regard to factors related to disease progression. Longitudinal cohort studies with ongoing follow-up allow for such investigation of confounders and adjustment as needed. On the issue of confounding, although biomarkers, that is, CD4+ count, have been shown to predict outcome in the HAART era, the progression associated with a given value in the HAART era differs from that observed long before HAART was available. For example, we previously showed that although CD4+ count at HAART initiation predicts progression, a person starting HAART when the CD4+ count is <200 cells/µl has a progression likelihood similar to that for someone with approximately 300 more CD4+ cells/µl in the natural history era (20). Thus, the effects of these characteristics measured in different eras do not have the same confounding relation. Regarding differences in prior use of therapy, although previous studies, including the Multicenter AIDS Cohort Study, showed that prior drug exposure was associated with a short-term effect of HAART on biomarkers (4, 31), in our study it was not a confounder for progression to AIDS, a finding consistent with other reports (12, 20, 27). In addition, prior antiretroviral therapy in this study refers to use of medications prior to the index visit and not prior to HAART; at HAART initiation (the time when prior antiretroviral therapy may modify HAARTs effect), the groups did not differ significantly, with 83.5 percent, 85.4 percent, and 73.9 percent of the D <200, D <350, and immediate groups, respectively, reporting a history of antiretroviral therapy.
A third important challenge involves maintaining, for the deferred groups, the protocol for initiating treatment. In a clinical trial, the protocol dictates that persons assigned to the deferred arms initiate HAART the first time they cross the designated treatment threshold. In a cohort study, however, those in the deferred groups do not necessarily initiate HAART when their CD4+ counts first cross the respective thresholds. In our cohort, these median delays in HAART initiation for those in the D <200 and D <350 groups were 1.8 years (25th, 75th percentiles = 0.8, 2.9) and 3.7 years (25th, 75th percentiles = 1.7, 6.1), respectively. When we limited the analysis to those who initiated treatment within 1.5 years of crossing their respective thresholds, the primary inferences held; that is, the excess risk associated with deferral to <200 cells/µl was 2.78 (p = 0.006), and the risk associated with deferral to <350 cells/µl was 0.70 (p = 0.546). Limiting the analysis to protocol adherers may improve validity in a clinical trial but would limit power and the inferences that can be drawn regarding treatment effectiveness.
Finally, a fourth issue to consider when interpreting the results from both a clinical trial and a cohort study is the generalizability of study findings to the underlying population. In most clinical trials, it is largely unknown, although comparisons can be made with external published data if available. In an observational cohort, we can compare disease progression in study participants and their peers not included in the analysis. Since all participants in our study were treated with HAART, two groups may not have been represented: 1) persons whose CD4+ counts did not decline to <350 cells/µl and therefore did not receive treatment and 2) those who progressed so rapidly that they developed AIDS and died before receiving treatment. When we examined all Multicenter AIDS Cohort Study participants whose CD4+ counts were 350499 cells/µl during the same calendar period as the index visit of HAART users, approximately 23 percent of the cohort did not progress to <350 CD4+ cells/µl after 3 years, up to July 1995. Including these "slower progressors" in our deferral groups would have minimized the observed differences with the immediate group.
As mentioned, very rapid progressors also may have been excluded. Of note, we did not exclude men who developed AIDS prior to the use of HAART. Because we allowed men who developed AIDS prior to initiating HAART to be included, our groups contained fast progressors, that is, those who rapidly transitioned from having CD4+ counts of >350 cells/µl to AIDS. This is the primary reason that we did not include death as an outcome; data for men who died prior to the initiation of HAART could not be captured. If death had been considered an outcome, it would have occurred only after treatment and not during the deferral period, thus introducing a bias across groups. However, the fastest progressors, that is, those whose disease progressed so rapidly that they died prior to July 1995, may have been excluded. When we included all AIDS-free men with counts of >350 cells/µl during the same calendar period as the index visit for HAART users, approximately 20 percent developed AIDS and died prior to July 1995. Given the rapidity of progression in these persons, it is unlikely that, even in a clinical trial, there would be ample opportunity to offer treatment. It is also not clear whether such treatment would be effective enough to prevent disease. Inclusion of these men in our deferral groups would have heightened the differences observed between the immediate and deferred groups. In summary, the biases introduced by excluding the slowest and fastest progressors from our deferral groups most likely counteracted each other.
As noted in the Results section of this paper, when we dichotomized the D <350 group to examine the slower progressors, no appreciable changes in the risk of AIDS were found. Thus, these slower progressors in the D <350 group did not explain the observed lack of difference in the risk of AIDS progression between the D <350 group and the immediate group. If a proportion of the immediate group was comprised of slower HIV progressors, it may partially explain the prognostic difference between the D <200 and immediate groups. In fact, the data suggest that slower progressors were included in the immediate group since their first seropositive visits occurred at the same time as those in the deferred groups, yet they were able to remain AIDS free and start HAART when their CD4+ counts were higher. Thus, the lack of difference between immediate treatment and deferral to <350 cells/µl is conservative, given this group of slower progressors.
Interestingly, recruitment began in early 2002 for a large, randomized trial to address the timing of HAART initiation. The study, known as SMART (Strategies for Management of Anti-Retroviral Therapies), will randomly assign approximately 6,000 persons to immediate (>350 cells/µl) or deferred (<250 cells/µl) treatment and follow them for 9 years (32). Given the time until definitive results are available from this trial, nested longitudinal cohort studies such as ours play an important role in providing timely, complementary information regarding patterns of therapeutic use as well as the population effectiveness of antiretroviral therapies (33). Because HAART was unavailable until late 1995 and was then initiated by persons at all stages of HIV infection, we capitalized on the "forced" deferral of initiation. Furthermore, collection of standardized longitudinal data enabled us to incorporate lead time.
One outstanding question is whether there is a threshold between 200 and 350 cells/µl at which HAART initiation should ideally occur. While the data presented did not indicate a significant excess risk associated with deferral to <275 cells/µl, our ability to investigate this question was limited by sample size considerations. By coincidence, this threshold was similar to that of 250 cells/µl currently being used in the SMART study (32). To address this question further, it will be of interest to pool similar data from multiple cohorts as well as to compare these results with those of clinical trials addressing similar issues.
![]() |
ACKNOWLEDGMENTS |
---|
The Multicenter AIDS Cohort Study includes the following: Baltimore, Maryland: Johns Hopkins Bloomberg School of Public HealthDr. Joseph B. Margolick (Principal Investigator), Dr. Haroutune Armenian, Dr. Barbara Crain, Dr. Adrian Dobs, Dr. Homayoon Farzadegan, Dr. Nancy Kass, Dr. Shenghan Lai, Dr. Justin McArthur, and Dr. Steffanie Strathdee; Chicago, Illinois: Howard Brown Health Center, The Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health ServicesDr. John P. Phair (Principal Investigator), Dr. Joan S. Chmiel (Co-Principal Investigator), Dr. Sheila Badri, Dr. Bruce Cohen, Dr. Craig Conover, Dr. Maurice OGorman, Dr. Frank Pallela, Dr. Daina Variakojis, and Dr. Steven M. Wolinsky; Los Angeles, California: University of California, UCLA Schools of Public Health and MedicineDr. Roger Detels and Dr. Beth Jamieson (Principal Investigators), Dr. Barbara R. Visscher (Co-Principal Investigator), Dr. Anthony Butch, Dr. John Fahey, Dr. Otoniel Martínez-Maza, Dr. Eric N. Miller, John Oishi, Dr. Paul Satz, Dr. Elyse Singer, Dr. Harry Vinters, Dr. Otto Yang, and Dr. Stephen Young; Pittsburgh, Pennsylvania: University of Pittsburgh, Graduate School of Public HealthDr. Charles R. Rinaldo (Principal Investigator), Dr. Lawrence Kingsley (Co-Principal Investigator), Dr. James T. Becker, Dr. Phalguni Gupta, Dr. John Mellors, Dr. Sharon Riddler, and Dr. Anthony Silvestre; Data Coordinating Center: Johns Hopkins Bloomberg School of Public HealthDr. Alvaro Muñoz (Principal Investigator), Dr. Lisa P. Jacobson (Co-Principal Investigator), Dr. Stephen Cole, Dr. Stephen J. Gange, Dr. Linda Ahdieh-Grant, Janet Schollenberger, Dr. Eric Seaberg, Dr. Michael Silverberg, Dr. Sol Su, and Traci E. Yamashita; Bethesda, Maryland: National Institutes of Health: National Institute of Allergy and Infectious DiseasesDr. Carolyn Williams; Bethesda, Maryland: National Cancer InstituteDr. Sandra Melnick. Internet Web site: http://www.statepi.jhsph.edu/macs/macs.html.
![]() |
NOTES |
---|
Correspondence to Dr. Linda Ahdieh Grant, Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 North Wolfe Street, Room E-7014, Baltimore, MD 21205 (e-mail: lahdieh{at}jhsph.edu).
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|