Greenbaum, Adena H; Wilson, Lucy E; Keruly, Jeanne C; Moore, Richard D; Gebo, Kelly A
As of 2004, 23% of those infected with HIV were older than 50 years of age . The increase in prevalence among older adults is due to increased survival of those treated with HAART, as well as new HIV infections among older people . Given the changing epidemiology of HIV, it is important to understand the effectiveness of antiretroviral treatment in older people.
Multiple studies have reported that older patients have worse HIV outcomes than younger patients [3–6]. However, most of these studies used data that preceded the availability of HAART. Although several recent small studies have found differences in clinical responses to HAART between older and younger groups, the results have been conflicting [7–22]. Some studies have found similar rates of HIV-1 RNA suppression in different age groups [8–16], whereas others have found better virologic response in older adults [17–22]. Among studies that have shown similar viral response between older and younger groups, some have shown that older patients have slower rates of CD4 cell recovery and a lower magnitude of CD4 cell increase [9,11], whereas others have noted no difference in CD4 cell response between age groups [12–16]. Silverberg et al.  reported better virologic suppression but worse immunologic response in those over 50 years compared with younger patients. However, results were attenuated when adjusted for adherence levels and duration of follow-up.
Few studies have evaluated the role of antiretroviral regimen on clinical outcomes in different age groups. Therefore, we set out to compare the effectiveness of HAART in older and in younger adults in a large urban clinic. The goal of this study is to compare responses to HAART in HIV-infected HAART-naive adults less than 40 years with those at least 50 years of age overall and by type of HAART regimen [protease inhibitor vs. nonnucleoside reverse transcriptase inhibitors (NNRTI)].
The Johns Hopkins University AIDS Service provides comprehensive primary and subspecialty medical care. At baseline, a comprehensive evaluation of medical and social histories, physical examination, and laboratory studies is recorded and is prospectively updated from the clinic-based medical record by trained data monitors every 6 months. Maintenance of the database and use of its contents for analysis are approved by the Institutional Review Board of the Johns Hopkins University School of Medicine.
This study included 906 HAART-naive patients who enrolled at the clinic between 16 February 1989 and 26 January 2006 and had HAART initiation dates between 13 December 1995 and 9 February 2006. Median follow-up time after HAART initiation was 46.1 months (range 4.0–126.0 months). Patients who were on HAART for less than 4 months or did not have a baseline CD4 cell count or HIV-1 RNA level were excluded from this analysis.
Demographic variables included age at HAART initiation, race (African–American, non-Hispanic whites, and other), and sex. HIV transmission risk factors included an injection drug use (IDU), men who had sex with men (MSM), and heterosexual activity with an HIV-infected individual or with a partner at high risk for HIV (HET). Race was dichotomized as African–American vs. all other races, and HIV risk factor as IDU vs. those with non-IDU risk factors (MSM, or HET, or both). Clinical variables included CD4 cell counts (cells/μl) and HIV-1 RNA levels (copies/ml) at HAART initiation and throughout a patient's follow-up time at the clinic. Time-updated variables included CD4 cell counts and HIV-1 RNA levels within 60 days prior to viral suppression, increase in CD4 cell count to 50 cells/μl, first opportunistic infection, and death. HAART was defined as concomitant use of three drugs from two classes [nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors, or a fusion inhibitor] for more than 120 days. HAART initiation periods were categorized as before 2003, or 2003, or after. Adherence data were collected using audio computer assisted self-interviews (ACASIs). Adherent was defined as patients reporting 100% adherence with all HAART medication in the 24 h before their interview. Opportunistic infections were defined by the 1993 revised classification system for HIV infection by the Centers for Disease Control and Prevention . Patients were considered eligible for Pneumocystis jiroveci peneumonia (PCP) or Mycobacterium avium complex (MAC) prophylaxis if they had one CD4 cell count of less than 200 or less than 50 cells/μl at any time during the study interval. Cause of death was dichotomized as AIDS related vs. non-AIDS related on the basis of distinctions made by trained chart abstractors and expert physician review. AIDS-related deaths included those related to opportunistic infections, AIDS-associated malignancies, and failure to thrive as specified in the 1993 AIDS-defining illnesses . Non-AIDS-related deaths included causes not directly associated with HIV infection.
To evaluate virologic suppression, we used HIV-1 RNA levels from all clinic visits since HAART initiation. Plasma HIV-1 RNA was categorized as undetectable (≤400 copies/ml) or detectable (>400 copies/ml).
We evaluated immunologic response by three methods: change in CD4 cell count from baseline and absolute increase in CD4 cell count from baseline. We measured change in CD4 cell count from baseline using CD4 cell count at HAART initiation and at clinic visits 6, 12, and 24 months after HAART initiation. CD4 cell counts at these intervals were calculated by averaging all CD4 cell counts recorded within 8 weeks before and after the 6-month, 12-month, and 24-month periods. Given the fact this is an observational cohort, 23.7% of the population did not have a CD4 cell count measurement at 6 months (±8 weeks) and 31.3% of the population did not have a CD4 cell count measurement at 12 months (±8 weeks) after HAART initiation. For these patients, we estimated 6-month CD4 cell counts by taking the average of the CD4 cell count at HAART initiation and at 12 months; estimates of the 12-month CD4 cell count, if not available, were done by averaging the 6-month and 18-month CD4 cell count. CD4 cell counts from all clinic visits since HAART initiation were included. Time to increase in CD4 cell count was days from HAART initiation to date of laboratory test when CD4 cell count had increased by 50 cells/μl or more. HIV disease progression was examined as time to new opportunistic infections after HAART initiation. Survival was analyzed on the basis of the clinic's death registry database.
Differences in changes in HIV-1 RNA and CD4 cell count between older and younger groups were calculated using the Student's t-test. Survival analysis included Kaplan–Meier estimates and Cox proportional hazards models using time to HIV-1 RNA suppression, increase in CD4 cell count by 50 cells/μl, new opportunistic infections, and all-cause mortality as the outcomes of interest. Estimated time to an event was calculated as time from HAART initiation to each outcome. Time to new opportunistic infections and time to death are reported as time until the first 25% of patients were diagnosed with opportunistic infections or died (which is equivalent to a hazard of new opportunistic infections of 0.75) with a 95% confidence interval (CI) for the hazard. Survival curves were statistically compared using log rank tests. Each outcome was analyzed using multivariate Cox proportional hazard models using clinical and demographic variables believed to be potential confounders. All multivariate regressions were adjusted for race, sex, HIV risk factor, history of opportunistic infections before HAART initiation, CD4 cell count and HIV-1 RNA at HAART initiation, and period of HAART initiation (before vs. after 1 January 2003). All reported P values are two sided and all statistical analysis were made using STATA 9.0 (College Station, Texas, USA) .
Analyses were repeated and stratified by treatment regimen on the basis whether regimens included at least one NNRTI or one protease inhibitor.
Individuals who were on both NNRTI-based and protease inhibitor based regimens (n = 87) were included with those on NNRTI-only regimens in sensitivity analyses for each endpoint. As an additional sensitivity analysis for viral suppression, we constructed survival curves and regression models for time to sustained viral suppression, defined as at least two consecutive HIV-1 RNA levels less than or equal to 400 copies/ml. Models were also constructed in a subset of patients (n = 439) who had recent adherence data from an ACASI. Additional models used time-updated HIV-1 RNA levels and CD4 cell counts for a subset of patients who had adequate data to calculate time-updated variables for each endpoint (viral suppression, n = 740; immune reconstitution, n = 734; first opportunistic infections, n = 132; death n = 208). All analyses were calculated in an ‘as-treated’ manner. For those patients who stopped HAART treatment while being followed at the clinic, the as-treated analysis included only data collected while they were on HAART. An intention-to-treat sensitivity analysis was also performed for each endpoint.
Older patients were more likely to be men (76.5 vs. 65.5%, P = 0.01) and less likely to report MSM as an HIV risk behavior (18.8 vs. 34.5%, P < 0.01) than were younger patients (Table 1). Older patients were more likely to be started on an NNRTI-based regimen than were younger patients (41.6 vs. 29.0%, P < 0.01).
The median time from enrolment until HAART initiation (younger 6.2 months vs. older 6.0 months, P = 0.9) and median duration on HAART did not differ by age group (younger 48.1 vs. older 36.5 months, P = 0.1) (Table 2).
The median time to first undetectable HIV-1 RNA level was shorter in older than in younger patients (3.2 vs. 4.4 months, P = 0.001) (Fig. 1a). When time to virologic suppression was stratified by treatment regimen, there was no difference by age in median time to suppression among those on NNRTIs (older 2.8 months vs. younger 3.0 months, P = 0.6) (Fig. 1b). However, among those on protease inhibitors, older patients suppressed more quickly than did younger patients (3.7 vs. 5.4 months, P < 0.002) (Fig. 1c). Of note, younger patients on NNRTIs suppressed more quickly than did those on protease inhibitors (3.0 vs. 5.4 months, P < 0.01), but there was no difference in time to suppression by treatment regimen in older patients (NNRTIs 2.8 months vs. protease inhibitors 3.7 months, P = 0.6).
There was no difference in immunologic response by age group for mean change in CD4 cell count or time to CD4 cell count increase by 50 cells/μl (Fig. 2). At 24 months, younger patients had on average an increase of 160 cells/μl (SD = 199) and older patients had an increase of 171 cells/μl (SD = 174, P = 0.8) (Fig. 2a). There was no difference in change in CD4 cell count by age when results were stratified by CD4 cell count and HIV-1 RNA at HAART initiation. Similarly, there was no difference by age in time to an absolute increase in CD4 cell count of 50 cells/μl (younger 3.3 months vs. older 3.4 months, P = 0.6) (Fig. 2b). Stratification by treatment regimen yielded similar results by age for both mean change in CD4 cell count and time to absolute increase by 50 cells/μl. Younger patients on NNRTIs had an earlier immune response than those on protease inhibitors (3.0 vs. 3.7 months, P = 0.04), but there was no difference in immune response by treatment regimen in older patients. There was no difference between age groups, race, sex, HIV risk factor, or HAART regimen between those who had estimated CD4 cell counts and those who did not.
Given the interrelationship between viral suppression and CD4 cell count recovery, we examined CD4 cell count recovery stratified by time to viral suppression. Time to absolute CD4 cell count of 50 cells/μl was associated with decreased time to viral suppression. CD4 cell count increased more quickly among those who suppressed in less than 3.9 months (median time to suppression for the entire population) than in those who suppressed after 3.9 months (time to increase in absolute CD4 cell count to 50 cells/μl; 2.3 vs. 5.4 months, P < 0.01).
After HAART initiation, younger patients had a higher incidence of at least one new opportunistic infection (30.5 vs. 21.5%, P < 0.01) than did older patients (Table 2). A higher percentage of younger patients were diagnosed with esophageal Candidiasis (15.2 vs. 8.0%, P = 0.02) and cerebral toxoplasmosis (2.5 vs. 0.0%, P = 0.05) as first opportunistic infection after HAART initiation. There were no differences by age in rate of diagnosis of the other opportunistic infections. The most commonly diagnosed first opportunistic infections after HAART initiation in both older and younger patients were Candidiasis, Herpes encephalitis (6.7% of older patients, 6.6% of younger patients), and PCP (6.0% of older patients, 10.5% of younger patients). There was no difference by age in MAC or PCP prophylaxis. Time to new opportunistic infections after HAART initiation was shorter in younger patients than in older ones [25% of younger patients diagnosed with opportunistic infections at 39.7 months (95% CI of 25th percentile survivor function 0.71–0.78) vs. 88.8 months (95% CI 0.62–0.83), P = 0.1] (Fig. 3a).
Older patients had shorter survival time than did younger patients [25% of younger patients died by 58.8 months (95% CI of the 25th percentile survivor function 0.71–0.78) vs. 36.2 months (95% CI 0.67–0.82), P = 0.02] (Fig. 3b) and also had higher overall mortality than did younger patients (35.6 vs. 27.3%, P = 0.04) (Table 2). When stratified by treatment regimen, survival was similar by age for patients on protease inhibitors [25% of younger patients died at 57.9 months (95% CI of 25th percentile survivor function 0.70–0.79) vs. 52.0 months for older patients (95% CI 0.64–0.84), P = 0.2], whereas among those on NNRTIs, survival was significantly longer for younger patients than in older patients [25% of younger patients died at 59.3 months (95% CI 0.65–0.82) vs. 34 months for older patients (95% CI 0.58–0.83), P = 0.02]. There was no difference in survival between treatment regimens when stratified by age. A similar percentage of younger and older patients died of AIDS-related causes (66.9 vs. 61.7%, P = 0.5) (Table 2). These cause included MAC (1.9%) and PCP (1.9%) among younger patients and advanced AIDS (3.7%), failure to thrive (3.7%), and HIV dementia (3.7%) among older patients. The most common non-AIDS-related causes of death among younger patients were pneumonia (23%), chronic renal failure (11%), stroke (6%), and hepatitis (6%) and those among older patients were hypertension/hypertensive urgency (17%) and cardiovascular disease (17%).
Cox proportional hazard regressions were used to identify factors associated with time to each outcome: virologic suppression, increase in CD4 cell count by 50 cells/μl, new opportunistic illness, and death (Table 3). In the adjusted analysis, older age was associated with increased likelihood of virologic suppression [adjusted hazard ratio (AHR) 1.26, 95% CI 1.03–1.55] and death (AHR 1.44, 95% CI 1.04–2.01). Older age was not associated with change in CD4 cell count or time to new opportunistic infections after HAART initiation. NNRTI-based regimens significantly increased the likelihood of virologic suppression (AHR 1.28, 95% CI 1.09–1.51), but were not associated with other outcomes. Initiating HAART after 2003 vs. before 2003 was associated with shorter time to virologic suppression (AHR 1.68, 95% CI 1.34–2.12) and earlier CD4 cell count increase (AHR 1.38, 95% CI 1.10–1.72), but not to increased survival.
Sensitivity analyses performed as an intention to treat (ITT) analysis showed similar results for all endpoints. The median time to first undetectable viral load was shorter in older patients than in younger ones (3.2 vs. 4.6 months, P < 0.01). As in the as-treated analysis, there were no differences in mean change of CD4 cell counts, time until CD4 cell count increase of 50 cells/μl or time until new opportunistic infection by age group. Overall trends in survival in the ITT analysis were similar to those in the as-treated analysis. Survival was greater in the as-treated analysis than in the ITT analysis. Less than half of younger patients died in the as-treated analysis, whereas younger patients had a median survival of 122 months in the ITT analysis. Survival was also greater for older patients in the as-treated analysis than in the ITT analysis (101 vs. 90 months).
Several other sensitivity analyses were performed. Consistent with time to first undetectable viral load, the median time to the second consecutive undetectable HIV-1 RNA was shorter in older patients than in younger patients (7.4 vs. 12.6 months, P < 0.01). In a subset analysis, after adjusting for other factors, suboptimal adherence to HAART was not associated with decreased time to suppression (AHR 0.91, 95% CI 0.73–1.13), immunologic response (AHR 0.89, 95% CI 0.72–1.10), new opportunistic infection (AHR 0.91, 95% CI 0.64–1.30), or survival (AHR 0.79, 95% CI 0.52–1.23). In a subset analysis using time-updated CD4 cell counts and HIV RNA-1 levels, older age was no longer associated with decreased time to suppression (AHR 1.06, 95% CI 0.82–1.30), or survival (AHR 1.80, 95% CI 0.79–4.10). NNRTI-based regimens were associated with decreased time to suppression (AHR 1.24, 95% CI 1.05–1.48) as in our primary analysis, but were also associated with earlier increase in CD4 cell count (AHR 1.22, 95% CI 1.03–1.44) in this sensitivity analysis. Initiating HAART after 2003 was associated with shorter time to virologic suppression (AHR 1.62, 95% CI 1.28–2.04), earlier increase in CD4 cell count (AHR 1.27, 95% CI 1.00–1.68), and longer time to new opportunistic infection (AHR 6.03, 95% CI 2.52–14.42).
In this study, older HIV-infected HAART-naive adults started on HAART achieved virologic suppression faster than did younger HIV-infected individuals. Also, time to increase in CD4 cell count did not differ by age group. Finally, mortality was higher in older patients, despite slower HIV disease progression.
Hinkin et al.  found that improved virologic response among older adults was due to better adherence to HAART. Silverberg et al.  found that controlling for adherence mitigated the differences in virologic responses between age groups. In this cohort, there was no difference in adherence reported by patients in each age category. Although sample size limits our ability to adjust for adherence when determining factors associated with virologic suppression, subset analysis of those for whom adherence data were available implies that adherence was not a factor in virologic suppression. This suggests that adherence was not a confounder in this population.
Despite increased virologic suppression in older patients than in younger ones, there was no difference in immune response between age groups. Although others have shown similar results regarding virologic suppression, previous longitudinal analyses showed depressed immunologic response in older patients [20–22]. CD4 cell count recovery has been shown to be inversely associated with age, and one hypothesis is that decreased immunologic responses among older patients may be due to thymic suppression [27,28]. Differences between study populations, including comorbidities such as hepatitis viruses and frailty, are potential variables that we could not account for and these could affect immunologic reconstitution . Individual variability in CD4 cell counts and accuracy of measurement techniques could attenuate differences between populations. We also did not measure duration of HIV infection, which has been shown to influence CD4 cell count .
Although older patients had fewer new opportunistic infections than did younger patients, not surprisingly, older patients had worse survival than younger patients. The percentage of AIDS-related deaths is similar between older and younger groups. This suggests that younger patients have more nonfatal opportunistic infections than older patients. Comorbid medical conditions, which will need to be evaluated in future studies, could also contribute to decreased survival in older patients.
This is one of the first studies to look at the effect of HAART regimen type on clinical response by age group. In multivariate analysis, NNRTI use was associated with more rapid virologic suppression and longer time to new opportunistic infections, but not with improved immunologic response or survival. Younger patients on NNRTI-based regimens suppressed more quickly and had slightly faster immunologic response than did younger patients on protease inhibitor based regimens. However, there were not differences by treatment regimen in older patients in any of the clinical outcomes. Patterson et al.  found immune reconstitution and viral suppression did not vary by treatment regimen when stratified by age. Consistent with literature that demonstrates increased effectiveness of current regimens, those who started on HAART regimens after 2003 suppressed faster with shorter time to increased CD4 count; however, starting HAART after 2003 was not a significantly associated with survival.
There are several potential limitations to this study. First, this study includes patients at only one site that has a relatively high proportion of minority race and injection drug users, and therefore may not generalize to all HIV clinics. Second, a small sample size limits our ability to comment on the significance of stratifications involving smaller subsets of the population, especially those addressing older patients on different treatment regimens. In addition, given the limited number of patients for whom adherence data are available, it is difficult to draw conclusions regarding the impact of adherence on clinical endpoints.
We did not control for informative censoring of older patients, who, due to shorter life expectancy are less likely to reach the clinical endpoints than younger patients. Also, we were not able to determine time of seroconversion or length of HIV infection. As with other studies, the older group of patients includes both those who were infected recently as well as those who have aged with HIV. As the HIV-infected population ages, future studies may need to evaluate differences in these two groups of patients, especially those relating to differences in immunological response.
Non-AIDS-defining comorbid medical conditions may be especially relevant in treating HIV in older people. The pathophysiology associated with comorbid medical conditions as well as pharmaceutical regimens associated with treating them could affect the progression of HIV as well as antiretroviral metabolism [31,32]. Future studies will need to examine long-term outcomes of HAART therapy, including the impact of comorbidities on HIV disease progression, potential drug–drug interactions, and potential differences in drug toxicity profiles in older adults.
The shift in the paradigm of HIV to a chronic disease has several implications for treatment. Age-specific treatment guidelines that have different recommendations for older and for younger patients may be warranted, with initiation of HAART at higher CD4 cell count for older than for younger patients. Given adequate immunologic response but decreased survival, additional study is needed to determine appropriate initiation of HAART therapy in older HIV-infected adults.
Supported by the National Institutes of Aging (R01 AG026250) and Drug Abuse, NIH (K23-DA00523, K24-DA00432, and R01-DA-11602). Dr Gebo also received support from the Johns Hopkins University Richard S. Ross Clinician Scientist Award. Dr Greenbaum received support from the Johns Hopkins Medical Student Research Fund and T32 Predoctoral Clinical Research Training Program.
Idea conception: A.G./L.E.W./K.A.G.
Data collection: J.C.K./R.D.M./K.A.G.
Data analysis: A.G./K.A.G.
Writing of manuscript: A.G.
Critical review of manuscript: L.E.W./J.C.K./R.D.M./K.A.G.
Financial sponsorship: A.G./R.D.M./K.A.G.
The results of this study were presented in part at the Infectious Diseases Society of America, San Diego, CA, October 2007.
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