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Starting HAART at >350 CD4s Results In Greater CD4 Increases; Study Recommends Starting HAART When CD4 Count is >350
 
 
  "CD4+ Cell Count 6 Years after Commencement of HAART in Persons with Sustained Virologic Suppression"
 
Clinical Infectious Diseases Feb 1, 2007;44:441-446
 
Richard D. Moore and Jeanne C. Keruly Johns Hopkins University School of Medicine, Baltimore, Maryland
 
"....In summary, after 6 years of suppressive therapy, patients who initiated HAART with a lower CD4+ cell count never achieve CD4+ cell counts that are comparable to those of patients who initiated treatment at CD4+ cell counts >350 cells/uL. We recommend that consideration be given to initiation of HAART at a CD4+ cell count >350 cells/L to achieve better immune recovery...
 
[In the group with >350 CD4 at baseline the median baseline CD4 was 450 and after 6 years the median CD4 was 800. This increase was much more than for patients with lower baseline CD4s.
For patients in the 200-350 CD4 group at baseline the median CD4 was 250 at baseline and 500 after 6 tears. For patients with <200 CD4s at baseline the median CD4 at baseline was 70 and 470 after 6 years (See Table below).]
 
....These data suggest that commencement of HAART at a lower CD4+ cell count will result in a CD4+ cell count that does not return to normal levels; this may be a reason to consider starting HAART before the CD4+ cell count decreases to <350 cells/uL.... we found that the highest CD4+ cell counts were achieved only when HAART was initiated at a baseline CD4+ cell count >350 cells/uL....
 
....only patients with a baseline CD4+ cell count of >350 cells/L had CD4+ cell counts that returned to nearly normal levels...
 
.... Patients who started receiving HAART when their CD4+ cell count was <350 cells/L did not achieve a CD4+ cell count that was as high as that achieved by other patients, and patients who started receiving HAART when their CD4+ cell count was <200 cells/uL achieved CD4+ cell counts that were low enough to be an indication for commencement of HAART under current antiretroviral treatment guidelines....
 
....The percentages of patients who achieved a CD4+ cell count of >500 cells/L after receiving 6 years of suppressive HAART were 42%, 66%, and 85% for those who started HAART with a CD4+ cell counts of <200, 201-350, and >350 cells/L, respectively. The percentages of patients who achieved a CD4+ cell count of >750 cells/uL after receiving 6 years of suppressive HAART were 12%, 21%, and 46% for those who started HAART with a CD4+ cell count <200, 201-350, and >350 cells/uL, respectively....
 
.... Multivariate regression analysis revealed that baseline CD4+ cell count is a significant predictor of subsequent CD4+ cell count response (table 2). Two analyses are shown; in the first, all covariates are included, whereas the second includes only those covariates that were statistically significant. In addition to baseline CD4+ cell count, both age 45 years and the transmission mode injection drug use were associated with a less robust CD4+ cell count response (P < .05). Sex, race, cornerstone antiretroviral drug, HIV-1 RNA load at start of treatment, HCV coinfection, and whether the final HIV-1 RNA load was <50 or <400 copies/mL were not associated with CD4+ cell count response (P > .10)...."
 
ABSTRACT

Background. Sustained suppression of the human immunodeficiency virus (HIV) type 1 RNA load with the use of highly active antiretroviral therapy (HAART) results in immunologic improvement, but it is not clear whether the CD4+ cell count increases to normal levels or whether it reaches a less-than-normal plateau. We characterized the increase in the CD4+ cell count in patients in clinical practice who maintained sustained viral suppression for up to 6 years.
 
Methods. All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients receiving primary HIV care in Baltimore, Maryland, who were observed for >1 year while receiving HAART and who had sustained suppression of the HIV RNA load at <400 copies/mL. We analyzed annual change in the CD4+ cell count for up to 6 years after the start of HAART, stratified by baseline CD4+ cell counts of <200, 201-350, >350 cells/uL, and we assessed the development of clinical events (death and new acquired immunodeficiency syndrome-defining illness) by Kaplan-Meier analysis.
 
Results.
A total of 655 patients were observed for a median of 46 months (range, 13-72 months). The median change from baseline to most recent CD4+ cell count was +274 cells/uL, with 92% of patients having an increase in CD4+ cell count.
 
By 6 years, the median CD4+ cell count was 493 cells/uL among patients with baseline CD4+ cell counts <200 cells/L, 508 cells/uL among those with baseline CD4+ cell counts of 201-350 cells/uL, and 829 cells/uL among those with baseline CD4+ cell counts >350 cells/L.
 
In addition to baseline CD4+ cell count, injection drug use and older age were associated with a lesser CD4+ cell count response, and duration of therapy was associated with a greater CD4+ cell count response.
 
Conclusion. Only patients with baseline CD4+ cell counts >350 cells/uL returned to nearly normal CD4+ cell counts after 6 years of follow-up. Significant increases were observed in all CD4+ cell count strata during the first year, but there was a lower plateau CD4+ cell count at lower baseline CD4+ cell strata. These data suggest that waiting to start HAART at lower CD4+ cell counts will result in the CD4+ cell count not returning to normal levels.
 
Background

Sustained suppression of HIV-1 RNA load associated with the use of HAART results in immunologic improvement, even among persons with low pretherapy CD4+ lymphocyte counts [1-3]. However, it is not clear whether the CD4+ cell count will return to normal with long-term suppression of HIV-1 RNA load, because previous studies have shown both continued increases in the CD4+ cell count over time and plateaus in the CD4+ cell count after receipt of only 1-2 years of suppressive therapy [4-8]. Present guidelines for when to initiate antiretroviral treatment suggest that therapy can be safely withheld until the patient has a CD4+ cell count <350 cells/uL. We wondered whether the CD4+ cell count level would improve to normal levels or whether it would reach a less-than-normal plateau if antiretroviral therapy was commenced at this recommended CD4+ cell count, even if HIV-1 RNA suppression was maintained, because continual HIV-1 RNA suppression should be an optimal clinical context for immune recovery. To date, to our knowledge, only 1 study has examined immune recovery in the context of suppressed HIV-1 RNA for >5 years [7]. Therefore, we conducted an analysis of a large clinical cohort of patients to characterize the increase in CD4+ cell count among patients observed in clinical practice who maintained sustained viral suppression for up to 6 years.
 
METHODS
 
Study design and population.
All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal, observational study of patients receiving primary HIV care in Baltimore, Maryland. The Johns Hopkins AIDS Service provides longitudinal primary and subspecialty care for a large proportion of HIV-infected individuals in the Baltimore metropolitan area. In 1990, the Johns Hopkins HIV Clinical Cohort was established to quantify the processes and the outcomes of care for HIV-infected patients seen in clinical practice. Enrollment of a patient in this cohort coincides with the date of the patient's first visit to the HIV clinic. After informed consent is obtained, information is collected from a variety of sources, including outpatient and inpatient medical records, the Johns Hopkins Health System automated databases, supplemental medical records from outside facilities, and vital records. Information is reviewed and abstracted by trained medical record technicians onto data collection forms; it is then entered into the study database. The information collected includes comprehensive demographic, clinical, laboratory, pharmaceutical, and psychosocial data. These data are collected and summarized at enrollment and at 6-month intervals thereafter. The details of the database design and follow-up have been described elsewhere [9].
 
Inclusion criteria. The population for this study consisted of HIV-infected patients enrolled in the cohort after 1 January 1998. In this group, we included all patients who were observed for at least 1 year while receiving continuous HAART, who had suppression of the HIV-1 RNA load to <400 copies/mL within 6 months after first receiving HAART, and who had sustained suppression of the HIV-RNA load at <400 copies/mL for at least 6 months after initially attaining an HIV-1 RNA load <400 copies/mL. An HIV-1 RNA load <400 copies/mL was used rather than <50 to 75 copies/mL, because the more sensitive PCR or branched DNA techniques for measuring HIV-1 RNA loads were not available throughout the period of time encompassed by this analysis. We excluded any patient who had a treatment interruption during therapy. HAART was defined as use of a protease inhibitor (PI) or nonnucleoside reverse-transcriptase inhibitor (NNRTI) with at least 2 nucleoside reverse-transcriptase inhibitors (NRTIs).
 
Analysis. We analyzed annual change in CD4+ lymphocyte count for up to 6 years after the start of HAART. The analysis of changes in the CD4+ cell count was limited to that follow-up period in which the HIV-1 RNA load remained <400 copies/mL. If, after 6 months of having an HIV-1 RNA level <400 copies/mL, the HIV-1 RNA level increased to >400 copies/mL, the analysis was censored at the time at which the HIV-1 RNA level first became >400 copies/mL if the increased value was confirmed by a second HIV-1 RNA level >400 copies/mL.
 
We determined the median (and range) in the absolute CD4+ cell count at baseline and annually thereafter. To be included in each annual analysis, the patient had to have a CD4+ cell count that was obtained within 3 months of the annual anniversary date of HAART commencement. The CD4+ cell count that was obtained closest to the annual anniversary date was used for analysis. The annual change in the CD4+ cell count was also determined and stratified on the basis of baseline CD4+ cell count (<200, 201-350, and >350 cells/L). Additional stratification variables included sex (male vs. female), race (white vs. black), HIV risk group (injection drug users, men who have sex with men, and other), age (<45 vs. >45 years old), starting cornerstone antiretroviral drug (PI, NNRTI, or both), hepatitis C virus (HCV) coinfection, baseline HIV-1 RNA load (<100,000 vs. >100,000 copies/mL), previous non-HAART antiretroviral treatment, and duration of HAART. Although we were unable to use an HIV-1 RNA load of 50 copies/mL as the threshold for viral suppression (because the more-sensitive assays were not available for several years after HAART was introduced), we also assessed whether the HIV-1 RNA load was <50 copies/mL or 51-400 copies/mL as of the last measured value.
 
A multivariate least-squares linear regression analysis was used to assess changes in CD4+ cell count on the basis of baseline CD4+ cell count and these other covariates. An initial analysis included all covariates. A final multivariate model was computed using a backward stepwise approach, retaining only those variables that were statistically significant. All analyses were done using SAS software, version 9 (SAS Institute).
 
RESULTS
 
A total of 655 patients who fulfilled the inclusion criteria were identified from the Johns Hopkins HIV Clinical Cohort. These 655 patients had a median duration of HAART use of 46 months (range, 13-72 months). The median age was 39 years. Sixty-nine percent of the subjects were male, and 70% were black. The mode of HIV transmission was injection drug use for 38%, male-male sex for 31%, and heterosexual intercourse for 22%. The demographic and clinical characteristics of each of the 3 CD4+ cell count strata of interest are shown in table 1. The only significant differences that were observed between groups were a lower prevalence of black race, a lower prevalence of injection drug use and a higher prevalence of male-male homosexual intercourse as transmission risks, and a lower median HIV-1 RNA load among patients with a CD4+ cell count >350 cells/uL than among those in the lower CD4+ cell count strata. The use of PIs was higher and the use of NNRTIs was lower in the CD4+ cell count >350 cells/uL stratum.
 

Deo-1.gif

The annual change in median CD4+ lymphocyte count after the start of HAART is plotted in figure 1. The number of patients who contributed data annually was as follows: baseline and year 1, 655 patients; year 2, 439 patients; year 3, 391 patients; year 4, 291 patients; year 5, 186 patients; and year 6, 122 patients. There were no significant differences based on baseline CD4+ cell count stratum for any year with regard to the number of patients who were in follow-up (all P values were >.15). The median change from baseline to last CD4+ cell count was +274 cells/L, with 92% of patients having an increase in CD4+ cell count. Overall, the median CD4+ cell count increased to 544 cells/L (interquartile range, 383-703 cells/L) by 6 years after the start of HAART. By 6 years, the median CD4+ cell count increased to 493 cells/L (interquartile range, 375-607 cells/L) among patients with a baseline CD4+ cell count <200 cells/L, to 508 cells/uL (interquartile range, 340-637 cells/uL) among those with a baseline CD4+ cell count of 201-350 cells/uL, and to 829 cells/uL (interquartile range, 626-1059 cells/uL) among those with a baseline CD4+ cell count >350 cells/uL (figure 1).
 

Median-2.gif

An analysis of the annual increase in CD4+ cell count revealed that, for baseline CD4+ cell counts of <200, 201-350, and >350 cellsu/L, the slope of the plotted CD4+ cell count increased significantly (P < .05, compared with the previous year) until year 4, when it reached a plateau, and did not undergo a further significant increase through year 6. The percentages of patients who achieved a CD4+ cell count of >500 cells/L after receiving 6 years of suppressive HAART were 42%, 66%, and 85% for those who started HAART with a CD4+ cell counts of <200, 201-350, and >350 cells/L, respectively. The percentages of patients who achieved a CD4+ cell count of >750 cells/uL after receiving 6 years of suppressive HAART were 12%, 21%, and 46% for those who started HAART with a CD4+ cell count <200, 201-350, and >350 cells/uL, respectively.
 
Multivariate regression analysis revealed that baseline CD4+ cell count is a significant predictor of subsequent CD4+ cell count response
(table 2). Two analyses are shown; in the first, all covariates are included, whereas the second includes only those covariates that were statistically significant. In addition to baseline CD4+ cell count, both age 45 years and the transmission mode injection drug use were associated with a less robust CD4+ cell count response (P < .05). Sex, race, cornerstone antiretroviral drug, HIV-1 RNA load at start of treatment, HCV coinfection, and whether the final HIV-1 RNA load was <50 or <400 copies/mL were not associated with CD4+ cell count response (P > .10).
 

tal-3.gif

DISCUSSION
Among patients receiving HAART who achieve durable suppression of the HIV load to <400 copies/mL, an increase in CD4+ cell count is achieved and maintained in all CD4+ cell strata to 6 years. However, only patients with a baseline CD4+ cell count of >350 cells/uL had CD4+ cell counts that returned to nearly normal levels. Patients who started receiving HAART when their CD4+ cell count was <350 cells/uL did not achieve a CD4+ cell count that was as high as that achieved by other patients, and patients who started receiving HAART when their CD4+ cell count was <200 cells/L achieved CD4+ cell counts that were low enough to be an indication for commencement of HAART under current antiretroviral treatment guidelines [10]. Notably, the slope of plotted CD4+ cell count values for each of the baseline CD4+ cell count strata reached a plateau by the fourth year of sustained viral suppression in all CD4+ cell count strata. Although this may not be an issue for persons who begin to receive therapy at higher CD4+ cell counts, an early plateau may not allow persons who begin therapy at lower nadir CD4+ cell counts to achieve full immune reconstitution. These data suggest that commencement of HAART at a lower CD4+ cell count will result in a CD4+ cell count that does not return to normal levels; this may be a reason to consider starting HAART before the CD4+ cell count decreases to <350 cells/uL.
 
Our analysis purposely took the approach of assessing CD4+ cell count response after the start of HAART only for those patients who maintained HIV-1 RNA load suppression. It is in these patients that one would expect the optimal CD4+ cell count response and clinical outcome. However, we found that the highest CD4+ cell counts were achieved only when HAART was initiated at a baseline CD4+ cell count >350 cells/uL. When HAART is initiated at lower CD4+ cell counts, the CD4+ cell count is less likely to return to "normal." It could be argued that achieving a CD4+ cell count >350 cells/uL is sufficient, although we believe that a higher CD4+ cell count would afford greater protection against clinical progression. We used a threshold HIV-1 RNA load of <400 copies/mL to define viral suppression, because the measurement of HIV-1 RNA load to a threshold of 50 copies/mL was not possible during the early HAART era, and to have used this definition would have decreased our sample size dramatically. However, when we examined whether the HIV-1 RNA load was <50 or <400 copies/mL at the last assessment, this variable was not associated with CD4+ cell count response.
 
In one study of 423 patients who maintained an HIV-1 RNA load <1000 copies/mL, the median CD4+ cell count after 4 years of HAART was <400 cells/uL for persons whose CD4+ cell count at baseline was 200 cells/L [2]. The median CD4+ cell count was >500 and >700 cells/uL for those with baseline CD4+ cell counts of 201-350 and >350 cells/L, respectively. Notably, the CD4+ cell count continued to increase through 4 years of HAART without evidence of a significant decline in the slope. In another study of 596 patients, 80% of whom maintained HIV-1 RNA suppression (viral load, <400 copies/mL), continued increases in the CD4+ cell count at 24 months of HAART were observed, although a lower baseline CD4+ cell count was a risk factor for a lower peak CD4+ cell count [3]. In contrast, a study of immunological recovery in 210 patients with a suppressed HIV-1 RNA load (<20 copies/mL) demonstrated that levels of both total and naive CD4+ cells increased through month 18 and stabilized thereafter, at an abnormal level, through month 36 of follow-up [4]. The median total CD4+ cell count for these patients was 270 cells/uL at baseline and increased to 380 cells/L at 36 months. In 861 patients, of whom about 75% maintained an HIV-1 RNA load <200 copies/mL, the CD4+ cell count increased through 3 years after the start of HAART but reached a plateau through year 5 [5]. Patients with a baseline CD4+ cell count <200 cells/uL had the lowest peak CD4+ cell count. In a study performed in the EuroSIDA cohort, both older age and a lower CD4+ cell count were associated with a lower increase in the CD4+ cell count at 12 months of HAART [6]. A study of 314 HIV-infected gay men for whom CD4+ cell counts were determined for at least 2 years after the initiation of potent antiretroviral therapy revealed that, regardless of CD4+ cell count at the time of initiation of HAART, CD4+ cell counts increased significantly in the first 2 years after initiation. However, from 2 to 3.5 years after initiation, these cell count values neither increased nor decreased [8]. A study from the Dutch AIDS Therapy Evaluation project Netherlands (ATHENA) cohort found that a lower CD4+ cell count at the start of antiretroviral therapy was associated with a lower plateau CD4+ cell count after 5-7 years [7]. Only this latter study and our analysis have examined CD4+ cell response out to 6 years in patients who maintained a suppressed HIV-1 RNA load, and both found that there is a plateau CD4+ cell count associated with a lower CD4+ cell count at the start of therapy.
 
We did not find an association between HCV coinfection and CD4+ cell count response. HCV coinfection was associated with a poorer CD4+ cell count response in a British Columbia cohort after 48 weeks of HAART [11]. Both HCV coinfection and hepatitis B virus coinfection were also associated with a poorer CD4+ cell count response at 4 weeks of HAART, but by 48 weeks, there was no difference in CD4+ cell count between HAART recipients with and HAART recipients without concordant viral hepatitis [12]. Patients with the risk factor of injection drug use experienced less of an increase in CD4+ cell count. Previous data have demonstrated that illicit drug use is a barrier to adherence to antiretroviral therapy [13]. However, among patients who have a suppressed HIV-1 RNA load, for whom adherence is unlikely to be a significant issue, a decrease in CD4+ cell response suggests a more direct effect of drug use on immune reconstitution. The ATHENA cohort also found that injection drug use was associated with a decreased CD4+ cell count response [7], a finding that agreed with results from a Spanish hospital cohort study [14].
 
There was no difference in CD4+ cell response with regard to whether the cornerstone antiretroviral drug in the HAART regimen was a PI or an NNRTI. Despite earlier concerns of a possible difference in immunologic response with NNRTI-based HAART, compared with PI-based HAART, in patients with advanced immunosuppression, recent observational [15, 16] and randomized clinical trial data suggest no significant differences in CD4+ cell count response for PI-based therapy versus NNRTI-based therapy [17].
 
An important caveat to our results is that we do not have data on the specific T lymphocyte subsets in our cohort. It is possible that the total CD4+ lymphocyte counts that we measured reflect changing proportions of naive and memory CD4+ lymphocytes. One previous study found that, although the naive CD4+ cell count tended to plateau at subnormal levels by 18 months of suppressive antiretroviral therapy, the total CD4+ cell count continued to increase [4]. The initial CD4+ cell count response to HAART is an increase in memory CD4+ cells, caused by redistribution from lymphoid tissues, rather than by de novo synthesis [18, 19].
 
In summary, after 6 years of suppressive therapy, patients who initiated HAART with a lower CD4+ cell count never achieve CD4+ cell counts that are comparable to those of patients who initiated treatment at CD4+ cell counts >350 cells/uL. We recommend that consideration be given to initiation of HAART at a CD4+ cell count >350 cells/uL to achieve better immune recovery.
 
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