Gandhi, Rajesh T. MD*; Spritzler, John ScD†; Chan, Ellen MSc†; Asmuth, David M. MD‡; Rodriguez, Benigno MD§; Merigan, Thomas C. MD∥; Hirsch, Martin S. MD*; Shafer, Robert W. MD∥; Robbins, Gregory K. MD, MPH*; Pollard, Richard B. MD‡; ACTG 384 Team
HIV-1 infection results in immunodeficiency by causing loss of CD4 cells. Antiretroviral therapy (ART) suppresses HIV-1 replication and leads to immune reconstitution in many patients.1 In addition to viral suppression, other factors may impact on CD4 cell reconstitution. However, there is limited information on the effect of baseline- and treatment-related factors on CD4 cell recovery. There is also controversy regarding whether immunologic recovery is affected by the choice of initial treatment regimen.2-5 Finally, the effect of different antiretroviral regimens on CD4 memory and naive cells and T cell activation is not certain. These issues may be best addressed by studying longitudinal immunologic outcomes in HIV-1-infected subjects participating in randomized treatment trials.
AIDS Clinical Trials Group (ACTG) 384 was a prospective randomized trial of different ART strategies in treatment-naive HIV-1-infected subjects.6,7 All study participants underwent longitudinal evaluation of T-cell counts, and a majority also had testing of naive and memory CD4 cell subsets, natural killer (NK) and B cells, and T-cell activation. Results from this study, as previously reported, showed that initial treatment strategy was not associated with differences in total CD4 cell count increase.6,7 We now report on the association between subject- and therapy-related characteristics and CD4 cell recovery in subjects enrolled in ACTG 384, including information from individuals followed in an optional extension phase of the study. We also present a detailed analysis of the changes in naive and memory CD4 cell subsets, NK and B cells, and T-cell activation after starting antiretroviral medication. This large prospective study allows us to evaluate the effect of baseline- and treatment-related factors on immunologic recovery after initiation of ART in antiretroviral-naive HIV-1-infected patients.
Nine hundred eighty antiretroviral-naive HIV-1-infected subjects in the United States (n = 898) and Italy (n = 82) were randomized to start stavudine/didanosine or zidovudine/lamivudine with nelfinavir, efavirenz, or both nelfinavir and efavirenz.6,7 The institutional review boards of participating sites approved the trial. T-cell counts were measured every 8 weeks for the first 48 weeks and then every 16 weeks through week 144. Plasma HIV-1 RNA (virus load [VL]) was measured every 4 weeks until week 24 and then every 8 weeks through week 144. Although not all enrollment sites had the capability to perform specialized flow cytometry, a substantial subset of US subjects (n = 623) had testing of naive and memory CD4 cells, activated T cells, and NK and B cells (comprehensive immunologic assessments) every 24 weeks through week 144.
In previous publications,6,7 the results of initial treatment assignment on total CD4 cell count were reported in 980 subjects who had a median follow-up of 2.3 years. Sixty-four percent of the subjects were followed in an optional 1-year extension study and had T cells measured every 16 weeks and VL assessed every 8 weeks; among these subjects, the median follow-up time was 3.4 years. This analysis included data from subjects on the original study and those who continued in the study extension. Subjects in the extension phase were slightly older (37 vs 34 years old) and more likely to be men (84% vs 78%) than subjects in the original study. There was no difference between subjects in the extension phase and those in the original study with respect to race, history of injection drug use, baseline CD4 cell count, or baseline VL.
Flow cytometric analysis was performed on fresh cells. Naive T cells were defined as those that stained positive for CD45RA and CD62L. Memory T cells were those that were positive for CD45RO and negative for CD45RA. Activated T cells were defined as CD3+ lymphocytes that stained positive for CD38 and HLA-DR. B cells were defined as those that stained positive for CD19. Natural killer cells were defined as those that stained positive for CD16 or CD56 and negative for CD3.
All analyses were performed using an intent-to-treat method. Where specified, we also conducted an "as treated" analysis, using only data from subjects who were on their first regimen. Statistical tests were two-sided exploratory without adjustments for multiple testing, at the 0.05 nominal level of significance. Continuous outcomes were compared between groups using the Wilcoxon rank sum, Kruskal-Wallis, or Jonckheere-Terpstra tests as appropriate. Paired continuous variables were tested with the Wilcoxon signed rank test. Categorical outcomes were compared using Fisher exact tests. Correlations were estimated using Spearman rank correlation coefficients. A multiple linear regression model regressing change in CD4 cell count on age, sex, baseline CD4 cell count, baseline log10 VL, initial treatment, and virologic suppression (VS) at the specified study week was fitted to assess the association between change in CD4 cell count and the following: (a) age, (b) sex, (c) baseline VL, and (d) VS after adjusting for the other covariates. Virologic suppression was defined as a VL of 50 copies/mL or less after initiation of ART. Statistical analyses were performed using SAS version 8 (SAS Institute Inc, Cary, NC) and Proc-StatXact version 5 (Cytel Software, Cambridge, MA).
The demographic characteristics for all 980 study participants (previously reported7) and the subset of 623 subjects who underwent comprehensive immunologic assessments (testing for naive and memory CD4 subsets, activated T cells, NK and B cells) are shown in Table 1. Among all 980 subjects, the median age was 36 years old; 82% were men, 35% were non-Hispanic blacks, and 17% were Hispanics. The median baseline CD4 cell count was 279/mm3, and the median VL was 87,000 (4.9 log10) copies/mL.
There was no difference in age, sex, baseline CD4 cell count, or baseline VL between the 623 subjects who had comprehensive testing and 275 US subjects who did not. There was a smaller proportion of Hispanic subjects among those who had comprehensive testing as compared with those who did not: 14% versus 28% (P < 0.0001, Fisher exact test). However, this difference seems to be related to the fact that sites that performed comprehensive assessments evaluated a lower proportion of Hispanic subjects than sites that did not (data not shown).
Change in Lymphocyte Counts After Initiation of Therapy
The median increase in the CD4 cell count was 294/mm3 at week 144 (Fig. 1A). During the first 8 weeks of therapy, the mean increase in CD4 cell count was 11/mm3 per week. Thereafter, there was a slower steady rise, without evidence of a sustained plateau through the first 144 weeks of treatment.
Subjects had an initial slight decrease in total CD8 cell count for the first 48 weeks, followed by subsequent increase (Fig. 1B). In the 623 subjects who had comprehensive assessments, there was only a small increase in the total number of NK cells, whereas the number of B cells increased substantially. The median number of B cells increased from 106/mm3 before initiation of therapy to 213/mm3 at week 144 (Fig. 1C).
Baseline Characteristics and CD4 Cell Recovery
We examined the association between sex and age and the change in total CD4 cell count after initiation of therapy. Men and women in this study did not differ in their age distribution. Before therapy, women had higher baseline CD4 cell counts (340/mm3 vs 273/mm3; P = 0.002) and lower VL (median, 4.7 vs 5.0 log10 copies/mL, P < 0.0001) than men. After initiation of therapy, subjects who were 40 years old or younger had a greater increase in CD4 cell count than those who were older than this age (Table 2). For example, at week 48, subjects who were 40 years old or younger had a median increase in CD4 cell count of 182/mm3 as compared with 135/mm3 for subjects who were older than 40 years (P = 0.0005). After adjusting for other factors that may affect immunologic recovery-sex, baseline VL, baseline CD4 cell count, VS at the specified time point, and initial treatment assignment-younger age remained associated with greater CD4 cell count increase at weeks 16, 24, 32, 40, 48, and 64 (data for week 48 shown in Table 3); this association was not significant in the multivariate analysis after week 64. In univariate analyses (Wilcoxon rank sum tests), we found that women had a greater CD4 cell count increase than men starting at week 48 and persisting through week 144 (Table 2). For example, at week 48, women had a median increase in CD4 cell count of 205/mm3 as compared with 164/mm3 for men (P = 0.009). Women also had a greater rise in CD4 cell percentage as compared with men (data not shown). In multiple regression models, the effect of sex on CD4 cell count increase was significant at weeks 48, 64, 80, and 96 after adjusting for baseline CD4 cell count, baseline VL, age, VS, and initial treatment assignment (Table 3; data not shown).
In this study, a higher proportion of men than women were non-Hispanic whites (51% vs 27%), and a higher proportion of women than men were non-Hispanic blacks (52% vs 31%). However, we found no evidence for an association between race/ethnicity and change in CD4 cell count after initiation of ART, indicating that race/ethnicity is not a confounder of the association between the other covariates and CD4 cell count change.
We also assessed the effect of baseline CD4 cell characteristics on the increase in CD4 cell count after initiation of therapy. In the 623 subjects who had comprehensive immunologic assessments, subjects with a higher baseline naive CD4 cell percentage had a greater increase in CD4 cell count at all time points, although the correlation coefficient was small (eg, r = 0.26 at week 48; P < 0.0001). Subjects who had a higher baseline naive/memory CD4 cell count ratio had a significantly greater CD4 cell count increase at all study time points (eg, r = 0.26 at wk 48; P < 0.0001). Younger age correlated with greater baseline naive CD4 cell percentage (r = −0.33) and naive/memory CD4 cell count ratio (r = −0.32) (both P values < 0.0001). For example, subjects aged 40 years or younger had a median naive/memory CD4 cell count ratio of 0.66 as compared with 0.36 for subjects aged older than 40 years (P < 0.0001). There was no evidence for a difference in baseline naive CD4 cell count or percentage between men and women.
We also examined the effect of baseline VL on the change in CD4 cell count. A higher baseline VL was associated with a greater increase in CD4 cell count through week 144. Subjects with higher baseline VL had lower baseline CD4 cell counts (r = −0.57; P < 0.0001). Even after adjustment for age, sex, baseline CD4 cell count, VS status, and initial treatment assignment, higher baseline VL remained associated with greater increase in CD4 cell count through week 144.
Virologic Response to Treatment and CD4 Cell Recovery
After initiation of ART, lower post-treatment VL, greater VL decline, and VS (VL ≤ 50 copies/mL) were associated with greater CD4 cell count gain in univariate regressions. In a multiple regression model that included age, sex, baseline CD4 cell count, baseline VL, and initial treatment assignment, VS was associated with greater CD4 cell count increase after adjustment for the other factors.
When we assessed immunologic recovery as a function of VS status (VL ≤ 50 copies/mL), we found a substantial proportion of subjects who had a lag between VS and achievement of an immunologic response (IR), defined as an increase from baseline in CD4 cell count of greater than 100/mm3. For example, at week 24, of the 608 subjects who had VS, 255 (42%) did not have an IR. Fifty percent of those subjects who had VS but not an IR at week 24 and who maintained VS at week 48 had an IR at week 48. With continued VS, the rate of IR increased among 148 subjects who maintained VS from weeks 24 to 144; 87% achieved an IR at week 144. Nevertheless, even after this prolonged VS, 13% of the subjects did not have an IR. Among the subjects who maintained VS from week 24 to 144, those who achieved an IR were younger than those who did not (median age, 35 vs 42 years; P = 0.005); among these subjects, there were no differences in sex, race/ethnicity, or injection drug use history in the immunologic responders versus nonresponders.
Initial Treatment Assignment and Immunologic Recovery
By intent-to-treat analysis, initial treatment assignment did not affect the CD4 cell count increase at week 96 (because a substantial proportion of subjects had changed therapy by week 144, we did not assess the effect of initial treatment assignment on CD4 cell count at this time point). When the analysis was limited to subjects on their first regimen, there was also no difference in CD4 cell count by treatment arm through week 144 (data not shown).
We found no evidence for a difference in the increase in CD4 cell count through week 144 in subjects assigned to the 2 different nucleoside backbones in this study: stavudine/didanosine or zidovudine/lamivudine (Fig. 2A). There was a significantly higher increase in median CD4 cell percentage in subjects randomized to initiate a zidovudine/lamivudine-containing regimen as compared with those who started with a stavudine/didanosine-containing regimen, although the differences were small (eg, at week 48, median increases of 8% vs 7%, respectively; P < 0.0001).
We also examined whether CD4 cell count recovery differed between subjects randomized to initiate therapy with a nelfinavir-containing regimen, an efavirenz-containing regimen, or a regimen containing both drugs. We found no evidence for a difference in the total CD4 cell count and the increase in CD4 cell count in these 3 groups (Fig. 2B).
Naive and Memory CD4 Cells After Starting ART
In the first few months after initiation of ART, there is typically an early increase in the number of memory CD4 cells followed by a slower rise in naive CD4 cells.8-10 In the 623 subjects who had comprehensive immunologic assessments, we found that the number of both memory and naive CD4 cells continued to increase at week 144, with no evidence of a plateau (Fig. 3A). Although there was a greater increase in the memory than in the naive CD4 cell count (median increase, 159 and 116, respectively, at week 144; P = 0.001), the fold increase in naive CD4 cells was greater than that in memory CD4 cells (median, 2.2- and 1.9-fold, respectively; P = 0.004). When we assessed the percentage of naive and memory CD4 cells, there was an increase in the percent naive cells for the first 48 weeks of therapy (P < 0.0001), whereas the percent memory cells declined slightly during this same interval (P = 0.002) (Fig. 3B). We found no evidence of any difference between the initial regimens in their effect on change in naive/memory CD4 cell count or percentage (data not shown).
T-Cell Activation After Initiation of ART
Uncontrolled HIV-1 infection is associated with high levels of T-cell activation,11,12 perhaps because of the enormous amounts of circulating viral antigen and immune dysregulation induced by CD4 cell depletion. In the 623 subjects who had measurements of lymphocyte activation, there was a rapid decline in activated T-cell percentage for the first 24 weeks of treatment (Fig. 4). The absolute CD8 cell count and the percent activated CD8 cells both declined in the first 24 weeks after initiation of therapy, and the changes in the 2 measures were correlated (eg, r = 0.32; P < 0.0001 at week 24). There was a greater decline in percent activated CD8 than in percent activated CD4 cells (median decrease, −19% vs −6%, respectively, at week 24); however, percent activated CD8 cells before therapy was higher than percent activated CD4 cells (49% vs 14%). Thus, at week 24, the median fold decrease in activated CD4 cell percentage was slightly greater than that in activated CD8 cell percentage (1.89- and 1.67-fold, respectively; P = 0.057). In subjects who had suppressed VL from weeks 24 to 144, the median percent activated CD4 cells was 6, and the median percent activated CD8 cells was 19.5 at week 144. We found no evidence that any of the 6 initial treatment regimens differed in their effect on reducing the percentage of activated CD4 or CD8 cells at week 144 (data not shown).
We also examined the effect of T-cell activation-as assessed by cell surface expression of both CD38 and HLA-DR-on change in CD4 cell count after starting therapy. Subjects with higher baseline percent CD8 cell activation had a greater increase in CD4 cell count from baseline to week 48 (r = 0.09; P = 0.04), but this effect was no longer statistically significant at subsequent weeks. We found no evidence for an association between baseline CD4 cell activation and change in CD4 cell count after ART initiation. In contrast, subjects who had higher levels of CD4 or CD8 cell activation after starting ART had smaller increases in CD4 cell count. For example, higher CD8 cell activation at week 48 was associated with lower CD4 cell count increases at week 48 (r = −0.13; P = 0.001). A higher activated CD4 percentage at week 48 was also associated with a lower CD4 cell count increase at week 48 (r = −0.20, P < 0.0001). The association between higher CD4 cell activation and lower change in CD4 cell count was seen even when the analysis was restricted to subjects who achieved an undetectable VL (≤50 copies/mL) at the time point for which the CD4 cell count was examined (data not shown). When the analysis was restricted to subjects who achieved an undetectable VL, the association between higher CD8 cell activation and lower change in CD4 cell count was statistically significant only at week 96 (data not shown).
When the association between CD4 cell recovery and expression of CD38 and HLA-DR were examined separately, we found that the percentage of CD38+ CD4 and CD8 T-cells at baseline was more strongly associated with CD4 cell reconstitution than the percentage of HLA-DR+ CD4 and CD8 cells (data not shown).
In this large prospective study of HIV-1-infected antiretroviral-naive subjects, we found that there was a steady rise in CD4 cell count after initiation of ART. Age of 40 years or younger, female sex, higher baseline naive/memory CD4 cell count ratio, and higher baseline VL were associated with a greater increase in CD4 cell count. Age, sex, and baseline VL were associated with CD4 cell rise even after adjusting for VS in a multiple regression model, indicating that there are factors that impact CD4 cell reconstitution after initiation of ART in addition to control of viremia. As expected, VS to 50 copies/mL or less was consistently associated with greater CD4 cell recovery. Although most subjects who maintained an undetectable VL had substantial immunologic recovery, 13% did not have a rise in CD4 cell count of greater than 100 cells/mm3 even after 144 weeks of VS. We did not find evidence that initial antiretroviral treatment assignment in this study affected total CD4 cell count recovery, reconstitution of naive/memory CD4 cells, or decline in T-cell activation.
In addition to recovering CD4 cells, subjects had a large increase in B-cell numbers after starting ART. HIV-1 infection impairs B-cell survival and function,13 perhaps by stimulating activation-induced cell death. Thus, suppression of viral replication may lead to improved B-cell survival and restoration of B-cell counts. This B-cell recovery may contribute to improved humoral immunity in HIV-1-infected patients who are successfully treated with ART.14
Many of the factors associated with greater CD4 cell recovery in this large prospective randomized study are consistent with findings in smaller retrospective or nonrandomized studies. Most studies suggest that younger subjects have a greater increase in CD4 cell count after therapy than older individuals.15 This may be because of the fact that younger individuals have a higher naive CD4 cell percentage and a higher naive/memory CD4 cell count ratio than older people, perhaps because of greater thymic function. In this study, HIV-1-infected subjects with a higher naive/memory CD4 cell ratio had a greater rise in CD4 cell count after ART. A similar finding has been seen in CD4 cell recovery after chemotherapy in subjects with cancer.16 These findings suggest that the CD4 naive/memory cell count ratio may be a general measure of the capacity for CD4 cell regeneration, although this must be confirmed in other studies.
The association between sex and CD4 cell recovery after ART is controversial.17-19 We found that women have a greater rise in CD4 cell count than men; this difference is statistically significant at week 48 and persists through week 96. Women in this study had higher baseline CD4 cell counts than men, but the association between sex and CD4 cell recovery persisted even after adjusting for baseline CD4 cell count (and for baseline VL, age, viral suppression, and treatment arm). One explanation for our findings is that women may normally have higher CD4 cell counts than men. In a study of HIV-1-negative individuals, women had approximately 100 more CD4 cells/mm3 than men; this number may be affected by estrogen and other hormonal influences.20 By suppressing HIV-1 replication, ART may lead to a greater increase in CD4 cell counts in women than in men because the normal homeostatic regulation of CD4 cell number is restored.
An important finding of ACTG 384 is that initial treatment assignment did not affect CD4 cell recovery, nor did it affect reconstitution of naive/memory CD4 cell subsets. Unlike other studies, we did not find evidence that different nucleoside backbones were associated with variable rises in CD4 cell count.2-5 Also, regimens that contained the protease inhibitor nelfinavir led to comparable CD4 cell gains as regimens containing the nonnucleoside reverse transcriptase inhibitor, efavirenz; combinations that included both did not lead to better CD4 cell recovery. Virologic suppression seems to be the most important treatment-related factor associated with CD4 cell count rise.
This study also demonstrates that both naive and memory CD4 cells are substantially regenerated in HIV-1-infected subjects who receive ART. In the first few months after initiating ART, there is a rapid increase in the number of memory CD4 cells followed by a slower rise in naive CD4 cells.8-10 In the current study, CD4 cell subsets were first assessed 6 months after treatment initiation, so we may have missed early changes. However, by 6 months after starting therapy, both naive and memory CD4 cell subsets had increased. Although the rise in the absolute numbers of memory CD4 cells was greater, the fold increase in naive CD4 cells exceeded that of memory CD4 cells. In fact, the percent memory CD4 cells declined slightly during the first year of therapy, whereas the percent naive CD4 cell increased. This finding suggests that ART leads to reconstitution of CD4 cells capable of responding to new antigens, which is consistent with the clinical improvement in most subjects who receive treatment.21
Finally, the results of this study add to accumulating data that persistent T-cell activation is associated with impaired immune regeneration.22 Excessive T-cell activation has been implicated in the pathogenesis of the CD4 cell depletion induced by HIV-1, perhaps through activation-induced cell death and impaired CD4 regeneration.11,12 Even after prolonged VS, the median percent activated CD4 and CD8 cells in subjects in this study remained higher than that seen in HIV-uninfected subjects.23 Whether pharmacologic reduction of T-cell activation will improve CD4 cell recovery is not known and is the subject of ongoing investigations.
The authors thank Meghan Geary, Minya Pu, Jessica Hass, Barbara Brizz, Bernadette Jarocki, and Jennifer Nowak for their invaluable assistance.
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