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Incomplete Peripheral CD4+ Cell Count Restoration in HIV-Infected Patients Receiving Long-Term Antiretroviral Treatment
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Clinical Infectious Diseases March 15 2009;48:787-794
Colleen F. Kelley,1,a Christina M. R. Kitchen,2,a Peter W. Hunt,3 Benigno Rodriguez,4 Frederick M. Hecht,3 Mari Kitahata,5 Heide M. Crane,5 James Willig,6 Michael Mugavero,6 Michael Saag,6 Jeffrey N. Martin,3 and Steven G. Deeks3
1Emory University, Atlanta, Georgia; 2University of California at Los Angeles, Los Angeles, and 3University of California, San Francisco; 4Case Western Reserve University, Cleveland, Ohio; 5University of Washington, Seattle; and 6University of Alabama at Birmingham, Birmingham "Depending on the mechanism for these suboptimal immunological outcomes, novel immune-based therapeutic approaches may be necessary to restore immunocompetence in these individuals."
"the primary limitation of current therapeutic strategies may be the inability to fully restore immunocompetence. Failure to restore a normal peripheral CD4+ cell count is associated with an increased risk of morbidity and mortality associated with conditions not previously thought to be AIDS related, including cardiovascular disease, fatal liver disease, and cancer."......"a significant subset of individuals clearly do not achieve the desired outcome, even after up to 10 years of treatment-mediated viral suppression. This appears to be particularly true among those individuals who delay therapy until their peripheral CD4+ cell count decreases to <200 cells/mm3, which is commonly done in both resource-rich and resource-poor regions"......"The risk of a suboptimal immunological response depends on the pretherapy nadir CD4+ cell count, age, and the degree of viral suppression, as has been seen by other researchers [1]. Whether such patients who do not achieve immunologic response will experience normalization of their CD4+ cell count with time is unclear, but it seems unlikely, because we could not detect strong evidence of ongoing increases in CD4+ cell count after year 7 among those who had yet to achieve a normal CD4+ cell count."
"The mechanisms underlying poor immunological outcomes during therapy are not clear. In the context of untreated HIV infection, immune activation-as measured by coexpression of CD38 and HLA-DR on T cells-is a strong and independent predictor of CD4+ cell loss and disease progression [22, 23]. This appears also to be true in the context of effective therapy [24, 25]. Other factors, such as thymic dysfunction [26], loss of gut mucosal integrity [27], T cell proliferation defects [28, 29], irreversible changes to the lymphoid infrastructure [30], and/or persistent viral replication [31, 32], may be involved. Careful biological assessment of those individuals with persistently low CD4+ cell counts during therapy is ongoing"
Excerpts from the published article.
ABSTRACT
Background.Although antiretroviral therapy has the ability to fully restore a normal CD4+ cell count (>500 cells/mm3) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4+ cell count, in part because no study has followed up patients for >7 years.
Methods..Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level <1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4+ cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques.
Results..The majority (83%) of the patients were men. The median CD4+ cell count at the time of therapy initiation was 201 cells/mm3 (interquartile range, 72-344 cells/mm3), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5-9.7 years). CD4+ cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4+ cell count >300 cells/mm3 were able to attain a CD4+ cell count >500 cells/mm3, 44% of patients who started therapy with a CD4+ cell count <100 cells/mm3 and 25% of patients who started therapy with a CD4+ cell count of 100-200 cells/mm3 were unable to achieve a CD4+ cell count >500 cells/mm3 over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4+ cell count <500 cells/mm3 at year 4 had evidence of a CD4+ cell count plateau after year 4. The frequency of detectable viremia ("blips") after year 4 was not associated with the magnitude of the CD4+ cell count change.
Conclusions.A substantial proportion of patients who delay therapy until their CD4+ cell count decreases to <200 cells/mm3 do not achieve a normal CD4+ cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4+ cell count over time, many do not. These individuals may have an elevated risk of non-AIDS-related morbidity and mortality.
The vast majority of patients who achieve and maintain an undetectable plasma HIV RNA level while receiving HAART exhibit sustained increases in their peripheral CD4+ cell count [1]. Most patients exhibit a rapid increase in the peripheral CD4+ cell count during the first 8-12 weeks of therapy. This is often followed by a more gradual increase until a normal CD4+ cell count is achieved [2, 3]. There exists, however, significant patient-to-patient heterogeneity with regard to peripheral CD4+ cell count outcomes; some patients apparently reach a plateau before normalization of their CD4+ cell count [4-8], although this phenomenon remains controversial [9, 10].
There is no clear consensus with regard to how to best define immunological success or failure in the context of durable treatment-associated viral suppression [1, 11]. Several studies have focused on rates of CD4+ cell count increases per year and have generally found that CD4+ cell counts continue to increase as long as the CD4+ cell counts remain lower than normal levels, although the rate of increase decreases after several years [10]. One limitation of these approaches is that they report the mean values in the population. Other studies have reported the proportion of patients who experience an increase in CD4+ cell count to the normal range. These studies have invariably found that a significant proportion of individuals have a persistently low CD4+ cell count, at least throughout the 3-7 years of observation [5, 6, 8, 10, 12].
There is a growing appreciation that a persistently low CD4+ cell count during treatment is associated with increased risk of both AIDS- and non-AIDS-related events (e.g., cardiovascular disease, liver disease, and cancer) [13-19]. Importantly, the clinical risk associated with lower CD4+ cell counts during therapy is evident across the entire CD4+ T cell range, with a patientfs overall prognosis approaching that of an HIV-negative individual only if CD4+ cell counts are consistently maintained at >500 cells/mm3 [18]. For these reasons, the recent Department of Health and Human Services guidelines suggest that a goal of therapy is to increase CD4+ cell counts to the normal range [11].
Because of the clinical significance of CD4+ cell counts during therapy and the lack of clarity with regard to CD4+ cell count increases during long-term therapy, we analyzed long-term changes in CD4+ cell count in a cohort of individuals who were selected on the basis of maintenance of an undetectable or low viral load. Because, in our previous studies, we did not see any evidence of a CD4+ cell count plateau during the first 4 years of therapy [9], we identified all patients who maintained undetectable or low viral loads for at least 4 years. In our primary analysis, we focused on outcomes after year 4 and in a secondary analysis. In our secondary analysis, we considered all data from after the initiation of therapy.
Factors associated with changes in CD4+ cell count after 4 years of HAART.--In the mixed-effects analysis, we found that the mean change in CD4+ cell count after 4 years of observation was higher in those with lower pretherapy nadir CD4+ cell counts (21, 23, 18, 5, and 2 cells/mm3 for patients with a pretherapy CD4+ cell count of <100, 101-200, 201-300, 301-400, and >400 cells/mm3, respectively). We also examined other factors that might be associated with changes in CD4+ cell count after year 4 of therapy. In multivariate analysis, age was the only factor consistently associated with CD4+ cell count increases; younger patients had greater increases than did the older patients (p=.009). Hepatitis C virus coinfection, sex, and pre-HAART nucleoside analogue exposure were not statistically significant predictors of CD4+ cell count increases during this period.
We used an expansive definition of virological success because of the lack of certainty regarding low-level viremia for long-term outcomes. The proportion of visits at which virus was detectable ("blips") was strongly associated with CD4+ cell count changes before year 4 (p<.001 ). There was, however, no association after year 4 (p=.85). There was a trend suggesting that the magnitude of the blip (rather than the frequency) was important, because higher-magnitude blips were associated with less robust CD4+ cell count increases (after year 4; p=.07).
A total of 16 patients had persistent low-level viremia (defined as having at least 50% of all viral loads after year 4 detectable but <1000 copies/mL). The median pre-HAART CD4+ cell count in these patients was 293 cells/mm3 (IQR, 184-429 cells/mm3). During a median follow-up period of 6 years (IQR, 5-7 years), 14 of these 16 patients achieved a normal CD4+ cell count.
Discussion
With >25 antiretroviral drugs from at least 6 therapeutic classes now available, it is likely that the vast majority of patients who are able to access and adhere to combination therapy will achieve durable viral suppression. Because effective therapy can dramatically reduce the risk of the classically defined AIDS complications, the primary limitation of current therapeutic strategies may be the inability to fully restore immunocompetence. Failure to restore a normal peripheral CD4+ cell count is associated with an increased risk of morbidity and mortality associated with conditions not previously thought to be AIDS related, including cardiovascular disease, fatal liver disease, and cancer. As we report here and as has been described elsewhere [4-6, 10], the vast majority of patients who have virological response to therapy exhibit sustained increases in their peripheral CD4+ cell count, with most individuals achieving a normal CD4+ cell count. However, a significant subset of individuals clearly do not achieve the desired outcome, even after up to 10 years of treatment-mediated viral suppression. This appears to be particularly true among those individuals who delay therapy until their peripheral CD4+ cell count decreases to <200 cells/mm3, which is commonly done in both resource-rich and resource-poor regions [8, 20, 21].
Most published reports have focused on the mean change in CD4+ cell count over a period of 3-7 years. Although such information is clearly important, it does not provide clarity with regard to whether there is a small subset of individuals who experience prolonged immunological "failure," which might be defined as reaching a plateau before CD4+ cell count normalization occurs. The situation may be analogous to viral load responses. Because most patients do well virologically, the focus is inevitably on the small proportion of failures rather than on the average response. Perhaps the most important observation from our current study is that there is a clear, albeit small, subset of individuals who do not experience normalization of their peripheral CD4+ cell count after 10 years of therapy. The risk of a suboptimal immunological response depends on the pretherapy nadir CD4+ cell count, age, and the degree of viral suppression, as has been seen by other researchers [1]. Whether such patients who do not achieve immunologic response will experience normalization of their CD4+ cell count with time is unclear, but it seems unlikely, because we could not detect strong evidence of ongoing increases in CD4+ cell count after year 7 among those who had yet to achieve a normal CD4+ cell count.
The mechanisms underlying poor immunological outcomes during therapy are not clear. In the context of untreated HIV infection, immune activation-as measured by coexpression of CD38 and HLA-DR on T cells-is a strong and independent predictor of CD4+ cell loss and disease progression [22, 23]. This appears also to be true in the context of effective therapy [24, 25]. Other factors, such as thymic dysfunction [26], loss of gut mucosal integrity [27], T cell proliferation defects [28, 29], irreversible changes to the lymphoid infrastructure [30], and/or persistent viral replication [31, 32], may be involved. Careful biological assessment of those individuals with persistently low CD4+ cell counts during therapy is ongoing.
There are several limitations to this study that deserve mention. First, inclusion in the study was limited to patients who were able to maintain HIV RNA levels <1000 copies/mL for 4 years; thus, generalizability of results is limited to patients who achieve this degree of viral suppression. Second, the level of detection for the viral load assays used in clinical practice decreased over time, thus complicating our blip analysis.. The fact that blips were more strongly associated with CD4+ cell count increases during the first 4 years of treatment than during the rest of the study period may reflect the fact that only high-level blips (HIV RNA level, >400 copies/mL) were detectable during that time. Third, we used an expansive definition for viral suppression, allowing patients to remain in the analysis if their plasma HIV RNA levels remained <1000 copies/mL. This was done because of the lack of certainty regarding the clinical significance of intermittent viremia [33]. In multivariable analysis, the frequency of blips had no impact on CD4+ cell count changes (after year 4), although the changing performance characteristics of the viral load assays may have influenced these findings. Only a small number of patients had persistent low-level viremia at each visit, and the outcomes in these patients were not appreciably different from those in the entire cohort. Fourth, many patients initiated therapy with an unboosted protease inhibitor, which is no longer considered to be the standard of care. It is unlikely, however, that the type of regimen used had a dramatic impact on outcomes, because patients were selected on the basis of viral load, and the level of residual viremia (among those with undetectable plasma HIV RNA levels) does not vary by regimen type [34].
In conclusion, patients who delay therapy until their CD4+ cell count decreases to <200 cells/mm3 may not achieve a normal CD4+ cell count, even after >10 years of otherwise effective therapy. A clear subset of individuals who do not achieve a normal CD4+ cell count by year 4 exhibit evidence of a plateau and may not be able to achieve a normal CD4+ cell count without other interventions. These individuals likely remain at risk for developing significant non-AIDS-related events [13]-an issue that we were not powered to address in this study. Depending on the mechanism for these suboptimal immunological outcomes, novel immune-based therapeutic approaches may be necessary to restore immunocompetence in these individuals.
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