Because self-reported CD4 nadir is subject to bias, and is most clinically relevant when plasma virologic suppression has been achieved, we conducted follow-up analyses to test the robustness of our findings in selected subgroups. These included individuals whose self-reported nadir was verified by documented laboratory measurements, those who had achieved virologic suppression in plasma and those whose nadir could be confirmed as occurring prior to ART initiation.
To validate self-reported CD4 nadir, we examined a subset of individuals who were followed longitudinally and who began the study reporting a nadir at least as high as the measured CD4 cell count at their first study visit. We then compared the nadir reported at the most recent visit with the CD4 cell count measured previously. In this subset, the difference between self-reported nadir and actual nadir was small (mean difference 28.6, SD 21.7) and not statistically significant (paired t-test; P = 0.20). Among the 1080 patients on CART, 589 (55%) had successful virologic suppression, defined as undetectable plasma viral load. In this subset, higher CD4 nadir was significantly associated with lower rates of NPI. Of these 589, 185 reported a nadir date that preceded their first exposure to CART, with the remainder reporting either a nadir date after CART initiation, or an uncertain date of initiation or CD4 nadir. In the subgroup of 185, the relationship between CD4 nadir and prevalence of NPI trended toward significance [odds ratio (OR) = 0.96, 95% confidence interval (CI) 0.91–1.01; P = 0.09].
We observed that HIV-infected individuals who never experienced low CD4 cell counts were relatively protected from NPI as compared with those with a history of severe immunosuppression. A regression analysis showed that the relationship between CD4 nadir and probability of impairment was continuous and monotonic across the range of nadirs in the cohort, without the evidence of an informative threshold or cutoff. To evaluate the robustness of the relationship between CD4 nadir and NPI risk, we performed follow-up analyses exploring several potential clinically important modifiers. First, as CD4 nadir is most relevant in the setting of successful ART, wherein sustained CD4 rises are frequently seen, especially when virologic suppression is reached, we analyzed the subset of participants who had achieved undetectable plasma viral load on CART regimens. The CD4 nadir–NPI relationship remained significant in this subset. Second, because non-HIV-related determinants of cognitive performance such as head injury or developmental disability might influence the level of CD4 at which CART was initiated or patients’ ability to adhere to their regimens, we performed follow-up analyses including only impaired patients meeting HAND criteria , which eliminated such confounding conditions. Again the CD4 nadir–NPI relationship remained significant in this subset. Similarly, the influence of nadir on NPI was significant in analyses adjusting for other covariates, such as ethnicity, sex and hepatitis C coinfection status.
The findings of this study have several limitations. First, we determined CD4 nadir by self-report, which is subject to recall bias. In fact, self-report is the usual method for assessing nadir in clinical practice. Previous studies have established the reliability and validity of self-reported CD4 cell counts in comparison with observed values [6,7]. However, to evaluate potential recall bias, we examined a subset of study participants followed longitudinally in whom the measured CD4 cell count at the baseline visit was in fact lower than their previously reported nadir. At subsequent visits, the nadirs recalled by such participants did not differ significantly, on average, from their actual measured nadirs, suggesting that self-report did not introduce a systematic bias, at least in this subgroup. Second, we were able to verify that the CD4 nadir was measured before the initiation of ART only in a subset of individuals (N = 185), with the remainder having either an unknown date or a nadir after the initiation of ART. Third, although no threshold effects were seen over the range of CD4 nadirs in this cohort, the number of individuals on CART with nadirs above 500 cells/μl was small (n = 24), yielding wide CIs for the estimation of neuropsychological risk associated with this nadir level. The small number of patients in this nadir range likely reflects previous treatment guidelines, which recommended treatment initiation only when CD4 cell counts fell under 350 cells/μl.
As this was an uncontrolled, observational study, certain factors might have confounded the association between nadir and NPI. For example, older participants or those with longer durations of HIV infection might have had lower nadirs and worse cognitive impairment than those who were younger or had shorter durations of HIV infection. To address this issue, we adjusted our models for age and estimated duration of HIV infection and found that nadir remained a significant predictor of NPI. Additionally, as participants with worse cognitive impairment might demonstrate poor ART adherence or be more likely to develop resistance, such individuals might have systematically lower nadirs. To address this limitation, we repeated our analyses with a subset of participants who demonstrated good adherence and antiviral efficacy by virtue of having undetectable viral loads on CART. In this subset, CD4 nadir remained a significant predictor of NPI. As this was an observational study, we were not able to exclude other unmeasured differences between the impaired and unimpaired participants. The analysis presented here does not preclude other factors influencing impairment rates, such as the CNS penetration of the specific ARVs used. This issue has been addressed in a prior review based on the CHARTER cohort .
Because lower CD4 cell counts are an indication to start ART, but the optimal CD4 cell count for treatment initiation remains a subject of debate, our findings have important clinical implications. The depth of immune suppression reached, as indexed by the CD4 nadir, might represent an important HIV ‘legacy event’ that causes irreversible neural injury, contributing to HAND. If true, then preventing severe or even moderate immunosuppression by initiating ART as soon as possible might reduce subsequent HAND risk. Our data support recent revisions to treatment guidelines that recommend ART use in patients with CD4 cell count higher than 350 cells/μl and raise the question of ART use with CD4 cell count higher than 500 cells/μl. Our findings further emphasize the importance of identifying HIV-seropositive patients early in the course of their illness and encouraging ART use to prevent later complications.
The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University, Mount Sinai School of Medicine, University of California, San Diego, University of Texas, Galveston, University of Washington, Seattle, Washington University, St Louis and is headquartered at the University of California, San Diego and includes:Director: Igor Grant, MD; Co-Directors: J. Allen McCutchan, MD, Ronald J. Ellis, MD, PhD, Thomas D. Marcotte, PhD; Center Manager: Donald Franklin Jr; Neuromedical Component: Ronald J. Ellis, MD, PhD (PI), J. Allen McCutchan, MD, Terry Alexander, RN; Laboratory, Pharmacology and Immunology Component: Scott Letendre, MD (PI), Edmund Capparelli, PharmD; Neurobehavioral Component: Robert K. Heaton, PhD (PI), J. Hampton Atkinson, MD, Steven Paul Woods, PsyD, Matthew Dawson; Virology Component: Joseph K. Wong, MD (PI); Imaging Component: Christine Fennema-Notestine, PhD (CoPI), Michael J. Taylor, PhD (CoPI), Rebecca Theilmann, PhD; Data Management Unit: Anthony C. Gamst, PhD (PI), Clint Cushman,; Statistics Unit: Ian Abramson, PhD (PI), Florin Vaida, PhD; Protocol Coordinating Component: Thomas D. Marcotte, PhD (PI), Rodney von Jaeger, MPH; Johns Hopkins University Site: Justin McArthur (PI), Mary Smith; Mount Sinai School of Medicine Site: Susan Morgello, MD (CoPI) and David Simpson, MD (CoPI), Letty Mintz, NP; University of California, San Diego Site: J. Allen McCutchan, MD (PI), Will Toperoff, NP; University of Washington, Seattle Site: Ann Collier, MD (CoPI) and Christina Marra, MD (CoPI), Trudy Jones, MN, ARNP; University of Texas, Galveston Site: Benjamin Gelman, MD, PhD (PI), Eleanor Head, RN, BSN; and Washington University, St Louis Site: David Clifford, MD (PI), Muhammad Al-Lozi, MD, Mengesha Teshome, MD.
Conflicts of interest
The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) is supported by award N01 MH22005 from the National Institutes of Health.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Government.
1. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, Prats A, Negredo E, Garolera M, et al. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients
. AIDS Res Hum Retroviruses
2. Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al. The prevalence and incidence of neurocognitive impairment in the HAART era
3. Tozzi V, Balestra P, Lorenzini P, Bellagamba R, Galgani S, Corpolongo A, et al. Prevalence and risk factors for human immunodeficiency virus-associated neurocognitive impairment, 1996 to 2002: results from an urban observational cohort
. J Neurovirol
4. Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study
5. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders
6. Kalichman SC, Rompa D, Cage M. Reliability and validity of self-reported CD4 lymphocyte count and viral load test results in people living with HIV/AIDS
. Int J STD AIDS
7. Valcour V, Yee P, Williams AE, Shiramizu B, Watters M, Selnes O, et al. Lowest ever CD4 lymphocyte count (CD4 nadir) as a predictor of current cognitive and neurological status in human immunodeficiency virus type 1 infection--The Hawaii Aging with HIV Cohort
. J Neurovirol
8. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, et al. CHARTER GroupValidation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system
. Arch Neurol
Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
CD4 nadir; combination antiretroviral therapy; HIV-associated neurocognitive disorders; neurocognitive impairment