Introduction
Since the beginning of the HIV/AIDS epidemic, HIV-associated neurocognitive disorders (HAND) have been commonly observed in infected populations (American Academy of Neurology AIDS Task Force
1991; Antinori et al.
2007). These conditions, ranging from subtle neuropsychological impairments to profoundly disabling HIV-associated dementia, are more frequently seen in advanced stages of HIV disease (AIDS) but can occur even in individuals having medically asymptomatic HIV infection (CDC 1993 Stage A; Grant et al.
1987; Heaton et al.
1995; White et al.
1995). Moreover, HAND confers an increased risk for early mortality, independent of medical predictors (Ellis et al.
1997a; Mayeux et al.
1993), and often interferes significantly with cognitively demanding activities of daily living (e.g., employment, medication management, driving; Heaton et al.
2004b; Hinkin et al.
2004; Marcotte et al.
1999,
2004).
The availability of combination antiretroviral therapy (CART) since 1996 has successfully controlled HIV viremia and improved immune function in many treated, HIV-infected (HIV+) patients, leading to dramatic improvements in medical morbidity and life expectancy. Clear improvement in neurological outcomes in the era of CART also has been achieved, with a significant drop in the rate of frank HIV-associated dementia (Dore et al.
2003; Robertson et al.
2007; Sacktor et al.
2002). Pre-CART prevalence estimates were approximately 16% in AIDS cases (McArthur et al.
1993), whereas more recent estimates are less than 5% (Heaton et al.
2010). Further benefits of CART on the broader spectrum of HAND have been suggested by studies of neurocognitive change in HIV + groups initiating CART regimens. A recent review of 15 such studies indicated that 11 found some improvement in neurocognitive test performance after an average of 6 months on CART, although most studies had relatively small sample sizes and did not control for practice effects on repeated testing (Joska et al.
2010).
Unfortunately, however, beneficial effects of CART on neurologic manifestations of HIV infection, especially HAND, have been less than complete (McArthur and Brew.
2010). Neurocognitive responses to CART have been varied across individuals, and studies of HAND in treated patients have documented high persisting rates of mild-to-moderate neurocognitive impairment (NCI). For example, Robertson et al. (
2007) assembled data on 1,160 HIV + patients involved in 14 different clinical trials involving CART. All participants completed a brief neurocognitive battery at least 20 weeks after randomization to treatment; 921 participants completed a follow-up exam 48 weeks later. Prevalence of NCI was 39% at baseline. Although 44% of those with NCI at baseline appeared to show CART-related improvement at follow-up (performed within the “normal” range, but with no apparent correction for practice effect), 21% of participants who were NC normal at baseline experienced incident impairment at follow-up. As a result, the total rate of NCI at follow-up was not very different from that at baseline (34% vs. 39%). In another study of persisting NCI on CART, Tozzi et al. (
2007) followed 94 treated patients for a mean of 5 years (multiple assessments). All had NCI at baseline, and 63% showed persisting impairment; however, this could be an underestimate because, again, it is unclear whether or not they controlled for practice effects on the neurocognitive tests. A third recent study reported HAND in 69% of 200 HIV + patients who had maintained good virologic response (undetectable HIV RNA in plasma on CART) over a median of 48 months (Simioni et al.
2010).
Causes of continuing high rates of HAND in the CART era are uncertain, but multiple non-exclusive possibilities have been suggested: irreversible brain injury prior to initiating CART, incomplete viral suppression in the central nervous system (CNS) due to poor CNS penetration of some commonly used antiretroviral drugs and/or presence of drug-resistant viral strains, the possibility that even very low levels of viral replication in the CNS could result in neural injury or dysfunction due to prolonged exposure to inflammatory responses and neurotoxic viral proteins, possible neurotoxicity of antiretroviral therapy (ART) drugs, and exposure to other conditions that may affect cognition in long-term survivors, such as increased rates of metabolic abnormalities and associated vascular pathology or increased B-amyloid deposition in the brain.
In sum, although the most severe form of HAND, HIV-associated dementia, appears to be much less common in the era of CART, questions remain about any long-term benefit of CART with respect to milder forms of HAND. These abnormalities remain highly prevalent, and it is unclear whether their nature, pathophysiological mechanisms, and clinical predictors have changed. Optimal comparison of HAND across time requires consistent definitions and testing, substantial representative cohorts, and sufficient knowledge of context including non-HIV (comorbid) conditions to achieve informative analysis.
This study compares baseline neuropsychological (NP) and neuromedical findings of two large cohorts of HIV + and HIV − participants who were recruited and assessed as part of a long-range program of research coordinated by the UCSD HIV Neurobehavioral Research Center (HNRC). Through collaborations with multiple institutions (listed in the acknowledgements), we performed comparable neuromedical and neurocognitive examinations on 857 participants from the pre-CART era and 936 from the CART era. Participants were recruited through advertisements and outreach to various communities and health care providers. It should be noted that these were not referral populations (i.e., not weighted to persons suspected or known to have neurologic disease). An almost identical NP test battery covering seven ability domains was used to classify HAND according to recently published international guidelines (Antinori et al.
2007). In order to provide comparable exclusions and minimize the effects of comorbid conditions on NP results, potential participants in both cohorts were carefully screened and excluded if they had any history of significant non-HIV-related risks for cognitive impairment. Rates of HAND were compared across eras in subgroups that were stratified by HIV serostatus and clinical stage of infection (HIV − controls vs. CDC 1993 stages A, B, and C). (Although the 2008 CDC classification system has de-emphasized the distinction between historic, asymptomatic, and mildly symptomatic HIV disease, we included all three stages in the current analyses to provide links with earlier studies of HAND and because most of our participants had been classified before the new guidelines were published (Centers for Disease Control
2008).) Immunological and virological predictors of HAND also were assessed and compared across eras. Finally, to explore possible qualitative differences in neurobehavioral outcomes, we compared severity and patterns of impairment across the seven ability domains for HIV + participants from the two eras.
Discussion
In one of the few prior direct comparisons of HAND in the pre-CART (
n = 272) and CART (
n = 251) eras, Sacktor et al. (
2002) found no significant difference in prevalence rates of NCI in large but demographically very different cohorts of HIV + patients who were comparably screened for comorbidities. However, the high rates of observed impairment (74.3% vs. 76%) may have occurred because both cohorts were specifically selected for being at high risk for NCI (low CD4 cell counts and/or clinical evidence of impairment).
A second previous direct comparison of pre-CART (
n = 51) and CART (
n = 90) era groups was conducted by Cysique et al. (
2004) in Australia. These investigators studied demographically similar HIV + groups in the same university clinic, in which participants all had AIDS (i.e., CDC stage A3, B3, or C) and were carefully screened for comorbid conditions but were not selected based upon perceived risk for NCI. A slightly different test battery was used with the pre-CART and CART era participants, but the use of normative standards based upon demographically matched HIV-uninfected (HIV−) controls from each era helped assure comparability of impairment classifications. Rates of NCI in this study were much more typical of clinical populations selected only for having strict comorbidity exclusions and were similar for the pre-CART and CART groups (41% vs. 39%). Interestingly, NCI patterns differed between the two groups, suggesting that patterns of CNS pathology may have changed in the CART era (Joska et al.
2010).
The current study is most similar to that of Cysique et al. (
2004) in that we assembled groups of participants who were not selected for being at high risk for NCI from the two treatment eras. The test batteries and methods for classifying NCI also were somewhat different in the two studies, and yet rates of NCI were quite similar for participants with comparable disease stage (all HIV-infected participants in the Cysique et al. study had AIDS): pre-CART rates were 41.1% for the Cysique et al. study versus 37.4% in the current study, and CART era rates were 38.8% in the Cysique et al. study versus 38.5% in this study.
The current study extended the findings of prior NCI comparisons in the two HIV treatment eras by providing data from large, well-characterized samples of HIV − controls and HIV + participants across the full spectrum of HIV disease. We found that CART era participants with medically asymptomatic or minimally symptomatic disease histories actually had a higher NCI rate than their pre-CART counterparts. This was true despite the facts that more CART-era participants who had remained medically asymptomatic were receiving antiretroviral therapy and that, as a group, they had comparably mild degrees of current immunosuppression and were much more likely to have viral suppression in both plasma and CSF. Although they had significantly higher rates of lifetime substance use disorders and longer durations of infection, treatment era differences in these factors were present at all disease stages and were unrelated to NCI in the CART era cohort. We suggest that the most important difference between CDC-A participants in the two eras that may have contributed to their different NCI rates is that participants in the CART era had much lower nadir CD4 cell counts. The era difference in nadir degree of immunosuppression (nadir CD4) is much larger for CDC-A than for the other disease stages, and low nadir CD4 was a robust predictor of NCI in both treatment eras. In fact, our finding regarding the importance of a low nadir CD4 as a risk for HAND has been reported now in multiple large studies in the USA ( Heaton et al.
2009; Robertson et al.
2007) and other countries (Cysique et al.
2009; Munoz-Moreno et al.
2008; Tozzi et al.
2005).
The fact that NCI was associated with being on ART only in the CART era raises the question of whether some of the newer ARV medications may have toxic effects on the CNS. Although this possibility cannot be ruled out and deserves further study, it cannot be adequately evaluated in a cross-sectional study because clinical decisions about when to initiate treatment are based upon indicators of disease severity (nadir CD4 and medical symptoms) that themselves are risks for NCI. In any event, the increased rate of NCI among CART era (vs. Pre-CART) participants who were medically asymptomatic (CDC stage A) cannot be explained by neurotoxic effects of ARVs because NCI was not significantly related to treatment status in these individuals.
There were intriguing shifts between pre-CART and CART eras when we focus on more severe NCI (i.e., those meeting Frascati neurocognitive criteria for HAD; Antinori et al.
2007). Whereas in CDC stage C disease, the rate of HAD level NCI in the CART era was less than half that of the pre-CART era (6.9% vs. 16.7%,
p < 0.01; Table
1), the rate of more severe NCI was actually higher in the CART era at CDC stage A (7.1% versus 3.6%,
p < 0.05). It is possible that the fact that CART era CDC stage As had a greater likelihood of experiencing prior CD4 < 200, plus their longer survival with chronic immune stimulation might be playing a role in increasing their risk for evolving brain (neurological) complications.
Prior studies in both pre-CART and CART eras have demonstrated associations between NCI and HIV RNA levels in the periphery (Childs et al.
1999; Ferrando et al.
1998; Nath et al.
2008) as well as in the CSF (Brew et al.
1997; Cysique et al.
2009; Ellis et al
1997b; Letendre et al.
2004; McArthur et al.
1997). However, recent reports indicate that viral suppression on treatment is not sufficient to avoid development or persistence of NCI (Marra et al.
2009; Simioni et al.
2010). Prior analyses of data from the current CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort (from which our CART era cases were drawn) suggested that the best neurocognitive outcomes may be associated with a combination of successful viral response to CART and absence of historical severe immunosuppression (nadir CD4 < 200; Heaton et al.
2010). In the present study, treated subgroups from neither era demonstrated an association between NCI and viral suppression in plasma; however, non-detectable virus in CSF was a positive indicator of normal cognitive function in the pre-CART subgroup only. Our findings support other observations that certain biomarkers of CNS disease that seemed promising in the pre-CART era (e.g., CSF viral load) are not so useful in the CART era (Cysique et al.
2005).
Both our study and the Cysique 2004 study found treatment era differences in pattern of NCI that might be consistent with a shift toward more cortical (vs. subcortical and white matter) involvement in the CART era. A problem with interpreting these differences as reflecting a shift toward greater cortical pathology is that the test battery is not specifically designed to detect such distinctions (e.g., more coverage of language and visuospatial functions would be desirable). Whether such differences in pattern of NCI are truly related to differences in type or distribution of HIV-related brain injury will require correlative work with studies that also employ neuroimaging or postmortem neuropathological analyses.
The limitations of this study include the fact that we cannot rule out cohort differences in this study that are unrelated to HIV or its treatment, especially given the demographic and HIV risk background differences in these samples, which mirror differences in the US epidemic over time (Centers for Disease Control and Prevention
1992,
1994,
1996,
2000,
2004,
2008). However, we attempted to adjust for demographic effects on neurocognitive test performances by using the same age-, education-, gender-, and ethnicity-corrected normative standards. Also, other than a trivial age difference between impaired and unimpaired participants (statistically significant only in pre-CART), none of these demographic variables related to NCI. Similarly, none of the lifetime or current psychiatric disorders assessed here (MDD and alcohol or other substance use disorders) were consistently related to NCI across treatment eras nor was the risk factor of “any IDU history” (per selection criteria, this was not current and not complicated by associated significant overdoses or traumatic brain injuries). Although HIV infection risk backgrounds also differed between treatment era cohorts, these were unrelated to NCI in the pre-CART era; in the CART era cohort, having “only heterosexual contact” was the sole reported HIV risk factor associated with a higher rate of NCI.
NCI was classified and characterized in our two treatment era cohorts using a largely overlapping test battery (11 of 14 individual test measures were the same) covering the same seven ability constructs and using the same standardized methods consistent with recently published guidelines for diagnosing HAND (Antinori et al.
2007). However, three of the individual test measures did differ and helped to measure attention/working memory, processing speed, and executive functioning in somewhat different ways. On the other hand, each of these ability domains had at least one common test measure across eras. To keep the assessments as comprehensive as possible, we elected to include the three substitute tests in the main analyses reported here; however, when we excluded these measures, rates of NCI did not change significantly across HIV serostatus and disease stage subgroups.
HIV viral loads in plasma and CSF were neither available nor standard of care throughout much of the pre-CART era and were not assayed in our research program until the later part of that era. Also, the limit of detectability was higher in these earlier assays (400 vs. 50 copies per milliliter in the CART era studies). As a consequence, we had very limited viremia and CSF viral load data for the pre-CART HIV + cohort, and an “undetectable” finding did not necessarily mean the same thing across treatment eras. Nevertheless, the availability of these determinations for pre-CART participants was linked only to timing of the assessments (no other selection bias). Also, to permit at least preliminary treatment era comparisons involving viral suppression on treatment, we retrieved and analyzed all available stored samples on pre-CART participants to obtain total sample sizes of 110 (55 each for plasma and CSF) with NCI and 176 (85 for plasma and 91 for CSF) without NCI. Impairment rates were similar for the pre-CART participants with and without viral load determinations, suggesting that the subgroups with viral load data were fairly representative. The main finding of a pre-CART association between NCI and failure of CSF viral suppression on treatment was statistically significant despite the reduced sample size (total N = 138) for this analysis.
In sum, we found high rates of NCI in large HIV + cohorts tested in the pre-CART and CART eras. The only significant treatment era difference was in the medically asymptomatic stage, in which a higher rate and severity of impairment was seen in the CART era participants. The latter CART era subgroup also had the largest discrepancy (relative to their pre-CART counterparts) in nadir CD4 cell counts. Due to the major degree of immune reconstitution and viral suppression seen with the CART-treated participants, current CD4s and viral loads were no longer significant indicators of risk for NCI. The fact that low nadir CD4 was a similarly robust predictor of impairment in both eras is consistent with the view that early severe immunosuppression may initiate at least partially irreversible changes in the CNS and that earlier treatment aimed at protecting patients from these processes may improve CNS outcomes (Heaton et al.
2010). In view of the persisting high rates of NCI in the CART era, especially in HIV + individuals with a history of low nadir CD4s, clinical trials are needed to assess the value of initiating treatment in neurocognitively normal persons before they become markedly immunosuppressed. This type of longitudinal study, in which treatment is not linked to evidence of advancing disease, also may provide the most interpretable information about potentially neurotoxic effects of ARVs.
Acknowledgments
The CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is supported by award N01 MH22005 from the National Institutes of Health.
The CNS HIV Antiretroviral 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; and Washington University, St. Louis, and is headquartered at the University of California, San Diego, and includes Director: Igor Grant, M.D.; Co-directors: J. Allen McCutchan, M.D., Ronald J. Ellis, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D., Terry Alexander, R.N.; Laboratory, Pharmacology, and Immunology Component: Scott Letendre, M.D. (P.I.), Edmund Capparelli, Pharm.D.; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Steven Paul Woods, Psy.D., Matthew Dawson; Virology Component: Joseph K. Wong, M.D. (P.I.); Imaging Component: Christine Fennema-Notestine, Ph.D. (P.I.), Terry L., Jernigan, Ph.D., Michael J. Taylor, Ph.D., Rebecca Theilmann, Ph.D.; Data Management Unit: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman,; Statistics Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Protocol Coordinating Component: Thomas D. Marcotte, Ph.D. (P.I.), Rodney von Jaeger, M.P.H.; Johns Hopkins University Site: Justin McArthur (P.I.), Mary Smith; Mount Sinai School of Medicine Site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P.; University of California, San Diego Site: J. Allen McCutchan, M.D. (P.I.), Will Toperoff, N.P.; University of Washington, Seattle Site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Trudy Jones, M.N., A.R.N.P.; University of Texas, Galveston Site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N.; and Washington University, St. Louis Site: David Clifford, M.D. (P.I.), Muhammad Al-Lozi, M.D., Mengesha Teshome, M.D.
The San Diego HIV Neurobehavioral Research Center (HNRC) group is affiliated with the University of California, San Diego; the Naval Hospital, San Diego; and the Veterans Affairs San Diego Healthcare System and includes: Director: Igor Grant, M.D.; Co-Directors: J. Hampton Atkinson, M.D., Ronald J. Ellis, M.D., Ph.D., and J. Allen McCutchan, M.D.; Center Manager: Thomas D. Marcotte, Ph.D.; Jennifer Marquie-Beck, M.P.H.; Melanie Sherman; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D., Scott Letendre, M.D., Edmund Capparelli, Pharm.D., Rachel Schrier, Ph.D., Terry Alexander, R.N., Debra Rosario, M.P.H., Shannon LeBlanc; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), Steven Paul Woods, Psy.D., Mariana Cherner, Ph.D., David J. Moore, Ph.D., Matthew Dawson; Neuroimaging Component: Terry Jernigan, Ph.D. (P.I.), Christine Fennema-Notestine, Ph.D., Sarah L. Archibald, M.A., John Hesselink, M.D., Jacopo Annese, Ph.D., Michael J. Taylor, Ph.D.; Neurobiology Component: Eliezer Masliah, M.D. (P.I.), Cristian Achim, M.D., Ph.D., Ian Everall, FRCPsych., FRCPath., Ph.D. (Consultant); Neurovirology Component: Douglas Richman, M.D. (P.I.), David M. Smith, M.D.; International Component: J. Allen McCutchan, M.D. (P.I.); Developmental Component: Cristian Achim, M.D., Ph.D. (P.I.), Stuart Lipton, M.D., Ph.D.; Participant Accrual and Retention Unit: J. Hampton Atkinson, M.D. (P.I.), Rodney von Jaeger, M.P.H.; Data Management Unit: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman (Data Systems Manager); Statistics Unit: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D., Reena Deutsch, Ph.D., Anya Umlauf, M.S., Tanya Wolfson, M.A.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government.