We found a low prevalence of NCI among HIV-infected persons diagnosed and managed early during the course of HIV infection, and nearly identical NCI rates among earlier and later HIV-infected patients in this cohort. Of note, most patients classified as later in their course of HIV infection met criteria by a longer duration of HIV infection, but the majority had preserved CD4 counts and few had prior AIDS-defining conditions. Further, the prevalence of NCI among our HIV-infected participants was not significantly greater than a matched HIV-uninfected group. These data provide important and novel information suggesting that the early recognition and management of HIV infection may be important in limiting NCI.
The importance of preventing NCI is severalfold as it impacts both the quantity and quality of life. Regarding survival, HIV-infected patients with NCI are at increased risk of death, even after controlling for other medical factors.3,19
Further, NCI can have a substantial impact on patients' daily functioning and their ability to pursue career endeavors.20
Finally, NCI may reduce antiretroviral adherence, hence adversely affecting the outcome of HIV-infected persons.17
Hence, preserving cognitive function among HIV-infected persons may be an important step in further improving quality and life expectancies of patients.
During the pre-HAART era, 16% of patients with AIDS had HIV dementia, with an annual incidence of 7%.21
After the introduction of HAART in 1996, there was a sharp decrease in HIV dementia; however, milder forms of neurocognitive disease continued to be diagnosed.4,22
Studies demonstrated that patients with symptomatic seroconverting illness as well as high HIV RNA levels and low CD4 counts early after infection were at highest risk.23,24
The prevalence of NCI in the HAART era has varied in prior studies, likely related to clinical disease stage, comorbid diseases, and other factors.6,7
A recent study found a NCI prevalence of 52% among HIV-infected patients seen at academic US HIV clinics regardless of comorbidity level.1
Our study found a much lower NCI rate (19%), but was similar to a recent study evaluating HIV-infected persons with suppressed HIV RNA levels.25
The relatively low prevalence in our study may be due to a combination of factors. Early diagnosis and active disease management, few comorbid conditions (low prevalence of concurrent medical conditions including HCV, illicit drug use, and alcohol), young age, frequent monitoring of vocational functioning, and the lack of AIDS events or low CD4 counts likely contributed to our low impairment rate. Further, despite the later group having HIV for a median of 11 years, their risk of NCI remained similar to the earlier group (median 2 years). This suggests that length of HIV duration itself may not be a risk factor if patients maintain good HIV control, avoiding AIDS-defining events and low nadir CD4 counts.6
In our study, HIV-infected persons had a similar prevalence of NCI compared to matched HIV-uninfected persons. Further, HIV-infected patients were not more likely to be impaired in any of the 7 cognitive domains. A recent Danish study found the overall risk of severe neurocognitive disorders is now similar among HIV-positive and -negative persons.3
It should be noted that the HIV-negative controls in this study are likely to be an accurate control population relative to prior studies, as the military is relatively homogeneous in regards to socioeconomic status, lifestyle, and other factors such as substance abuse.
Early events in HIV infection such as loss of vital CD4 reserves and uncontrolled HIV replication may trigger irreversible CNS damage and may cause the "residual" NCI seen in long-term survivors. Prospective studies are needed to determine if early diagnosis and initiation of antiretroviral therapy would reduce the burden of NCI among HIV-infected persons.26
A recent study showed that patients with early HIV infection had similar neurocognitive functioning compared to HIV-uninfected persons, suggesting that detrimental effects of HIV on the brain may not occur immediately, potentially providing an opportunity for early intervention.27
Clinical trials are underway, including a substudy of the Strategic Timing of Antiretroviral Treatment (START) trial, examining neurocognitive functioning among those treated immediately compared to later in their disease course.
We did not detect strong associations between immunologic or virologic control and the presence of NCI. A low CD4 nadir was not associated with NCI as seen in other studies1,2,7,9
including a recent study which suggested that these factors may lead to structural brain damage.28
Our lack of association may reflect that few of our patients experienced very low CD4 nadirs, or that CD4 nadirs are not predictive in persons who are managed early in infection and who avoid reaching very low counts (<200 cells/mm3
). Regarding current HIV counts, we noted a marginal association between higher current CD4 counts and CD4 recovery with NCI. Interestingly, when restricting our analyses to participants receiving HAART with a HIV RNA <50 copies/mL, these associations became stronger. We examined the association of PI use (which may result in higher CD4 counts, but has limited CNS penetration) and found no associations between specific antiretroviral class and NCI. These data suggest a possible immunologic component, such as immune reconstitution inflammatory syndrome–like reaction, in the pathogenesis of NCI; further studies are needed. Finally, we found no associations between HAART use and NCI. Although prior studies have shown that cognition improves shortly after HAART initiation,5,29
our data suggest that NCI may persist despite ongoing HAART use, signifying that chronic neuronal inflammation and injury may continue. Since the benefit of HAART is incomplete,30,31
strategies to prevent the initial development of NCI are paramount.
The prevalence of NCI among our HIV-uninfected persons was higher than expected with the estimated rate in the general population of 16%.32
Although the reasons for this are unknown, it may have been due to self-selection bias as this group was enrolled from different settings (military bases) than the HIV-positive group (within HIV clinics). There were also differences in education and ethnicity, which may have contributed to the observed differences. The HIV-infected group had a reasonable proportion of individuals with higher degrees (e.g., Master, PhD, MD), whereas only one individual in our HIV-uninfected group had a higher degree. It may be that the more highly educated subjects in our HIV-infected group have greater levels of cognitive reserve, making declines due to HIV infection less likely. Moreover, our normative data adjust for African American and Caucasian ethnicities; the higher proportion of Hispanic and “other” ethnicities in our HIV-uninfected group may not have been appropriately corrected for among the HIV-uninfected group, leading to higher rates of NCI.
Our study had some limitations. We conducted a cross-sectional study, hence could not assess temporality or causation between factors of interest and the development of NCI. Furthermore, the low prevalence of NCI may have limited our ability to identify associated factors. We also evaluated a distinct population consisting of military members who may differ from other HIV-infected populations; however, our data provide important information about NCI in an optimized setting of early diagnosis, comprehensive medical care, stable socioeconomic factors, and few comorbidities (e.g., illicit drug use, HCV). Further, our data provide important information about the cognitive functioning of HIV-positive military personnel, and suggest that rather than disqualifying all seropositive members from performing certain occupations (e.g., aviators) due to concerns of NCI, it may be more prudent to perform neurocognitive testing in these groups.33
Additionally, our study advocates for formal neurocognitive testing as self-reports of neurocognitive complications were more strongly related to depressed mood than cognitive functioning. Since we evaluated a US military population consisting of mostly men, our study cannot be generalized to women. Finally, the main objective of the study was to determine the prevalence of NCI among HIV-infected persons, and it was not specifically powered for comparisons to the HIV-uninfected arm.
HIV-infected persons diagnosed and managed early in infection have low rates of NCI, which are comparable to those of HIV-uninfected persons. Patients with longstanding HIV infection (median >10 years) had similar NCI rates compared to those with more recent infection, suggesting that early management and avoidance of comorbid conditions may be important in preserving cognitive function.