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Disparities in Study Findings on Neurologic Function in HIV
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"Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons"
- full text below following this list of links to recently reported studies finding what I would call somewhat discrepant results
Neurology Jan 2013......Nancy F. Crum-Cianflone, David J. Moore, Scott Letendre, et al.
This study finds: "Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons......the prevalence of NCI among our HIV-infected participants was not significantly greater than a matched HIV-uninfected group.....matched HIV-uninfected (HIV-) military beneficiaries......NCI was diagnosed among 38 (19%, 95% confidence interval 14%-25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV- patients." and authors Conclude: "HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment."
from Jules: Immediately below are links to studies finding neurologic abnormalities in early HIV infection, immediately post infection & early thereafter. This study published in January 2013 in Neurology reports neurocognitive impairment was 19% in HIV+ on HAART & "Fifteen of the HIV-uninfected participants (30%, 95% CI 17%-43%) had NCI (figure). The percentage with NCI among HIV-infected vs HIV-uninfected persons was not statistically significantly different (p = 0.09)." Perhaps the numbers of participants in the study were too small to detect a statistically significant difference between 19% vs 30%, the HIV-negative comparison group were "military beneficiaries so perhaps that is not really a good comparison group. But for me it is disturbing the disparities between these findings of this studies & previous ones & the inconclusiveness of not being able to understand how HIV affects clinically & in real life patients & the affect of HAART. WE spend hundreds of millions of dollars on HIV research & we can't answer this & frankly some other questions very well, is rather disconcerting.
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Risk of Stage 1 AIDS Dementia 12% Over 2 Years in Asymptomatic People (CROI 2011)
http://www.natap.org/2011/CROI/croi_128.htm
The investigators stressed that nadir CD4 count before antiretroviral therapy begins is significantly associated with persistent injury and neurocognitive impairment. They argued that their findings underline the need for routine central nervous system monitoring in people with HIV and the need to begin antiretroviral therapy at earlier stages of HIV infection.
HIV Affects Brain Immediately After Infection with HIV RNA in the CSF & Inflammation & Brain Injury Continues Unfolding During Chronic Infection & There is a Need for Routine Monitoring (CROI 2011)
http://www.natap.org/2011/CROI/croi_123.htm
"Acute HIV infection is associated with detectable virus in CSF as early as 5 days post exposure. CSF HIV RNA was detected in 13/16 subjects with the 3 undetectable cases equally distributed in F-I, F-II, and F-III. CSF HIV RNA was detected as early as 5 days post estimated exposure. CNS inflammatory markers are noted early as detected by CSF cytokines and MRS metabolites. The CSF cytokine pattern may differ from that in plasma during acute infection........The Chicago Early HIV Infection Cohort was established to evaluate the presence and extent of brain injury within approximately the first year of infection.....Conclusions: This intensive brain volumetric analysis finds loss of gray matter early in the course of infection......
The 2nd study looks at patients within the first year of HIV-infection and looked at the 2-month timepoint and found damage: "intensive volumetric analysis finds consistent pattern of loss of brain gray matter early in the clinical course of HIV-infection......We evaluated 43 HIV seropositive......The window period since infection ranged from 0.205 (<70 days) to 80.5, and was estimated to average <1 year in this sample: 20 HIV+ subjects were HAART naive......Brain gray matter was significantly reduced in the HIV group (p = 0.05). Further examination indicated reductions in left (p = 0.02) and right (p = 0.04) cerebral cortex, and significant enlargement of the third ventricle (p = 0.04).""
Brain tCho/Cr is Elevated in Acute HIV within the First Month of Infection: 'brain inflammation in acute infection/immediate HAART may normalize or improve inflammation or perhaps prevent damage'......(CROI 2012)
http://www.natap.org/2012/CROI/croi_158.htm
The patients in this cohort have been infected for less than a month.....inflammation is present in the brain the first days after HIV infection as evidenced by elevated choline.creatine, an indication of relative immune cellular infiltration.....All were treated with HAART immediately upon identification and the choline normalized. This likely means that cellular infiltration is reduced or stopped......So, this appears to be evidence for the brain (not just the CSF) to be abnormal within weeks of HIV infection by alterations in choline within brain tissue during the first month after infection, and this appears to be controlled with immediate institution of HAART. Whether this has a long-term impact on preservation of brain in not known (authors are trying to figure this out). Unfortunately, even if it does, it is not terribly practical to apply, since it is very hard to identify HIV so early on a public health basis, but it does help to understand the timing of brain involvement and recognize that the brain is a common early target.
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Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons
Neurology Jan 2013
"Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons This study described the prevalence of neurocognitive impairment among 200 HIV-infected (HIV1) patients and 50 HIV-negative controls. HIV 1 patients diagnosed and managed early during the course of HIV infection had a lower prevalence of neurocognitive impairment. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment......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."
"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."
"Of the 200 HIV-infected participants, 100 were classified as earlier stage (<6 years of HIV infection since diagnosis, no prior AIDS-defining condition, and CD4 nadir >200 cells/mm3), and 100 as later stage (not meeting all 3 criteria). 91% were documented HIV seroconverters with a median seroconversion window of 1.2 years. The study population consisted of a population with low prevalence of substance use-18% used tobacco, 5.5% consumed ≥6 alcoholic drinks per week, and 3.5% used illicit drugs.HIV+ patients had a median age of 36 years. A control group of military beneficiaries (n = 50) were matched to the HIV-infected subjects by age (<35 vs 35-50 years), gender, race/ethnicity (Caucasian vs other), and rank (officer vs enlisted vs other including retirees and spouses)."
"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."
"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."
Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons
Neurology Jan 2013
Nancy F. Crum-Cianflone, David J. Moore, Scott Letendre, et al.
Abstract
Objective: To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls.
Methods: We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV-) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm3) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests.
Results: HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm3, and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm3). NCI was diagnosed among 38 (19%, 95% confidence interval 14%-25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV- patients.
Conclusions: HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.
GLOSSARY
BDI=Beck Depression Inventory;
CI=confidence interval;
GDS=Global Deficit Score;
HAART=highly active antiretroviral therapy;
HCV=hepatitis C virus;
IQR=interquartile range;
NCI=neurocognitive impairment;
OR=odds ratio
Despite the availability of highly active antiretroviral therapy (HAART), HIV-infected persons remain at risk for neurocognitive impairment (NCI).1 Although severe forms of neurologic disease (e.g., HIV-associated dementia) have declined, the risk of other forms of NCI remains elevated compared to the general population.1,-,4 The burden of NCI among HIV-infected persons remains substantial, occurring in approximately half (range 18%-73%) of patients.1,5,-,7
Since most studies have evaluated HIV-positive patients with unknown dates of HIV seroconversion and 35%-45% of newly diagnosed HIV-positive patients in the United States meet AIDS-defining criteria within 1 year of diagnosis,8 elevated rates of NCI may result from late diagnosis and uninhibited viral replication in the CNS causing irreversible brain injury prior to diagnosis or initiation of therapy. A history of AIDS and low nadir CD4 counts has been associated with NCI.1,2,9 However, few studies have determined the rate of NCI among HIV-positive patients managed in an optimized setting of early diagnosis, free access to care, and few concurrent comorbidities.
We determined the prevalence of NCI among US military HIV-infected persons who have routine HIV testing, mandatory follow-up evaluations after diagnosis, open access to early antiretroviral treatment, and low rates of comorbidities including active substance use. We assessed the prevalence of neurocognitive impairment evaluating HIV-positive patients both earlier (i.e., <6 years of HIV infection since diagnosis, no AIDS-defining condition, and CD4 nadir >200 cells/mm3) and later in the course of HIV infection, and compared these participants with a matched HIV-uninfected group of military beneficiaries.
Study design and participants
We performed a cross-sectional study among 200 HIV-infected and 50 HIV-uninfected military beneficiaries (active duty members, retirees, or dependents). All active duty members, including those in this analysis, are HIV seronegative upon entry into military service and undergo repeated mandatory HIV testing. Active duty members who become HIV-positive are evaluated by an HIV specialist at least semiannually, and all military beneficiaries have open access to early antiretroviral treatment and low rates of comorbidities including active substance use.
Of the 200 HIV-infected participants, 100 were classified as earlier stage (<6 years of HIV infection since diagnosis, no prior AIDS-defining condition, and CD4 nadir >200 cells/mm3), and 100 as later stage (not meeting all 3 criteria). A control group of military beneficiaries (n = 50) were matched to the HIV-infected subjects by age (<35 vs 35-50 years), gender, race/ethnicity (Caucasian vs other), and rank (officer vs enlisted vs other including retirees and spouses). Inclusion criteria for both HIV-infected and HIV-uninfected groups included military beneficiaries who were 18-50 years of age. Exclusion criteria were current/recent suicidal ideation, inability or unwillingness to complete the neuropsychological battery, and presence of an acute medical condition that could impact the participant's ability to complete the tests (e.g., febrile illness). The control group had an HIV-negative ELISA test within 1 year of study enrollment.
RESULTS
Study population
Two hundred HIV-infected persons were studied (table 1); 91% were documented HIV seroconverters with a median seroconversion window of 1.2 years. The study population consisted of a population with low prevalence of substance use-18% used tobacco, 5.5% consumed ≥6 alcoholic drinks per week, and 3.5% used illicit drugs. Sixty-four percent were receiving HAART, which was initiated a median of 1.3 years after HIV diagnosis at a median CD4 count of 333 (IQR 248-423) cells/mm3; 81% had a HIV RNA <50 copies/mL at the time of enrollment. Among those off HAART, their median CD4 count was 523 (IQR 417-685) cells/mm3. Characteristics by earlier vs later stage HIV-infected persons are shown in table 1. The HIV-negative control group (n = 50) was similar to the HIV-infected group except they were less likely to be African American and more likely to be "other" races, less likely to have a higher education degree, and less likely to have hypertension (table 1).
Prevalence of NCI among HIV-infected persons
NCI (GDS ≥ 0.5) was diagnosed among 38 (19%, 95% CI 14%-25%) HIV-infected participants. The prevalence of NCI was similar among earlier and later stage patients (18% vs 20%, p = 0.72). Later stage patients were more likely to have impairments in verbal fluency, learning, and recall, although none were statistically different from earlier stage patients (figure). The number of domains in which participants were impaired was also similar between earlier and later stage HIV participants (earlier 1.27 and later 1.31, p = 0.84).
We evaluated the association between self-reported cognitive problems ("Do you feel that you have a problem with memory loss or cognitive functioning?") and battery-identified NCI and found no relationship of self-reported cognitive complaints with NCI (OR 1.3, p = 0.53) or with the mean GDS (p = 0.44). Among the 55 participants who complained of cognitive issues, 12 (22%) had NCI, whereas 26 (18%) of those who did not complain of cognitive issues had NCI (p = 0.53). Those with symptoms of depression (BDI ≥ 20) were more likely to self-report cognitive dysfunction compared to those without depression (73% vs 24%, p < 0.001); however, there was no association of depression with NCI or with GDS.
Prevalence of NCI among HIV-uninfected persons
Fifteen of the HIV-uninfected participants (30%, 95% CI 17%-43%) had NCI (figure). The percentage with NCI among HIV-infected vs HIV-uninfected persons was not statistically significantly different (p = 0.09). HIV-infected persons had elevated rates of impairment in speed of information processing, attention/working memory, and recall, but none were significantly different from HIV-uninfected persons (all p values > 0.05). HIV-uninfected participants were more likely to have impairment in learning than HIV-infected persons (p = 0.01) (figure). Additional models adjusting for years of education and ethnicity compared HIV-infected to HIV-uninfected participants for the outcomes of NCI and each domain, separately, showed similar nonsignificant findings.
Factors associated with neurocognitive impairment among HIV-infected persons
Factors associated with NCI among HIV-infected participants in the univariate models are shown in table 2. No demographic, behavioral, or medical history variable was significantly associated with NCI. A higher number of years of education was associated with NCI (OR 1.2 per year, p = 0.02). Regarding HIV-specific factors, a higher current CD4 count (OR 1.07 per 50 cells/mm3, p = 0.08) and higher CD4 recovery (OR 1.07 per 50 cells/mm3, p = 0.10) were marginally associated with NCI (table 2).
In a multivariate model including factors of interest (age, gender, race, years HIV seropositive, and cumulative years on antiretroviral therapy) and univariate factors with a p value ≤0.15, only more years of education was associated with NCI (OR 1.24 per year, p = 0.02). Current CD4 count continued to have a marginal association with NCI (OR 1.07, p = 0.07); no association was found with either CD4 nadir or CD4 recovery. Analyses were also performed stratified by earlier vs later stage and for each neurocognitive domain with similar findings (data not shown).
We repeated our analyses restricted to HIV-infected participants receiving HAART who had an HIV RNA level <50 copies/mL. Similar associations were noted with additional findings that higher CD4 cell counts (OR 1.10 per 50 cells/mm3, p = 0.04) and greater CD4 recovery (OR 1.15 per 50 cells/mm3, p = 0.01) were significantly associated with NCI. The nadir CD4 count, HIV RNA level, and HAART information were not associated with NCI (data not shown).
DISCUSSION
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.
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