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Presence of Neurocognitive Impairment Requires More Potent HAART & Special Considerations
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"Neurocognitive Impairment and Survival in a Cohort of HIV-Infected Patients Treated with HAART"
AIDS Research and Human Retroviruses
Aug 2005, Vol. 21, No. 8: 706-713
Valerio Tozzi
National Institute for Infectious Diseases Lazzaro Spallanzani, 00149 Rome, Italy. Et al
The study primary objective was to determine whether the presence of cognitive impairment, including the milder forms not associated with appreciable symptomatic or functional impact, had an impact on mortality in patients receiving HAART.
ED NOTE from Jules Levin. In this study HIV+ patients with NCI (neurological impairment) were more likely to have HCV suggesting as many studies have found that HCV contributes to cognitive impairment. The study finds patients with NCI were less likely to achieve viral suppression <50 copies/ml, had higher viral levels when not virally suppressed, & had a 3-fold higher risk of death. The study findings suggest patients should be clinically evaluated early for NCI and should receive the most potent HAART regimen & receive other considerations in trying to make sure they achieve & sustain <50 copies/ml of HIV. Studies suggest patients with cognitive impairment have lower adherence rates, which of course affect ability to achieve & sustain undetectable HIV. If you can identify who has NCI you can provide additional adherence tools. ......"our findings highlight the importance of fully suppressive antiretroviral therapy in patients with HIV-related
NCI.....since virological failure is common in clinical practice, being reported in 30-70% of patients, the assessment of cognitive function should be used in routine practice not only for its potential to reveal HIV-related CNS damage, but also for its association with reduced survival in a relevant proportion of patients: those with persistent viremia despite HAART. Finally, our results highlight the clinical relevance of HIV-related CNS involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective."
"....Patients with neurocognitive impairment (NCI) were more frequently men and intravenous drug users, they tended to be older and less educated, they had a lower baseline CD4 cell count and a more advanced HIV disease stage, and, finally, they showed a higher prevalence of positive HCV serology....
.....durable virological suppression under HAART was achieved by 119 out of 188 unimpaired patients (63.3%) and by 111 out of 224 impaired patients 49.6% (p=0.007). Among the 166 patients that started HAART after the NP examination, a significant difference between impaired and unimpaired patients was seen after 12 months of HAART. The proportion of patients with plasma HIV RNA below 50 copies/ml at month 12 was 27% (16 of 58) in impaired patients and 51.9% (28 of 54) in unimpaired subjects (p=0.012). Moreover, impaired patients showed higher plasma HIV RNA levels when compared with unimpaired subjects (p=0.001)....
..... After 84 months of observation, the estimated survival proportions in unpaired or unimpaired patients were 68.5% and 84.9%, respectively (p=0.001)......
..... At multivariate analysis, among patients who failed to achieve or to maintain virological suppression during HAART, those with NCI had a nearly 3-fold higher risk of death than unimpaired ones (HR 2.9, 95% CI: 1.2-7.1).....
..... Consistent with previous observations, that showed an association between systemic virological suppression and neuropsychological performance, in our study population NCI was also associated with virological failure to HAART..... Patients with NCI were both more likely to experience a virological failure and had a significantly poorer virological response at month 12 of HAART. Moreover, in agreement with previous studies, virological failure was strongly associated with reduced survival....
..... It is possible that NCI could influence survival in patients failing HAART through several mechanisms......impaired patients might die sooner because
of less effective use of potent, but complex, current antiretroviral regimens.....adherence..... It is also possible that HIV disease might progress more rapidly in patients with NCI as a consequence of an increased and independent viral replication in the neurological compartment."
SUMMARY
Before the introduction of HAART, HIV-associated neurocognitive impairment (NCI) was recognized as an independent risk factor for death. Since 1996, we conducted a prospective study to assess whether NCI still represents a negative prognostic factor for mortality. Patients were administered measures of neurocognitive function (a battery of 17 neuropsychological tests), clinical and neurological evaluation, laboratory testing, and brain imaging studies.
Subjects for this analysis were enrolled at the National Institute for Infectious Diseases Lazzaro Spallanzani (Rome, Italy). Since 1996, 456 consecutive HIV-positive patients were screened for the presence of NCI. The study was conducted in the context of usual clinical care according to an internal protocol
approved by the local Ethics Committee. Patients were eligible if they had either symptoms of suspected NCI or symptomatic HIV infection and/or CD4 cell
count below 300/ l. Patients with opportunistic infections or tumors of the CNS
(n =9), with non-HIV-related major neurological or psychiatric disorders (n =10), or those using illicit drugs or sedative-hypnotics or opioid-analgesics (n 25) were excluded. The 412 remaining patients were referred for neuropsychological
(NP) evaluation. The day of completing the NP examination was considered the day of enrollment into the study. After enrollment the 412 patients were prospectively evaluated and they represent this study group.
Among the 412 enrolled patients, 224 (54.4%) were neurocognitively impaired and 188 (45.6%) were neurocognitively unimpaired. A durable virological suppression under highly active antiretroviral therapy (HAART) was achieved by 63.3% of unimpaired patients and by 49.6% of impaired patients (p = 0.007).
Overall, 47 deaths were recorded, 38 among impaired and 9 among unimpaired patients. At 84 months, the estimated survival proportions in impaired and unimpaired patients were 68.5% and 84.9%, respectively (p < 0.001). At univariate analysis the virological response to HAART was the variable most strongly associated with survival, since patients with virological failure had a nearly 10-fold increased risk of death than those with durable virological suppression (HR = 9.9, 95% CI: 3.9-25.0).
After stratification for virological response to HAART, an increased risk of death for neurocognitively impaired patients was seen only among the 182 patients with virological failure (HR: 2.9, 95% CI: 1.2-7.1), while the survival probability of the 230 patients with durable virological suppression was not affected by neurocognitive impairment (p = 0.89).
Our results highlight the clinical relevance of HIV-related central nervous system (CNS) involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective.
INTRODUCTION
HIV-1 INFECTION CAN BE COMPLICATED BY NEUROCOGNITIVE
IMPAIRMENT (NCI), associated with central nervous system (CNS) involvement by HIV itself, characterized by cognitive slowing, impairment of memory and attention, disturbances in processing speed, and behavioral manifestations.1 The most severe form of HIV-related NCI is HIV-1-associated dementia (HIV-D) that, before the introduction of highly active antiretroviral therapy (HAART) as a standard of care, developed in more than 20% of HIV-infected patients.
In addition to HIV-D, some patients may develop less severe forms of NCI,
either a subclinical impairment or a mild impairment interfering, at least mildly, with day-to-day functioning, known as minor cognitive motor disorder (MCMD).
The introduction of HAART as a standard of care has dramatically reduced the incidence rate of HIV-D as an AIDS-defining disease.2 However, the reduced incidence of HIV-D underestimates the overall prevalence of HIV-related NCI. Ferrando and colleagues3 reported an estimated prevalence of nearly 20% of the less severe form of NCI in symptomatic HIV-positive patients in the early HAART era. With regard to HIV-D, some reports showed an unchanged prevalence,4 while others showed an increase in HIV-D prevalence.5
The data from observational cohorts are consistent with neuropathologic studies that consistently show a high prevalence of HIV-D. As a matter of fact, HIV-D continues to be detected in at least 25% of autopsies,6 with a trend toward an increase in prevalence in the era of HAART.7 Thus HIV-related NCI still represents an important complication of advanced HIV disease.
HIV-related NCI has been shown to be associated with reduced health-related quality of life scores,8 low CD4 cell count,9 anemia, low body mass index,10 older age, and advanced disease. 11 In the second half of the 1990s the introduction of HAART as a standard of care both dramatically improved survival
and modified risk factors for mortality of HIV-infected patients.12-14 Today the deaths still occurring among HIV-infected patients appear to occur mainly in subgroups of subjects. Low CD4 count, virological failure, HAART,15,16 and, possibly, coinfection with hepatitis C virus (HCV)17 are among the factors associated with increased risk of death. Before HAART introduction, HIV-associated NCI was also recognized as an independent risk factor for death.18 The mortality of patients with HIV-related NCI in the HAART era is less characterized. In particular, a survival disadvantage for patients with NCI in the
HAART era has not been established. Therefore, we conducted a prospective observational study to determine whether NCI represents a negative prognostic factor for survival in patients treated with HAART.
DISCUSSION
In this study, we prospectively investigated the association of HIV-related NCI with survival in an observational cohort of patients receiving HAART. The study hypothesis was that the presence of NCI would be significantly associated with reduced survival. We found that NCI was independently associated with reduced survival only among the patients experiencing virological failure, while the survival probability of patients with a durable virological suppression was not affected by NCI. An additional findings was that patients with NCI had a poorer virological response to HAART when compared with subjects without NCI.
At baseline, NCI was associated, as already reported, with older age, lower education, intravenous drug use as the HIV transmission modality, low CD4 cell count,9 advanced HIV disease, 11 and positive HCV serology.22
Consistent with previous observations, that showed an association between systemic virological suppression and neuropsychological performance,23 in our study population NCI was also associated with virological failure to HAART. Patients with NCI were both more likely to experience a virological failure and had a significantly poorer virological response at month 12 of HAART. Moreover, in agreement with previous studies,16 virological failure was strongly associated with reduced survival.
At univariate analysis, virological failure was the strongest predictor of mortality in our cohort, since patients failing HAART had a nearly 10-fold increased risk of death than those with durable virological suppression. Given the strong association of virological failure with mortality and the association of NCI with virological response to HAART, we estimated the risk of death after stratification for virological response to HAART. Among individuals with durable virological suppression, the risk of death was not influenced by NCI. However, among those with virological failure, after controlling for neurocognitive impairment, age, HIV transmission modality, positive HCV serology, CDC clinical stage, and baseline CD4 count and viral load, mortality was significantly higher in impaired individuals, revealing a nearly 3-fold increased risk of death.
It is possible that NCI could influence survival in patients failing HAART through several mechanisms. Since cohort studies have shown that continuing antiretroviral therapy, even in the presence of persistent viremia, can provide immunological and virological benefit24 and decreases the risk of disease progression and death,25 impaired patients might die sooner because of less effective use of potent, but complex, current antiretroviral regimens. This hypotheses is consistent with recent observations that showed an association between NCI and reduced adherence to HAART.26 It is also possible that HIV disease might progress more rapidly in patients with NCI as a consequence of an increased and independent viral replication in
the neurological compartment. Data from the literature indicate that the presence of AIDS dementia complex (ADC) is associated with delayed virus elimination from the cerebrospinal fluid (CSF) during HAART, and that a divergent evolution of HIV may occur in the CSF, leading to the emergence of resistant mutants not detected in the periphery.27
Some study limitations are worth stressing. Both adherence and CSF studies were not performed; thus our hypotheses on the potential mechanisms of reduced survival in patients with NCI failing HAART remain a matter of speculation. Second, our patients might not be fully representative of people with
HIV infection, since the inclusion criteria may have selected for more patients with cognitive impairment. Finally, the use of one standard deviation below the normative mean on at least in two neuropsychological tests or two standard deviations below the mean on at least one test to define a patient as cognitively
impaired could have led to an increased rate of impairment.
Our primary objective was to determine whether the presence of cognitive impairment, including the milder forms not associated with appreciable symptomatic or functional impact, had an impact on mortality in patients receiving HAART. Thus, taken together, these limitations do not diminish the importance of the relationship between cognitive functioning and survival.
Our study may have implications for optimal management of HIV-infected patients. First, our findings highlight the importance of fully suppressive antiretroviral therapy in patients with HIV-related NCI. Second, since virological failure is common in clinical practice, being reported in 30-70% of patients, the assessment of cognitive function should be used in routine practice not only for its potential to reveal HIV-related CNS damage, but also for its association with reduced survival in a relevant proportion of patients: those with persistent viremia despite HAART. Finally, our results highlight the clinical relevance of HIV-related CNS involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective.
METHODS
Study measures
Comprehensive clinical evaluation and laboratory testing were performed at enrollment. Epidemiological and demographic data were obtained, and a general physical examination was performed. Current and past medications were recorded. The following data were abstracted from the patient's clinical records at enrollment: duration of HIV infection, HIV disease stage, treatment history, CD4 cell count, plasma HIV RNA, and routine laboratory testing. Disease stage was classified according to CDC criteria. Routine laboratory measures were targeted to detect HIV-related complications, drug-related adverse events, and clinical events that could affect cognitive function. After clinical laboratory evaluations, patients were administered standardized neuropsychological testing.
Neuropsychological testing. At enrollment, a detailed NP assessment was performed through a battery of 17 standardized NP tests administered by a trained neuropsychologist (P.B.), requiring approximately 90 min to complete. Tests were selected to include a spectrum of different cognitive domains: mental
flexibility (Trail Making B, Stroop Color Word, Controlled Oral-Word), concentration and speed of mental processing (Trail Making A, WAIS-R Digit Span, WAIS-R Digit Symbol, Corsi Cube Test, Stroop Word and Color), memory [Rey Auditory Verbal Learning Test (RAVLT), Rey Complex Figure (delayed), Babcook Story Recall Test], visuospatial and constructional
[Rey Complex Figure (Copy Trial)], and fine motor functioning (Lafayette Grooved Pegboard). The score of each test was adjusted for age, gender, and years of education.19,20 Subjects were classified as having or not having an NCI based on performance relative to the normative data. NCI was defined as performing below one standard deviation from the normative mean on at least two NP tests, or two standard deviations below the mean on at least one test.
Neurological examination and diagnostic criteria for cognitive impairment. NP testing was used to identify subjects with cognitive impairment. The diagnosis of NCI also required the exclusion, by neurological examinations, laboratory measures, and brain imaging studies, of other conditions that could explain
the finding. A brain MRI was performed in impaired patients to exclude confounding concomitant illnesses. The AAN criteria21 were used to determine whether the degree of impairment met the criteria for HIV-D or for cognitive impairment without dementia.
Antiretroviral treatment, virological response to therapy, and follow-up
HAART regimens were prescribed as best judged by the treating physician. Since at enrollment only 166 patients were antiretroviral naive, two different analyses were performed to assess virological response to HAART. For all the 412 study patients, response to HAART was defined as durable suppression, if the patient achieved and maintained a plasma viral load below 80 copies/ml or virological failure, if the patient either failed to achieve undetectable viral load or experienced a confirmed virological rebound to more then 1000 copies/ml after having achieved an undetectable viral load. Moreover, for the 166 patients who
were antiretroviral naive at enrollment, the virological response was assessed comparing both mean plasma HIV RNA levels and the proportion of patients with plasma HIV RNA below 50 copies at baseline and during the first 12 months of treatment. The main end point was death from any cause.
RESULTS
Baseline patient's characteristics and antiretroviral treatment
Among the 412 HIV-infected patients investigated, 224 (54.4%) were diagnosed as neurocognitively impaired and 188 (45.6%) were diagnosed as neurocognitively unimpaired. There were several statistically significant differences between the two groups. Patients with NCI were more frequently men and intravenous drug users, they tended to be older and less educated, they had a lower baseline CD4 cell count and a more advanced HIV disease stage, and, finally, they showed a higher prevalence of positive HCV serology.
At enrollment 166 patients were antiretroviral naive, 65 patients, enrolled during 1996 and 1997, were receiving mono or dual nucleoside reverse transcriptase inhibitor (NRTI) regimens, and the remaining 181 patients were receiving HAART consisting of either a PI or a non-NRTI (NNRTI) combined with NRTIs. The mean duration of antiretroviral drug exposure at enrollment was 19 months. Both the antiretroviral drug exposure and the duration of previous antiretroviral treatment did not differ between impaired and unimpaired patients.
Virological response to HAART
HAART regimens prescribed at enrollment did not differ between impaired and unimpaired patients and consisted in a PI-based regimen in 291 patients, in an NNRTI-based regimens in 113 patients, and in triple NRTI regimens including abacavir in 8 patients. Overall, a durable virological suppression under HAART was achieved by 119 out of 188 unimpaired patients (63.3%) and by 111 out of 224 impaired patients 49.6% (p=0.007). Among the 166 patients that started HAART after the NP examination, a significant difference between impaired and unimpaired patients was seen after 12 months of HAART. The proportion of patients with plasma HIV RNA below 50 copies/ml at month 12 was 27% (16 of 58) in impaired patients and 51.9% (28 of 54) in unimpaired subjects (p=0.012). Moreover, impaired patients showed higher plasma HIV RNA levels (mean: 3.41, standard deviation: 1.42 log copies/ml) when compared with unimpaired subjects (mean: 2.56, standard deviation: 1.22, log copies/ml) (p=0.001).
Follow-up and causes of death
The median follow-up period was 32.4 months (range: 3.3-93.9). Overall, 47 deaths were recorded: 38 among impaired and 9 among unimpaired patients.
The causes of death were AIDS-related conditions in 33 patients (70.3%), liver failure in 8 patients (17.0%), suicide in 2 patients (4.3%), and myocardial
infarction, heroin overdose, breast cancer, and unknown cause in one patient each (2.1%). After 84 months of observation, the estimated survival proportions in unpaired or unimpaired patients were 68.5% and 84.9%, respectively (p 0.001).
At univariate analysis the virological response to HAART was the variable most strongly associated with survival. Patients with virological failure had a nearly 10-fold increased risk of death than those with durable virological suppression (HR
9.9, 95% CI: 3.9-25.0). Given the strong association of virological failure with mortality and the association of NCI with virological response to HAART, the role of NCI on survival was analyzed after stratification for virological response to
HAART. The survival probability of the 230 patients with a durable virological suppression was not affected (p 0.89) by NCI, whereas NCI strongly influenced (p 0.001) the survival of the 182 patients with virological failure. At multivariate analysis, among patients who failed to achieve or to maintain virological suppression during HAART, those with NCI had a nearly 3-fold higher risk of death than unimpaired ones (HR 2.9, 95% CI: 1.2-7.1).
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