According to the multi-process theory of prospective memory (ProM), time-based tasks rely more heavily on strategic processes dependent on prefrontal systems than do event-based tasks. Given the prominent frontostriatal pathophysiology of HIV infection, one would expect HIV-infected individuals to demonstrate greater deficits in time-based versus event-based ProM. However, the two prior studies examining this question have produced variable results. We evaluated this hypothesis in 143 individuals with HIV infection and 43 demographically similar seronegative adults (HIV−) who completed the research version of the Memory for Intentions Screening Test, which yields parallel subscales of time- and event-based ProM. Results showed main effects of HIV serostatus and cue type, but no interaction between serostatus and cue. Planned pair-wise comparisons showed a significant effect of HIV on time-based ProM and a trend-level effect on event-based ProM that was driven primarily by the subset of participants with HIV-associated neurocognitive disorders. Nevertheless, time-based ProM was more strongly correlated with measures of executive functions, attention/working memory, and verbal fluency in HIV-infected persons. Although HIV-associated deficits in time- and event-based ProM appear to be of comparable severity, the cognitive architecture of time-based ProM may be more strongly influenced by strategic monitoring and retrieval processes.
AIDS dementia complex; Episodic memory; Executive functions; Neuropsychological assessment
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC90).
Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography–tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir.
Twenty-nine matched CSF–plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma.
Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.
HIV; antiretroviral therapy; central nervous system; protein binding
Optimal antiretroviral therapy (ART) effectiveness depends upon medication adherence, which is a complex behavior with many contributing factors including neurocognitive function. Pharmacy refill records offer a promising and practical tool to assess adherence.
A substudy of the CHARTER (CNS HIV Anti-Retroviral Therapy Effects Research) study was conducted at the Johns Hopkins University (JHU) and the University of Washington (UW). Pharmacy refill records were the primary method to measure ART adherence, indexed to a “sentinel” drug with the highest central nervous system penetration effectiveness score.
Standardized neuromedical, neuropsychological, psychiatric and substance use assessments were performed at enrollment and at 6 months. Regression models were used to determine factors associated with adherence and the relationships between adherence and change in plasma and cerebrospinal fluid HIV RNA concentrations between visits.
Among 80 (33 JHU, 47 UW) participants, the mean adherence score was 86.4% with no difference by site. In the final multivariable model, better neurocognitive function was associated with better adherence, especially among participants who were at JHU, male, and HIV-infected for a longer time-period. Worse performance on working memory tests was associated with worse adherence. Better adherence predicted greater decreases in cerebrospinal fluid HIV RNA between visits.
Poorer global neurocognitive functioning and deficits in working memory were associated with lower adherence defined by a pharmacy refill record measure, suggesting that assessments of cognitive function, and working memory in particular, may identify patients at risk for poor ART adherence who would benefit from adherence support.
HIV; adherence; cognitive impairment; pharmacy refill records; HAND; CPE
The HIV Dementia Scale (HDS) was developed to screen for HIV-associated Neurocognitive Disorders (HAND), but concerns have persisted regarding its substandard sensitivity. This study aimed to examine the classification accuracy of the HDS using raw and norm-based cutpoints, and to evaluate the contribution of the HDS subtests to predicting HAND.
1,580 HIV-infected participants from 6 U.S. sites completed the HDS, and a gold standard neuropsychological battery, on which 51% of participants were impaired. Results: Sensitivity and specificity to HAND using the standard raw HDS cutpoint were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, while visuomotor construction contributed the least. A modified raw cutpoint of 14 yielded sensitivity of 66% and specificity of 61%, with cross-validation. Using norms also significantly improved sensitivity to 69% with a concomitant reduction of specificity to 56%, while the positive predictive value declined from 75% to 62% and negative predictive value improved from 54% to 64%. The HDS showed similarly modest rates of sensitivity and specificity among subpopulations of individuals with minimal comorbidity and successful viral suppression.
Findings indicate that while the HDS is a statistically significant predictor of HAND, particularly when adjusted for demographic factors, its relatively low diagnostic classification accuracy continues to hinder its clinical utility. A raw cutpoint of 14 greatly improved the sensitivity of the previously established raw cutscore, but may be subject to ceiling effects, particularly on repeat assessments.
HIV; cognition; HIV-associated neurocognitive disorders; screening measures; HIV dementia scale
Despite immune recovery in individuals on combination antiretroviral therapy (CART), the frequency of HIV-associated neurocognitive disorders (HANDs) remains high. Immune recovery is typically achieved after initiation of ART from the nadir, or the lowest historical CD4. The present study evaluated the probability of neuropsychological impairment (NPI) and HAND as a function of CD4 nadir in an HIV-positive cohort.
One thousand five hundred and twenty-five HIV-positive participants enrolled in CNS HIV Antiretroviral Therapy Effects Research, a multisite, observational study that completed comprehensive neurobehavioral and neuromedical evaluations, including a neurocognitive test battery covering seven cognitive domains. Among impaired individuals, HAND was diagnosed if NPI could not be attributed to comorbidities. CD4 nadir was obtained by self-report or observation. Potential modifiers of the relationship between CD4 nadir and HAND, including demographic and HIV disease characteristics, were assessed in univariate and multivariate analyses.
The median CD4 nadir (cells/μl) was 172, and 52% had NPI. Among impaired participants, 603 (75%) had HAND. Higher CD4 nadirs were associated with lower odds of NPI such that for every 5-unit increase in square-root CD4 nadir, the odds of NPI were reduced by 10%. In 589 virally suppressed participants on ART, higher CD4 nadir was associated with lower odds of NPI after adjusting for demographic and clinical factors.
As the risk of NPI was lowest in patients whose CD4 cell count was never allowed to fall to low levels before CART initiation, our findings suggest that initiation of CART as early as possible might reduce the risk of developing HAND, the most common source of NPI among HIV-infected individuals.
CD4 nadir; combination antiretroviral therapy; HIV-associated; neurocognitive disorders; neurocognitive impairment
While performance-based tests of everyday functioning offer promise in facilitating diagnosis and classification of HIV-associated neurocognitive disorders (HAND), there remains a dearth of well-validated instruments. In the present study, clinical correlates of performance on one such measure (i.e., Medication Management Test—Revised; MMT-R) were examined in 448 HIV+ adults who were prescribed antiretroviral therapy. Significant bivariate relationships were found between MMT-R scores and demographics (e.g., education), hepatitis C co-infection, estimated premorbid IQ, neuropsychological functioning, and practical work abilities. MMT-R scores were not related to HIV disease severity, psychiatric factors, or self-reported adherence among participants with a broad range of current health status. However, lower MMT-R scores were strongly and uniquely associated with poorer adherence among participants with CD4 T-cell counts <200. In multivariate analyses, MMT-R scores were predicted by practical work abilities, estimated premorbid functioning, attention/working memory, learning, and education. Findings provide overall mixed support for the construct validity of the MMT-R and are discussed in the context of their clinical and research implications for evaluation of HAND.
HIV; medication management; neuropsychological functioning; adherence; construct validity; instrumental activities of daily living
In HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated.
Prospective, comparative, single-center, cross-sectional cohort study.
Clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression.
Of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4–5.5).
Elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.
antiretroviral; HIV; sensory neuropathy; triglyceride
HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy (CART) and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. CHARTER is a U.S. based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G (odds ratio [95% confidence interval] = 0.27 [0.11-0.65]; p = 0.004) and T489C (odds ratio [95% confidence interval] = 0.41 [0.21-0.80]; p = 0.009). These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups are associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups (odds ratio [95% confidence interval] = 0.29 [0.12-0.71]; p = 0.007 and odds ratio [95% confidence interval] = 0.42 [0.18-1.0]; p = 0.05, respectively). In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.
genetics; mitochondria; HIV-related neurological diseases; peripheral neuropathy
Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART).
Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204).
Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters.
Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt.
High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggests that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.
HIV; depression; suicide
To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis.
Design and methods
AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses.
Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein–Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis.
Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.
HIV leukoencephalopathy; antiretroviral therapy
To evaluate the efficacy of a single dose of intravenous zoledronate for the treatment of HIV-associated osteopenia and osteoporosis.
A double-blinded, randomized, placebo-controlled, 12 month trial of 5 mg intravenous zoledronate dose to treat 30 HIV-infected men and women with osteopenia and osteoporosis.
Following zoledronate or placebo infusions, participants were followed for 12 months on daily calcium and vitamin D supplements. Lumbar spine and hip bone density was assessed at baseline, 6 and 12 months. Biomarkers of bone metabolism were measured at baseline, 2 weeks, 3, 6, 9, and 12 months. Student’s t-test and repeated measure analyses were used to evaluate bone density and bone marker changes over time.
In the 30 HIV-infected men (27) and women (3) in the trial, median T-scores at entry were -1.7 for the lumbar spine and -1.4 for the hip. Median CD4 count was 461 cells/μL, 93% had HIV-RNA viral loads <400 copies/mL, and 97% were taking antiretroviral medications. Bone density measured either absolutely or as sex-adjusted T-scores significantly improved in zoledronate recipients as compared to minimal changes in those receiving placebo. Bone resorption markers significantly decreased over the study period in the zoledronate recipients as compared to placebo controls. No acute infusion reactions were detected, but one patient developed uveitis, a recognized complication of zoledronate, which responded to therapy.
In this small study, annual zoledronate appears to be a safe and effective therapy for HIV-associated bone loss.
metabolic bone diseases; osteoporosis; zoledronic acid; HIV; bisphosphonates
Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = −0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC50 for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.
to measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations.
Total maraviroc was measured by reverse phase high performance liquid chromatography with tandem mass spectrometry while ultrafiltration was used for unbound maraviroc.
Maraviroc was detected in all nine CSF/plasma pairs with a median CSF total concentration of 2.4 ng/mL. CSF concentrations exceeded the 50% inhibitory concentration (IC50) of wild-type CCR5-tropic HIV-1 in all specimens.
CSF concentrations are lower than expected based on plasma concentrations and physicochemical characteristics. Unbound maraviroc plasma concentrations may be informative in estimating concentrations in CSF.
cerebrospinal fluid; HIV; 50% inhibitory concentration; maraviroc; pharmacokinetics
Drug and alcohol use have been associated with a worse prognosis in short-term and cross-sectional analyses of HIV-infected populations, but longitudinal effects on adherence to antiretroviral therapy (ART) and clinical outcomes in advanced AIDS are less well characterized. We assessed self-reported drug and alcohol use in AIDS patients, and examined their association with non-adherence and death or disease progression in a multicenter observational study. We defined non-adherence as reporting missed ART doses in the 48 hours before study visits. The association between drug use and ART non-adherence was evaluated using repeated measures generalized estimating equation (GEE) models. The association between drug and alcohol use and time to new AIDS diagnosis or death was evaluated via Cox regression models, controlling for covariates including ART adherence. Of 643 participants enrolled between 1997–1999 and followed through 2007, at entry 39% reported ever using cocaine, 24% amphetamines, and 10% heroin. Ongoing drug use during study follow-up was reported by 9% using cocaine, 4% amphetamines, and 1% heroin. Hard drug (cocaine, amphetamines, or heroin) users had 2.1 times higher odds (p=0.001) of ART non-adherence in GEE models and 2.5 times higher risk (p=0.04) of AIDS progression or death in Cox models. Use of hard drugs was attenuated as a risk factor for AIDS progression or death after controlling for non-adherence during follow-up (HR=2.11, p=0.08), but was still suggestive of a possible adherence-independent mechanism of harm. This study highlights the need to continuously screen and treat patients for drug use as a part of ongoing HIV care.
Substance use; drug use; alcohol use; HIV/AIDS; Outcomes; Adherence; Antiretroviral Therapy; Mortality
Reliable detection and quantification of longitudinal cognitive change are of considerable importance in many neurological disorders, particularly to monitor central nervous system effects of disease progression and treatment. In the current study, we developed normative data for repeated neuropsychological (NP) assessments (6 testings) using a modified Standard Regression-Based (SRB) approach in a sample that includes both HIV-uninfected (HIV−, N=172) and neuromedically stable HIV-infected (HIV+, N=124) individuals. Prior analyzes indicated no differences in NP change between the infected and uninfected participants. The norms for change included correction for factors found to significantly affect follow-up performance, using hierarchical regression. The most robust and consistent predictors of follow-up performance were the prior performance on the same test (which contributed in all models) and a measure of prior overall NP competence (predictor in 97% of all models). Demographic variables were predictors in 10%-46% of all models and in small amounts; while test retest interval contributed in only 6% of all models. Based on the regression equations, standardized change scores (z-scores) were computed for each test measure at each interval; these z scores were then averaged to create a total battery change score. An independent sample of HIV− participants who had completed 8 of the 15 tests was used to validate an abridged summary change score. The normative data are available in an electronic format by email request to the first author. Correction for practice effects based on normative data improved the consistency of NP impairment classification in a clinically stable longitudinal cohort after baseline.
Normative data; longitudinal studies; regression; regression change score; SRB; practice effect
HIV-negative individuals with a family history of dementia (FHD) are more likely to develop dementia than those without a FHD. Whether FHD increases risk for neuropsychological (NP) impairment in HIV+ persons is unknown. As part of a multi-site study into HIV-Associated Neurocognitive Disorders (HAND), we captured FHD with a free-response, self-report question, and assessed NP performance with a comprehensive battery of tests. We examined HIV+ persons with (n=190) and without (n=916) self-reported FHD. Despite the fact that the FHD group had factors typically associated with better NP performance (e.g., higher CD4 counts and estimated verbal IQ [VIQ]), persons with FHD had significantly worse NP ability than those without FHD as measured by a Global Deficit Score (GDS) (FHD mean=0.66; No FHD mean=0.55; p<0.05). Thus, FHD appears to be a risk factor for HAND; the mechanism(s) underlying how FHD contributes to NP impairment among HIV+ persons warrants study.
HIV; AIDS; Cognition; Aging; Dementia
Substantial work on the peripheral and central nervous system complications of HIV was presented at the 16th Conference on Retroviruses and Opportunistic Infections. Six studies of more than 4500 volunteers identified that distal sensory polyneuropathy remains common, ranging from 19% to 66%, with variation based on disease stage, type of antiretroviral therapy, age, and height. Eight studies of more than 2500 volunteers identified that neurocognitive disorders are also common, ranging from 25% to 69%, with variation based on stage of disease, antiretroviral use, diabetes mellitus, and coinfection with hepatitis viruses. Therapy-focused studies identified that resistance testing of cerebrospinal fluid (CSF)-derived HIV may improve management of people with HIV-associated neurologic complications, that poorly penetrating antiretroviral therapy is associated with persistent low-level HIV RNA in CSF, and that efavirenz concentrations in CSF are low but in the therapeutic range in most individuals. Neuroimaging reports identified that people living with HIV had abnormal findings on magnetic resonance imaging (gray matter atrophy, abnormal white matter), magnetic resonance spectroscopy (lower neuronal metabolites), and blood-oxygen-level dependent functional magnetic resonance imaging (lower cerebral blood flow). Other important findings on the basic neuroscience of HIV and diagnosis and management of neurologic opportunistic infections are discussed.
For patients with HIV/AIDS, highly active antiretroviral therapy (HAART) is currently the only effective therapy for progressive multifocal leukoencephalopathy (PML), a viral-induced demyelinating disease caused by polyomavirus JC. Immune reconstitution inflammatory syndrome (IRIS) following initiation of HAART can cause paradoxical clinical deterioration in patients with established PML. Because the onset of PML follows soon after initiation of HAART in some cases (unmasking), we investigated the role IRIS plays in unmasked PML. We reviewed records of 20 PML cases seen from 1997–2006 at the UCSD HIV primary care clinic. Eight cases presented with PML symptoms within 6 months of initiating HAART (referred to hereafter as unmasked PML), six patients were diagnosed with PML before initiating HAART, and six were diagnosed more than 6 months after starting HAART. Patients with unmasked PML constituted forty percent of our series, had relatively long survival, and commonly (50%) had lesions exclusively in the posterior fossa, a localization not previously reported with such a high prevalence. Only 3 of the 8 patients with unmasked PML had IRIS reactions as evidenced by contrast enhancement around lesions on MRI, suggesting that IRIS is not necessary for the pathogenesis of this syndrome.
HIV; PML; HAART; IRIS; immune reconstitution
We investigated interactions between HIV and aging on brain function demands using functional magnetic resonance imaging (fMRI). A multiple regression model studied the association and interaction between fMRI measures, HIV serostatus, and age for 26 HIV infected (HIV+) and 25 seronegative (HIV−) subjects. While HIV serostatus and age independently affected fMRI measures, no interaction occurred. Functional brain demands in HIV+ subjects were equivalent to ~15–20 year older HIV− subjects. Frailty parallels between HIV and aging could result from continued immunological challenges depleting resources and triggering increased metabolic demands. fMRI could be a non-invasive biomarker to assess HIV in the brain.
HIV neurological disorders; aging; functional magnetic resonance imaging (fMRI); cerebral blood flow and metabolism
Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
HIV; Combination antiretroviral therapy; HIV dementia
Acute/early HIV infection is a period of high risk for HIV transmission. Better understanding of behavioral aspects during this period could improve interventions to limit further transmission. Thirty-four participants with acute/early HIV infection from six U.S. cities were assessed with the Mini International Diagnostic Interview, Beck Depression Inventory II, State-Trait Anxiety Inventory, Brief COPE, and an in-depth interview. Most had a pre-HIV history of alcohol or substance use disorder (85%); a majority (53%) had a history of major depressive or bipolar disorder. However, post-diagnosis coping was predominantly adaptive, with only mild to moderate elevations of anxious or depressive mood. Respondents described challenges managing HIV in tandem with pre-existing substance abuse problems, depression, and anxiety. Integration into medical and community services was associated with adaptive coping. The psychiatric context of acute/early HIV infection may be a precursor to infection, but not necessarily a barrier to intervention to reduce forward transmission of HIV among persons newly infected.
Acute HIV infection; psychiatric disorder; substance use disorder; coping
Sensory neuropathy (SN) is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy. Metabolic syndrome (MetS), a cluster of risk factors for atherosclerosis and microvascular disease, is associated with SN in HIV-uninfected (HIV−) persons. We examined if MetS or its components predispose individuals to HIV-SN.
From a prospective multicenter cohort of 1,556 HIV+ subjects, a subgroup (n=130) with fasting laboratory tests and SN assessment was selected.
SN was defined by symmetrically decreased reflexes or sensation loss in the legs. MetS was defined by presence of ≥3 risk factors: mean arterial pressure (MAP) ≥100 mm Hg; triglycerides (TRG) ≥150 mg/dl and high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males, <50 mg/dL for females; body mass index (BMI) >25 kg/m2; plasma glucose (GLU) ≥100 mg/dl and self-reported diabetes (DM II). Multivariate logistic regression examined the association between HIV-SN and MetS.
After controlling for HIV-SN risk factors- age, CD4 current, length of HIV infection, use of dideoxynucleoside reverse transcriptase inhibitors and protease inhibitors; MetS was not associated with HIV-SN (p=0.72). However, when each MetS component was assessed, elevated TRG was a significant risk factor for HIV-SN. From the larger cohort, both DM II (OR=1.4, p<0.01) and elevated TRG (OR=1.4, p=0.01) were risk factors for HIV-SN.
The risk of HIV-SN was increased for DM II and elevated TRG, but not other MetS components. Both increase the risk of SN in HIV- populations, but the mechanism(s) remains unclear.
HIV; sensory neuropathy; metabolic syndrome; highly active antiretroviral therapy
Metabolic syndrome (MetS) is a cluster of risk factors, including elevated mean arterial pressure (MAP), atherogenic dyslipidemia (elevated triglycerides [TRG]), abdominal obesity (increased body mass index [BMI]), glucose intolerance (elevated glucose [GLU]), and prothrombotic/inflammatory state (increases in uric acid [UA]), that are associated with increased risk of cerebrovascular disease. We studied if an association existed between MetS components and human immunodeficiency virus (HIV)-associated cryptogenic strokes—those not caused by HIV complications, endocarditis, or stimulant abuse. We performed a retrospective case-control study. Eleven cryptogenic strokes were identified from 2346 HIV-infected (HIV+) participants. Each case was matched by age, sex, and date of stroke diagnosis to five HIV+ controls without stroke. Nonparametric stratified Wilcoxon ranked sum tests with subsequent mixed effect logistic regression determined the influence of each MetS component on HIV-associated cryptogenic stroke. Although each MetS component appeared higher for HIV+ cases with cryptogenic strokes than HIV+ controls, only MAP (odds ratio [OR] = 5.70, 95% confidence interval [CI] = 1.15–28.3) and UA (OR = 1.88, 95% CI = 1.06–3.32) were statistically different. A significantly higher percentage of HIV-associated cryptogenic stroke cases met criteria for MetS (4/11 = 36%) compared to HIV+ controls (6/55 = 11%). This observational study suggests a possible role for MetS components in HIV+ cryptogenic stroke cases. Although MetS is defined as a constellation of disorders, elevated hypertension and hyperuricemia may be involved in stroke pathogenesis. Reducing MetS component levels in HIV+ patients could therefore protect them from subsequent stroke.
HIV; metabolic syndrome; stroke
Protease inhibitors may not penetrate into the central nervous system in therapeutic concentrations, which may allow ongoing HIV replication and injury. The objective of this study was to determine atazanavir penetration into cerebrospinal fluid (CSF).
Single random plasma or paired plasma and CSF samples were drawn from participants enrolled in a multicenter, observational cohort study and taking atazanavir with or without ritonavir between October 2003 and October 2005.
Plasma samples were assayed by high performance liquid chromatography and immunoassay; lower limit of detection was 45 ng/ml. CSF samples were assayed by immunoassay (ARK ATV-test); lower limit of detection was 5 ng/ml.
One hundred and seventeen participants (43 ± 7.7 years, 79% men, 81 ± 15 kg) had plasma or plasma and CSF paired samples drawn a median (interquartile range) of 10 (5–17) h postdose. Median (interquartile range) plasma atazanavir concentrations with or without ritonavir were 1278 (525–2265) and 523 (283–1344) ng/ml. The median (interquartile range) CSF concentrations with or without ritonavir were 10.3 (<5–21.1) and 7.9 (6.6–22) ng/ml. Nineteen of 79 (24%) CSF samples were less than 5 ng/ml. CSF concentrations were less than 1% of plasma concentrations and near the atazanavir wild-type IC50 of 1–11 ng/ml.
Atazanavir CSF concentrations are highly variable and 100-fold lower than plasma concentrations, even with ritonavir boosting. CSF concentrations of atazanavir do not consistently exceed the wild-type IC50 of atazanavir and may not protect against HIV replication in the CSF.
atazanavir; central nervous system; cerebrospinal fluid; pharmacology; protease inhibitors