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Background HIV and malaria are associated with immunological perturbations and neurocognitive disorders even when asymptomatic. However, the effect of asymptomatic malaria (AM) in HIV-infected adults on neurocognitive impairment (NCI) is not well understood. This study investigated the biomarkers of systemic inflammation and neurocognition in dually infected Nigerian adults. Methods We assessed the HIV and AM status of 269 adults and measured their global and domain-specific neurocognition and depression using standardized measures. Blood levels of sCD14 and sCD163 were also measured. Results The mean age of the participants (n = 269) was 33 years, 62% were women, and AM among HIV+ and HIV- was similar (36% versus 37%). NCI was found in 23% (62/269) of participants. HIV+/AM+ had a higher prevalence of impaired learning and executive functions and were more depressed than HIV-/AM- or HIV+/AM-. HIV+ with CD4 T-cell counts ≤200/µL were more impaired in the learning domain than those with >200/µL. HIV+/AM+ group had higher levels of sCD14 compared to the other 3 groups and higher levels of sCD163 than the HIV-/AM- group. Higher levels of sCD14 and sCD163 were each associated with NCI. The sCD163 (log10) levels were higher for those with 1+ versus 2+ parasitemia level. Conclusions HIV and AM coinfection was associated with an increased risk of reduced learning and executive functions, and elevated systemic inflammation. Mood was more depressed in HIV patients with than those without AM. The mechanisms and long-term effects on neurocognition and depression among HIV+/AM+ individuals should be studied because this coinfection is common globally. more...

BackgroundDuring antiretroviral therapy, HIV RNA can be detected in cerebrospinal fluid (CSF) when it is undetectable in plasma, a condition termed 'CSF viral escape'. The aim of the current study was to determine the prevalence and risk factors for CSF viral escape in two large cohorts in the USA.MethodsA total of 1264 HIV-infected volunteers enrolled in two US cohorts at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was less than 50 copies/ml while receiving stable antiretroviral therapy (ART) (>6 months) and if they had HIV RNA measured in CSF at their most recent visit between 2003 and 2011. Potential risk factors were identified using univariable and multivariable regression.ResultsCSF viral escape was detected in 55 adults (4.4%; 95% CI: 3.4-5.6), who had a median CSF HIV RNA of 155 copies/ml [interquartile range (IQR: 80-283)]. Patients with or without CSF viral escape had similar rates of neurocognitive impairment (38.2 vs. 37.7%; P = 0.91). CSF viral escape was independently associated with the use of ritonavir-boosted protease inhibitors [odds ratio (OR): 2.0; 95% CI: 1.1-3.8] or unboosted atazanavir (OR: 5.1; 95% CI: 1.3-16.1), CSF pleocytosis (OR: 7.6; 95% CI: 4.2-13.7) and abnormal CSF total protein (OR: 2.1; 95% CI: 1.1-3.7).ConclusionsIn this large study of aviremic patients receiving ART, CSF viral escape was uncommon and was linked to evidence of central nervous system inflammation and the use of protease inhibitors, but not with worse neurocognitive performance. more...

Dysregulated iron transport and a compromised blood-brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis-ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)-as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p= 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p= 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p= 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p= 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p&nbsp more...

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection. more...

Author(s): Jumare, Jibreel; El-Kamary, Samer S; Magder, Laurence; Hungerford, Laura; Umlauf, Anya; Franklin, Donald; Ghate, Manisha; Abimiku, Alashʼle; Charurat, Man; Letendre, Scott; Ellis, Ronald J; Mehendale, Sanjay; Blattner, William A; Royal, Walter; Marcotte, Thomas D; Heaton, Robert K; Grant, Igor; McCutchan, John A | Abstract: BackgroundRisk of cognitive impairment is increased among persons with high or low body mass index in HIV- and HIV+ populations in resource-rich settings. We examined this association among HIV+ patients in 3 resource-limited settings.MethodsThis secondary analysis included data of 761 HIV+ volunteers pooled from 3 prospective cohort studies conducted in China (n = 404; 53%), India (n = 200; 26%), and Nigeria (n = 157; 21%). World Health Organization (WHO) weight classifications were based on body mass index. T scores, adjusted for demographics and practice effects, were derived from a 7-domain neuropsychological battery. Neurocognitive impairment (NCI) was defined as global deficit score of ≥0.5.ResultsOverall, prevalence of NCI at baseline was 27.7% (similar across all cohorts). The overweight/obese and underweight constituted 37.3% and 15.5% of the total participants, respectively. In a multivariable logistic regression of pooled longitudinal data, adjusting for clinical and demographic variables, the odds of global NCI were 38% higher among the overweight/obese as compared to normal weight participants [odds ratio: 1.38 (95% confidence interval: 1.1 to 1.72); P = 0.005]. Similarly, the odds of global NCI were 39% higher among the underweight as compared to normal weight participants [odds ratio: 1.39 (95% confidence interval: 1.03 to 1.87); P = 0.029].ConclusionsNCI among HIV-1-infected patients was more prevalent in both overweight/obese and underweight than normal weight individuals in 3 resource-limited settings, confirming observations in resource-rich settings. Mechanisms underlying these associations are unclear but likely differ for underweight and overweight persons. more...

PurposeTo determine potential associations between histologic features of pediatric nonalcoholic fatty liver disease (NAFLD) and estimated quantitative magnetic resonance diffusion-weighted imaging (DWI) parameters.Materials and methodsThis prospective, cross-sectional study was performed as part of the Magnetic Resonance Assessment Guiding NAFLD Evaluation and Treatment (MAGNET) ancillary study to the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Sixty-four children underwent a 3T DWI scan (b-values: 0, 100, and 500 s/mm2 ) within 180 days of a clinical liver biopsy of the right hepatic lobe. Three parameters were estimated in the right hepatic lobe: apparent diffusion coefficient (ADC), diffusivity (D), and perfusion fraction (F); the first assuming exponential decay and the latter two assuming biexponential intravoxel incoherent motion. Grading and staging of liver histology were done using the NASH CRN scoring system. Associations between histologic scores and DWI-estimated parameters were tested using multivariate linear regression.ResultsEstimated means ± standard deviations were: ADC: 1.3 (0.94-1.8) × 10-3 mm2 /s; D: 0.82 (0.56-1.0) × 10-3 mm2 /s; and F: 17 (6.0-28)%. Multivariate analyses showed ADC and D decreased with steatosis and F decreased with fibrosis (P < 0.05). Associations between DWI-estimated parameters and other histologic features were not significant: ADC: fibrosis (P = 0.12), lobular inflammation (P = 0.20), portal inflammation (P = 0.27), hepatocellular inflammation (P = 0.29), NASH (P = 0.30); D: fibrosis (P = 0.34), lobular inflammation (P = 0.84), portal inflammation (P = 0.76), hepatocellular inflammation (P = 0.38), NASH (P = 0.81); F: steatosis (P = 0.57), lobular inflammation (P = 0.22), portal inflammation (P = 0.42), hepatocellular inflammation (P = 0.59), NASH (P = 0.07).ConclusionIn children with NAFLD, steatosis and fibrosis have independent effects on DWI-estimated parameters ADC, D, and F. Further research is needed to determine the underlying mechanisms and clinical implications of these effects.Level of evidence1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1149-1158. more...

HIV disproportionately affects Black and Latino people in the United States, but data on longitudinal neurocognitive patterns for these groups are scarce. This study evaluated the incidence and predictors of neurocognitive decline by ethnicity/race in a cohort of Black, Latino, and White people living with HIV (PLWH). Participants included 499 PLWH (43.5% White, 42.7% Black, 13.8% Latino; mean age at baseline = 43.5) from the six-site CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Participants completed comprehensive neurocognitive and neuromedical evaluations over 3-7 study visits for an average of 2.8 years (SD = 1.1). Interpertation of neurocognitive change was based on published methods using regression-based norms that correct for baseline performance and practice effects. Survival analyses investigated the relationship between ethnicity/race and neurocognitive change, and predictors of neurocognitive decline. In follow-up, 108 participants (21.6%) declined, 311 (62.3%) remained stable, and 80 (16.0%) improved. In Cox proportional hazard models, hazard ratios for neurocognitive decline were increased for Latinos compared to Whites (HR = 2.19, 95%CI = 1.32-3.63, p = .002) and Blacks (HR = 1.87, 95%CI = 1.14-3.04, p = .01). Including significant covariates (baseline nadir CD4, hepatitis C Virus, and VACS Index: a composite marker of physical health among PLWH)did not significantly decrease the elevated risk for decline among Latinos. We found that Latino PLWH appear to have higher risk of neurocognitive decline compared to White and Black PLWH. Traditional markers of HIV disease and physical health at baseline did not explain this elevated risk of neurocognitive decline. Future research examining economic, socio-environmental, and culturally-relevant biomedical factors may help to explain this observed ethnic/racial disparity in longitudinal neurocognitive function in HIV. more...

Summary Cognitive impairment is common in HIV-infected individuals, as is syphilis. Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system early in disease. We hypothesized that HIV-infected patients with a history of syphilis or neurosyphilis would have more cognitive impairment than HIV-infected individuals without these infections. Eighty-two of 1574 enrollees in CHARTER, a prospective, observational study, had reactive serum rapid plasma reagin (RPR) tests. They were matched to 84 controls with non-reactive RPR by age, gender, ethnicity and HIV risk factor. Participants underwent comprehensive neuropsychological (NP) evaluations. RPR results were confirmed and serum fluorescent treponemal antibody absorption (FTA-ABS) test reactivity determined at a central laboratory. Sera from 101 of 166 participants were FTA-ABS reactive, indicating past or current syphilis. Among the 136 individuals without confounding conditions, compared with patients who had never had syphilis, those with prior syphilis had a greater number of impaired NP test domains (1.90 SD [1.77] versus 1.25 [1.52], P = 0.03), a higher global deficit score (0.47 [0.46] versus 0.31 [0.33], P = 0.03), and more were impaired in the NP learning domain (36 [42.9%] of 84 versus 13 [25.0%] of 52, P = 0.04). These effects of prior syphilis remained after controlling for education and premorbid intelligence. more...

BackgroundAnemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown.MethodsWe evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4(+) T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments.ResultsHAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01).ConclusionsAnemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons. more...

Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment. more...

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, whereas 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 of wild-type CC chemokine receptor 5-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. more...

Objective: To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study. Methods: In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55). Results: NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for. Conclusions: As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons. more...

Sensory neuropathy (HIV-SN) is a common cause of pain in HIV-infected people. Establishing a diagnosis of HIV-SN is important, especially when contemplating opioid use in high-risk populations. However physical findings of HIV-SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self-report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV-SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV-SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self-report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self-report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV-infected patients reporting symptoms consistent with HIV-SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV-SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history. more...

Objective: To rigorously evaluate the time course of cognitive change in a cohort of individuals with HIV-associated neurocognitive disorders (HAND) initiating combination antiretroviral therapy (CART), and to investigate which demographic, laboratory, and treatment factors are associated with neuropsychological (NP) outcome (or “any NP improvement”). Methods: Study participants included 37 HIV+ individuals with mild to moderate NP impairment who initiated CART and underwent NP testing at 12, 24, 36, and 48 weeks thereafter. NP change was assessed using a regression-based change score that was normed on a separate NP-stable group thereby controlling for regression toward the mean and practice effect. Mixed-effect regression models adjusting for loss to follow-up were used to evaluate the time course of cognitive change and its association with baseline and time-varying predictors. Results: In persons with HAND initiating CART, cognitive improvement happens soon after initiation (13% at week 12), but more often 24, 36, and up to 48 weeks after initiation (up to 41%), with fewer than 5% demonstrating significant worsening. In multivariate analyses, unique predictors of NP improvement included more severe baseline NP impairment and higher CART CNS penetration index. Greater viral load decrease was associated with NP improvement only in univariate analyses. Conclusion: Clinically meaningful neuropsychological improvement seemed to peak around 24–36 weeks after combination antiretroviral therapy initiation and was prolonged over the 1-year study period. This study also provides new evidence that benefit may be maximized by choosing antiretroviral medications that reach therapeutic concentrations in the CNS. more...

Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)-related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante-mortem levels of cognitive performance in AIDS patients. Three-dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin-immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life. It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV-associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease. more...

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance ( P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits ( P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns ( P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS. more...

OBJECTIVE:While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). METHODS:A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. RESULTS:The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2-10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. CONCLUSIONS:This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression. more...

Objective: To correlate self-reported antiretroviral adherence with virologic suppression. Design: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. Setting: Five university-affiliated HIV clinics. Patients: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 × 10 6 cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. Intervention: Individualized, unrestricted antiretroviral therapy. Measurements: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. Results: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log 10 copies/ml increase in HIV RNA and a loss of 19 × 10 6 CD4 cells/l compared with a 1.1 log 10 copies/ml decrease in HIV RNA and an increase of 72 × 10 6 CD4 cells/l in those reporting 100% adherence (P = 0.02). Conclusion: Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy. more...

We measured the concentrations of the neuron-specific protein, tau, in the cerebrospinal fluid (CSF) of 32 neurologically characterized HIV-infected (HIVpos) subjects and nine matched seronegative (HIVneg) controls using a sensitive ELISA assay. Of 32 HIVpos subjects, nine had HIV-associated neurocognitive disorders, and nine had clinically diagnosed peripheral neuropathies. CSF tau levels in subjects with HIV-associated neurocognitive disorders were similar to those in HIVneg subjects (185 +/- 83 vs. 223 +/- 106 pg/ml; P = 57). CSF tau levels in HIVpos subjects with peripheral neuropathies did not differ from those without neuropathies (320 +/- 190 vs. 251 +/- 185; P = 23). In summary, CSF tau levels were not elevated in patients with HIV-associated neurologic disease. more...

To determine whether cerebrospinal fluid (CSF) viral burden measurements can assist in the evaluation of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we quantified HIV type 1 (HIV-1) RNA in CSF. Because previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV-1 RNA levels in plasma may influence CSF viral burden, these variables were examined as potential modifying factors. HIV-1 RNA levels were quantified by using a reverse transcriptase-polymerase chain reaction assay. Performance on a comprehensive neuropsychological (NP) battery was noted in 97 prospectively enrolled, HIV-infected subjects. Among subjects with acquired immunodeficiency syndrome (AIDS) ( more...

Objective: To determine if mortality is increased in individuals with human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders less severe than frank dementia. Design: A prospective cohort study; median duration of follow-up was 2.4 years. Kaplan-Meier analysis and Cox proportional hazards models were used to compare survival times according to neurocognitive classification. Setting: University-based research unit. Participants: A volunteer sample of 414 individuals seropositive for HIV-1. Subjects were classified at their base-line evaluation as neuropsychologically (NP) normal or abnormal (impaired in ≥2 NP test domains). A subgroup of NP abnormal subjects met operational criteria for HIV-associated minor cognitive motor disorder; the remaining subjects were designated NP impaired. Subjects with frank dementia were excluded. Main Outcome Measure: Mortality. Results: At the baseline evaluation, 256 (62%) of 414 subjects were designated normal; 109 (26%), NP impaired; and 49 (12%), minor cognitive motor disorder. One hundred six participants (26%) died during follow-up. Compared with the NP normal group, the unadjusted relative risk (RR) of death for all NP abnormal subjects (minor cognitive motor disorder and NP impaired) was significantly increased (RR, 1.7; 95% confidence interval [CI], 1.2-2.6;P Conclusions: The HIV-infected individuals with NP impairment had a higher risk of dying than those without impairment. This was particularly true for those meeting syndromic diagnostic criteria. more...

Prevention of opportunistic infections contributes to improved quality of life and survival in individuals with acquired immunodeficiency syndrome (AIDS). Agents which are more effective and convenient, less costly, and better tolerated are needed for multiple organism primary prophylaxis. Azithromycin, an azalide with high and prolonged intracellular levels, promises to provide protection against Mycobacterium avium complex (MAC) disease in those with advanced AIDS when given weekly. A large trial comparing rifabutin (300 mg daily), a currently approved primary prophylactic agent for MAC, with azithromycin (1200 mg weekly) has been completed and is under analysis. If weekly azithromycin provides equivalent or better protection from disseminated MAC, the cost, effectiveness and convenience of MAC prophylaxis may be improved. more...

LIFE stress, mood, and other psychosocial factors may help to explain variability in HIV (human immunodeficiency virus) disease progression. Attempts to support this notion empirically have produced mixed findings; several studies report a positive relationship between psychosocial factors and various indicators of disease progression or immune function (e.g., Evans et al. 1992; Goodkin et. al. 1992), whereas others have failed to detect any association (e.g., Perry et. al. 1992). more...

Cytomegalovirus (CMV) causes five distinct neurological syndromes in patients with AIDS: retinitis, myelitis/polyradiculopathy, encephalitis with dementia, ventriculoencephalitis, and mononeuritis multiplex. The clinical syndromes associated with CMV ventriculoencephalitis and diffuse encephalitis in patients with AIDS have only recently been clearly described despite the fact that multiple neuropathologic descriptions of CMV in the brain have been published over the past decade. Even more-subtle levels of cognitive impairment have been detected in patients with CMV retinitis who are also at increased risk of developing diffuse CMV encephalitis. Demonstration of CMV DNA in the CSF with use of the polymerase chain reaction may provide both a sensitive and specific method for diagnosis of these syndromes. The effectiveness of aggressive early treatment of CMV syndromes in the nervous system, with the exception of retinitis, is unclear and warrants formal trials. more...

Retinitis due to cytomegalovirus (CMV) infection is a widely recognized complication of advanced disease due to human immunodeficiency virus type 1 (HIV-1). Less appreciated are other neurological manifestations of CMV infection in persons with AIDS. Dr. J. Allen McCutchan has comprehensively reviewed the various clinical presentations of CMV neurological disease as well as the methods of diagnosis, the neuropharmacology of available antiviral agents, the results of therapy, and the potential for prevention of these sequela of advanced immunosuppression. As the ability to prevent diseases such as Pneumocystis carinii pneumonia, bacteremia secondary to Mycobacterium avium, tuberculosis, serious fungal infections, and toxoplasma cerebritis is increasing, physicians must now treat more HIV-1-infected persons with CMV disease. This AIDS Commentary provides a timely update of the current state of our knowledge regarding this serious problem. more...

To evaluate the validity of the Quality of Well-Being Scale (QWB) for studies of patients with human immunodeficiency virus (HIV) disease, 514 men were studied who were divided among four categories: Centers for Disease Control and Prevention (CDC) Group A (N = 272), CDC-B (N = 81), CDC-C (N = 47), and uninfected male controls (N = 114). The QWB and a variety of medical, neuropsychological, and biochemical measures were administered to all participants. When QWB scores were broken down by HIV group, the CDC-C group was significantly lower (.614) than the CDC-B (.679), CDC-A (.754), or control group (.801). The difference between Groups CDC-C and CDC-A was about .14 units of well-being, which suggests that individuals lose 1/7 equivalents of 1 well year of life for each year they are in Group CDC-C in comparison to the asymptomatic group (Group CDC-A). In comparison to the controls, this would equal a 1-year of life loss for each seven infected individuals. The QWB was shown to be significantly associated with CD4+ lymphocytes (p < .001), clinician ratings of neuropsychological impairment (p < .04), neurologists ratings of dysfunction (p < .001), and all subscales of the Profile of Mood States. Baseline QWB scores were significant prospective predictors of death over a median follow-up time of 30 months. Multivariate models demonstrated high covariation between predictors of QWB. It was concluded that the QWB is a significant correlate of biological, neuropsychological, neurological, psychiatric, and mortality outcomes for male HIV-infected patients. more...

Background : During HAART, HIV RNA can be detectable (>50 cop/mL) in CSF when it is undetectable in plasma, a condition termed CSF viral escape (CVE). The aim of the current analysis was to determine the prevalence and risk factors for CVE in two large US cohorts. Methods : 1,264 volunteers enrolled in CHARTER or HNRP at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was undetectable while on stable HAART (>6 months) and if they had CSF collected. Potential risk factors were identified using univariable and multivariable analysis. Odds ratios for detected risk factors were calculated. Results : Mean age was 46 years, 82% were men, 70% had AIDS, 22% were HCV+, 49% were Caucasians, median CD4 nadir was 129, and 38% were cognitively impaired. CVE was present in 55 (4.35%) with a median HIV RNA in CSF of 155 (IQR 80-283). The table summarizes the main analysis results. CVE was associated with longer durations of HIV disease, higher platelet count, higher total serum protein, and higher CSF white blood cells (WBCs). CVE was also associated with treatment-associated factors, including use of boosted PIs and unboosted atazanavir. Conclusions: In this large, cross-sectional analysis, CVE was uncommon in subjects on effective HAART. A combination of disease and treatment factors were associated with CVE. The associations with higher levels of CSF WBCs, blood platelets, and serum total protein may reflect greater immune activation. Treatment with PI-based HAART was particularly associated with CVE, especially if unboosted atazanavir was part of the regimen. CVE was not associated with neurocognitive impairment. Prospective analyses are needed for better characterization of CVE. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Perez Valero I et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18189 http://www.jiasociety.org/index.php/jias/article/view/18189 | http://dx.doi.org/10.7448/IAS.15.6.18189 more...

Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment. more...

Treatment of cryptococcal meningitis with amphotericin B or fluconazole is often unsuccessful; in only 35%-40% of cases do CSF cultures become negative by 10 weeks after initiation of such therapy. We conducted a prospective, open-label clinical trial involving persons with AIDS to determine whether the rate of clinical success would improve when fluconazole (400 mg daily) was combined with flucytosine (150 mg/kg daily). At the conclusion of 10 weeks of therapy, 75% (95% confidence interval, 58%-87%) of 32 subjects' CSF cultures were negative. The Kaplan-Meier estimate of clinical success at 10 weeks was 63% (95% confidence interval, 48%-82%). The median time to negativity of the CSF culture was 23 days. Toxic side effects that were sufficiently severe to lead to the withdrawal of flucytosine were observed in nine subjects (28%). In this pilot study of fluconazole combined with flucytosine, the rate of clinical success at 10 weeks was greater than that previously reported with regard to the use of fluconazole alone or amphotericin B alone. more...

The aim of this rater-blinded randomized study was to evaluate the efficacy and side effects of haloperidol and thioridazine in the treatment of new-onset psychosis in HIV-positive individuals. Participants were 13 men who had no history of psychosis prior to infection with HIV, and whose psychosis was not attributable to delirium or to non-HIV-related organic factors. Participants were evaluated at baseline after at least one month without neuroleptic treatment and then weekly for six weeks of the experimental treatment using several rating scales. The mean daily dose in chlorpromazine equivalents was 124 mg. Both neuroleptics produced modest but significant reduction in overall level of psychosis and in positive symptoms, but not in negative symptoms. All the haloperidol-treated patients developed extrapyramidal side effects and required treatment with anticholinergic medication, whereas three of the five thioridazine-treated patients had noticeable side effects. We make recommendations for the treatment of HIV-associated psychosis with neuroleptics. more...

This research describes major stressors in the lives of women who have been infected with the human immunodeficiency virus (HIV). Thirty-one HIV antibody positive (HIV+) women infected primarily through heterosexual contact participated in a two hour semi-structured interview detailing the circumstances, context. and consequences of all stressful life events and dificulties experienced within the preceding six months. Qualitative methods of data analyses were utilized (Miles & Huberman, 1984). HIV-related life events and difficulties were classified into primary and secondary stressors based on the stress process model (Pearlin et al., 1981). Problems arising directly from one's seropositivity were defined as primary stressors. Stressful life events and difficulties occuring in other role areas were defined as secondary stressors. Six categories of HIV-related stressors were identified and quantified primary stressors were health-related, and included both gyecological probiems (e.g., amenorrhea) and gene... more...

Monocytes/macrophages (M/M) are the major host of human immunodeficiency virus (HIV) in solid tissues. However, blood monocytes are nonpermissive for HIV infection, indicating that M/M activation or differentiation is necessary for HIV replication. Since M/M are activated during immune responses, we investigated the effect of T-cell activation on HIV expression in M/M derived from peripheral blood of HIV-infected individuals. Previously, we reported that coculture of monocytes from HIV-infected donors with T cells and mitogens resulted in M/M differentiation and HIV expression. Production of HIV by M/M from infected donors required direct contact between monocytes and T cells (for the first 24 h), and the response to alloantigens, but not mitogens, was restricted to HLA-DR. In this study, we found that HIV was more readily recovered from M/M of asymptomatic HIV seropositive donors (69%) than from M/M of symptomatic donors (57%). Viral antigens (e.g., inactivated herpes simplex virus) could initiate the immune response and HIV expression. The ability of noninfected T cells to activate HIV expression in M/M and observations that treatments of M/M with antibodies to deplete T cells did not reduce HIV expression suggested that the monocytes were endogenously infected. To define the aspects of immune activation specifically involved in initiating HIV expression in M/M, interactions of M/M and T cells and participation of cytokines were investigated. The T cell which activated M/M was CD4+ CD8-. Fixed allogeneic cells are known to induce T-cell activation but were not able to serve as antigen for M/M differentiation, suggesting that M/M may need to function as antigen-presenting cells to receive the signal to differentiate and express HIV. Blocking of M/M-T-cell interaction with antibodies directed against LFA-1 or interleukin-1 prevented HIV expression. However, inhibition of later stages of T-cell activation, such as blocking of interleukin-2 receptors, did not diminish HIV expression in M/M. Consistent with the requirement for cell-cell contact between M/M and T cells, a variety of cytokines were unable to initiate HIV replication in M/M. The ability of T cells to induce cellular differentiation and HIV replication in M/M in vitro suggests that initiation of an immune response to an antigen, such as an opportunistic pathogen, could be a mechanism by which HIV disseminates to tissues in vivo. more...

Many researchers interested in sexual orientation can be separated into two camps: The "lumpers," who try to reduce sexual classifications to as small a number of categories as possible, and the "splitters," who try to show differences among groups and individuals that make classification schemes increasingly difficult and/or intricate. We report factor analyses of the Klein Grid (a questionnaire with 21 sexual orientation items) to see how many factors emerge in two samples of strikingly different origins. In both samples, the first factor to emerge loaded substantially on all of the Klein Grid's 21 items. This factor accounted for a majority of the variance. In both samples, a second, correlated factor emerged which indexed a separation between most of the items and those having to do with social and/or emotional preferences. In both samples, a third correlated factor also emerged, but this factor differed between the two populations: one refined the social/emotional distinction and the other distinguished ideal behavior from past and current behavior. We conclude on the basis of our analysis that both the lumpers and the splitters are correct. more...

Objectives: To establish whether symptomatic seroconverting illness in HIV infected people is associated with more rapid development of neurological impairment. Methods: 166 HIV infected subjects with a known date of HIV infection enrolled in a longitudinal study of neurocognitive function were stratified by whether or not they had experienced a symptomatic serconverting illness. Results: 29 of 166 (17.5%) dated HIV seroconverters had a history of symptomatic seroconverting illness. Though baseline neurocognitive function was similar, subjects with a symptomatic seroconverting illness developed clinical neurocognitive impairment significantly more rapidly than their asymptomatic counterparts in a survival analysis model (636 v 1075 days till impaired). Conclusion: Symptomatic seroconverting illness predisposes to more rapid neurocognitive impairment. Key Words: HIV; seroconverting illness; neurocognitive impairment more...

• Patients with acquired immunodeficiency syndrome frequently suffer peripheral neuropathy. We investigated its prevalence and relationship to clinical stage of human immunodeficiency virus (HIV) infection using quantitative sensory testing and nerve conduction testing. Vibratory threshold was determined in the right great toe and index finger of 179 men seropositive for HIV (28 with acquired immunodeficiency syndrome [AIDS] or AIDS-related complex [ARC], 151 asymptomatic) and 32 HIV-seronegative controls. None had clinical peripheral neuropathy. Abnormal threshold was control mean plus 2.5 SDs. In the toe, 10 (36%) of 28 subjects with AIDS or ARC had abnormal vibratory thresholds, compared with seven (5%) of 151 asymptomatic seropositive subjects and none of 32 controls. A subgroup of 168 seropositive subjects underwent nerve conduction testing. Abnormality rates were similar, but abnormalities of nerve conduction coincided with quantitative sensory testing abnormalities in only half the cases. Mean (±SD) vibratory threshold was significantly greater in subjects with AIDS or ARC (3.00±0.51 vibratory units) than in asymptomatic subjects (1.56±0.27 vibratory units) and controls (1.63±0.54 vibratory units). Finger abnormality rates did not differ, although subjects with AIDS or ARC had greater mean vibratory threshold. Subclinical peripheral neuropathy is thus related to stage of HIV infection and is present by quantitative sensory testing in 36% of patients with AIDS or ARC. more...

OBJECTIVES AND DESIGN Because macrophages are the predominant immune cell and the predominant infected cell in the brains of patients with HIV encephalitis, we studied macrophage and immune activation-associated factors in the cerebrospinal fluid (CSF) from 39 autopsied AIDS cases for whom complete neuropathologic evaluation of the brain was available. RESULTS CSF HIV p24 antigen was present in less than one-third of cases (11 out of 39). Less than half of the autopsies with moderate to severe parenchymal infection by HIV had high levels of CSF p24, although all autopsies with elevated levels of HIV p24 had moderate to severe HIV encephalitis. Elevated levels of cytokines, beta 2-microglobulin, neopterin, and quinolinic acid were observed. CONCLUSIONS Although many of the CSF findings showed a strong correlation with each other, none showed a strong correlation with the severity of HIV infection of the brain itself. The absence of a close association between CSF abnormalities and HIV encephalitis could reflect the abundance of complicating opportunistic infections in these terminally ill patients or the inadequacy of CSF as a marker of basal ganglia involvement in HIV encephalitis. These findings complicate interpretation of clinical studies of CSF in patients with AIDS where neuropathologic evaluation is unavailable. more...

Patients undergoing bronchoscopy for possible pneumocystis pneumonia were studied retrospectively to characterize the impact of common viral pathogens on the course of advanced human immunodeficiency virus (HIV) disease and atypical pneumonia. In 327 episodes, Pneumocystis carinii was found in 220 (67%), cytomegalovirus (CMV) in 145 (44%), and herpes simplex virus in 16 (5%). Early deterioration in oxygenation and use of intensive care was less common in CMV-positive patients. Neither CMV nor P. carinii was a predictor of mortality in multivariate analyses. CMV was not associated with an increased prevalence of later CMV disease. Isolation of CMV from the bronchoalveolar lavage fluid of these patients was not an indication for antiviral therapy. Pulmonary shedding of CMV may be associated with a decreased inflammatory response to P. carinii. The outcome of HIV-associated atypical pneumonia where no clear pulmonary pathogen is found on routine evaluation was no better than that of treated P. carinii pneumonia. more...

Plasma and cerebrospinal fluid (CSF) indinavir concentrations were measured by high-performance liquid chromatography. The median concentration in plasma exceeded that in CSF 10-fold. The modeled CSF curve was flat at 155 nM, and the estimated ratio of the areas under the CSF and plasma concentration-time curves was 6%. We conclude that CSF indinavir concentrations are lower than levels in plasma but exceed the clinical 95% inhibitory concentration range. more...

Macrophages are major reservoirs of human immunodeficiency virus (HIV) in the tissues of infected humans. As monocytes in the peripheral blood do not show high levels of infection, we have investigated the expression of HIV in T-cell-activated, differentiated macrophages. Peripheral blood mononuclear cells were isolated from HIV-seropositive individuals and stimulated with antigens or mitogens, and the nonadherent fraction was removed. Macrophages were cultured alone for 2 weeks, and HIV expression was assessed. Results from p24 antigen capture assays demonstrated that the presence of autologous T cells and concanavalin A or autologous T cells and allogeneic cells for the initial 24 h of culture induced HIV expression in 35 of 47 (74%) HIV-seropositive patients tested. The macrophage monolayers could be immunostained with anti-HIV antibodies to reveal discrete infectious centers, indicating that complete virus replication was occurring in the macrophages and that infection of adjacent cells was mediated by cell-cell contact. Time course studies of the interval of coculture of the adherent and nonadherent cells indicated that 24 h (but not 2 h) was sufficient for induction of HIV in the macrophages. Direct contact between the adherent cells and activated T cells was required as well. Since the presence of autologous T cells also appeared to be necessary, induction of HIV expression in macrophages may be genetically restricted. HIV-seronegative nonadherent cells were able to induce HIV expression in macrophages from HIV-seropositive donors, demonstrating that the virus originated in the monocytes and was reactivated in the context of a classic T-cell-mediated immune reaction. The high percentage of monocytes from HIV-seropositive donors which can be induced to replicate HIV by activated T cells suggests that infection of monocytes may be critical to the pathogenesis of this lentivirus infection. more...

The in vivo interaction of human cytomegalovirus (HCMV) with leukocytes from a group of immunosuppressed patients was studied using specific subgenomic DNA probes and in situ cytohybridization. Study subjects had no recognized disease due to HCMV or had HCMV retinitis or colitis. Viral nucleic acid was detected in lymphocytes, monocytes, and polymorphonuclear leukocytes (PMNL). PMNL were consistently hybridization-positive for HCMV RNA and DNA in patients with HCMV viremia. Monocytes were occasionally positive by hybridization and lymphocytes were rarely positive. These findings demonstrate that the HCMV genome is expressed in PMNL of viremic patients and that PMNL may play an important role in virus dissemination. more...

The main objective of this study was to investigate the association between human CSF leptin levels and neuropsychological (NP) performance in the setting of HIV infection. We hypothesized that human CSF leptin levels positively correlate with NP performance. Leptin is an adipocyte-derived hormone that influences brain development and function, particularly learning and memory, in the mouse model. The extent to which leptin contributes to neurocognitive functioning in humans is less clear. A cross-sectional evaluation of CSF leptin and NP performance was performed. Leptin levels in CSF and serum samples from 59 HIV-positive men were measured by ELISA. Comprehensive, standardized NP testing was used to determine impairment status in global and specific domains. Lower CSF leptin levels and reduced leptin uptake into the central nervous system (CNS) correlated with impaired learning and memory performance in both univariate and multivariate analyses. In multivariate analyses, lower CSF leptin levels and reduced CNS leptin uptake were associated with worse NP performance in learning and memory, adjusting for CD4 nadir, antiretroviral treatment exposure, and HIV RNA levels in CSF. Low CSF leptin levels are associated with poorer performance in learning and memory among HIV-infected men adjusting for usual predictors of HIV-associated neurocognitive impairment. This association is consistent with prior in vitro and animal data suggesting leptin has a trophic or facilitatory role in the hippocampus, above and beyond its role in hypothalamic regulation. more...

To identify the sources of HIV virions in CSF by modeling treatment-associated HIV dynamics.We postulated a model in which cell-free CSF virions originate from two major sources, namely, systemic non-CNS and CNS tissues, the latter including brain parenchyma and meninges. The model predicted that with initiation of antiretroviral therapy, the acute-phase decline in CSF HIV RNA levels would be controlled by the kinetics of the dominant virion source (systemic versus CNS). Based on prior observations, we hypothesized that the dominant source of CSF virions would shift from systemic to CNS in more advanced disease.Three patient groups were studied: Group 1 (n = 5): nondemented, with early HIV disease (CD4+ lymphocytesor = 400/microL) or pleocytosis (CSF leukocytesor = 4/microL); Group 2 (n = 5): nondemented, with advanced HIV disease (CD4+400/microL) and no pleocytosis; Group 3 (n = 2): patients with HIV-associated dementia (HAD). All patients began a new, highly active antiretroviral treatment regimen and underwent serial lumbar punctures and phlebotomies.For patients in Group 2, the rate of decline in CSF HIV RNA was slower than in plasma (p0.00001). For Group 1, the rate of decline in CSF was not different from plasma (p0.25). Patients with HAD showed high CSF HIV RNA after 5 to 6 weeks of treatment despite a 100-fold decrease in plasma HIV RNA.CSF and plasma HIV dynamics became increasingly independent in advanced HIV disease, and the compartmental discrepancy was largest in HAD. Our findings suggest that viral replication in CNS tissues may constitute a major, independent source of CSF HIV RNA. In patients with HAD, brain parenchyma itself may be the principal CNS tissue source, and CNS-targeted treatment strategies may be required to eradicate this infection. more...

ObjectiveTo compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease.DesignComparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C.SettingLongitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif.ParticipantsEighty-six HIV-1-positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness.Main outcome measuresRegional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest.ResultsMedically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test, P=.02 and P=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+ lymphocyte count.ConclusionsIn the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+ cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness. more...

Background and Objectives: Neurocognitive impairment is common in human immunodeficiency virus (HIV)-infected subjects. The relationship of sexually transmitted diseases to neurocognitive changes is unknown. Goal: To establish whether HIV-infected patients with a history of syphilis or gonorrhea have a higher rate of neurocognitive dysfunction. Study Design: Neurocognitive function was measured by a battery of quantitative tests in a 453-person HIV-infected cohort and a 219-person HIV-seronegative control group. Neurocognitive function was then correlated with histories of either syphilis or gonorrhea to assess for possible relationships between these sexually transmitted diseases and neurologic impairment. Results: Human immunodeficiency virus-infected subjects with a history of either syphilis or gonorrhea tended to perform worse on neurocognitive testing than their counterparts. This difference could not be explained by educational attainment, age, race or CD4 cell count, and was not noted in the HIV-uninfected control subjects. Conclusions: Sexually transmitted diseases in HIV-infected subjects are correlated with neurocognitive impairment through an unidentified mechanism. more...

To investigate the association of antigen specific CD4 T cell activation with HIV disease progression and AIDS-related central nervous system damage, T cell proliferation responses to HIV, CMV, and HSV were evaluated in infected individuals. CD4 T cell loss and neurocognitive impairment were assessed at 6-mo intervals. Individuals with known times of seroconversion who responded to more HIV peptides were at greater risk of progressing to < 200 CD4 T cells (P = 0.04) and dying (P = 0.03) than those with responses to fewer peptides. A positive correlation (0.52) was seen between the breadth of the HIV proliferation response and HIV plasma RNA levels. Higher proliferation responses to CMV and HSV were also associated with more rapid CD4 loss (P = 0.05). HLA phenotyped individuals (n = 150) with two HLA-DR alleles associated with response to more HIV peptides and CMV (DR-2,5,w6,10) were less likely to develop neurocognitive (P = 0.002) and neurologic impairment (P = 0.04), but were not protected from CD4 loss and death. Thus, the ability to generate a greater T cell proliferation response to HIV and opportunistic herpes viruses may lead to resistance to central nervous system damage, but also risk of more rapid HIV disease progression. more...

To determine the relationship between levels of Mycobacterium avium complex (MAC) in blood and tissues, histopathologic examination and quantitative MAC cultures were done on blood samples and tissue samples of 7 organs at autopsy of 10 AIDS patients who had been treated for MAC bacteremia. Blood and tissue cultures were negative for MAC for 3 of the patients and positive for 7. The numbers of MAC colony-forming units in the blood and tissues were highly correlated. The highest concentrations of MAC were observed in the reticuloendothelial organs, with a maximum of 6.9 log10 cfu/g in mesenteric lymph nodes and 6.8 log10 cfu/g in spleen. Histopathologic findings paralleled quantitative cultures and were consistent with entry of MAC via lymphatics through the gastrointestinal tract, followed by hematogenous dissemination. more...

We tested the hypothesis that increases in tumor necrosis factor alpha (TNF-alpha) induced by human immunodeficiency virus (HIV) are associated with the increases in slow-wave sleep seen in early HIV infection and the decrease with sleep fragmentation seen in advanced HIV infection. Nocturnal sleep disturbances and associated fatigue contribute to the disability of HIV infection. TNF-alpha causes fatigue in clinical use and promotes slow-wave sleep in animal models. With slow progress toward a vaccine and weak effects from current therapies, efforts are directed toward extending productive life of HIV-infected individuals and shortening the duration of disability in terminal illness. We describe previously unrecognized nocturnal cyclic variations in plasma levels of TNF-alpha in all subjects. In 6 of 10 subjects (1 control subject, 3 HIV-seropositive patients with CD4+ cell number > 400 cells per microliters, and 2 HIV-positive patients with CD4+ cell number < 400 cells per microliters), these fluctuations in TNF-alpha were coupled to the known rhythm of electroencephalogram delta amplitude (square root of power) during sleep. This coupling was not present in 3 HIV-positive subjects with CD4+ cell number < 400 cells per microliters and 1 control subject. In 5 HIV subjects with abnormally low CD4+ cell counts ( < 400 cells per microliters), the number of days since seroconversion correlated significantly with low correlation between TNF-alpha and delta amplitude. We conclude that a previously unrecognized normal, physiological coupling exists between TNF-alpha and delta amplitude during sleep and that the lessened likelihood of this coupling in progressive HIV infection may be important in understanding fatigue-related symptoms and disabilities. more...

Few if any studies before the AIDS epidemic suggested that male homosexuals may on average have higher levels of depression than male heterosexuals. However, several samples of homosexual and bisexual men in HIV studies suggest that depression and anxiety are high in these populations, and that this psychiatric morbidity began before the AIDS epidemic. We tested the hypothesis that high childhood gender nonconformity (CGN) is associated with depression and anxiety, and so might account for differences in these variables among samples of homosexuals. A total of 254 homosexual or bisexual male subjects were assessed for depression, anxiety, and associated symptoms using various self-report and interview measures, as well as for CGN (using the Freund Feminine Gender Identity scale, FGI). For comparison purposes only, we also evaluated the subjects for the DSM-III diagnosis of Ego-Dystonic Homosexuality. Highly gender nonconforming men (high FGI scores) were more likely to have current symptoms of anxiety and depression by self-report, and to have had a lifetime history of depression by clinical interview. This association was more often due to FGI items dealing with childhood than adulthood. When the FGI was broken into subscales by a prior factor analysis, stepwise regression suggested that the subscale measuring core gender identity nonconformity (so-called "gender dysphoria") was more reliably associated with depression and anxiety than were the factors measuring nonconformity in the areas of masculine and feminine gender roles, or genitoerotic (sexual) roles. This subscale was also the only FGI measure correlating with Ego-Dystonic Homosexuality. AIDS (CDC stage and HIV serostatus) and age did not account for these findings. We conclude that the often-reported higher levels of depression, anxiety, and associated symptoms among homosexual and bisexual men in AIDS studies are more common in the subgroup of such men who are gender dysphoric. Theoretical and clinical implications of these data are discussed. more...

Individuals infected with the human immunodeficiency virus-Type 1 (HIV-1), are at increased risk for neurobehavioral impairment, particularly in later stages of the disease. Even patients in the medically asymptomatic or minimally symptomatic stages of infection may show mild deficits on comprehensive neuropsychological (NP) test batteries, although the clinical significance of such deficits remains uncertain. The present study used vocational difficulties as markers of clinical significance of NP impairment. In a sample of 289 HIV-infected, nondemented men, those who evidenced NP impairment had a higher unemployment rate (p < .001) than did their unimpaired counterparts. In HIV-positive subjects who remained employed, NP impairment was strongly associated with subjective decreases in job-related abilities. Neither depression nor medical symptoms could explain the relationship between the NP impairment and employment problems. These results are consistent with previous studies investigating other neuropsychiatric disorders, which suggest that even mild NP impairment can interfere with employment status. From this standpoint, such impairment in HIV-infected persons may be described as "clinically significant." more...