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Jayraan Badiee,
David J Moore,
J Hampton Atkinson,
Florin Vaida,
Mickey Gerard,
Nichole A Duarte,
Donald Franklin,
Ben Gouaux,
J Allen McCutchan,
Robert K Heaton,
Justin McArthur,
Susan Morgello,
David Simpson, Ann Collier,
Christina M Marra,
Benjamin Gelman,
David Clifford,
Igor Grant
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ABSTRACT: 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, suggest 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.
Journal of affective disorders 07/2011; 136(3):993-9. · 3.76 Impact Factor
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Lucette A Cysique,
Donald Franklin,
Ian Abramson,
Ronald J Ellis,
Scott Letendre, Ann Collier,
David Clifford,
Benjamin Gelman,
Justin McArthur,
Susan Morgello,
David Simpson,
J Allen McCutchan,
Igor Grant,
Robert K Heaton
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ABSTRACT: 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 analyses 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 e-mail 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.
Journal of Clinical and Experimental Neuropsychology 03/2011; 33(5):505-22. · 2.13 Impact Factor
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David Croteau,
Scott Letendre,
Brookie M Best,
Ronald J Ellis,
Sheila Breidinger,
David Clifford, Ann Collier,
Benjamin Gelman,
Christina Marra,
Gilbert Mbeo,
Allen McCutchan,
Susan Morgello,
David Simpson,
Lauren Way,
Florin Vaida,
Susan Ueland,
Edmund Capparelli,
Igor Grant
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ABSTRACT: HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC(50)) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4(+) cell count was 276/μl, and 28% of CD4(+) cell counts were below 200/μl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r(2), 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC(50) for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.
Antimicrobial Agents and Chemotherapy 09/2010; 54(12):5156-60. · 4.84 Impact Factor
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Ronald J Ellis,
Debralee Rosario,
David B Clifford,
Justin C McArthur,
David Simpson,
Terry Alexander,
Benjamin B Gelman,
Florin Vaida, Ann Collier,
Christina M Marra,
Beau Ances,
J Hampton Atkinson,
Robert H Dworkin,
Susan Morgello,
Igor Grant
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ABSTRACT: To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus-associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Six US academic medical centers.
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95% confidence interval, 1.8-2.5] per 10 years), lower CD4 nadir (1.2 [1.1-1.2] per 100-cell decrease), current CART use (1.6 [1.3-2.8]), and past "D-drug" use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3-2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
Archives of neurology 05/2010; 67(5):552-8. · 6.31 Impact Factor
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Brookie M Best,
Scott L Letendre,
Eileen Brigid,
David B Clifford, Ann C Collier,
Benjamin B Gelman,
Justin C McArthur,
J Allen McCutchan,
David M Simpson,
Ronald Ellis,
Edmund V Capparelli,
Igor Grant
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ABSTRACT: 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.
AIDS (London, England) 02/2009; 23(1):83-7. · 4.91 Impact Factor
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ABSTRACT: Abstract
Background
Cerebrospinal fluid (CSF) pleocytosis may be seen in asymptomatic HIV-infected individuals. This finding complicates interpretation of CSF abnormalities when such individuals are evaluated for other central nervous system infections. The goal of this study was to determine the relationship between CSF pleocytosis, central nervous system (CNS) antiretroviral penetration, adherence to antiretroviral medication regimens, neurological symptoms and performance on neuropsychological tests.
Methods
Clinically stable HIV-infected individuals at any peripheral blood CD4+ T cell count or any plasma viral load were asked to attend study visits at entry and every 6 months thereafter for at least one year. At each visit, they underwent a standardized neurological and medication history; neurological examination; a brief neuropsychological test battery: venipuncture; lumbar puncture; and assessment of medication adherence. Generalized estimating equations (GEE) were used to assess the relationships between CSF pleocytosis and other variables.
Results
CSF pleocytosis was independently and significantly related to lack of current antiretroviral use (OR 5.9, 95% CI 1.8–18.6, p = 0.003), CD4 count > 200/ul (OR 23.4, 95% CI 3.1–177.3, p = 0.002) and detectable plasma HIV RNA (OR 3.3, 95% CI 1.1–9.4, p = 0.03). At visits where antiretrovirals were used, and taking into account detectable plasma HIV RNA, an antiretroviral regimen that contained two or more agents with good CNS penetration conferred a trend toward lower odds of CSF pleocytosis (OR 0.45, 95% CI 0.18–1.12, p = 0.087).
Conclusion
CSF pleocytosis is a characteristic of HIV disease that varies significantly with easily identifiable clinical and laboratory features. Use of antiretroviral agents decreases the odds of pleocytosis. This association may be stronger when the regimen contains two or more agents with good CNS penetration.
BMC Infectious Diseases. 01/2007;
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ABSTRACT: Uncontrolled studies have suggested a benefit, after treatment discontinuation, of initiating highly active antiretroviral therapy (HAART) during primary human immunodeficiency virus (HIV) infection. We assessed whether initiation of HAART within 2 weeks of (acute treatment) or between 2 weeks and 6 months after (early treatment) HIV seroconversion was associated with improvements in the viral load and the CD4+ T cell count after discontinuation of treatment in an observational cohort.
Subjects from the multicenter Acute Infection and Early Disease Research Program cohort were enrolled in the present study within 6 months of HIV seroconversion and self-selected whether to initiate HAART. Subjects who received acute (n=13) or early (n=45) treatment received HAART for at least 12 weeks and then subsequently stopped treatment, whereas untreated subjects (n=337) declined treatment. HIV RNA levels and CD4+ T cell counts at 24, 48, and 72 weeks after treatment cessation in the 2 treatment groups were compared with those noted in the untreated group during the same periods of observation after enrollment.
The acute treatment group had lower mean HIV RNA levels at 24 weeks without therapy (-0.48 log(10) copies/mL [95% confidence interval {CI}, -0.82 to -0.13 log(10) copies/mL]) and higher mean CD4+ T cell counts (112 cells/ mu L [95% CI, 20-205 cells/ microL]), compared with the untreated group at 24 weeks. The differences in the laboratory values for the acute treatment group versus the untreated group at 72 weeks without therapy were as follows: for the HIV RNA level, -0.35 log(10) copies/mL (95% CI, -0.91 to 0.21 log(10) copies/mL) and, for the CD4 T+ cell count, 112 cells/ microL (95% CI, -15 to 213 cells/ microL). The early treatment group had lower HIV RNA levels at 24 weeks than did the untreated group, but differences were no longer apparent by week 48; CD4+ T cell counts were higher in the early treatment group at week 24 (116 cells/ microL [95% CI, 75-157 cells/ microL]) and week 72 (70 cells/ microL [95% CI, 2-138 cells/ microL]).
Initiation of HAART within 2 weeks of antibody seroconversion was associated with viral load and CD4+ T cell count benefits for 24 weeks after termination of HAART, with there being trends toward a longer-term benefit. Later initiation of HAART was associated with a persistent but decreasing CD4+ T cell count benefit and a loss of the viral load benefit by week 72 after discontinuation of treatment.
The Journal of Infectious Diseases 10/2006; 194(6):725-33. · 6.41 Impact Factor
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ABSTRACT: Abstract
Background
While hearing loss in HIV-infected people after beginning nucleoside reverse transcriptase inhibitors (NRTIs) has been reported, there have been no prospective studies that measured hearing changes longitudinally in treatment-naïve HIV-infected subjects following initiation of regimens containing NRTIs. The goal of this study was to conduct a prospective assessment of the contribution of zidovudine (ZDV) and didanosine (ddI) to hearing loss
Methods/design
A prospective observational pilot study to determine whether ZDV or ddI, alone or in combination, are associated with sensorineural hearing loss in HIV-infected persons. Changes in hearing levels at all frequencies and in low and high frequency pure tone averages were measured at baseline, 16, and 32 weeks after initiating antiretroviral therapy.
Discussion
Treatment with ZDV and ddI did not result in loss of hearing, even after taking into account noise exposure, immune status and age. The results of this prospective pilot study do not support the notion that treatment with nucleoside antiretrovirals damages hearing.
BMC Infectious Diseases. 01/2006;
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Andrew R Zolopa,
Laura C Lazzeroni,
Alex Rinehart,
Françoise Brun Vezinet,
François Clavel, Ann Collier,
Brian Conway,
Roy M Gulick,
Mark Holodniy,
Carlo-Frederico Perno,
Robert W Shafer,
Douglas D Richman,
Mark A Wainberg,
Daniel R Kuritzkes
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ABSTRACT: Resistance testing is considered standard of care in HIV medicine, but there is no standard interpretation system for genotype tests. We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes.
Genotypes from clinical specimens were sent to an international panel of 12 resistance experts. Phenotypic susceptibility testing of these clinical isolates was performed with antivirogram. Experts predicted phenotype fold change category (<2.5-fold change, 2.5-4.0-fold change, >4.0- to 7.0-fold change, >7.0- to 10-fold change, >10- to 20-fold change, or >20-fold change) and predicted expected drug activity for each of 16 antiretroviral drugs. Experts were also asked to make treatment recommendations on the basis of the genotype.
The experts predicted the exact phenotype fold change category correctly 44% of the time, but they varied widely by antiretroviral drug (range, 25%-74%). The highest accuracy was observed for lamivudine (74%) and the nonnucleoside reverse transcriptase inhibitors (66%-69%). Experts generally predicted higher levels of resistance to the remaining nucleoside reverse transcriptase inhibitors than what was found by phenotypic testing. Agreement among experts in predicting phenotype fold change category ranged widely depending on the drug (median agreement, 42% [range, 28%-74%]); the same pattern was observed in predicting expected drug activity (median agreement, 45% [range, 32%-87%]). Experts agreed on treatment recommendations in a median of 79% of instances, and recommendations were consistent over time, with blinded retesting.
Although their ability to predict phenotype from a genotype varied for individual antiretroviral drugs, this expert panel had a high degree of agreement in deriving treatment recommendations from the genotype.
Clinical Infectious Diseases 08/2005; 41(1):92-9. · 9.15 Impact Factor
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ABSTRACT: Hydroxyurea (HU) has preferential activity in virus reservoirs not effectively targeted by current antiretroviral drug regimens, but concern for potential toxicity has precluded its routine use. The effect of adjunct HU on T cell proliferative responses and phenotypic markers was examined in a randomized study of 39 chronically HIV-1-infected patients with virological suppression on potent antiretroviral therapy. While patients in the HU arm showed modest declines in the median CD4(+) T cell counts (total, -151 cells/mm(3); naive, -91 cells/mm(3)), no significant differences were noted in the Candida, HIV-1 p24, and HIV-1 gp160 responses between the treatment arms following 24 weeks of therapy. In conclusion, although adjunct HU was associated with modest declines in the CD4(+) T cell counts, there was no significant adverse effect on helper T cell function. Further trials to address the role of HU in HIV-1 treatment may be appropriate after careful selection of HU dose and the adjunct drugs to avoid nonhematological toxicity.
AIDS Research and Human Retroviruses 09/2004; 20(8):807-12. · 2.25 Impact Factor
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ABSTRACT: AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (n = 8), the median predose indinavir concentration (C(0)) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1000 mg of indinavir every 12 h with nelfinavir (n = 10), the median indinavir C(0) was <10 ng/ml (range, <10 to 3740 ng/ml; six subjects had a value of <10 ng/ml), and the C(12 h) was 44 ng/ml (range, <10 to 4236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1200 mg of indinavir every 12 h with nelfinavir (n = 7) had a C(0) of 146 ng/ml (range, 58 to 5215 ng/ml) and a C(12 h) of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h]; P < 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median C(0) value for nelfinavir (n = 9) was 1,779 ng/ml (range, <187.5 to 4579 ng/ml), and the C(12 h) was 1554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir.
Antimicrobial Agents and Chemotherapy 04/2004; 48(3):918-23. · 4.84 Impact Factor
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ABSTRACT: Primary HIV-1 infection refers to the events surrounding the acquisition of HIV-1 infection. It is commonly associated with a nonspecific clinical syndrome that occurs within 2 to 4 weeks after exposure in 40% to 90% of persons acquiring HIV-1. Patients identified prior to seroconversion often have plasma titers in excess of 500,000 copies/mL. Over time, plasma HIV-1 RNA titers decrease and eventually reach a "set point." Treatment of primary HIV-1 infection with highly active antiretroviral therapy does not prevent establishment of chronic infection. However, it potentially may decrease the viral set point, prevent evolution of resistant mutants, preserve immune function, improve clinical outcome, and possibly allow for viral control after withdrawal of antiretroviral therapy. Transmission of viral strains with decreased susceptibility to antiviral drugs increases the difficulty of choosing an antiretroviral regimen. Other medications, including immunomodulators, are under study as adjuvant therapy for treatment of primary HIV-1 infection.
Current Infectious Disease Reports 03/2002; 4(1):81-87.
