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Biomedical subjects

Ann C Collier

Publications and source records attributed to Ann C Collier.

At least 19 recordsLinked to original sources
PubMed2007

Pretreatment factors associated with 3-year (144-week) virologic and immunologic responses to potent antiretroviral therapy.

OBJECTIVE: To examine pretreatment factors associated with longer term (144 weeks) responses to antiretroviral therapy (ART). METHODS: Of 1498 ART-naive subjects randomized to ART regimens, including > or =3 agents, 1083 patients who had plasma HIV RNA (vRNA) levels and CD4 cell counts at baseline and week 144 were analyzed. Primary baseline factors evaluated were CD4 cell count, vRNA level, gender, race, and age, using multivariable Cox, log-binomial, and linear regression models. RESULTS: Shorter time to achieving a vRNA level <50 copies/mL was associated with lower baseline vRNA level (P < 0.001), older age (P = 0.007), and lower baseline CD4 cell count (P = 0.055). After adjusting for race, gender, and baseline CD4 cell count, older age was associated with a vRNA level <50 copies/mL at week 144 (P = 0.018). Greater CD4 count increases from baseline to week 144 (mean = 284 cells/microL) were seen in younger men, blacks, and subjects with higher pretreatment vRNA levels; the effect of pretreatment vRNA level was most apparent in women. CONCLUSIONS: Older age was the most important baseline predictor of a vRNA level <50 copies/mL at week 144; lower pretreatment vRNA level and older age were the most important predictors of time to a vRNA level <50 copies/mL. The influence of pretreatment factors on increases in CD4 cell counts differed between men and women.

Adult↗
PubMed2006

Screening for acute HIV infection: lessons learned.

Human immunodeficiency virus (HIV) nucleic acid testing is increasingly being used by researchers and public health screening programs to identify highly infectious, HIV antibody-negative individuals with acute HIV infection. We present cases to illustrate unusual instances of acute HIV screening, which include "window period" testing and the discovery of low-level HIV RNA.

Acute Disease↗
PubMed2006

Abacavir hypersensitivity reaction in primary HIV infection.

OBJECTIVE: To evaluate risk factors associated with the abacavir hypersensitivity reaction during primary HIV infection (PHI). DESIGN: Acute HIV Infection and Early Disease Research Program protocol (AIEDRP) AI-02-001 provided antiretroviral therapy including abacavir. This retrospective analysis evaluated variables potentially associated with hypersensitivity in the cohort enrolled in AI-02-001 at the University of Washington Primary Infection Clinic. METHODS: Cases of suspected hypersensitivity were identified prospectively and reviewed retrospectively using a standardized case definition. Controls were the remaining cohort without hypersensitivity. Univariate analyses were performed by linear logistic regression. RESULTS: Nine (18%) of 50 individuals treated with abacavir developed suspected hypersensitivity. Two of nine cases and no controls were HLA-B5701 positive. When antiretroviral medications were started, cases had lower mean CD8 T-cell percentage and plasma HIV RNA value. After 2 weeks on abacavir, cases had a lower mean HIV RNA value and a trend towards greater decrease in RNA. Cases began abacavir a median of 103 days after HIV acquisition compared to 48 days for controls. There was no significant in vitro abacavir-specific lymphoproliferation or IFN-gamma production in peripheral blood mononuclear cells from individuals following the suspected hypersensitivity reaction. CONCLUSIONS: Abacavir use during PHI may be associated with increased risk of hypersensitivity. As in chronic infection, HLA-B5701 is associated with the abacavir hypersensitivity reaction in PHI. Although levels of CD8 T cells and HIV RNA may be risk factors for hypersensitivity, the observed association may be due to correlation with HLA-B5701. The interesting temporal association of hypersensitivity with initiation of abacavir later in PHI merits future investigation.

Adult↗
PubMed2006

Lower genitourinary tract sources of seminal HIV.

OBJECTIVE: To investigate genital tract sources of HIV-1, we conducted extensive genitourinary sampling of 23 seropositive men without urethritis who shed HIV in their seminal plasma. DESIGN: Semen was collected, then samples were obtained for HIV RNA in blood plasma, urethral fluid, pre-prostate massage fluid/urine (PMF/U) and post-PMF/U, and expressed prostatic secretions. Systematic transrectal ultrasound-guided prostate biopsies obtained from multiple prostate areas were evaluated for HIV RNA and DNA. RESULTS: Seminal HIV RNA levels correlated with HIV RNA levels in urethral fluid and post-PMF/U and with prostate biopsies HIV DNA, but not with expressed prostatic secretions HIV RNA. However, only the HIV RNA level in post-PMF/U independently predicted that in semen (2.77-fold change in semen for each 10-fold change in post-PMF/U; 95% confidence interval, 1.0-7.7) accounting for one third of the seminal HIV RNA level variation, irrespective of adjustment for antiretroviral therapy. CONCLUSIONS: These data indicate that distal genitourinary sources other than the prostate appear to be the major source of seminal HIV in men without clinical urethritis or prostatitis. Because the HIV RNA level in blood plasma is not reliable as an independent clinical predictor of virus levels in seminal plasma, these findings also extend the concept that the male genital tract is a distinct virological compartment from blood.

Adult↗
PubMed2006

A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naïve people.

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.

Adult↗
PubMed2006

Verapamil P-glycoprotein transport across the rat blood-brain barrier: cyclosporine, a concentration inhibition analysis, and comparison with human data.

To predict the magnitude of P-glycoprotein (P-gp)-based drug interactions at the human blood-brain barrier (BBB), rodent studies are routinely conducted where P-gp is chemically inhibited. For such studies to be predictive of interactions at the human BBB, the plasma concentration of the P-gp inhibitor must be comparable with that observed in the clinic. Therefore, we determined the in vivo EC(50) of P-gp inhibition at the rat BBB using verapamil as a model P-gp substrate and cyclosporine A (CsA) as the model P-gp inhibitor. Under isoflurane anesthesia, male Sprague-Dawley rats were administered i.v. CsA to achieve pseudo steady-state CsA blood concentrations ranging from 0 to approximately 12 microM. Then, an i.v. tracer dose of [(3)H]verapamil was administered, and 20 min after verapamil administration, the animals were sacrificed for determination of blood, plasma, and brain (3)H radioactivity by scintillation counting. The percentage increase in the brain/blood (3)H radioactivity (relative to 0 microM CsA) was described by the Hill equation with E(max), 1290%; EC(50), 7.2 microM; and gamma, 3.8. Previously, using [(11)C]verapamil, we have shown that the human brain/blood (11)C radioactivity was increased by 79% at 2.8 microM CsA blood concentration. At an equivalent CsA blood concentration, the rat brain/blood (3)H radioactivity was increased by a remarkably similar extent of 75%. This is the first time that an in vivo CsA EC(50) of P-gp inhibition at the rat BBB has been determined and the magnitude of such inhibition was compared between the rat and the human BBB at the same blood CsA concentration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Primary HIV infection education: knowledge and attitudes of HIV-negative men who have sex with men attending a public health sexually transmitted disease clinic.

BACKGROUND: Although many individuals who acquire HIV are symptomatic, primary HIV infection (PHI) is infrequently diagnosed, even after the integration of RNA testing into HIV screening programs. Until more individuals with PHI seek evaluation, the public health impact of RNA testing is likely to be small. OBJECTIVE: To describe knowledge of PHI and attitudes toward health care-seeking behavior for symptoms consistent with PHI in men who have sex with men (MSM). METHODS: Between April 2004 and March 2005, HIV-negative MSM attending the Public Health-Seattle and King County sexually transmitted disease (STD) clinic completed an anonymous, self-administered, written questionnaire. RESULTS: Ninety-six (64%) of 150 subjects named > or =1 symptom associated with PHI. Only 18 (39%) of 46 men who knew PHI could resemble influenza would seek care for flu-like symptoms. Fifteen (65%) of 23 men reporting a week-long febrile illness with rash in the preceding year sought health care, but only 7 (30%) were tested for HIV. CONCLUSIONS: Although most subjects identified some symptoms of PHI, relatively few would seek care for such symptoms. MSM seeking attention for febrile illnesses were infrequently tested for HIV. Increased symptom recognition, health care-seeking behavior, and routine HIV RNA testing are needed if PHI screening programs are to have meaningful impact.

Acute Disease↗
PubMed2006

Selection on the human immunodeficiency virus type 1 proteome following primary infection.

Typically during human immunodeficiency virus type 1 (HIV-1) infection, a nearly homogeneous viral population first emerges and then diversifies over time due to selective forces that are poorly understood. To identify these forces, we conducted an intensive longitudinal study of viral genetic changes and T-cell immunity in one subject at < or =17 time points during his first 3 years of infection, and in his infecting partner near the time of transmission. Autologous peptides covering amino acid sites inferred to be under positive selection were powerful for identifying HIV-1-specific cytotoxic-T-lymphocyte (CTL) epitopes. Positive selection and mutations resulting in escape from CTLs occurred across the viral proteome. We detected 25 CTL epitopes, including 14 previously unreported. Seven new epitopes mapped to the viral Env protein, emphasizing Env as a major target of CTLs. One-third of the selected sites were associated with epitopic mutational escapes from CTLs. Most of these resulted from replacement with amino acids found at low database frequency. Another one-third represented acquisition of amino acids found at high database frequency, suggesting potential reversions of CTL epitopic sites recognized by the immune system of the transmitting partner and mutation toward improved viral fitness in the absence of immune targeting within the recipient. A majority of the remaining selected sites occurred in the envelope protein and may have been subjected to humoral immune selection. Hence, a majority of the amino acids undergoing selection in this subject appeared to result from fitness-balanced CTL selection, confirming CTLs as a dominant selective force in HIV-1 infection.

Amino Acid Sequence↗
PubMed2005

A randomized study of serial telephone call support to increase adherence and thereby improve virologic outcome in persons initiating antiretroviral therapy.

BACKGROUND: Adherence to antiretroviral therapy is difficult, and methods to increase it are needed. METHODS: We tested the impact of supportive telephone calls in an adherence substudy of a treatment trial. Subjects initiating antiretroviral therapy received either each site's usual adherence support measures or usual support measures and scripted serial telephone calls (16 calls during 96 weeks). RESULTS: A total of 282 subjects enrolled: 140 in the usual support measures group and 142 in the calls group. A total of 75% of expected calls were completed. Virologic failure occurred in 97 (34%) subjects: 52 (37%) of those in the usual support measures group and 45 (32%) of those in the calls group; time to virologic failure was not different (P=.32). In each group, >72% of subjects reported > or =95% adherence, with no difference between groups. Independent predictors of higher rates of virologic failure were <95% adherence, receiving the 4-drug regimen with nelfinavir, and female sex; older age was associated with decreased likelihood of virologic failure. Receiving the 4-drug regimen with nelfinavir, higher stress scores, older age, and higher call completion rates were independently associated with higher adherence. CONCLUSIONS: Serial telephone calls did not improve virologic outcome but had an impact on self-reported adherence.

Adult↗
PubMed2005

Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results.

OBJECTIVE: To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk. DESIGN: Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects. METHODS: A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001). RESULTS: Amprenavir mean area under the curve over 12 h (AUC0-12 h) and concentration at 12 h (C12 h) (microg/ml) were, respectively, 42.7 microg x h/ml (range, 33.1-55.1) and 2.4 microg/ml (range, 1.4-3.2) in arm B and 17.4 microg x h/ml (range, 4.6-41.3) and 0.9 microg/ml (range, 0.2-2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P < or = 0.0001). Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 microg x h/ml (range, 60.3-119.3) and 6.3 microg/ml (range, 2.2-9.2) in arm A and 54.4 microg x h/ml (range, 23.5-112.2) and 3.0 microg/ml (range, 0.4-7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P < or = 0.0008). Ritonavir exposure was not significantly different between arms. CONCLUSION: APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

Adult↗
PubMed2005

Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography.

BACKGROUND: Numerous knockout mouse studies have revealed that P-glycoprotein (P-gp) significantly limits drug distribution across the mouse blood-brain barrier (BBB). To determine the importance of P-gp at the human BBB, we developed a state-of-the-art, noninvasive, quantitative imaging technique to measure P-gp activity by use of carbon 11-labeled verapamil as the P-gp substrate and cyclosporine (INN, ciclosporin) as the P-gp inhibitor. METHODS: In brief, 11C-verapamil (approximately 0.2 mCi/kg) was administered to healthy volunteers (n = 12 [6 women and 6 men]) as an intravenous infusion over a period of approximately 1 minute before and after at least a 1-hour infusion of cyclosporine (2.5 mg x kg(-1) x h(-1)). Arterial blood samples and brain positron emission tomography images were obtained at frequent intervals for 45 minutes. Both blood and plasma radioactivity contents were determined in each verapamil sample. The content of verapamil and its metabolites in the 20- and 45-minute plasma samples was determined by a rapid solid-phase extraction method. The brain uptake of 11C-radioactivity (brain area under the curve [AUCbrain ]/blood area under the curve [AUCblood]) was determined in the presence and absence of cyclosporine. RESULTS: The AUCbrain/AUCblood ratio of 11C-radioactivity was increased by 88% +/- 20% (1.02 +/- 0.18 versus 0.55 +/- 0.10, P < .001) in the presence of cyclosporine (mean blood concentration, 2.8 +/- 0.4 micromol/L) without affecting 11C-verapamil metabolism or plasma protein binding. The corresponding increases for the brain white and gray matter were 84% +/- 13% and 84% +/- 18%, respectively. CONCLUSIONS: This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Clinical validation of the NeuroScreen.

The NeuroScreen comprises two easily administered components: the Brief NeuroCognitive Screen (BNCS), designed to estimate the frequency of human immunodeficiency virus (HIV)-associated cognitive disorders; and the Brief Peripheral Neuropathy Screen (BPNS), for distal sensory polyneuropathy (DSPN) in HIV. In this study, both the NeuroScreen and a more extensive standardized validation neurodiagnostic evaluation were administered to HIV-positive subjects (N = 301) enrolled in two large cohort studies at multiple sites. BNCS performance was summarized in the form of a demographically adjusted mean z-score, the NPZ3. The area under the receiver-operating characteristic (ROC) curve for the BNCS as compared to the reference standard neuropsychological (NP) evaluation was 0.74 (95% confidence interval [CI] 0.69, 0.79). Using a cut-point of -0.33 on the NPZ3 provided a correct classification rate of 68%, with roughly balanced sensitivity (65%) and specificity (72%). Under the assumption of a 30% prevalence of cognitive impairment, the calculated positive predictive value (PPV) of the BNCS was 86%. Relative to its reference standard, a modified Total Neuropathy Score (TNS) administered by a neurologist, the BPNS gave a similar correct diagnostic classification rate of 78%; sensitivity 49% [95%, 60%]; specificity 88% [95% Cl82%, 91%]. Under the assumption of a 40% prevalence of DSPN, the PPV of the BPNS was 72%. These predictive values suggest that the NeuroScreen will be useful for tracking trends in the prevalence of HIV-associated neurologic disease in large cohorts in the era of combination antiretroviral therapy. However, because it yields substantial numbers of false positives and negatives, the NeuroScreen may be less useful in evaluating individual patients.

AIDS Dementia Complex↗
PubMed2004

Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection.

AMD3100 is a CXCR4 receptor inhibitor with anti-HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 microg/kg/h. Forty HIV-infected patients with an HIV RNA level >5000 copies/mL on stable antiretroviral (ARV) regimens or off therapy were enrolled. Syncytium-inducing (SI) phenotype in an MT-2 cell assay was required in higher dose cohorts. Most subjects were black (55%), male (98%), and off ARV therapy. HIV phenotype was SI (30%), non-SI (45%), or not tested (25%). One patient (5 microg/kg/h) had serious and possibly drug-related thrombocytopenia. Two patients (40 and 160 microg/kg/h) had unexpected, although not serious, premature ventricular contractions. Most patients in the 80- and 160-microg/kg/h cohorts had paresthesias. Steady-state blood concentration and area under the concentration-time curve were dose proportional across all dose levels; the median terminal elimination half-life was 8.6 hours (range: 8.1-11.1 hours). Leukocytosis was observed in all patients, with an estimated maximum effect of 3.4 times baseline (95% confidence interval: 2.9-3.9). Only 1 patient, the patient whose virus was confirmed to use purely CXCR4 and who also received the highest dose (160 microg/kg/h), had a significant 0.9-log10 copies/mL HIV RNA drop at day 11. Overall, however, the average change in viral load across all patients was +0.03 log10 HIV RNA. Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.

Anti-HIV Agents↗
PubMed2004

Association of T cell proliferative responses and phenotype with virus control in chronic progressive HIV-1 disease.

The role of T cell immunity in virus control during chronic infection was examined in 79 human immunodeficiency virus type 1 (HIV-1)-infected subjects randomized to receive antiretroviral therapy. HIV-1 p24-specific responses were detected in 20% of the subjects at baseline, increasing to 28% of the subjects at weeks 16-24. Induction of virologic suppression was associated with lower plasma HIV-1 RNA levels and a higher percentage of Fas+ CD8+ T cells at baseline, whereas maintenance of suppression was associated with higher CD4+ T cell counts and, marginally, with a higher percentage of Fas+ CD4+ T cells at weeks 16-24. These findings indicate that Fas coexpression on T cells, in addition to plasma HIV-1 RNA levels and CD4+ T cell counts, may predict virologic outcome.

Anti-HIV Agents↗
PubMed2004

Primary HIV Infection.

Primary HIV infection refers to the events surrounding acquisition of HIV infection. It is associated with a nonspecific clinical syndrome that occurs 2 to 4 weeks after exposure in 40% to 90% of individuals acquiring HIV. Patients identified before seroconversion often have very high plasma HIV RNA titers that, without treatment, gradually decrease to reach a set point. Treatment of primary HIV infection with highly active antiretroviral therapy does not prevent establishment of chronic infection. However, very early therapy could potentially decrease the viral set point, prevent viral diversification, preserve immune function, improve clinical outcomes, and decrease secondary transmission. These benefits have not yet been definitely demonstrated. Transmission of viral strains with decreased susceptibility to antiviral drugs has led to recommendations for resistance testing in primary infection before initiation of therapy. Immunomodulators and vaccines are also under study as adjuvant therapy for treatment of primary HIV infection.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Genetic basis of hypersusceptibility to protease inhibitors and low replicative capacity of human immunodeficiency virus type 1 strains in primary infection.

The initial virus strains from as many as 12% of individuals with primary human immunodeficiency virus (HIV) infection have a 50% inhibitory concentration </=0.4-fold that of HIV type 1(NL4-3) (HIV-1(NL4-3)) to ritonavir (hypersusceptibility [HS]). There is also substantial variation in replicative capacity (RC) or an in vitro assay of the contributions of protease (PR) and reverse transcriptase to viral fitness. In chronically infected antiretrovirally treated patients, amprenavir HS has been associated with the mutation N88S in PR, but this mutation is not seen in untreated patients. In this study, virus strains from 182 cases of primary HIV infection were analyzed, and a highly significant association between HS and low RC (</=10% that of HIV-1(NL4-3)) was observed (P < 10(-6)). Multivariate analysis was used to determine the genotypic basis of ritonavir HS, analyzing all polymorphic amino acid sites and insertions from p7gag through PR. Decision tree models developed on the entire Gag-plus-PR data set and on PR alone gave overall correct classifications of 73 and 72%, respectively, on cross-validation. They were also able to predict low RC, with sensitivities of 69 and 62% and specificities of 84 and 70%, respectively. The analysis shows that ritonavir HS in untreated primary HIV infection is not associated with single mutations but with combinations of amino acids at polymorphic sites and that the same genotypes which confer HS to PR inhibitors confer low RC. This supports the view that variation in PR function is directly responsible for variation in fitness among strains in primary infection.

Decision Trees↗
PubMed2003

A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease.

To compare long-term virologic benefits of antiretroviral regimens in persons with advanced human immunodeficiency virus (HIV) disease, a randomized, open-label study was conducted of 517 subjects with no or limited previous experience with antiretroviral therapy. Subjects received lamivudine plus zidovudine and indinavir (indinavir group), efavirenz plus indinavir (efavirenz + indinavir group), or nelfinavir plus indinavir (nelfinavir + indinavir group) and were monitored for 2.1 years. Virologic failure was lower in the efavirenz + indinavir group (P=.04) and higher in the nelfinavir + indinavir group (P=.006), compared with that in the indinavir group. No difference in grade 3 or 4 adverse event rates in the efavirenz + indinavir group (P=.97) and a trend toward an increased rate in the nelfinavir + indinavir group (P=.07), compared with the indinavir group, were noted. A 4-drug regimen containing efavirenz plus indinavir resulted in a superior virologic response, whereas one containing nelfinavir plus indinavir resulted in an inferior response and a greater likelihood of toxicity.

Adult↗