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AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00118898","term_id":"NCT00118898"}}NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h−1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

Innovative techniques, potentially using technology, to improve adherence to antiretroviral therapy (ART), may help patients with HIV who struggle with self-care. This qualitative study compared patient and provider participants’ perspectives on ART adherence and text messaging as a tool to promote adherence. Thirteen providers and 14 HIV-infected patients identified four main themes: 1). facilitators and 2). barriers to using text message reminders as a medium for ART medication reminders; 3). framing of text message reminders; and 4). patient responsibility and autonomy in management of their health and wellness. Ease of use, access, convenience, and confidentiality were cited as benefits of a text message based adherence intervention; while access, cost, difficulty manipulating cellular phones, lack of knowledge/education, and confidentiality were cited as potential barriers. Providers, but not patients, also identified patient apathy and time burden as potential barriers to a text message based adherence reminder system. Patients and providers felt that personalization of messages, attention to timing, and confidentiality of messages were key factors for a successful text message based adherence reminder system. Both providers and patients felt that patient responsibility and autonomy over an individual’s own health care is an important issue in adherence to medical care. The majority of patients and providers felt that a text message based adherence reminder system would be beneficial. While patients and providers had many similar views on factors influencing adherence with ART and the use of text messaging to improve adherence, there were some divergent views between the two groups.

Background: HIV medication nonadherence is a major problem, yet many providers lack the time and training to carefully ask patients about their adherence. Objective: To design and pilot a technology-assisted intervention, for use in clinical settings, to identify nonadherent patients. Methods: The intervention uses audio computer-assisted self-interview (ACASI) to improve the assessment of adherence and medication-related problems. Patients completed a touch screen computer ACASI which generated graphic clinician and patient reports for discussion during the clinical encounter. Results: 72 patients and 11 providers participated in this study. The patients easily completed the ACASI. Adherence was 63% (3-day) and 47% (30-day). Using the ACASI, 22% of patients identified themselves as nonadherent, when their providers perceived them as adherent. Conclusions: This ACASI-based intervention is easy to use and helps identify nonadherence. The pilot test engendered enhancements including the addition of phone-based adherence counseling. A larger trial is underway to evaluate whether the intervention leads to improved HIV-related outcomes.

Background. Retention in care for human immunodeficiency virus (HIV)–infected patients is a National HIV/AIDS Strategy priority. We hypothesized that retention could be improved with coordinated messages to encourage patients' clinic attendance. We report here the results of the first phase of the Centers for Disease Control and Prevention/Health Resources and Services Administration Retention in Care project. Methods. Six HIV-specialty clinics participated in a cross-sectionally sampled pretest-posttest evaluation of brochures, posters, and messages that conveyed the importance of regular clinic attendance. 10 018 patients in 2008–2009 (preintervention period) and 11 039 patients in 2009–2010 (intervention period) were followed up for clinic attendance. Outcome variables were the percentage of patients who kept 2 consecutive primary care visits and the mean proportion of all primary care visits kept. Stratification variables were: new, reengaging, and active patients, HIV RNA viral load, CD4 cell count, age, sex, race or ethnicity, risk group, number of scheduled visits, and clinic site. Data were analyzed by multivariable log-binomial and linear models using generalized estimation equation methods. Results. Clinic attendance for primary care was significantly higher in the intervention versus preintervention year. Overall relative improvement was 7.0% for keeping 2 consecutive visits and 3.0% for the mean proportion of all visits kept (P

Adherence to antiretroviral therapy (ART) represents one of the strongest predictors of progression to AIDS, yet it is difficult for most patients to sustain high levels of adherence. This study compares the efficacy of a personalized cell phone reminder system (ARemind) in enhancing adherence to ART versus a beeper. Twenty-three HIV-infected subjects on ART with self-reported adherence less than 85% were randomized to a cellular phone (CP) or beeper (BP). CP subjects received personalized text messages daily; in contrast, BP subjects received a reminder beep at the time of dosing. Interviews were scheduled at weeks 3 and 6. Adherence to ART was measured by self-report (SR, 7-day recall), pill count (PC, past 30 days at baseline, then past 3 weeks), Medication Event Monitoring System (MEMS; cumulatively at 3 and 6 weeks), and via a composite adherence score constructed by combining MEMS, pill count, and self report. A mixed effects model adjusting for baseline adherence was used to compare adherence rates between the intervention groups at 3 and 6 weeks. Nineteen subjects completed all visits, 10 men and 9 females. The mean age was 42.7 ± 6.5 years, 37% of subjects were Caucasian and 89% acquired HIV heterosexually. The average adherence to ART was 79% by SR and 65% by PC at baseline in both arms; over 6 weeks adherence increased and remained significantly higher in the ARemind group using multiple measures of adherence. A larger and longer prospective study is needed to confirm these findings and to better understand optimal reminder messages and user fatigue.

Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results: One hundred eighteen subjects were randomized. Virologic failure (

Initiation of combination antiretroviral therapy (ART) results in higher total CD4 cell counts, a surrogate for immune reconstitution. Whether the baseline CD4 cell count affects reconstitution of immune cell subsets has not been well characterized.Using data from 978 patients (621 with comprehensive immunological assessments) from the AIDS [Acquired Immunodeficiency Syndrome] Clinical Trials Group protocol 384, a randomized trial of initial ART, we compared reconstitution of CD4(+), CD4(+) naive and memory, CD4(+) activation, CD8(+), CD8(+) activation, B, and natural killer cells among patients in different baseline CD4(+) strata. Reference ranges for T cell populations in control patients negative for human immunodeficiency virus (HIV) infection were calculated using data from AIDS Clinical Trials Group protocol A5113.Patients in the lower baseline CD4(+) strata did not achieve total CD4(+) cell counts similar to those of patients in the higher strata during 144 weeks of ART, although CD4(+) cell count increases were similar. Ratios of CD4(+) naive-memory cell counts and CD4(+):CD8(+) cell counts remained significantly reduced in patients with lower baseline CD4(+) cell counts (or=350 cells/mm(3)). These immune imbalances were most notable for those initiating ART with a baseline CD4(+) cell countor=200 cells/mm(3), even after adjustment for baseline plasma HIV RNA levels.After nearly 3 years of ART, T cell subsets in patients with baseline CD4(+) cell counts350 cells/mm(3) achieved or approached the reference range those of control individuals without HIV infection. In contrast, patients who began ART withor=350 CD4(+) cells/mm(3) generally did not regain normal CD4(+) naive-memory cell ratios. These results support current guidelines to start ART at a threshold of 350 cells/mm(3) and suggest that there may be immunological benefits associated with initiating therapy at even higher CD4(+) cell counts.

Objectives. The Centers for Disease Control and Prevention (CDC) recommends offering human immunodeficiency virus (HIV) testing to all patients in all high HIV-prevalence clinical settings. We evaluated programmatic aspects of HIV testing across multiple clinical settings within a single medical center. Methods. We analyzed programmatic data of HIV testing in the Urgent Care Center (UCC), inpatient floors, outpatient primary care, a non-clinical Drop-In Center, and Emergency Department (ED). HIV testing was by oral mucosal transudate, venous blood samples, or rapid testing fingersticks, with Western blot confirmation. We compared the sociodemographics and behavioral risks of individuals undergoing HIV testing across the five sites and estimated costs per person tested and per HIV-positive test result. Results. From 2002 to 2004, 16,750 HIV tests were conducted, with 229 (1.4%) previously unreported HIV infections diagnosed among 16,696 valid test results. HIV-positive prevalence was 1.5% for the UCC, 1.5% at the Drop-In Center, 1.4% for primary care, 1.2% for inpatient, and 0.6% in the ED. Behavioral risks were most prevalent in the UCC and the Drop-In Center. The cost per test was lowest in the UCC and highest in the Drop-In Center. The cost per previously unreported HIV infection was lowest in the UCC ($1,980) and highest in the ED ($9,724). Conclusions. Although a significant number of HIV infections were identified, the number of tests performed represents

In HIV/AIDS, symptoms of depression or post-traumatic stress may interfere with important self-care behaviors such as the ability to adhere to one's medical treatment regimen. However, these problems may frequently go undetected in HIV care settings. The present study used brief self-report screening measures of depression and post-traumatic stress disorder (PTSD) in the HIV/AIDS care settings to examine (1) frequency of positive screens for these diagnoses; (2) the degree to which those with a positive screen were prescribed antidepressant treatment; and (3) the association of continuous PTSD and depression symptom scores, and categorical (screening positive or negative) PTSD and depression screening status, to each other and to ART adherence as assessed by the Medication Event Monitoring System, regardless of antidepressant treatment. Participants were 164 HIV-infected individuals who took part in a multisite adherence intervention study in HIV treatment settings in Massachusetts. Available data from 5 time points was used, yielding 444 data points. Participants screened positive for PTSD at 20% of visits, and depression at 22% of visits. At visits when participants screened positive for both depression and PTSD, 53.6% of the time they were on an antidepressant. Those who screened positive for PTSD were more likely to also screen positive for depression. In multiple regression analyses that included both continuous and dichotomous PTSD and depression and controlled for shared variance due to clustering of multiple observations, only depression contributed significant unique variance, suggesting the primary role of depression and the secondary role of PTSD in poor adherence in individuals with HIV.

Documented treatment rates for Hepatitis C virus (HCV) infection are low. Within this cohort of HCV-infected patients (N = 373), participants who were not actively injecting drugs or not co-infected with HIV were most likely to initiate HCV treatment. Persons of white race and HIV-infected participants with a CD4 count above 200 were also more likely to have initiated HCV treatment. We defined five factors as potentially modifiable, and found almost all (90%) of the cohort had at least one such factor. Participants with more than one of these factors were least likely to initiate treatment. The proportion of patients receiving treatment increased as their number of modifiable risk factors decreased (p < 0.01, for trend). Focused strategies to overcome these potentially modifiable factors may be indicated to increase HCV treatment in affected populations.

Self-reported measures of antiretroviral adherence vary greatly in recall time periods and response tasks. To determine which time frame is most accurate, we compared 3-, 7-day, and 1-month self-reports with data from medication event monitoring system (MEMS). To determine which response task is most accurate we compared three different 1-month self-report tasks (frequency, percent, and rating) to MEMS. We analyzed 643 study visits made by 156 participants. Over-reporting (self-report minus MEMS) was significantly less for the 1-month recall period (9%) than for the 3 (17%) or 7-day (14%) periods. Over-reporting was significantly less for the 1-month rating task (3%) than for the 1-month frequency and percent tasks (both 12%). We conclude that 1-month recall periods may be more accurate than 3- or 7-day periods, and that items that ask respondents to rate their adherence may be more accurate than those that ask about frequencies or percents.

Objectives: To measure the prevalence of gonorrhea, chlamydia, and human immunodeficiency virus (HIV) infection among emergency department (ED) patients who accept screening, and to assess treatment outcomes and risks for infection. Methods: Research staff offered voluntary testing for gonorrhea and chlamydia (by urine transcription-mediated amplification) and HIV (by enzyme immunoassay/Western blot of oral mucosal transudate) to ED patients. Pediatric (15–21 years) and adult (22–29 years) patients were eligible for gonorrhea and chlamydia testing; patients aged 15–54 years were eligible for HIV testing. The authors surveyed behavioral risks of patients accepting HIV testing. Results: From November 2003 to May 2004, 497 of 791 eligible pediatric patients (63%) and 1,000 of 2,180 eligible adult patients (46%) accepted screening for gonorrhea, chlamydia, and/or HIV. There were 41 patients infected with gonorrhea, chlamydia, or both among 380 pediatric patients (10.8%) and 11 of 233 adult patients (4.7%); 14 of 52 patients (27%) were treated presumptively by ED clinicians. Through study efforts, 33 of the 38 remaining patients were treated (90% overall treatment). Eight HIV infections were diagnosed: seven of 969 adult patients (0.7%) and one of 459 pediatric patients (0.2%); five HIV-infected patients (63%) received test results, and three (38%) attended an HIV clinic. Gonorrhea or chlamydia infection in pediatric patients was associated with multiple sex partners, same-sex intercourse, and suspicion of sexually transmitted diseases by the ED clinician. Conclusions: The high prevalence of gonorrhea and/or chlamydia infection among pediatric ED patients tested supports consideration of expanded screening. Targeted HIV screening with rapid tests merits exploration in the authors' ED, given the low-moderate numbers of patients identified through screening, receiving test results, and linked to care.

CD8 T cells are classified as naı̈ve, effector, or memory cells on the basis of CD45RA, CD62L, and CCR7 expression. Sequential engagement of cell-surface CD62L and CCR7 receptors is required for efficient trafficking to lymphoid tissue by means of high endothelial venules. Naı̈ve CD8 T cells are CCR7+CD62L+ CD45RA+, whereas long-term memory cells are CCR7+CD62L+CD45RA−. Effector cytotoxic T cells are thought to be CCR7−CD45RA+. The distribution of CD8 subsets and cytolytic protein expression in healthy donors and donors seropositive for human immunodeficiency virus (HIV) were compared. In HIV-infected subjects, CCR7− CD8 T cells expanded at the expense of naı̈ve and long-term memory cells. In both healthy donors and HIV-infected donors, CCR7+ CD8 T cells were uniformly negative for perforin. In all subsets, perforin and granzyme A were not coordinately expressed, with perforin expression being more tightly regulated. The properties of CD8 T cells specific for cytomegalovirus, Epstein-Barr virus (EBV), and HIV were studied by staining with major histocompatibility complex peptide tetramers. Antigen-specific cells for chronic infections with these viruses were uniformly CCR7− and predominantly CD62L−. In 2 HIV-seropositive donors, 3- to 4-fold fewer EBV-tetramer–positive cells were present in lymph nodes compared with blood. Antigen-specific CD8 T cells are therefore preferentially excluded from lymphoid sites, even when infection is primarily in lymphoid tissue. This may protect lymphoid tissues from immunopathological changes but compromise immune defense against viruses, such as HIV and EBV, that target lymphocytes. HIV-specific CD8 T cells do not express CD45RA, whereas EBV- and CMV-specific CD8 T cells are heterogeneous in CD45RA+expression. Lack of CD45RA expression may indicate incomplete differentiation of HIV-specific CD8 T cells to cytotoxic T cells.

The functional status of circulating human immunodeficiency (HIV)-specific CD8 T cells in chronically infected subjects was evaluated. By flow cytometry, only 5 of 7 subjects had detectable CD8 T cells that produced IFN-γ after stimulation with HIV-infected primary CD4 T cells. In 2 subjects, the frequency of IFN-γ–producing cells increased 4-fold when IL-2 was added to the culture medium; in another subject, IFN-γ–producing cells could be detected only after IL-2 was added. IFN-γ–producing cells ranged from 0.4% to 3% of CD8 T cells. Major histocompatibility complex–peptide tetramer staining, which identifies antigen-specific T cells irrespective of function, was used to evaluate the proportion of HIV-specific CD8 T cells that may be nonfunctional in vivo. CD8 T cells binding to tetramers complexed to HIV gag epitope SLYNTVATL and reverse transcriptase epitope YTAFTIPSI were identified in 9 of 15 and 5 of 12 HLA-A2–expressing seropositive subjects at frequencies of 0.1% to 1.1% and 0.1 to 0.7%, respectively. Freshly isolated tetramer-positive cells expressed a mixed pattern of memory and effector markers. On average, IFN-γ was produced by less than 25% of tetramer-positive CD8 T cells after stimulation with the relevant gag or reverse transcriptase peptide. In all subjects tested, freshly isolated CD8 T cells were not cytolytic against peptide-pulsed B lymphoblastoid cell line or primary HIV-infected CD4 T-cell targets. Exposure to IL-2 enhanced the cytotoxicity of CD8 T cells against primary HIV-infected CD4 targets in 2 of 2 subjects tested. These results suggest that a significant proportion of HIV-specific CD8 T cells may be functionally compromised in vivo and that some function can be restored by exposure to IL-2.

Central nervous system (CNS) aspergillosis is a relatively uncommon complication of human immunodeficiency virus (HIV) infection. We describe 6 patients with the acquired immunodeficiency syndrome (AIDS) who developed CNS aspergillosis, and we review a total of 33 cases of CNS aspergillosis among HIV-infected individuals that were diagnosed by histology and/or culture. All patients were diagnosed with advanced HIV infection. Major risk factors for the disease included neutropenia and corticosteroid use. The most common presenting symptoms were nonspecific neurologic manifestations including headache, cranial or somatic nerve weakness or paresthesia, altered mental status, and seizures. The most common sites of additional Aspergillus involvement were the lungs, sinuses, ears, and orbits, while in one-fourth of the cases CNS was the only site of Aspergillus infection. The final diagnosis of CNS aspergillosis was made on autopsy in more than half the cases, and medical treatment of CNS aspergillosis was unsuccessful in all cases. CNS aspergillosis should be included in the differential diagnosis of HIV-infected patients who present with nonspecific neurologic symptoms and signs. If we take into account the much higher prevalence of invasive aspergillosis of the lungs, the findings in the present report suggest that CNS aspergillosis in HIV-infected individuals occurs more often as a result of direct extension from the sinuses, orbits, and ears than through hematogenous spread from the lungs. Physicians should be aware that the CNS might be the only site of Aspergillus involvement and include CNS aspergillosis in the differential diagnosis of HIV-infected patients presenting with focal neurologic signs and symptoms, especially when the head CT reveals hypodense lesions.

Local TNF-alpha production in different organs may affect HIV replication and pathogenesis. Alveolar macrophages (AMs) obtained by bronchoalveolar lavage from asymptomatic HIV-seropositive and HIV-seronegative individuals did not spontaneously release TNF-alpha, but LPS stimulation of these cells significantly increased TNF-alpha production. We tested whether NF-kappa B affects TNF-alpha production by AMs using N-tosyl-cmd SClcmd /SC-phenylalanine chloromethylketone (TPCK) or N-benzoyl-cmd SClcmd /SC-tyrosine ethyl ester (BTEE), which inhibit the degradation of I kappa B, or tricyclodecan-9-yl-xanthogenate-potassium (D609), which inhibits phospholipase C. Alveolar macrophages were exposed to LPS alone and with the chemical protease inhibitors TPCK, BTEE, and D609. NF-kappa B DNA binding induced by LPS treatment of AMs was inhibited by TPCK, BTEE, and D609. These agents also inhibited TNF-alpha mRNA and TNF-alpha protein production. After 24 h, the levels of TNF-alpha mRNA reached equilibrium, as assessed by RT-PCR. The levels of NF-kappa B mRNA remained constant under all conditions. The levels of I kappa B-alpha mRNA were similar after 30, 60, and 180 min, but the I kappa B-beta mRNA concentration was initially low and increased over time under all conditions. I kappa B-alpha and I kappa B-beta protein production was not affected by the chemical protease inhibitors. Our data show that TNF-alpha production by LPS-stimulated AMs from asymptomatic HIV-seropositive and -seronegative individuals is regulated via the phospholipase C pathway and by NF-kappa B DNA binding activity without obvious changes in I kappa B-alpha or I kappa B-beta protein concentrations.

Presentation of Case A 37-year-old man was admitted to the hospital because of fever, chills, and diffuse lymphadenopathy. Eight weeks before this admission, the patient entered a rehabilitation hospital for alcohol detoxification. He had a two-week history of fever, chills, myalgia, and a sore throat. The white-cell count was 2100 per cubic millimeter. He had a seizure disorder for which he took carbamazepine; at the rehabilitation hospital, phenobarbital was substituted for the carbamazepine. Treatment with human granulocyte colony-stimulating factor was begun. Five blood-culture specimens were negative. Treatment with oxacillin and gentamicin was ineffective, and the patient was transferred to this . . .

Objectives: To determine the nutritional changes that occur in HIV-infected patients receiving protease inhibitor (PI) therapy and to determine the effects of PI treatment on physical functioning and health perceptions in patients with HIV infection. Design: Longitudinal data analysis of 38 patients from a large Nutrition and HIV cohort. Methods: Patients were included if they had started PI therapy after enrollment in the cohort, if they had taken the drug for at least 4 months without interruption and if data on weight, body composition and viral loads were available. Results: Mean person-months of follow-up was 8.1 months before and 12.2 months after PI treatment. Weight (1.54 kg, P < 0.0001), body mass index (0.50 kg/m 2 , P < 0.0001), physical functioning (8.52 points, P = 0.0006) and current health perception (6.7 points, P = 0.01) increased significantly, and the daily caloric intake increase was close to significance (915.5 kJ/day, P = 0.06), after treatment with Pl. Lean body mass did not change. Patients who responded to PI therapy with decreased viral load (n = 28) had significantly greater weight gain per month than non-responders, Conclusions: Pl therapy of HIV infection is associated with weight gain and improvement in quality of life indices. The weight gain is mainly in fat mass, with no change in lean body mass (skeletal muscle). Optimal therapy of HIV-infected patients with weight loss may require highly active antiretroviral therapy combined with an anabolic stimulus such as exercise, anaboli steroids or human growth hormone.

OBJECTIVE A Phase II, open-label, randomized, parallel-arm, multicentre trial to compare the antiviral activity and safety of two formulations of saquinavir (SQV), soft gelatin (SQV-SGC) and hard gelatin (SQV-HGC) capsules, in combination with two nucleoside reverse transcriptase inhibitors (NRTI), in antiretroviral-naive, HIV-1-infected individuals. PARTICIPANTS A total of 171 people of > or = 13 years, with plasma HIV-1 RNA levels > or = 5000 copies/ml, who had received no protease inhibitor therapy, < or = 4 weeks NRTI therapy and no antiretroviral treatment within 28 days of screening. Eighty-one people were randomized to the SQV-HGC group and 90 to the SQV-SGC group. A total of 148 patients completed 16 weeks of therapy. INTERVENTION Therapy for 16 weeks with either SQV-SGC 1200 mg or SQV-HGC 600 mg, both three times a day, in combination with two NRTI. RESULTS Using an on-treatment analysis, patients taking SQV-SGC had a larger reduction in plasma HIV-1 RNA than those taking SQV-HGC (-2.0 versus -1.6 log10 copies/ml). Eighty per cent of those on SQV-SGC had < 400 copies HIV RNA/ml, compared with 43% in the SQV-HGC group (P = 0.001). A statistically significant difference in the area under the curve (AUC) values between the SQV-SGC and SQV-HGC arms (-1.7 versus -1.5 log10 copies/ml, respectively; P = 0.0054) was observed when withdrawals prior to week 12, major protocol violators and patients with < 75% compliance were excluded from the analysis; however, the difference between the values for the intent-to-treat population was not significant (P = 0.1929). Adverse events (mostly mild) included diarrhoea and nausea. CONCLUSIONS SQV-SGC was generally well tolerated and gave significantly more potent suppression of plasma HIV-1 RNA in antiretroviral-naive patients than SQVHGC.

We infused six human immunodeficiency virus (HIV)-seropositive subjects with autologous CD8+ cytotoxic T cells (CTLs) enriched for HIV-specific cytotoxicity targeted against a diversity of HIV epitopes in gp120, gag p17 and p24, and nef. There was no toxicity and no subject deteriorated clinically. In the first 2 weeks, CD4 counts increased for all subjects and plasma viremia decreased in five of six subjects. Twenty-four weeks later, the mean values of all measures of viral burden and surrogate markers of HIV infection were either unchanged or improved, but none of the changes was statistically significant. Two subjects continued to have decreased cell-associated viral burden and another subject had more than doubled CD4 cell count. HIV-specific CTL activity increased in most subjects. The increase in CD4 T-cell counts in the first weeks after the infusion suggests that antiviral CTLs of diverse specificities do not play a significant role in CD4 T-cell decline. The lack of any acute toxicity or adverse effect on viral burden suggests that therapy with antiviral CTLs deserves further study.

Recombinant human tumor necrosis factor (TNF) binding protein-1 (r-h TBP-1) and recombinant human soluble dimeric TNF receptor (rhu TNFR:Fc) were used to determine the relative contributions of TNF to phorbol myristate acetate (PMA) and cytokine-induced human immunodeficiency virus type 1 (HIV-1) replication in chronically infected cell lines. Treatment of HIV-1-infected promonocytic U1 cells with r-h-TBP-1 or rhu TNFR:Fc reduced PMA-induced HIV-1 p24 antigen production in a concentration-dependent manner, with a maximal inhibition of approximately 90%. Maximal inhibition of p24 antigen production in T-lymphocytic ACH-2 cells was 47% with r-hTBP-1 and 42% with rhu TNFR:Fc. r-hTBP-1 and rhu TNFR:Fc also decreased p24 antigen synthesized by U1 cells in response to other stimuli, including phytohemagglutinin (PHA)-induced supernatant, granulocyte-macrophage colony-stimulating factor, interleukin-6, and TNF. Addition of r-hTBP-1 to U1 cells during the last 4 h of a 24 h incubation with PMA still inhibited p24 antigen production by 15%. U1 cells stimulated with 10(-7) M PMA released approximately 1 ng/ml endogenous TBP-1 with an initial peak observed at 1 h and a second peak at 24 h after PMA stimulation. r-hTBP-1 also partially reversed inhibition of U1 cellular proliferation caused by PMA. Both r-hTBP-1 and rhu TNFR:Fc blocked PMA induction of nuclear factor (NK)- kappa B DNA-binding activity in U1 cells in association with decreases in HIV-1 replication. We conclude that soluble TNF receptors can inhibit stimuli-induced HIV-1 expression and NK- kappa B DNA-binding activity in chronically infected U1 cells.

Cytotoxic T lymphocytes that specifically lyse HIV-1-infected cells occur at uncommonly high frequency in the blood of infected individuals. The CTL response is dominated by the recognition of a small number of peptides encoded by HIV-1 structural and regulatory genes. These two facts have enabled us to develop potent HIV-specific CTL lines from the blood of infected patients without AIDS opportunistic infections by ex vivo culture of nonspecifically stimulated T cell lines with autologous antigen-presenting cells (APCs) preincubated with immunodominant HIV-1 peptides. After one selection, HIV-specific cytotoxicity is enhanced 1.4- to sixfold. Frequency analysis of the T cell line from 1 patient revealed that after exposure to peptide-incubated autologous B-LCLs, the frequency of CTLs specific for the gp160-expressing APCs was enhanced 6-fold and, after a second exposure, 11-fold compared to the nonselected T cell line. Because the APCs used for the frequency analysis were EBV-transformed B-LCLs, some of the specific CTLs in the culture recognized the EBV-expressing APCs. HIV-specific cytotoxicity is enhanced without augmentation of EBV-specific cytotoxicity when PBMCs are used as APCs. Because T cell lines enhanced for HIV-1 specificity are highly cytotoxic and can be expanded to approximately 10(9)-10(10) cells/ml of blood, they may be useful for laboratory research or for immunotherapy.

Background QuantiFERON ® -TB Gold (QFT-G), an interferon-gamma release assay, is approved for the diagnosis of latent tuberculosis infection (LTBI). It is unknown if patients at high risk for LTBI will more readily accept LTBI treatment based on tuberculosis skin testing (TST) or QFT-G. Methods Prospectively enrolled participants were interviewed, were read an informational paragraph on QFT-G, completed a questionnaire and were tested with QFT-G. Results A total of 230 consecutive participants with a history of hepatitis C virus infection and active or past illicit drug use were enrolled and underwent QFT-G testing: 77% had recent TST, 82% were human immuno- deficiency virus co-infected, 87% had a history of injection drug use, and 52% a history of homelessness. Of the 230 participants, 148 (64%) stated a preference for TST compared to QFT-G. The majority would take treatment based on either test (68%). A minority of patients (20%) stated a willingness to take LTBI treatment based on TST alone. Black race was associated with a willingness to take treatment based on TST (OR 2.72, 95%CI 1.05-7.10). Conclusions Patients at high risk for LTBI were found to prefer TST to QFT-G. Most would accept treatment based on either test, and a subset stated unwillingness to take treatment based on QFT-G results. Outreach and education should accompany QFT-G roll-out in high-risk urban populations.

Electronic reminder systems have been available for decades, yet medication adherence remains poor. Most systems rely on simple alarms and do not address other determinants of health-related behavior. This paper describes a collaborative awareness system for chronic disease medication adherence that relies on patient self-reflection and clinician support. Visualizations of adherence performance, including estimated plasma concentration graphs and a dynamic, personalized, disease-state simulation, are available to the patient (cell phone and internet media display) and clinician (computer) in real-time. The clinician can send asynchronous video messages of advice and encouragement to the patient regularly. A pilot was conducted with four HIV positive patients for four weeks. Three patients who started with suboptimal adherence improved (93.0% to 99.1%, 83.0% to 96.3%, and 63.9% to 81.3%). One patient who started with optimal medication adherence (>95%) maintained this level. All four patients appreciated the rich feedback and wanted to continue using the system.

Coinfection with hepatitis C (HCV) significantly increases the risk of acute and chronic renal disease in HIV-infected individuals. However, the burden of acute kidney injury (AKI) directly attributable to HIV among HCV-infected individuals and associated risk factors are not well understood. Within a prospective cohort, AKI episodes were identified by a rise in creatinine of 0.5 mg/dL. Incidence of first AKI events was calculated for HIV/HCV coinfected versus HCV monoinfected subjects, and multivariable analyses using Cox proportional hazards were performed to identify predictors of AKI. Throughout the study period, 35% HIV/HCV coinfected and 17% HCV monoinfected subjects developed AKI, with incidence of 8.74/100 person-years and 3.53/100 person-years, respectively (hazard ratio (HR) 2.48; [95% confidence interval (CI) 1.50, 3.74]). In multivariable analysis, HIV coinfection (HR 2.19 [1.33, 3.62]), decompensated cirrhosis (HR 6.64 [3.81, 11.6]), and cocaine use (HR 2.06 [1.15, 3.71]) were independently associated with AKI. HCV genotype, HCV viral load, hazardous drinking, and heroin use were not associated with AKI. Study limitations included potential misclassification bias of HCV-infected individuals as serial HIV antibody testing was not routinely performed after study entry, and inability to adjust for tenofovir use in multivariable analysis. In conclusion, among subjects with HCV infection, decompensated cirrhosis, HIV coinfection, and cocaine use are associated with increased risk of AKI. These findings highlight the importance of preventing and treating cirrhosis, controlling HIV coinfection, and reducing cocaine use in HIV/HCV coinfected persons.

Studies have demonstrated that plasma samples collected and stored frozen using vacutainer plasma preparation tubes (PPT) may result in falsely elevated viral load (VL) values with the Roche COBAS TaqMan HIV-1 v1.0 test. At the University of Connecticut Health Center, a total of 349 samples from HIV-1-infected patients on HAART were collected and stored frozen in PPT. Viral load (VL) results were obtained using the Roche COBAS TaqMan HIV-1 v2.0 test (CTM v2.0) and Abbott RealTime HIV-1 assay (RealTime HIV-1). Of the 349 samples, 260 (74.5%) had VL values that differed by >0.5log10copies/mL; 64 of these were quantified by both assays. The remaining 196 samples were detected by CTM v2.0 but not detected in RealTime HIV-1: 62 of the most discordant samples in this category (CTM v2.0 detected/RealTime HIV-1 not detected) were further analyzed using two nested RT-PCR assays targeting pol integrase: full-length (864nt) and a highly conserved subregion (134nt). No HIV-1 RNA was detected in the discordant samples, confirming RealTime HIV-1 results. The increase in VL reactivity with the CTM v2.0 assay was presumably due to proviral DNA captured by the CTM total nucleic acid extraction chemistry but not the RNA-specific extraction procedure used in RealTime HIV-1. These results suggest that using CTM v2.0 with samples frozen in PPT could have significant clinical implications for HIV-1 patient management.

Physicians' limited knowledge of patients' antiretroviral adherence may reduce their ability to perform effective adherence counseling.We conducted a randomized, cross-over study of an intervention to improve physicians' knowledge of patients' antiretroviral adherence. The intervention was a report given to the physician before a routine office visit that included data on Medication Event Monitoring System and self-reported data on antiretroviral adherence, patients' beliefs about antiretroviral therapy, reasons for missed doses, alcohol and drug use, and depression. We audio recorded 1 intervention and 1 control visit for each patient to analyze differences in adherence-related dialogue.One hundred fifty-six patients were randomized, and 106 completed all 5 study visits. Paired audio recorded visits were available for 58 patients. Using a linear regression model that adjusted for site and baseline Medication Event Monitoring System adherence, adherence after intervention visits did not differ significantly from control visits (2.0% higher, P = 0.31, 95% confidence interval: -1.95% to 5.9%). There was a trend toward more total adherence-related utterances (median of 76 vs. 49.5, P = 0.07) and a significant increase in utterances about the current regimen (median of 51.5 vs. 32.5, P = 0.0002) in intervention compared with control visits. However, less than 10% of adherence-related utterances were classified as "problem solving" in content, and one third of physicians' problem-solving utterances were directive in nature.Receipt of a detailed report before clinic visits containing data about adherence and other factors did not improve patients' antiretroviral adherence. Analyses of patient-provider dialogue suggests that providers who care for persons with HIV may benefit from training in adherence counseling techniques.

Noninvasive markers of liver fibrosis correlate with the stage of liver fibrosis, but have not been widely applied to predict liver-related mortality.We assessed the ability of two indices of liver fibrosis, aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fib-4, and two markers of extracellular matrix metabolism, hyaluronic acid (HA) and YKL40, to predict liver mortality in a prospective cohort of hepatitis C virus (HCV)-infected individuals with and without HIV coinfection. These were compared with two established prognostic scores, the Child-Pugh-Turcotte (CPT) and model of end-stage liver disease (MELD) scores.A total of 303 subjects, of whom 207 were HIV positive at study entry, were followed up for a mean period of 3.1 years. There were 33 deaths due to liver disease. The ability of each test and score to predict 3-year liver mortality was expressed as the area under the receiver operator curve. The area under the receiver operator curve 95% confidence intervals were: HA 0.92 (0.86-0.96), CPT 0.91 (0.79-0.96), APRI 0.88 (0.80-0.93), Fib-4 0.87 (0.77-0.92), MELD 0.84 (71-0.91). In multivariate analyses HA, APRI, and fib-4 were independent predictors of mortality when included in models with MELD or CPT.Noninvasive markers of liver fibrosis are highly predictive of liver outcome in HCV-infected individuals with and without HIV coinfection. These markers seem to have a prognostic value independent of CPT and MELD.

The increasing use of corticosteroids, immune modulators, and biologics as a mainstay of therapy in certain Crohn's disease and ulcerative colitis patients have placed these inflammatory bowel disease (IBD) patients at increased risk for a variety of infections, many of which are preventable by prior vaccination. This article provides a review of the issues surrounding immunizations in the IBD patient and a practical guide for clinicians regarding the appropriate vaccinations to administer both before and during immunosuppressive therapy.

The enhanced-sensitivity Trofile assay (Monogram Biosciences) was used to retest coreceptor use at both study screening and study entry for 118 treatment-experienced subjects in AIDS Clinical Trials Group A5211 who had CCR5-tropic (R5) virus detected by the original Trofile assay at study screening. Among 90 recipients of vicriviroc, a significantly (P< .001) greater mean reduction in HIV-1 RNA was observed in 72 subjects with R5 virus versus 15 subjects reclassified as having dual/mixed-tropic viruses at screening: -1.11 versus -0.09 log(10) copies/mL at day 14 and -1.91 versus -0.57 log(10) copies/mL at week 24, respectively. Results suggest that the enhanced-sensitivity assay is a better screening tool for determining patient eligibility for CCR5 antagonist therapy.

Detection of CXCR4-using human immunodeficiency virus by the Trofile assay was compared to that by assays using virus isolates or replication-competent recombinants. Concordance with the Trofile assay was good, but assays using replicating viruses did not increase substantially the ability to detect the presence of CXCR4-using virus.

Ninety percent to 95% of the adult human population carries Epstein-Barr virus (EBV) as a chronic latent infection; the vast majority of these patients experience no serious sequelae. Healthy adults experience episodes of transient EBV viremia, with EBV DNA levels in whole blood usually

Natural History of HIV Infection and Evolution of Antiretroviral Therapy.- Evolution and Pathogenesis of the Involvement of the Cardiovascular System in HIV Infection.- Pathogenesis of Antiretroviral Treatment-Associated Metabolic Syndrome.- Pathology of Cardiac Complications in HIV Infection.- Pathology of Peripheral and Coronary Vessels in AIDS Patients.- Echocardiographic Findings in HIV-Infected Patients.- Cardiac MRI in Diagnosis of Myocardial Disease in HIV-Infected Patients.- Coronary Heart Disease in HIV-Infected Patients: Epidemiology.- Coronary Artery Disease in HIV-Infected Patients: Clinical Presentation, Pathophysiology, Prognosis, Prevention and Treatment.- Cerebrovascular Disease in HIV-Infected Patients.- Peripheral Arterial Disease in HIV-Infected Patients: Atherosclerosis and Vasculitic Syndromes.- HIV-Associated Pulmonary Hypertension.- Coagulative Disorders in HIV-Infected Patients.- Cardiovascular Complications in HIV-Infected Children.- Cardiac Surgery and the Human Immunodeficiency Virus.- Cardiological Emergencies in HIV-Infected Patients.- Guidelines for the Prevention of Cardiovascular Risk in HIV-Infected Patients Treated with Antiretroviral Drugs.- Appendindix 1: Cardiovascular Monitoring of HIV-Infected Subjects and Cardiovascular Risk Stratification and Prevention of Cardiovascular Disease in Patients Receiving HAART.- Appendinx 2: Interactions Between Antiretrovirals and Drugs Commonly Used to Treat Cardiovascular Diseases.- Subject index.

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-α) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-α activity, as measured by the TNF-α/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-α is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-α production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam3Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-α in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-α production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.

Interleukin (IL)-10 suppresses synthesis of the pro-inflammatory cytokines tumor necrosis factor (TNF)alpha, IL-1beta, and interferon (IFN)gamma. Since pro-inflammatory cytokines have been implicated in the production of human immunodeficiency virus type 1 (HIV-1), cytokine synthesis in whole blood cultures were determined during a 4-week course of subcutaneous IL-10 injections in 33 HIV-1-infected patients. Patients were randomized into four groups: placebo (nine), IL-10 at 1 microg/kg/day (nine), IL-10 at 4 microg/kg/day (six) and IL-10 at 8 microg/kg three times per week (nine). Whole blood was obtained at the beginning and conclusion of the study and was stimulated for 24 hours with the combination of IL-18 plus lipopolysaccharide. TNFalpha production in stimulated whole blood was reduced three and six hours after the first injection of IL-10 compared to subjects injected with the placebo. After four weeks of treatment, production of IFNgamma was suppressed in a greater number of patients in the IL-10 treatment groups compared to subjects in the placebo group. Similarly, IL-1beta production was lower in the IL-10 treatment groups compared to subjects receiving placebo. In contrast, after four weeks of IL-10, circulating levels of the anti-inflammatory TNF soluble receptor p55 increased dose-dependently compared to placebo subjects. Patient heterogeneity and small sample size presented difficulties in establishing statistical significance. Although the cytokine changes in our study did not demonstrate statistically significant changes, the data nevertheless reveal that four weeks of IL-10 therapy in HIV-1 infected subjects produced the anticipated suppression of pro-inflammatory cytokines.

Background. Vicriviroc, an investigational CCR5 inhibitor, demonstrated short-term antiretroviral activity in a phase 1 study. Methods. The present study was a double-blind, randomized phase 2 study of vicriviroc in treatment-experienced, human immunodeficiency virus (HIV)-infected subjects experiencing virologic failure while receiving a ritonavir-containing regimen with an HIV -1 RNA level ≥5000 copies/mL and CCR5-using virus. Vicriviroc at 5, 10, or 15 mg or placebo was added to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. The primary end point was the change in plasma HIV-1 RNA levels at day 14; secondary end points included safety/tolerability and HIV-1 RNA changes at week 24. Results. One hundred eighteen subjects were randomized with a median HIV-1 RNA level of 36,380 (4.56 log 10 ) copies/mL and a median CD4 cell count of 146 cells/mm 3 . At 14 days and 24 weeks, mean changes in HIV-1 RNA level (log 10 copies/mL) were greater in the vicriviroc groups (-0.87 and -1.51 [5 mg], -1.15 and -1.86 [10 mg], and -0.92 and -1.68 [15 mg]) than in the placebo group (+0.06 and -0.29) (P

BACKGROUND: Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors. METHODS: We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression. RESULTS: Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 178 [corrected] (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/ micro L vs. 170 cells/ mu L; P

Despite ongoing evidence that one quarter of HIV-infected people in the United States are unaware of their infection, widespread implementation of the Centers for Disease Control and Prevention's 1993 recommendations regarding routine inpatient HIV testing has not occurred. This study compares two HIV testing strategies: the initial phase of inpatient HIV testing (1999-2001) utilized a physician-referral-based system. The second phase (2001-2003) included the first 2 years' experience with having trained HIV counselors directly approach inpatients regarding their willingness to undergo voluntary HIV counseling and testing (VCT) without physician referral. This latter phase was prompted by a patient attitude survey demonstrating favorable responses to unsolicited approaches by staff regarding HIV testing. Barriers to implementing the latter strategy are discussed and initial experience with rapid HIV testing on this service is also presented. Referral-based testing yielded 2.3 patient referrals (6.4% of total admissions) resulting in 1.2 HIV tests and 0.7 counseling only sessions per day. Nonreferral based testing resulted 6.2 HIV tests and another 3.0 counseling-only sessions per day. HIV VCT on an inpatient service is feasible but challenging. Most patients respond favorably to being approached for VCT. Routinely offering HIV tests to inpatients yields higher testing rates than physician referral-based systems and increases the number of patients who know their HIV status. Recommendations for implementing routing HIV testing on an inpatient service are made.

To assess the proportion of hospitalized patients who tested positive for human immunodeficiency virus (HIV) by a routine inpatient testing service, as recommended by the Centers for Disease Control and Prevention, who might not have been identified had routine testing not been offered.In this retrospective cohort study, the medical records of patients who tested HIV positive by the inpatient testing service between 1999 and 2003 were compared with the medical records of inpatients who tested HIV negative by the inpatient testing service and the medical records of patients who tested HIV positive in ambulatory settings. We compared HIV risk factors, discharge diagnoses, CD4 cell counts, and HIV RNA concentrations.A total of 243 patients participated in this study: 81 patients who tested HIV positive and 81 who tested HIV negative by the inpatient testing service, and 81 patients who tested HIV positive in ambulatory settings. Both HIV-positive inpatients and HIV-positive outpatients had similar frequencies of HIV risk factors (46% vs 43%; P=.75). Both groups differed significantly from HIV-negative inpatients (4%; P.001). Comparing HIV-positive inpatients with HIV-positive outpatients, CD4 cell counts were lower (196 vs 371 cells/mm3; P.001), and HIV RNA levels were higher (4.61 vs 4.09 Iog, HIV RNA; P=.001). At diagnosis, 64 HIV-positive inpatients (79%) met criteria for acquired immunodeficiency syndrome compared with 21 HIV-positive outpatients (26%) (P.001).Patients who tested HIV positive through inpatient testing have more advanced disease than those identified as outpatients. Half of these patients would not have been identified had testing not been routinely offered. Routine inpatient HIV testing offers an important opportunity to identify patients with HIV infection.

The envelope protein (gp120) of human immunodeficiency virus (HIV) contains highly conserved mannosylated oligosaccharides. These glycoconjugates contribute to resistance to antibody neutralization, and binding to cell surface lectins on macrophages and dendritic cells. Mannose-binding lectin (MBL) binds to gp120 and plays a role in defence against the virus. In this study it is demonstrated that surfactant protein D (SP-D) binds to gp120 and inhibits HIV infectivity at significantly lower concentrations than MBL. The binding of SP-D was mediated by its calcium-dependent carbohydrate-binding activity and was dependent on glycosylation of gp120. Native dodecameric SP-D bound to HIV gp120 more strongly than native trimeric SP-D. Since one common polymorphic form of SP-D is predominantly expressed as trimers and associated with lower blood levels, these individuals may have less effective innate defence against HIV. A chimeric protein containing the N-terminal and collagen domains of SP-D linked to the neck and carbohydrate-recognition domains of MBL (called SP-D/MBLneck+CRD) had greater ability to bind to gp120 and inhibit virus replication than either SP-D or MBL. The enhanced binding of SP-D/MBLneck+CRDwas dependent on assembly into higher molecular mass multimers (i.e. a trimeric form of the chimera did not bind to a greater extent than MBL). Hence, the enhanced binding of SP-D compared with MBL results from distinctive properties of its N-terminal and/or collagen domains. SP-D is present in lung and airway fluids, as well as in blood and various mucosal locations, and could, like MBL, play a role in restricting HIV transmission or replicationin vivo.

Both host and viral factors play an important role in the pathogenesis of human immunodeficiency virus (HIV)-associated bran injury. In this study, the authors examined the interactions between tumor necrosis factor (TNF)-alpha, CXCR4, the alpha chemokine receptor, and three HIV isolates, including the T-tropic viruses, HIV-1(MN) and HIV-1(IIIB), and the dual tropic virus, HIV-1(89.6). The authors show by flow cytometry that treatment of differentiated SK-N-MC cells with TNF-alpha induces a significant increase in the cell surface expression of CXCR4 in a time- and dose-dependent manner. The effect is partly regulated at the level of transcription. To assess the biological significance of this finding, we show that TNF-alpha potentiates the ability of the above mentioned HIV isolates to induce neuronal apoptosis and that the effect is significantly reduced by pretreating cells with monoclonal antibodies to either CXCR4 and TNF-alpha. Together these results suggest that TNF-alpha may render neuronal cells vulnerable to the apoptotic effects of HIV by increasing the cell surface expression of CXCR4 and thus identify another mechanism by which TNF-alpha contributes to the pathogenesis of HIV-associated brain injury.

The effect of atazanavir on P-glycoprotein (P-gp) expression and activity, as well as its inhibitory potency against CYP3A activity, was evaluated in vitro. Induction of P-gp activity and expression was studied using LS180V cells. P-gp inhibition was studied using both LS180V cells and Caco-2 cells. P-gp activity was assessed by measuring P-gp-mediated rhodamine 123 (Rh123) transport, and P-gp expression was determined using SDS-polyacrylamide gel electrophoresis/Western blot analysis. CYP3A inhibition was tested using triazolam hydroxylation in human liver microsomes (HLM). Extended (3-day) exposure of LS180V cells to 30 microM atazanavir caused a 2.5-fold increase in immunoreactive P-gp expression as well as a concentration-dependent decrease of intracellular Rh123 to a mean 45% (S.D. 5.2%) of control. Acute exposure (2 h) of LS180V cells to atazanavir increased intracellular Rh123 concentrations up to 300% of control at 100 microM atazanavir. At 30 microM and above, acute atazanavir exposure reversed P-gp induction caused by 3-day pretreatment with 10 microM ritonavir. P-gp inhibition was also observed in Caco-2 cells, causing an effect comparable to that observed for the known P-gp inhibitor verapamil (50% of control). In HLM, atazanavir was an inhibitor of triazolam hydroxylation, with inhibitory potency greatly increased by preincubation. IC50 values with and without preincubation were 0.31 microM (S.D. 0.13) and 5.7 microM (S.D. 4.1), respectively. Thus, atazanavir is an inhibitor and inducer of P-gp as well as a potent inhibitor of CYP3A in vitro, suggesting a potential for atazanavir to cause drug-drug interactions in vivo.

Think HIV offered HIV counseling, testing, and referral to patients at 4 Massachusetts urgent care centers from January to September 2002. We compared the positive diagnosis yield of Think HIV with that of state-funded HIV counseling, testing, and referral sites. Think HIV found an HIV prevalence of 2.0% compared with 1.9% identified by self-referral testing. Urgent care center–based routine HIV counseling, testing, and referral programs are feasible, can have high positive diagnosis yields, and should be the standard of care in high HIV prevalence areas.

Enfuvirtide is the first fusion inhibitor to be approved by the Food and Drug Administration for the treatment of chronic human immunodeficiency virus (HIV) infection in adults and children 6 years and older. The drug is a synthetic peptide derived from a naturally occurring amino acid sequence known as heptad repeat 2 (HR2) found in gp41, a viral transmembrane glycoprotein that facilitates fusion with host cells. By mimicking the activity of HR2 and competitively binding to a second region of gp41, heptad repeat 1 (HR1), enfuvirtide prevents interaction between HR1 and HR2 and inhibits the conformational change of gp41 that is necessary for fusion of virions to host cells. The safety and efficacy of enfuvirtide have been studied only in antiretroviral-experienced persons. Preliminary data from two multicenter phase III clinical trials (T-20 versus Optimized Regimen Only [TORO 1, TORO 2]) suggest that the drug is safe and efficacious in heavily pretreated subjects through 24 weeks. By week 24, in TORO 1 and TORO 2, respectively, mean changes in HIV RNA concentrations of -1.7 and -1.4 log10 copies/ml were observed in subjects receiving enfuvirtide plus an optimized background (OB) regimen, compared with changes of -0.8 and -0.7 log10 copies/ml in subjects receiving an OB regimen alone. Resistance to enfuvirtide has been identified in vitro and in vivo. Most resistant variants contain mutations in the HR1 region of gp41 (positions 36-45). In phase III clinical trials, numerous substitutions within this critical region were associated with faster time to virologic failure over 24 weeks. Overall, enfuvirtide appears to be well tolerated and acceptable to patients despite a high rate of injection site reactions (> 90%). Bacterial pneumonia and eosinophilia occurred more frequently in subjects taking enfuvirtide than in those taking an OB regimen alone in phase III trials; however, no causal relationship was established. Like most drugs with peptide structures, enfuvirtide appears to have a low potential for metabolic drug-drug interactions. The approved dosage is 90 mg twice/day by subcutaneous injection in adults and 2 mg/kg twice/day in children older than 6 years. Enfuvirtide is an addition to antiretroviral therapy since it targets a new step in the HIV life cycle. Given the complexity of its production and administration, however, it is likely to be most useful in antiretroviral-experienced patients.

Human immunodeficiency virus type 2 (HIV-2), the second human retrovirus known to cause AIDS, is endemic to West Africa but is infrequently found outside this region. We present a case series of 10 HIV-2--infected individuals treated in the United States. Physicians applied the principles of highly active antiretroviral therapy (HAART), normally used in treating HIV type 1, with modifications considered appropriate for treating HIV-2. CD4+ cell count, HIV-2 virus load, and clinical status were found to correlate well, providing evidence that HIV-2 virus load is useful in managing treatment of patients with HIV-2 who are receiving therapy. However, HAART regimens with predicted efficacy for treatment of HIV type 1 infection are not as efficacious for treatment of HIV-2. Controlled clinical trials of HIV-2-infected patients receiving various HAART regimens are needed to provide therapeutic guidance to the medical community.

Metabolic disorders in HIV-infected patients, especially those receiving highly active antiretroviral therapy (HAART) regimens containing protease inhibitors, are associated with insulin resistance. These metabolic disorders include fat redistribution, diabetes, and hypertriglyceridemia. Thiazolidinediones (TZDs) are used to treat patients with diabetes secondary to insulin resistance, and TZDs are being studied in HAART-related metabolic disorders. We studied the effects of TZDs (peroxisome proliferator-activated receptor-gamma [PPARgamma] agonists) and a PPARalpha agonist on HIV replication and TNFalpha production in peripheral blood mononuclear cells (PBMCs) acutely infected with HIV-1, in a chronically infected monoblastoid cell line (U1) and in alveolar macrophages (AMs) from HIV-infected subjects and uninfected controls. Rosiglitazone, ciglitazone, troglitazone, and PgJ (PPARgamma agonists) as well as fenofibrate (PPARalpha agonist) inhibited HIV replication in both PBMCs and U1 cells. These agents also inhibited TNFalpha production, but the magnitude of TNFalpha inhibition was not directly correlated with the quantitative decreases in HIV replication. In AMs, ciglitazone, rosiglitazone, and troglitazone reduced TNFalpha production. We hypothesize that alterations in mitogen-activated protein kinase signaling pathways have contemporaneous and interrelated effects on HIV replication, cytokine production, and lipid metabolism. Modulation of these pathways using PPAR agonists may improve the metabolic alterations during HAART in conjunction with desirable decreases in HIV replication and TNFalpha production.