Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy.

BACKGROUND: Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. METHODS: Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. RESULTS: The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. CONCLUSIONS: Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors. CLINICAL TRIALS REGISTRATION: NCT00031486.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza.

BACKGROUND: Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS: From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS: The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Improving the quality of manuscript reviews: impact of introducing a structured electronic template to submit reviews.

OBJECTIVE: The purpose of this study is to evaluate the impact of structured electronic templates on the quality of manuscript reviews. MATERIALS AND METHODS: Twenty-five gastrointestinal and genitourinary reviewers for the American Journal of Roentgenology were included in this investigation. Reviewers were selected and anonymized on the basis of having reviewed one or more manuscripts during period 1 (January 2008 through December 2009). All manuscript reviews were given a review quality score. Reviewers with at least one suboptimal review (i.e., a quality review score of < 3 on a scale of 1 to 4, with 1 being poor and 4 being an excellent review) were selected for further follow-up. During period 1, the reviewers received minimal guidance regarding the expectations of a high-quality review. During period 2 (August 2010 through August 2011), the reviewers meeting the criteria selected for follow-up received a structured electronic template outlining the review process. Reviews were again scored for review quality and were compared with a paired Student t test. RESULTS: The mean (± SD) and median review quality scores were 2.07 ± 0.44 and 2.0, respectively, for period 1 and 3.02 ± 0.89 and 3.0, respectively, for period 2. There was a 1-point improvement during period 2 after the introduction of the structured electronic template. Most of the reviews (19/25 [76%; 95% CI, 55%-91%]) improved after introduction of the structured electronic template, whereas only two of 19 worsened. Review scores significantly increased after introduction of the structured electronic templates (mean increase, 0.95 ± 0.92; t = 5.13; p < 0.0001). By specialty, the 13 gastrointestinal reviewers increased their score by 0.39 (p = 0.03), and the 12 genitourinary reviewers increased their score by 1.55 points (p < 0.0001). CONCLUSION: The introduction of a structured electronic template significantly improved the quality of manuscript reviews submitted.

Vaccine prevention of maternal cytomegalovirus infection.

BACKGROUND: Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. METHODS: In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. RESULTS: We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CONCLUSIONS: CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.)

Preclinical evaluation of ex vivo expanded/activated γδ T cells for immunotherapy of glioblastoma multiforme.

We have previously shown that expanded/activated γδ T cells from healthy donors are cytotoxic to GBM cell lines and primary GBM explants. In this report, we examined the therapeutic effect of intracranial infusion of expanded/activated γδ T cells on human minimal and established U251 tumor xenografts in athymic nude mice. Immunohistochemistry was used to determine the presence of NKG2D ligands on cell lines and tumors, and blocking studies were used to determine the effect of these ligands on γδ T cell recognition. Expanded/activated γδ T cells were prepared by 18-day culture in RPMI, human serum (HS), anti-CD2, IL-12, IFN-γ, and OKT-3. Anti-GBM activity of the cell product was assessed using in vitro cytotoxicity assays against the GBM cell line U251MG in suspension and in adherent culture. Ex vivo expanded/activated γδ T cells were of the effector/memory phenotype, expressed Th1 cytokines, and effectively killed U251 cells in vitro. Xenografts were prepared using a U251 cell line following transfection with a firefly luciferase gene to monitor tumor progression. Mice treated with γδ T cells showed slower progression of both new and established GBM xenografts versus mice that received vehicle only as determined by photon emission over time. Median survival was improved in all γδ T cell treated groups between 32 and 50 days by Kaplan-Meier analysis. U251 cells expressed ULBP-2 and ULBP-3, although blocking of these reduced in vitro cytotoxicity of γδ T cells to U251MG by only 33 and 25%, respectively. These studies show that expanded/activated γδ T cells can mediate killing of new or established GBM xenografts, reduce tumor progression, and constitute a potentially effective novel immunotherapeutic strategy against GBM.

Substance abuse treatment in an urban HIV clinic: who enrolls and what are the benefits?

Substance abuse treatment (SAT) is important for HIV medical care. Characteristics of those who choose SAT and effects of SAT on HIV clinical outcomes are not understood. We compared patients who enrolled and did not enroll in a SAT program offered within an HIV clinic, and evaluated the effect of SAT on CD4 T-cell counts and HIV plasma viral load (VL). Subjects were assessed and invited to enroll in SAT. Enrollees chose to receive psychological and psychiatric treatment, or motivational enhancement and relapse prevention, or residential SAT. We used logistic regressions to determine factors associated with enrollment (age, race, sex, HIV transmission risk factors, CD4 T-cell counts, and VL at assessment). A two-period (assessment and six months after SAT) data analysis was used to analyze the effect of SAT on CD4 T-cell count and log VL controlling for changes in HIV therapy. We find that, compared to Decliners (N=76), Enrollees (N=78) were more likely to be females (29.5% vs. 6.6%, OR=5.32, 95% CI 1.61-17.6), and to report injection drug use (IDU) as the HIV transmission risk factor (23.1% vs. 9.2%, OR=3.92, CI 1.38-11.1). Age (37.2 vs. 38.4), CD4 T-cell count (377.3 vs. 409.2), and log VL (3.21 vs. 2.99) at assessment were similar across the two groups (p>0.05). After six months, Enrollees and Decliners' CD4 T-cell counts increased and log VL decreased. SAT did not affect the change in CD4 T-cell count (p=0.51) or log VL (p=0.73). Similar results were found for patients with CD4 T-cell count < or =350 at assessment. In this small sample of HIV-infected patients with a limited follow-up period, women were more likely to enroll in SAT than men, and SAT reached those who needed it, e.g., IDUs. We did not find an effect of SAT on HIV clinical outcomes.

Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone.

PURPOSE: To ascertain predictors of distant brain failure (DBF) in patients treated initially with stereotactic radiosurgery alone for newly diagnosed brain metastases. We hypothesize that these factors may be used to group patients according to risk of DBF. METHODS AND MATERIALS: We retrospectively analyzed 100 patients with newly diagnosed brain metastases treated from 2003 to 2005 at our Gamma Knife radiosurgery facility. The primary endpoint was DBF. Potential predictors included number of metastases, tumor volume, histologic characteristics, extracranial disease, and use of temozolomide. RESULTS: One-year actuarial risk of DBF was 61% for all patients. Significant predictors of DBF included more than three metastases (hazard ratio, 3.30; p = 0.004), stable or poorly controlled extracranial disease (hazard ratio, 2.16; p = 0.04), and melanoma histologic characteristics (hazard ratio, 2.14; p = 0.02). These were confirmed in multivariate analysis. Those with three or fewer metastases, no extracranial disease, and nonmelanoma histologic characteristics (N = 18) had a median time to DBF of 89 weeks vs. 33 weeks for all others. One-year actuarial freedom from DBF for this group was 83% vs. 26% for all others. CONCLUSIONS: Independent significant predictors of DBF in our series included number of metastases (more than three), present or uncontrolled extracranial disease, and melanoma histologic characteristics. These factors were combined to identify a lower risk subgroup with significantly longer time to DBF. These patients may be candidates for initial localized treatment, reserving whole-brain radiation therapy for salvage. Patients in the higher risk group may be candidates for initial whole-brain radiation therapy or should be considered for clinical trials.

Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis.

BACKGROUND: Coccidioidomycosis can be difficult to treat with available therapies, particularly in patients with progressive or disseminated disease. Posaconazole is a new azole antifungal with potent activity against Coccidioides species, the causative agent of coccidioidomycosis. METHODS: Twenty patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis were enrolled in a multicenter trial to study the safety and tolerability of posaconazole therapy, with efficacy as a secondary end point. Patients received posaconazole (400 mg/day) in capsule formulation for up to 6 months. Safety was evaluated on the basis of the occurrence of adverse events. A satisfactory efficacy response was defined as a >or=50% reduction in the Mycoses Study Group score from baseline. RESULTS: Seventeen (85%) of 20 patients had a satisfactory response to treatment. The median duration of treatment was 173 days. Paired baseline and end-of-treatment culture results for Coccidioides species were available for 4 patients, all of whom converted from being positive to being negative for Coccidioides species. Relapse was experienced by 3 of 9 patients who did not receive antifungal therapy during the follow-up period. In general, posaconazole therapy was well tolerated, with 12 of 20 patients reporting adverse events that were possibly or probably related to treatment. The most common adverse events were dry mouth (in 5 patients [25%]) and headache (in 3 patients [15%]). CONCLUSIONS: Courses of posaconazole therapy that were up to 6 months in duration were well tolerated in patients with coccidioidomycosis. Although this study was limited by the number of patients enrolled, it clearly demonstrates that posaconazole shows promise in the treatment of patients with coccidioidomycosis and warrants additional investigation in a full-scale clinical trial.

Distribution of health care expenditures for HIV-infected patients.

BACKGROUND: Health care expenditures for persons infected with human immunodeficiency virus (HIV) in the United State determined on the basis of actual health care use have not been reported in the era of highly active antiretroviral therapy. METHODS: Patients receiving primary care at the University of Alabama at Birmingham HIV clinic were included in the study. All encounters (except emergency room visits) that occurred within the University of Alabama at Birmingham Hospital System from 1 March 2000 to 1 March 2001 were analyzed. Medication expenditures were determined on the basis of 2001 average wholesale price. Hospitalization expenditures were determined on the basis of 2001 Medicare diagnostic related group reimbursement rates. Clinic expenditures were determined on the basis of 2001 Medicare current procedural terminology reimbursement rates. RESULTS: Among the 635 patients, total annual expenditures for patients with CD4+ cell counts <50 cells/microL (36,533 dollars per patient) were 2.6-times greater than total annual expenditures for patients with CD4+ cell counts > or =350 cells/microL (13,885 dollars per patient), primarily because of increased expenditures for nonantiretroviral medication and hospitalization. Expenditures for highly active antiretroviral therapy were relatively constant at approximately 10,500 dollars per patient per year across CD4+ cell count strata. Outpatient expenditures were 1558 dollars per patient per year; however, the clinic and physician component of these expenditures represented only 359 dollars per patient per year, or 2% of annual expenses. Health care expenditures for patients with HIV infection increased substantially for those with more-advanced disease and were driven predominantly by medication costs (which accounted for 71%-84% of annual expenses). CONCLUSIONS: Physician reimbursements, even with 100% billing and collections, are inadequate to support the activities of most clinics providing HIV care. These findings have important implications for the continued support of HIV treatment programs in the United States.

Effect of HSV-IL12 Loaded Tumor Cell-Based Vaccination in a Mouse Model of High-Grade Neuroblastoma.

We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor.

A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis.

BACKGROUND: Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. METHODS: Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. RESULTS: Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. CONCLUSIONS: Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.

A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40.

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, fluconazole prophylaxis is associated with reductions in the rate of fungal infection. However, concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections. METHODS: We performed a randomized, open-label trial that compared oral fluconazole given continuously (200 mg 3 times weekly; the "continuous fluconazole arm") with fluconazole that was provided only for episodes of orophayngeal candidiasis (OPC) or esophageal candidiasis (EC) (the "episodic fluconazole arm") in HIV-infected persons with CD4+ T cell counts of <150 cells/mm3 and a history of OPC. The primary study end point was the time to development of fluconazole-refractory OPC or EC, which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days, respectively. RESULTS: A total of 413 subjects were randomized to receive continuous fluconazole, and 416 were randomized to receive episodic fluconazole. After 42 months, 17 subjects (4.1%) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections, compared with 18 subjects (4.3%) in the episodic fluconazole arm, with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months (P=.88, by log-rank test) or before the end of the study (P=.97, by the log-rank test). Continuous fluconazole therapy was associated with fewer cases of OPC or EC (0.29 vs. 1.08 episodes per patient-year; P<.0001) and fewer invasive fungal infections (15 vs. 28 episodes; P=.04, by chi2 test), but not with improved survival, compared with episodic fluconazole therapy. CONCLUSION: Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC, compared with episodic fluconazole therapy, in HIV-infected patients with access to active antiretroviral therapy.

Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS.

BACKGROUND: In patients with moderate to severe histoplasmosis associated with AIDS, the preferred treatment has been the deoxycholate formulation of amphotericin B. However, serious side effects are associated with use of amphotericin B. OBJECTIVE: To compare amphotericin B with liposomal amphotericin B for induction therapy of moderate to severe disseminated histoplasmosis in patients with AIDS. DESIGN: Randomized, double-blind, multicenter clinical trial. SETTING: 21 sites of the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. PATIENTS: 81 patients with AIDS and moderate to severe disseminated histoplasmosis. MEASUREMENTS: Clinical success, conversion of baseline blood cultures to negative, and acute toxicities that necessitated discontinuation of treatment. RESULTS: Clinical success was achieved in 14 of 22 patients (64%) treated with amphotericin B compared with 45 of 51 patients (88%) receiving liposomal amphotericin B (difference, 24 percentage points [95% CI, 1 to 52 percentage points]). Culture conversion rates were similar. Three patients treated with amphotericin B and one treated with liposomal amphotericin B died during induction (P = 0.04). Infusion-related side effects were greater with amphotericin B (63%) than with liposomal amphotericin B (25%) (P = 0.002). Nephrotoxicity occurred in 37% of patients treated with amphotericin B and 9% of patients treated with liposomal amphotericin B (P = 0.003). CONCLUSION: Liposomal amphotericin B seems to be a less toxic alternative to amphotericin B and is associated with improved survival.

Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma.

Human γδ T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 mice and measured circulating γδ T cell count, phenotype, Vγ/Vδ repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10-12 post-injection and at end stage. Circulating γδ T cells transiently increased and upregulated Annexin V expression at post-tumor day 10-12 followed by a dramatic decline in γδ T cell count at end stage. T cell receptor repertoire showed no changes in Vγ1, Vγ4, Vγ7 or Vδ1 subsets from controls at post-tumor day 10-12 or at end stage except for an end-stage increase in the Vδ4 population. Approximately 12% of γδ T cells produced IFN-γ. IL-17 and IL-4 producing γδ T cells were not detected. Tumor progression was the same in TCRδ-/- C57BL/6 mice as that observed in WT mice, suggesting that γδ T cells exerted neither a regulatory nor a sustainable cytotoxic effect on the tumor. WT mice that received an intracranial injection of γδ T cells 15m following tumor placement showed evidence of local tumor growth inhibition but this was insufficient to confer a survival advantage over untreated controls. Taken together, our findings suggest that an early nonspecific proliferation of γδ T cells followed by their depletion occurs in mice implanted with syngeneic GL261 gliomas. The mechanism by which γδ T cell expansion occurs remains a subject for further investigation of the mechanisms responsible for this immune response in the setting of high-grade glioma.

Duration of highly active antiretroviral therapy regimens.

The median duration of highly active antiretroviral therapy (HAART) regimens was reported to be 11.8 months in one US study, but that study included both treatment-experienced and treatment-naive patients. The duration of initial HAART regimens for treatment-naive patients alone has not been reported. We selected 405 antiretroviral-naive patients who were seen at the University of Alabama at Birmingham HIV Outpatient Clinic from 1 January 1996 through 9 October 2001, and we assessed the duration of initial and successive HAART regimens in this group. Any antiretroviral medication change, excluding dosage changes, that lasted >or=14 days was considered to indicate the start of a new regimen. The median duration of regimens was determined by Kaplan-Meier analysis, and proportional hazards regression was used to identify factors associated with shorter duration of initial regimen. The median duration of initial regimens was 1.6 years, and medication toxicity-associated events were the cause of one-half of discontinuations. Only a history of opportunistic infection and injection drug use were significantly associated with shorter regimen duration.

Immunologic and virologic consequences of temporary antiretroviral treatment interruption in clinical practice.

To determine the long-term immunologic and virologic effects of antiretroviral treatment interruptions, a retrospective analysis of an ongoing observational database was performed at a university HIV clinic. All patients who began highly active antiretroviral therapy (HAART) after January 1, 1996 and (1) were HAART experienced for >/=90 days, (2) had a treatment interruption (TI) for >/=30 days, (3) resumed HAART for >/=30 days, and (4) had CD4(+) cell counts performed pre- and post-TI were included. Main outcome measures included the following: Immunologic success was defined as a post-TI CD4(+) cell count >90% of the pre-TI CD4(+) cell count (post-TI/pre-TI, >90%). Virologic success was defined as a post-TI viral load (VL) less or equal to twice the pre-TI VL (post-TI/pre-TI,

Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis.

BACKGROUND: Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. METHODS: Infants < or =12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. RESULTS: Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (< or =50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally > or =50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. CONCLUSIONS: The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.

Utility of real-time antifungal susceptibility testing for fluconazole in the treatment of candidemia.

Our study prospectively examined the use of real-time antifungal susceptibility testing among 119 patients with candidemia at a large tertiary university medical center over a 1-year period. Susceptibility results to fluconazole were reported to physicians a mean of 5.1 days after the initial positive blood culture for Candida. Physicians believed that receiving antifungal susceptibility testing results was helpful and not infrequently altered therapy on the basis of results. Outcomes, including mortality and resolution of infection, among 20 (17%) patients with fluconazole-resistant and fluconazole-susceptible dose-dependent isolates were relatively poor compared to those among patients with fluconazole-susceptible isolates, but probably reflect severity of illness. Routine susceptibility testing as an adjunct to the treatment of candidemia has significant potential and warrants further study.

CMV-independent lysis of glioblastoma by ex vivo expanded/activated Vδ1+ γδ T cells.

Vδ2(neg) γδ T cells, of which Vδ1+ γδ T cells are by far the largest subset, are important effectors against CMV infection. Malignant gliomas often contain CMV genetic material and proteins, and evidence exists that CMV infection may be associated with initiation and/or progression of glioblastoma multiforme (GBM). We sought to determine if Vδ1+ γδ T cells were cytotoxic to GBM and the extent to which their cytotoxicity was CMV dependent. We examined the cytotoxic effect of ex vivo expanded/activated Vδ1+ γδ T cells from healthy CMV seropositive and CMV seronegative donors on unmanipulated and CMV-infected established GBM cell lines and cell lines developed from short- term culture of primary tumors. Expanded/activated Vδ1+ T cells killed CMV-negative U251, U87, and U373 GBM cell lines and two primary tumor explants regardless of the serologic status of the donor. Experimental CMV infection did not increase Vδ1+ T cell--mediated cytotoxicity and in some cases the cell lines were more resistant to lysis when infected with CMV. Flow cytometry analysis of CMV-infected cell lines revealed down-regulation of the NKG2D ligands ULBP-2, and ULBP-3 as well as MICA/B in CMV-infected cells. These studies show that ex vivo expanded/activated Vδ1+ γδ T cells readily recognize and kill established GBM cell lines and primary tumor-derived GBM cells regardless of whether CMV infection is present, however, CMV may enhance the resistance GBM cell lines to innate recognition possibly contributing to the poor immunogenicity of GBM.