Long-Term Infectious and Noninfectious Outcomes of Monthly Alemtuzumab as a Calcineurin Inhibitor- and Steroid-Free Regimen for Pancreas Transplant Recipients.

Multiple doses of alemtuzumab for immunosuppressive therapy of patients with hematologic malignancies and hematopoietic stem cell transplant have been associated with a high rate of infection. In transplantation, limited alemtuzumab dosing has been successfully used as induction immunosuppression. The effect of multiple doses of alemtuzumab, used as maintenance therapy to minimize steroid and/or calcineurin inhibitor toxicity in solid organ transplant recipients, is unknown. We evaluated the infectious and noninfectious outcomes of 179 pancreas transplant recipients treated with alemtuzumab for induction and maintenance therapy (extended alemtuzumab exposure (EAE)) from 2/28/2003 through 8/31/2005, compared with 159 pancreas transplant recipients with standard induction and maintenance (SIM) therapy performed before (1/1/2002 until 12/31/2002) and after (1/1/2006 until 12/31/2006) the implementation of EAE. EAE was associated with higher risk of overall infections (hazard ratio (HR) 1.33 (1.06-1.66), P=0.01), bacterial infections (HR 1.33 (1.05-1.67), P=0.02), fungal infections (HR 1.86 (1.28-2.71), P < 0.01), and cytomegalovirus infections (HR 2.29 (1.39-3.77), P < 0.01). In addition, EAE was associated with higher risk of acute cellular rejection (HR 2.09 (1.46-2.99), P < 0.01). In conclusion, while a limited alemtuzumab dosing is safe and effective for induction therapy in pancreas transplantation, EAE combined with steroid and calcineurin minimization is associated with a high risk of infectious complications and acute cellular rejection.

Reduction of immune activation with chloroquine therapy during chronic HIV infection.

Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38(+) HLA-DR(+) CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals.

Bacteremia and central line infection caused by Bosea thiooxidans.

We describe a case of central venous catheter infection and bacteremia caused by Bosea thiooxidans, which has not been previously described in the literature. Bosea spp. is a gram-negative bacterium that has been isolated from hospital water supplies and may become an important cause of nosocomial infections.

HIV type 1 cervicovaginal reservoirs in the era of HAART.

Highly active antiretroviral therapy (HAART) does not lead to viral eradication, due to HIV-1 residual disease. We investigated whether the cervicovaginal tract serves as a viral reservoir. Seven out of eight cervicovaginal fluids were positive for cell-free HIV-1, by supersensitive reverse transcriptase-polymerase chain reactions (RT-PCR), with a detection limit of 1 copy/ml. No viral outgrowth, intracellular proviral DNA, or viral RNA was detected from cervicovaginal lavage and ecto- and endocervical cells. The cervicovaginal tract of patients on HAART is likely not a major solid tissue reservoir for HIV-1. Nonetheless, the presence of even low cell-free HIV-1 RNA in cervicovaginal secretions continues to suggest the importance of practicing protected sex, even in the era of HAART.

Detection of antiretroviral resistance in HIV-1.

Resistance testing should be readily available to every clinician who specializes in HIV/AIDS. Based in part on requests we receive in our laboratory, we believe that the use of resistance testing is expanding. However, selecting an initial antiretroviral treatment regimen or changing a failing one according to the test results is complex and inexact and requires knowledgeable interpretation to maximize the clinical benefit. Future studies about viral fitness and other viral, host, and pharmacologic factors responsible for disease progression likely will facilitate more precise application of resistance testing to the clinical setting.

Phase I/II trial of the anti-HIV activity of mifepristone in HIV-infected subjects ACTG 5200.

BACKGROUND: Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug's safety and anti-HIV activity. METHODS: A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte counts >or=350 cells per cubic millimeter who had no recent antiretroviral therapy. RESULTS: Fifty-six male and 1 female subjects with a median entry CD4+ lymphocyte count of 555 cells per cubic millimeter and plasma HIV-1 RNA of 15,623 copies per milliliter were accrued. Forty-five subjects (78.9%) were available for endpoint analysis. In each arm, changes from baseline to day 28 in plasma HIV-1 RNA and CD4+ lymphocyte count were not significantly different from zero (no change). There was no relationship between mifepristone trough concentrations and plasma HIV-1 RNA. Day 28 morning plasma cortisol levels were significantly higher in the 150 mg and 225 mg arms compared with placebo, confirming biologic activity, and returned to baseline by day 56. Serum lipids did not change during the trial. Fasting blood sugar was 2.5 mg/dL higher on day 28 in the mifepristone arms, but the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) did not change. Three subjects (7.3%) receiving mifepristone developed a grade 2 rash. CONCLUSIONS: Mifepristone at doses of 75-225 mg daily was safe and well-tolerated, but did not show significant anti-HIV activity.

CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection.

BACKGROUND: Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients. OBJECTIVE: To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy. METHODS: CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations. RESULTS: A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/microl; 2.0 and 1.7 for counts of 200-350 cells/microl; and 0.7 and 0.7 for counts greater than 350 cells/microl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50-0.62, P < 0.01) and 14% (95% confidence interval for hazard ratio 0.77-0.96, P = 0.01), respectively, for each 100 cell/microl higher latest CD4+ count. CONCLUSION: Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/microl.

Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases.

BACKGROUND: Low CD4+ increases risk for both AIDS- and non-AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate duration of immune depletion. METHODS: We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up. RESULTS: Mean pretreatment CD4+ was 221 cells/microL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/microL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (>or=50 cells/muL; rate = 2.7/100 person-years) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01). CONCLUSIONS: Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.

Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue.

Human immunodeficiency virus type 1 (HIV-1) central nervous system (CNS) infection in children is associated with impaired brain growth and neurodevelopmental delays. Neural progenitors are critical for neurogenesis. Human multipotential neural progenitors grown in culture are permissive for HIV-1 infection, but it is not known if infection of these cells occurs in vivo. Brain tissue from pre-highly active antiretroviral therapy (HAART) era pediatric acquired immunodeficiency syndrome (AIDS) patients was examined for evidence of HIV-1 infection of nestin-positive neural progenitors by in situ hybridization; or after laser microdissection harvest, DNA extraction, and polymerase chain reaction (PCR). HIV-1 or viral DNA was identified in nestin-positive cells in four of seven HIV-1-infected children, suggesting in vivo infection of neural progenitors.

A randomized crossover study to determine bioequivalence of generic and brand name nevirapine, zidovudine, and lamivudine in HIV-negative women in India.

Low-cost generic antiretroviral drugs are available in resource-limited settings for treatment of HIV infections. However, few bioequivalence data in specific populations in which these generics are likely to be used are available. We conducted a randomized crossover bioequivalence study of generic and brand name formulations of nevirapine, zidovudine, and lamivudine in HIV-negative Indian women using US Food and Drug Administration (FDA) criteria. Subjects took single doses of all formulations separated by a 14-day washout period. Plasma concentrations were measured over 96 hours during each study period. Average bioequivalence was determined using natural log-transformed maximum concentration (C(max)) and area-under-the-concentration-time curve (AUC) mean ratio data. Fifteen Indian women were enrolled. The 90% confidence intervals for nevirapine (14 subjects) and lamivudine (15 subjects) C(max), AUC from 0 to the last measurable time point (AUC(0-t)), and AUC from 0 to infinity (AUC(0-infinity)) mean ratios and zidovudine (15 subjects) AUC(0-t) and AUC(0-infinity) mean ratios were all within 0.80 to 1.25. However, the 90% confidence interval for zidovudine C(max) mean ratio was 0.70 to 1.46. Generic and brand name nevirapine and lamivudine met FDA average bioequivalence criteria. Lack of average bioequivalence for zidovudine was found for C(max) but is not expected to be clinically significant, because the total AUC values were similar between formulations.

A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis.

BACKGROUND: Characterizing virus-host interactions during self-limited infectious mononucleosis could explain how Epstein-Barr virus (EBV) replication is normally controlled and provide insight into why certain immunocompromised patients fail to contain it. METHODS: University students had an average of 7 clinical and virologic evaluations during acute infectious mononucleosis. EBV was quantified in 697 samples of oral wash fluid, whole blood, peripheral blood mononuclear cells (PBMCs), and plasma by a real-time (TaqMan) polymerase chain reaction (qEBV) assay developed in our laboratory. RESULTS: Twenty of 25 subjects had serologically confirmed primary EBV infection. EBV was cleared from whole blood by a first-order process with a median half-life of 3 days, and its quantity was associated with severity of illness (r2=0.82). Oral shedding persisted at a median of >or=1x104 copies/mL for 32 weeks and was unrelated to severity of illness. Subjects with nonprimary EBV infection shed virus intermittently, and median quantities for all samples became undetectable within 4 weeks. CONCLUSIONS: Using a novel qEBV assay, we demonstrated that young adults with primary EBV infection rapidly cleared virus from blood but not from the oropharynx. High oral concentrations of EBV in asymptomatic persons who have resumed normal activities support the concept that infectious mononucleosis is most likely acquired by kissing.

Alterations in the C-terminal region of the HIV-1 accessory gene vpr do not confer clinical advantage to subjects receiving nucleoside antiretroviral therapy.

The C terminus of the human immunodeficiency virus type 1 (HIV-1) accessory protein vpr acts in viral cell cycle arrest, nuclear localization, and apoptosis. Polymorphisms in this region are described in series of long-term nonprogression cases. We determined vpr sequences of archived baseline specimens from 96 participants in a historical trial of single- versus double-nucleoside reverse-transcriptase inhibitors. These sequences were then analyzed by study-entry and -outcome characteristics such as baseline absolute CD4(+) T cell count, prior treatment, CD4(+) T cell response, and clinical endpoints. Frequency of C-terminal mutations did not correlate to any measures of disease intensity. Changes in that portion of vpr did not attenuate disease.

Intensification and stimulation therapy for human immunodeficiency virus type 1 reservoirs in infected persons receiving virally suppressive highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) has led to significant changes in mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1) epidemic. Nevertheless, because of molecular mechanisms of viral persistence, HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study protocol, as a novel intensification to attack cryptic viral replication; low-dose OKT3 was then administered, followed by a course of interleukin-2, to stimulate latent provirus. Replication-competent virus was undetectable after treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial periods during which no antiretroviral therapy was administered, the patients developed plasma viral rebound. This translational approach combines novel intensification and stimulation therapy to deplete residual HIV-1 reservoirs. Additional experimental approaches must be developed if HIV-1 eradication is to become possible in patients receiving virally suppressive HAART.