Modeling brain lentiviral infections during antiretroviral therapy in AIDS.

Understanding HIV-1 replication and latency in different reservoirs is an ongoing challenge in the care of patients with HIV/AIDS. A mathematical model was created to describe and predict the viral dynamics of HIV-1 and SIV infection within the brain during effective combination antiretroviral therapy (cART). The mathematical model was formulated based on the biology of lentiviral infection of brain macrophages and used to describe the dynamics of transmission and progression of lentiviral infection in brain. Based on previous reports quantifying total viral DNA levels in brain from HIV-1 and SIV infections, estimates of integrated proviral DNA burden were made, which were used to calibrate the mathematical model predicting viral accrual in brain macrophages from primary infection. The annual rate at which susceptible brain macrophages become HIV-1 infected was estimated to be 2.90×10-7-4.87×10-6 per year for cART-treated HIV/AIDS patients without comorbid neurological disorders. The transmission rate for SIV infection among untreated macaques was estimated to be 5.30×10-6-1.37×10-5 per year. An improvement in cART effectiveness (1.6-48%) would suppress HIV-1 infection in patients without neurological disorders. Among patients with advanced disease, a substantial improvement in cART effectiveness (70%) would eradicate HIV-1 provirus from the brain within 3-32 (interquartile range 3-9) years in patients without neurological disorders, whereas 4-51 (interquartile range 4-16) years of efficacious cART would be required for HIV/AIDS patients with comorbid neurological disorders. HIV-1 and SIV provirus burdens in the brain increase over time. A moderately efficacious antiretroviral therapy regimen could eradicate HIV-1 infection in the brain that was dependent on brain macrophage lifespan and the presence of neurological comorbidity.

A risk-stratified approach to cytomegalovirus prevention in pediatric solid organ transplant recipients.

Optimal strategies to prevent cytomegalovirus (CMV) disease following pediatric solid organ transplantation remain controversial. The purpose of this study was to review the outcomes of a risk-stratified strategy that uses a hybrid or prophylactic strategy for donor (D)+ recipient (R)- patients, a preemptive strategy for D+R+/D-R+, and clinical follow-up alone for D-R+ patients. A retrospective chart review was undertaken at the Stollery Children's Hospital in Edmonton, Alberta for pediatric solid organ transplants 2004 through 2010. Transplants were risk-stratified according to D/R CMV serostatus, organ group, and type of induction or rejection immunosuppression. The incidence of DNAemia and CMV disease and adverse effects from prophylaxis were analyzed. The study included 197 recipients. CMV DNAemia was detected in 49 of 197 recipients (24.8%), and CMV disease occurred in eight of 197 (4%) of which all but one were D+R-. All recovered. Seventeen of 142 recipients who received prophylaxis (12%) had hematologic toxicity. No other toxicities were identified. In conclusion, A risk-stratified approach resulted in very low rates of CMV disease with minimal adverse effects. Lowering the dosage rather than stopping antivirals in the face of neutropenia has the potential to further lower the rate of CMV disease.

The Changing Epidemiology of Posttransplant Lymphoproliferative Disorder in Adult Solid Organ Transplant Recipients Over 30 Years: A Single-center Experience.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a complication of solid organ transplantation (SOT) associated with Epstein-Barr virus (EBV). METHODS: We analyzed the incidence of and risk factors for PTLD among adult SOT recipients at our center over 30 years (1984-2013). We also compared PTLD incidence before and after a prevention strategy of EBV viral load monitoring in EBV serology mismatched patients was adapted in 2001 (ie, transplant era 1 [1983-2001] vs era 2 [2002-2013]). RESULTS: Among 4171 SOT patients, 109 developed PTLD. Cumulative incidence at 1, 10, and 20 years posttransplant was 0.95, 2.3, and 3.5 per 100 person-years, respectively. Beyond the first year peak of almost exclusively EBV-positive PTLD, a lower incidence of PTLD, predominantly EBV negative, persisted for 20 years. Thoracic transplant (hazard ratio [HR], 2.1; P = 0.007) and negative EBV serology (HR, 7.7; P < 0.001) were independent risk factors for PTLD on multivariate Cox regression analysis. EBV seronegativity significantly increased risk of early (HR, 18.5) and EBV-positive PTLD (HR, 14.2), as well as late (HR, 4.9) and EBV-negative PTLD (HR, 3.6) on univariate analyses. Risk of early PTLD was significantly reduced in the recent transplant era (0.8% era 2 vs 1.9% era 1 at 5 years, P = 0.002); this reduction was seen in recent era EBV seropositive (P = 0.035 at 5 years) but not seronegative recipients (P = 0.90 year 5), suggesting lack of impact of viral load monitoring. CONCLUSIONS: Adult SOT recipients face a prolonged risk of late PTLD, whereas risk of early PTLD may have declined in recent years.