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3.  Compartmentalized Cytomegalovirus Replication and Transmission in the Setting of Maternal HIV-1 Infection 
In human immunodeficiency virus–infected women, cervical cytomegalovirus (CMV) reactivation during pregnancy was correlated with higher CMV levels in breast milk. Low maternal CD4 count and high CMV levels in breast milk were independently associated with infant CMV infection.
Background. Cytomegalovirus (CMV) infection is associated with adverse outcomes in human immunodeficiency virus (HIV)–exposed infants. Determinants of vertical CMV transmission in the setting of maternal HIV-1 infection are not well-defined.
Methods. CMV and HIV-1 levels were measured in plasma, cervical secretions, and breast milk of 147 HIV-1–infected women to define correlates of maternal CMV replication and infant CMV acquisition.
Results. Although few women had detectable CMV in plasma (4.8%), the majority had detectable CMV DNA in cervical secretions (66%) and breast milk (99%). There was a strong association between cervical CMV detection during pregnancy and later breast milk levels (β = 0.47; P = .005). Plasma HIV-1 level and CD4 counts were associated with CMV in the cervix and breast milk. However HIV-1 levels within the cervix and breast milk were not associated with CMV within these compartments. Maternal breast milk CMV levels (hazard ratio [HR], 1.4; P = .003) and maternal CD4 < 450 cells/mm3 (HR, 1.8; P = .008) were independently associated with infant CMV acquisition; each log10 increase in breast milk CMV was associated with a 40% increase in infant infection. The breast milk CMV level required to attain a 50% probability of CMV transmission increased with higher maternal CD4 counts, increasing from 3.55 log10 CMV DNA copies/mL at a CD4 count of 350 cells/mm3 to 5.50 log10 CMV DNA copies/mL at a CD4 count of 1000 cells/mm3.
Conclusions. Breast milk CMV levels and maternal CD4 count are major determinants of CMV transmission in the setting of maternal HIV-1. Maternal immune reconstitution or lowering breast milk CMV levels may reduce vertical CMV transmission.
PMCID: PMC3905754  PMID: 24192386
cytomegalovirus; human immunodeficiency virus; neonates; opportunistic infection; compartmentalization
4.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
5.  Rosuvastatin Treatment Reduces Markers of Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy 
Soluble CD14, a marker of monocyte activation and independent predictor of mortality in HIV disease, is reduced by rosuvastatin treatment. Monocyte tissue factor expression in HIV-infected subjects is reduced by rosuvastatin treatment, potentially reducing thrombotic risk.
Background. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist.
Methods. The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)–infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8+CD38+HLA-DR+ ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1).
Results. After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (−13.4% vs 1.2%, P = .002) and in proportions of tissue factor–positive patrolling (CD14DimCD16+) monocytes (−38.8% vs −11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation.
Conclusions. Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy.
Clinical Trials Registration NCT01218802.
PMCID: PMC3905756  PMID: 24253250
HIV-1; monocytes; tissue factor; rosuvastatin
6.  Antifungal Prophylaxis Associated With Decreased Induction Mortality Rates and Resources Utilized in Children With New-Onset Acute Myeloid Leukemia 
Patients with newly diagnosed acute myeloid leukemia initiated on antifungal prophylaxis were found to have lower induction mortality and resource utilization rates compared to those not receiving prophylaxis.
Background. Invasive fungal infections cause significant morbidity and mortality for children with acute myeloid leukemia (AML). Data on the comparative effectiveness of antifungal prophylaxis in this population are limited.
Methods. A pediatric AML cohort was assembled from the Pediatric Health Information System database using ICD-9 codes and pharmacy data. Antifungal prophylaxis status was determined by pharmaceutical data review within 21 days of starting induction chemotherapy. Patients were followed until end of induction, death, or loss to follow-up. Cox regression analyses compared induction mortality and resources utilized between patients receiving and not receiving antifungal prophylaxis. A propensity score accounted for variation in demographic factors, location of care, and severity of illness at presentation.
Results. Eight hundred seventy-one AML patients were identified; the induction case fatality rate was 3.7%. In the adjusted Cox regression model, patients receiving antifungal prophylaxis (57%) had a decreased hazard for induction mortality (hazard ratio [HR], 0.42; 95% confidence interval [CI], .19–.90). Children receiving prophylaxis were less frequently exposed to broad-spectrum gram-positive (incidence rate ratio [IRR], 0.87; 95% CI, .79–.97) and antipseudomonal β-lactam agents (HR, 0.91; 95% CI, .85–.96), had fewer blood cultures (IRR, 0.78; 95% CI, .71–.86), and had fewer chest CT scans (IRR, 0.73; 95% CI, .60–.88).
Conclusions. Antifungal prophylaxis in pediatric AML patients was associated with reduced induction mortality rates and supportive care resources. Further investigation is necessary to determine whether antifungal prophylaxis should include antimold activity.
PMCID: PMC3905759  PMID: 24270167
antifungal prophylaxis; pediatric; leukemia; AML
7.  Recurrent Urinary Tract Infections Among Women: Comparative Effectiveness of 5 Prevention and Management Strategies Using a Markov Chain Monte Carlo Model 
In our Monte Carlo model comparing management strategies for recurrent urinary tract infections in women, we found that nitrofurantoin prophylaxis was most effective, but most expensive to the payer. Other strategies resulted in payer savings but were less efficacious.
Background. Recurrent urinary tract infections (UTIs) are a common problem among women. However, comparative effectiveness strategies for managing recurrent UTIs are lacking.
Methods. We performed a systematic literature review of management of women experiencing ≥3 UTIs per year. We then developed a Markov chain Monte Carlo model of recurrent UTI for each management strategy with ≥2 adequate trials published. We simulated a cohort that experienced 3 UTIs/year and a secondary cohort that experienced 8 UTIs/year. Model outcomes were treatment efficacy, patient and payer cost, and health-related quality of life.
Results. Five strategies had ≥2 clinical trials published: (1) daily antibiotic (nitrofurantoin) prophylaxis; (2) daily estrogen prophylaxis; (3) daily cranberry prophylaxis; (4) acupuncture prophylaxis; and (5) symptomatic self-treatment. In the 3 UTIs/year model, nitrofurantoin prophylaxis was most effective, reducing the UTI rate to 0.4 UTIs/year, and the most expensive to the payer ($821/year). All other strategies resulted in payer cost savings but were less efficacious. Symptomatic self-treatment was the only strategy that resulted in patient cost savings, and was the most favorable strategy in term of cost per quality-adjusted life-year (QALY) gained.
Conclusions. Daily antibiotic use is the most effective strategy for recurrent UTI prevention compared to daily cranberry pills, daily estrogen therapy, and acupuncture. Cost savings to payers and patients were seen for most regimens, and improvement in QALYs were seen with all. Our findings provide clinically meaningful data to guide the physician–patient partnership in determining a preferred method of prevention for this common clinical problem.
PMCID: PMC3871790  PMID: 24065333
urinary tract infection; recurrent; management
9.  Modeling the Impact of Interventions Along the HIV Continuum of Care in Newark, New Jersey 
This article presents a mathematical model of HIV transmission in Newark, New Jersey, a hotspot of the US HIV epidemic. We model the impact of interventions along the continuum of care, showing a potential substantial decrease in mortality but limited reduction in incidence.
Background. The human immunodeficiency virus (HIV) epidemic in Newark, New Jersey, is among the most severe in the United States. Prevalence ranges up to 3.3% in some groups. The aim of this study is to use a mathematical model of the epidemic in Newark to assess the impact of interventions along the continuum of care, leading to virologic suppression.
Methods. A model was constructed of HIV infection including specific care-continuum steps. The model was calibrated to HIV/AIDS cases in Newark among different populations over a 10-year period. Interventions applied to model fits were increasing proportions tested, linked and retained in care, linked and adherent to treatment, and increasing testing frequency, high-risk-group testing, and adherence. Impacts were assessed by measuring incidence and death reductions 10 years postintervention.
Results. The most effective interventions for reducing incidence were improving treatment adherence and increasing testing frequency and coverage. No single intervention reduced incidence in 2023 by >5%, and the most effective combination of interventions reduced incidence by approximately 16% (2%–24%). The most efficacious interventions for reducing deaths were increasing retention, linkage to care, testing coverage, and adherence. Increasing retention reduced deaths by approximately 27% (24%–29%); the most efficacious combination of interventions reduced deaths in 2023 by approximately 52% (46%–57%).
Conclusions. Reducing HIV deaths in Newark over a 10-year period may be a realizable goal, but reducing incidence is less likely. Our results highlight the importance of addressing leaks across the entire continuum of care and reinforcing efforts to prevention new HIV infections with additional interventions.
PMCID: PMC3871792  PMID: 24140971
HIV; care continuum; mathematical model
10.  Church Attendance in Men Who Have Sex With Men Diagnosed With HIV Is Associated With Later Presentation for HIV Care 
This study found an interdependent association between church attendance and sexual behavior on timing of HIV diagnosis and presentation into care.
We demonstrate an interdependent relationship between sexual behavior and church attendance on timing of human immunodeficiency virus (HIV) diagnosis and presentation for care. Men who have sex with men (MSM) and who attend church are more likely to present with lower CD4+ T-lymphocyte counts than MSM who do not attend church.
PMCID: PMC3871793  PMID: 24198225
HIV; AIDS; religion; church attendance
11.  Seasonal Drivers of Pneumococcal Disease Incidence: Impact of Bacterial Carriage and Viral Activity 
The drivers of invasive pneumococcal disease seasonality are unknown. We found that pediatric cases with a pneumonia diagnosis peaked in winter and were associated with respiratory syncytial virus (RSV), whereas nonpneumonia cases peaked in autumn and were associated with variations in bacterial carriage.
Background. Winter-seasonal epidemics of pneumococcal disease provide an opportunity to understand the drivers of incidence. We sought to determine whether seasonality of invasive pneumococcal disease is caused by increased nasopharyngeal transmission of the bacteria or increased susceptibility to invasive infections driven by cocirculating winter respiratory viruses.
Methods. We analyzed pneumococcal carriage and invasive disease data collected from children <7 years old in the Navajo/White Mountain Apache populations between 1996 and 2012. Regression models were used to quantify seasonal variations in carriage prevalence, carriage density, and disease incidence. We also fit a multivariate model to determine the contribution of carriage prevalence and RSV activity to pneumococcal disease incidence while controlling for shared seasonal factors.
Results. The seasonal patterns of invasive pneumococcal disease epidemics varied significantly by clinical presentation: bacteremic pneumococcal pneumonia incidence peaked in late winter, whereas invasive nonpneumonia pneumococcal incidence peaked in autumn. Pneumococcal carriage prevalence and density also varied seasonally, with peak prevalence occurring in late autumn. In a multivariate model, RSV activity was associated with significant increases in bacteremic pneumonia cases (attributable percentage, 15.5%; 95% confidence interval [CI], 1.8%–26.1%) but was not associated with invasive nonpneumonia infections (8.0%; 95% CI, −4.8% to 19.3%). In contrast, seasonal variations in carriage prevalence were associated with significant increases in invasive nonpneumonia infections (31.4%; 95% CI, 8.8%–51.4%) but not with bacteremic pneumonia.
Conclusions.The seasonality of invasive pneumococcal pneumonia could be due to increased susceptibility to invasive infection triggered by viral pathogens, whereas seasonality of other invasive pneumococcal infections might be primarily driven by increased nasopharyngeal transmission of the bacteria.
PMCID: PMC3871795  PMID: 24190895
pneumococcal; co-infections; RSV; seasonality; pneumonia
12.  Clinical Features of Candidiasis in Patients With Inherited Interleukin 12 Receptor β1 Deficiency 
Owing to impaired interleukin 17 immunity, interleukin 12βR1 (IL-12βR1)–deficient patients have mucocutaneous candidiasis, which is usually recurrent or persistent in spite of antifungal treatment. Candidiasis may be the first clinical manifestation in IL-12βR1–deficient patients.
Background. Interleukin 12Rβ1 (IL-12Rβ1)–deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12–dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23–dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency.
Results. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin.
Conclusions. Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.
PMCID: PMC3871796  PMID: 24186907
Interleukin-12 receptor β1 chain; primary immunodeficiency; Candida; Mycobacterium; Salmonella
13.  The Natural History of Influenza Infection in the Severely Immunocompromised vs Nonimmunocompromised Hosts 
Severely immunocompromised individuals infected with influenza are different from the influenza infected that are nonimmunocompromised. Issues to consider during medical management include asymptomatic shedding, development of multi-drug resistance during prolonged antiviral therapy, and the potential high risk of pulmonary involvement.
Introduction. Medical advances have led to an increase in the world's population of immunosuppressed individuals. The most severely immunocompromised patients are those who have been diagnosed with a hematologic malignancy, solid organ tumor, or who have other conditions that require immunosuppressive therapies and/or solid organ or stem cell transplants.
Materials and methods. Medically attended patients with a positive clinical diagnosis of influenza were recruited prospectively and clinically evaluated. Nasal washes and serum were collected. Evaluation of viral shedding, nasal and serum cytokines, clinical illness, and clinical outcomes were performed to compare severely immunocompromised individuals to nonimmunocompromised individuals with influenza infection.
Results. Immunocompromised patients with influenza had more severe disease/complications, longer viral shedding, and more antiviral resistance while demonstrating less clinical symptoms and signs on clinical assessment.
Conclusions. Immunocompromised patients are at risk for more severe or complicated influenza induced disease, which may be difficult to prevent with existing vaccines and antiviral treatments. Specific issues to consider when managing a severely immunocompromised host include the development of asymptomatic shedding, multi-drug resistance during prolonged antiviral therapy, and the potential high risk of pulmonary involvement.
Clinical trials registration, identifier NCT00533182.
PMCID: PMC3871797  PMID: 24186906
influenza A; influenza; immunocompromised host; stem cell transplant
14.  Point-of-Care Diagnosis and Prognostication of Cryptococcal Meningitis With the Cryptococcal Antigen Lateral Flow Assay on Cerebrospinal Fluid 
The cryptococcal antigen (CRAG) lateral flow assay (LFA) had 100% sensitivity and specificity on cerebrospinal fluid samples. Pretreatment LFA titers correlated with quantitative cultures (R2 = 0.7) and predicted 2- and 10-week mortality. The CRAG LFA is an accurate diagnostic assay for CSF and should be considered for point-of-care diagnosis of cryptococcal meningitis.
PMCID: PMC3864499  PMID: 24065327
HIV; cryptococcal meningitis; diagnosis; point-of-care; sub-Saharan Africa
15.  Prehypertension, Hypertension, and the Risk of Acute Myocardial Infarction in HIV-Infected and -Uninfected Veterans 
We found increased acute myocardial infarction risk among hypertensive and prehypertensive HIV-infected veterans compared to normotensive uninfected veterans, independent of confounding comorbidities.
Background. Compared to uninfected people, human immunodeficiency virus (HIV)–infected individuals may have an increased risk of acute myocardial infarction (AMI). Currently, HIV-infected people are treated to the same blood pressure (BP) goals (<140/90 or <130/80 mm Hg) as their uninfected counterparts. Whether HIV-infected people with elevated BP have excess AMI risk compared to uninfected people is not known. This study examines whether the association between elevated BP and AMI risk differs by HIV status.
Methods. The Veterans Aging Cohort Study Virtual Cohort (VACS VC) consists of HIV-infected and -uninfected veterans matched 1:2 on age, sex, race/ethnicity, and clinical site. For this analysis, we analyzed 81 026 people with available BP data from VACS VC, who were free of cardiovascular disease at baseline. BP was the average of the 3 routine outpatient clinical measurements performed closest to baseline (first clinical visit after April 2003). BP categories used in the analyses were based on criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Analyses were performed using Cox proportional hazards regression.
Results. Over 5.9 years (median), 860 incident AMIs occurred. Low/high prehypertensive and untreated/treated hypertensive HIV-infected individuals had increased AMI risk compared to uninfected, untreated normotensive individuals (hazard ratio [HR], 1.60 [95% confidence interval {CI}, 1.07–2.39]; HR, 1.81 [95% CI, 1.22–2.68]; HR, 2.57 [95% CI, 1.76–3.76]; and HR, 2.76 [95% CI, 1.90–4.02], respectively).
Conclusions. HIV, prehypertensive BP, and hypertensive BP were associated with an increased risk of AMI in a cohort of HIV-infected and -uninfected veterans. Future studies should prospectively investigate whether HIV interacts with BP to further increase AMI risk.
PMCID: PMC3864500  PMID: 24065316
blood pressure; prehypertension; HIV; myocardial infarction
16.  Nondisclosure of HIV Status in a Clinical Trial Setting: Antiretroviral Drug Screening Can Help Distinguish Between Newly Diagnosed and Previously Diagnosed HIV Infection 
In The HIV Prevention Trials Network 061 study, 155 human immunodeficiency virus (HIV)–infected men reported no prior HIV diagnosis; 83 of those men had HIV RNA levels of <1000 copies/mL at enrollment. Antiretroviral drug testing revealed that 65 of the 83 (78.3%) men were on antiretroviral treatment. Antiretroviral drug testing can help distinguish between newly diagnosed and previously diagnosed HIV infection.
PMCID: PMC3864502  PMID: 24092804
HIV; antiretroviral; self-report; MSM; new diagnosis
17.  Priapism Induced by Boceprevir-CYP3A4 Inhibition and α-Adrenergic Blockade: Case Report 
A 44 year-old Caucasian male presented to the emergency department with a three day history of priapism requiring a surgically performed distal penile shunt. A drug-drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin and/or quetiapine, resulting in additional α-adrenergic blockade.
A 44-year-old white man presented to the emergency department with a 3-day history of priapism requiring a surgically performed distal penile shunt. A drug–drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin, and/or quetiapine, resulting in additional α-adrenergic blockade.
PMCID: PMC4049070  PMID: 24092799
priapism; boceprevir; α-adrenergic; drug interaction; quetiapine
18.  Cytomegalovirus Vaccines 
An effective cytomegalovirus (CMV) vaccine could prevent the majority of birth defects caused by congenital CMV infections. Candidate vaccines in clinical evaluation include live attenuated, protein subunit, DNA, and viral-vectored approaches. Subunit approaches have focused on the CMV proteins pp65 and IE1 as important inducers of cytotoxic T cells and glycoprotein B (gB) as an important inducer of neutralizing antibodies. A vaccine comprised of recombinant gB protein with MF59 adjuvant reduced the incidence of primary infection by 50%. Recent revelations regarding CMV entry pathways into different cell types suggest a possible course for improvement. A 5-subunit pentameric complex is uniquely required for endothelial and epithelial cell entry. Sera from naturally infected subjects contain high-potency neutralizing activities specific for this complex, whereas the gB/MF59 vaccine fails to induce comparable neutralizing activities. A vaccine's ability to induce salivary antibodies that neutralize epithelial cell entry may be especially important for preventing oral transmission as the first cells infected are presumably epithelial cells of the oral mucosa. In addition, recent evidence suggests that antibodies can inhibit postentry CMV spread between endothelial and epithelial cells. Such activities may serve to limit viral replication in tissues or impair dissemination to the placenta and fetus. Thus, inclusion of epitopes derived from the pentameric complex may provide enhanced efficacy by inducing potent neutralizing/spread-inhibiting antibodies that target virus replication in a broad spectrum of cell types. Next-generation vaccine candidates in preclinical development incorporate peptides, subunits, or multisubunit complexes representing parts or all of the pentameric complex. Approaches include peptides, recombinant proteins, DNA, replication-defective viral vectors, genetically disabled CMV, and inactivated CMV virions. The diversity of novel strategies under development engenders optimism that a successful candidate will emerge.
PMCID: PMC3836572  PMID: 24257427
cytomegalovirus; congenital infection; vaccine
19.  Congenital Cytomegalovirus Infection: Audiologic Outcome 
The association between congenital cytomegalovirus (CMV) infection and sensorineural hearing loss (SNHL) was first described almost 50 years ago. Studies over the intervening decades have further described the relationship between congenital CMV infection and SNHL in children. However, congenital CMV infection remains a leading cause of SNHL in children in the United States and the world today. As more CMV infections are identified, it is important to recognize that infants who are born to seroimmune mothers are not completely protected from SNHL, although their hearing loss is often milder than that seen in CMV-infected infants following primary maternal infections. Late-onset and progressive hearing losses occur following congenital CMV infection, and CMV-infected infants should be evaluated regularly to provide for early detection of hearing loss and appropriate intervention. Fluctuating hearing loss that is not explained by concurrent middle ear infections is another characteristic of CMV-related hearing loss in children. Challenges still remain in predicting which children with congenital CMV infection will develop hearing loss and, among those who do develop loss, whether or not the loss will continue to deteriorate.
PMCID: PMC3836573  PMID: 24257423
cytomegalovirus; congenital infection; sensorineural hearing loss
20.  Assessment of Liver Fibrosis by Transient Elastography in Patients With HIV and Hepatitis B Virus Coinfection in Nigeria 
We describe the prevalence and risk factors for advanced liver fibrosis (≥9.3 kPa) using transient elastography in human immunodeficiency virus (HIV)–monoinfected and HIV/HBV (hepatitis B virus)–coinfected, antiretroviral naive adults in Nigeria. HBV coinfection and HBV DNA levels significantly increased the risk of advanced fibrosis in HIV and HIV/HBV patients, respectively.
PMCID: PMC3840401  PMID: 24014732
HIV; HBV; liver fibrosis; Africa
22.  High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda 
The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.
PMCID: PMC3840403  PMID: 24051866
hepatitis C virus; ELISA; Africa
23.  Respiratory Syncytial Virus Lower Respiratory Disease in Hematopoietic Cell Transplant Recipients: Viral RNA Detection in Blood, Antiviral Treatment, and Clinical Outcomes 
Respiratory syncytial virus (RSV) RNA detection in plasma or serum may be a marker for lung injury and poor outcomes in hematopoietic cell transplant recipients with RSV lower respiratory disease. Treatment with aerosolized ribavirin appeared protective against overall and pulmonary mortality.
Background. Respiratory syncytial virus (RSV) pneumonia after hematopoietic cell transplant (HCT) is associated with severe morbidity. Although RSV RNA has been detected in serum from patients with RSV lower respiratory disease (LRD) after HCT, the association with clinical outcomes has not been well established in multivariable models. Additionally, the role of antiviral treatment in HCT recipients has not been previously analyzed in multivariable models.
Methods. We retrospectively identified HCT recipients with virologically confirmed RSV LRD and tested stored plasma/serum samples by quantitative reverse transcription polymerase chain reaction for RSV RNA. Risk factors for RSV RNA detection and the impact of RSV RNA in serum and antiviral therapy on outcomes were analyzed using multivariable Cox models.
Results. RSV RNA was detected in plasma or serum from 28 of 92 (30%) patients at a median of 24.5 days following HCT and 2 days following LRD. In multivariable models, neutropenia, monocytopenia, thrombocytopenia, and mechanical ventilation increased the risk of plasma/serum RSV RNA detection; lymphopenia and steroid use did not. RSV RNA detection increased the risk of overall mortality in multivariable models (adjusted hazard ratio [aHR], 2.09 [P = .02]), whereas treatment with aerosolized ribavirin decreased the risk of overall mortality and pulmonary death (aHR, 0.33 [P = .001] and aHR 0.31 [P = .003], respectively).
Conclusions. RSV RNA detection in plasma or serum may be a marker for lung injury and poor outcomes in HCT recipients with RSV LRD. Treatment with aerosolized ribavirin appeared to be protective against overall and pulmonary mortality.
PMCID: PMC3840404  PMID: 24065324
respiratory syncytial virus; RSV; hematopoietic cell transplant; antiviral therapy
24.  Contact Investigation for Active Tuberculosis Among Child Contacts in Uganda 
In a large prospective study in Kampala, Uganda, we found that case investigation can be effective (10% yield) in early detection of active tuberculosis in children <15 years old, with 71% culture confirmation.
Background. Tuberculosis is a large source of morbidity and mortality among children. However, limited studies characterize childhood tuberculosis disease, and contact investigation is rarely implemented in high-burden settings. In one of the largest pediatric tuberculosis contact investigation studies in a resource-limited setting, we assessed the yield of contact tracing on childhood tuberculosis and indicators for disease progression in Uganda.
Methods. Child contacts aged <15 years in Kampala, Uganda, were enrolled from July 2002 to June 2009 and evaluated for tuberculosis disease via clinical, radiographic, and laboratory methods for up to 24 months.
Results. Seven hundred sixty-one child contacts were included in the analysis. Prevalence of tuberculosis in our child population was 10%, of which 71% were culture-confirmed positive. There were no cases of disseminated tuberculosis, and 483 of 490 children (99%) started on isoniazid preventative therapy did not develop disease. Multivariable testing suggested risk factors including human immunodeficiency virus (HIV) status (odds ratio [OR], 7.90; P < .001), and baseline positive tuberculin skin test (OR, 2.21; P = .03); BCG vaccination was particularly protective, especially among children aged ≤5 years (OR, 0.23; P < .001). Adult index characteristics such as sex, HIV status, and extent or severity of disease were not associated with childhood disease.
Conclusions. Contact tracing for children in high-burden settings is able to identify a large percentage of culture-confirmed positive tuberculosis cases before dissemination of disease, while suggesting factors for disease progression to identify who may benefit from targeted screening.
PMCID: PMC3840405  PMID: 24077055
pediatric; child; tuberculosis; risk factors; contact tracing
25.  Changes in the Timing of Antiretroviral Therapy Initiation in HIV-Infected Patients With Tuberculosis in Uganda: A Study of the Diffusion of Evidence Into Practice in the Global Response to HIV/AIDS 
Among patients with HIV-associated tuberculosis, the extent to which recommendations regarding early initiation of antiretroviral therapy are routinely implemented remain unknown. Two Ugandan clinics demonstrated improved rates of antiretroviral therapy initiation in association with changing guidelines and emerging scientific evidence
Background. We aimed to determine the extent to which emerging evidence and changing guidelines regarding timing of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)–infected patients with tuberculosis influenced “real-world” clinical practice in Uganda.
Methods. We evaluated ART-naive, HIV-infected adults starting tuberculosis therapy at 2 HIV clinics in Uganda between 26 August 2006 and 29 September 2012. We used multivariate regression to calculate associations between 4 calendar periods reflecting publication of seminal clinical studies or changes in guidelines and timing of ART after tuberculosis therapy initiation.
Results. For patients with CD4 counts <50 cells/µL, the fraction starting ART within 14 and 30 days of initiating tuberculosis therapy increased from 7% to 14% and from 14% to 86% over the period of observation. The fraction of patients with CD4 counts >50 cells/µL starting ART within 60 days increased from 16% to 28%. After adjustment for sociodemographic factors, when comparing the most recent with the earliest calendar period, the rate of ART initiation increased by 4.57-fold (95% confidence interval [CI], 1.76-fold to 11.86-fold) among patients with baseline CD4 counts ≤50 cells/µL and by 5.43-fold (95% CI, 3.16- fold to 9.31-fold) among those with baseline CD4 counts >50 cells/µL.
Conclusions. We observed large changes in clinical practice during a period of emerging data and changing guidelines among HIV-infected patients with tuberculosis. Nonetheless, a significant proportion of individuals with higher CD4 cell counts do not start ART within recommended time frames. Targeted dissemination and implementation efforts are still needed to achieve target levels in practice.
PMCID: PMC3840406  PMID: 24065326
tuberculosis; HIV; antiretroviral therapy; implementation; diffusion

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