John L. Schmitz

Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells

Objectives:Valproic acid and intensified antiretroviral therapy may deplete resting CD4+ T-cell HIV infection. We tested the ability of valproic acid to deplete resting CD4+ T-cell infection in patients receiving standard antiretroviral therapy. Methods:Resting CD4+ T-cell infection was measured in 11 stably aviremic volunteers twice prior to, and twice after Depakote ER 1000 mg was added to standard antiretroviral therapy. Resting CD4+ T-cell infection frequency was measured by outgrowth assay. Low-level viremia was quantitated by single copy plasma HIV RNA assay. Results:A decrease in resting CD4+ T-cell infection was observed in only four of the 11 patients. Levels of immune activation and HIV-specific T-cell response were low and stable. Valproic acid levels ranged from 26 to 96 μg/ml when measured near trough. Single copy assay was performed in nine patients. In three patients with depletion of resting CD4+ T-cell infection following valproic acid, single copy assay ranged from less than 1–5 copies/ml. Continuous low-level viremia was observed in three patients with stable resting CD4+ T-cell infection (24–87, 8–87, and 1–7 copies/ml respectively) in whom multiple samples were analyzed. Conclusion:The prospective addition of valproic acid to stable antiretroviral therapy reduced the frequency of resting CD4+ T-cell infection in a minority of volunteers. In patients in whom resting CD4+ T-cell infection depletion was observed, viremia was rarely detectable by single copy assay.

The prevalence of trichomoniasis in young adults in the United States

Background and Objectives: The prevalence of trichomoniasis in the general population of the United States is unknown. This study provides the first population-based prevalence estimates of trichomoniasis among young adults in the United States. Methods: The National Longitudinal Study of Adolescent Health (Add Health) is an ongoing prospective cohort study. In a cross-sectional analysis of Wave III of Add Health (N = 12,449), we determined the prevalence of trichomoniasis using a polymerase chain reaction assay. Results: The estimated overall prevalence of trichomoniasis in U.S. young adults was 2.3% (95% confidence interval [CI], 1.8–2.7%). The prevalence was slightly higher among women (2.8%; 95% CI, 2.2–3.6%) than men (1.7%; 95% CI, 1.3–2.2%). The prevalence increased with age and varied by region, with the south having the highest prevalence (2.8%; 95% CI, 2.2–3.5%). The prevalence was highest among black women (10.5%; 95% CI, 8.3–13.3%) and lowest among white women (1.1%; 95% CI, 0.8–1.6%). Among men, the prevalence was highest among Native Americans (4.1%; 95% CI, 0.4–29.3%) and blacks (3.3%; 95% CI, 2.2–4.9%), and lowest among white men (1.3%; 95% CI, 0.9–1.8%). Conclusions: Trichomoniasis is moderately prevalent among the general U.S. population of young adults and disturbingly high among certain racial/ethnic groups.

Liver allograft antibody‐mediated rejection with demonstration of sinusoidal C4d staining and circulating donor‐specific antibodies

The importance of antibody‐mediated rejection (AMR) in ABO‐compatible liver transplantation is controversial. Here we report a prospective series of liver recipients with a preoperative positive crossmatch. To establish the diagnosis of AMR in liver recipients, the criteria described for kidney allografts were adopted. In approximately 10% of 197 liver transplants, we observed a positive T and B cell flow crossmatch before transplantation. Fifteen of 19 patients converted to negative crossmatches early after transplantation and displayed normal liver function while they were on routine immunosuppression. Four patients maintained positive crossmatches. Three of the 4 met the criteria for AMR and showed evidence of graft dysfunction, the presence of donor‐specific antibodies (DSAs), morphological tissue destruction with positive C4d linear staining on the graft sinusoidal endothelium, and improved function with attempts to eliminate DSAs. A persistently positive crossmatch after liver transplantation may lead to early, severe AMR and liver failure. C4d staining in the liver sinusoidal endothelium should alert one to the possibility of AMR. In our experience, patients with a positive crossmatch should have it repeated at 2 weeks and, if it is positive, again at 3 to 5 weeks. Recipients with an unknown preoperative crossmatch who develop early cholestasis of unclear etiology should be crossmatched or tested for the presence of DSAs to evaluate for AMR. Liver Transpl, 2011.

Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation

BACKGROUND Lung transplantation is limited by chronic lung allograft dysfunction. Acute cellular rejection (ACR) is a risk factor for allograft dysfunction; however, the role of antibody-mediated rejection (AMR) is not well characterized. METHODS This was a retrospective review from 2007 to 2011 of lung transplant recipients with human leukocyte antigen (HLA) antibody testing using Luminex (Luminex Corp, Austin, TX) single-antigen beads. Statistics included Fishers exact test for significance. RESULTS Donor-specific antibodies (DSA) developed in 13 of 44 patients. Of the 13 with DSA, 12 had cystic fibrosis compared with 18 of 31 in the non-DSA group (p = 0.035). Of those with DSAs, 23.1% occurred within the first year, and 69.2% occurred between 1 and 3 years. Twelve of 13 DSA patients had anti-HLA DQ specificity compared with 2 of 31 non-DSA patients (p = 0.0007). AMR developed in 10 of the 13 DSA patients compared with 1 of 31 non-DSA patients (p = 0.0001). The DSA group experienced 2.6 episodes/patient of cellular rejection vs 1.7 episodes/patient in the non-DSA group (p = 0.059). Bronchiolitis obliterans syndrome developed in 11 of 13 in the DSA group vs 10 of 31 in the non-DSA group (p = 0.0024). In the DSA group, 11.5% HLAs matched compared with 20.4% in the non-DSA group (p = 0.093). AMR developed in 11 of 22 patients in the non-DSA HLA group compared with 0 of 22 in the group without non-DSA HLA antibodies (p = 0.002). Survival at 1 and 3 years was 92% and 36% in the DSA group, respectively, and 97% and 65% in the non-DSA group. CONCLUSIONS DSAs and non-DSAs occur frequently after lung transplantation. DSAs are prevalent in the cystic fibrosis population and are associated with AMR, bronchiolitis obliterans syndrome, and possibly, ACR.

Prevalence of HIV Infection Among Young Adults in the United States: Results From the Add Health Study

OBJECTIVES We estimated HIV prevalence rates among young adults in the United States. METHODS We used survey data from the third wave of the National Longitudinal Study of Adolescent Health, a random sample of nearly 19000 young adults initiated in 1994-1995. Consenting respondents were screened for the presence of antibodies to HIV-1 in oral mucosal transudate specimens. We calculated prevalence rates, accounting for survey design, response rates, and test performance. RESULTS Among the 13184 participants, the HIV prevalence rate was 1.0 per 1000 (95% confidence interval [CI] = 0.4, 1.7). Gender-specific prevalence rates were similar, but rates differed markedly between non-Hispanic Blacks (4.9 per 1000; 95% CI=1.8, 8.7) and members of other racial/ethnic groups (0.22 per 1000; 95% CI=0.00, 0.64). CONCLUSIONS Racial disparities in HIV in the United States are established early in the life span, and our data suggest that 15% to 30% of all cases of HIV occur among individuals younger than 25 years.

Isolated Donor Specific Alloantibody-Mediated Rejection after ABO Compatible Liver Transplantation

Antibody‐mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno‐transplantation, but its role after ABO compatible liver transplantation is controversial.

DRB1*15 Allele Is a Risk Factor for PR3-ANCA Disease in African Americans

Anti-neutrophil cytoplasmic autoantibody (ANCA) disease rarely occurs in African Americans and risk factors for the disease in this population are unknown. Here, we genotyped MHC class II alleles and found that, among African Americans, those with proteinase 3-ANCA (PR3-ANCA) had 73.3-fold higher odds of having HLA-DRB1*15 alleles than community-based controls (OR 73.3; 95% CI 9.1 to 591). In addition, a disproportionate number of African American patients carried the DRB1*1501 allelic variant of Caucasian descent rather than the DRB1*1503 allelic variant of African descent. Among Caucasians, those with PR3-ANCA had 2.2-fold higher odds of carrying DRB1*1501 than controls (OR 2.2; 95% CI 1.2 to 4.0). A validation study supported by the Vasculitis Clinical Research Consortium confirmed the strong association between the DRB1*15 allele and PR3-ANCA disease, among African Americans. Furthermore, we found that DRB1*1501 protein binds with high affinity to amino acid sequences of sense-PR3, purportedly an antigenic epitope, and to the amino acid sequence complementary to this epitope in vitro. Peptides of sense-PR3 and complementary-PR3 also bound to TNF-α-induced surface expression of DRB1*1501 on peripheral neutrophils. Taken together, these data suggest HLA-DRB1*15 alleles contribute to the pathogenesis of PR3-ANCA disease.

Metabolic and Immune Activation Effects of Treatment Interruption in Chronic HIV-1 Infection: Implications for Cardiovascular Risk

Background Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk. Methodology ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with <200 HIV RNA copies/mL and CD4 cell count ≥500 cells/µL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/µL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels. Principal Findings By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (−0.73 (−1.19, −0.18) mmol/L, p<0.0001), LDL, HDL cholesterol (−0.36(−0.73,−0.03)mmol/L, p = 0.0007 and −0.05(−0.26,0.03), p = 0.0033, respectively) and triglycerides decreased (−0.40 (−0.84, 0.07) mmol/L, p = 0.005). However the TC/HDL ratio remained unchanged (−0.09 (−1.2, 0.5), p = 0.2). Glucose and insulin levels did not change (p = 0.6 and 0.8, respectively). After TI there was marked increase in immune activation (CD8+/HLA-DR+/CD38+ cells, 34% (13, 43), p<0.0001) and soluble TNFR2 (1089 ng/L (−189, 1655), p = 0.0008) coinciding with the rebound of HIV viremia. Conclusions Our data suggests that interrupting antiretroviral therapy does not reduce cardiovascular disease (CVD) risk, as the improvements in lipid parameters are modest and overshadowed by the decreased HDL levels. Increased immune cell activation and systemic inflammatory responses associated with recrudescent HIV viremia may provide a more cogent explanation for the increased cardiovascular risk associated with treatment interruption and HIV infection. Trial Registration ClinicalTrials.gov NCT00015704

Selective screening for chlamydial infection: which criteria to use?☆

BACKGROUND Screening sexually active women for Chlamydia trachomatis is necessary to detect asymptomatic infections. Selective screening is a common strategy because universal screening is too costly in many settings. In order to guide local programs in the choice of selective screening criteria, we examined the performance of previously proposed screening criteria for C. trachomatis. METHODS A clinic-based, cross-sectional study was conducted in public family planning and sexually transmitted disease (STD) clinics in ten counties in North Carolina. Women (n = 4471 in family planning and n = 2201 in STD clinics) undergoing pelvic examination were enrolled consecutively. Nine sets of screening criteria, including age alone, were compared using sensitivity, specificity, number of tests required and receiver-operator characteristic (ROC) analysis. All women underwent testing with ligase chain reaction assay of cervical specimens to identify C trachomatis infection. RESULTS The prevalence of C. trachomatis was 7.8% and 11.0% in family planning and STD clinics, respectively. The sensitivities of published criteria ranged from 0.50 to 0.97. Specificities ranged from 0.05 to 0.66. In family planning clinics, the best performing criteria would detect 84% of infections while screening 51% of women. In STD clinics, the same criteria would detect 83% of infections but require testing 67% of women. Testing women aged < or =22 would detect 77% of infections in family planning and 74% of infections in STD clinics, while testing 51% and 48% of the women, respectively. CONCLUSIONS When site-specific criteria cannot be developed, age alone is an acceptable strategy for selective screening for chlamydial infection.

Sinusoidal C4d deposits in liver allografts indicate an antibody-mediated response: Diagnostic considerations in the evaluation of liver allografts†

There is a paucity of data concerning the correlation of complement component 4d (C4d) staining in liver allografts and antibody‐mediated rejection. Data about the location and character of C4d deposits in native and allograft liver tissues are inconsistent. We performed C4d immunofluorescence (IF) on 141 fresh‐frozen liver allograft biopsy samples and native livers, documented the pattern of C4d IF staining, and correlated the findings with the presence of donor‐specific alloantibodies (DSAs). A linear/granular sinusoidal pattern of C4d IF was noted in 18 of 28 biopsy samples obtained after transplantation from patients with positive crossmatch and detectable donor‐specific alloantibody (pos‐XM/DSA) findings. None of the 59 tested biopsy samples from patients with negative crossmatch and detectable donor‐specific alloantibody (neg‐XM/DSA) findings were C4d‐positive (P < 0.001). No significant association was found between pos‐XM/DSA and C4d IF staining in other nonsinusoidal liver compartments. To compare the results of sinusoidal C4d staining with IF and 2 immunohistochemistry (IHC) techniques, C4d IHC was performed on 19 liver allograft biopsy samples in which a sinusoidal pattern of C4d IF had been noted. Sinusoidal C4d IHC findings were negative for 17 of the 19 biopsy samples; 2 showed weak and focal staining, and both patients had pos‐XM/DSA findings. Portal vein endothelium staining was present in only 1 IF‐stained biopsy sample (pos‐XM/DSA) but in 11 IHC‐stained biopsy samples (2 of the 11 samples had neg‐XM/DSA findings). We conclude that sinusoidal C4d deposits detected by IF in frozen tissue samples from liver allograft recipients correlate with the presence of DSAs and an antibody‐mediated alloresponse. These observations are similar to findings reported for other solid organ transplants and can provide relevant information for patient management. Further validation of IHC techniques for C4d detection in liver allograft tissue is required. Liver Transpl 18:641–658, 2012.