by
Lesley S. Park;
Janet P. Tate;
Keith Sigel;
David Rimland;
Kristina Crothers;
Cynthia Gibert;
Maria C. Rodriguez-Barradas;
Matthew Bidwell Goetz;
Roger J. Bedimo;
Sheldon T. Brown;
Amy C. Justice;
Robert Dubrow
Objective: Utilizing the Veterans Aging Cohort Study, the largest HIV cohort in North America, we conducted one of the few comprehensive comparisons of cancer incidence time trends in HIV-infected (HIV+) versus uninfected persons during the antiretroviral therapy (ART) era.
Design: Prospective cohort study.
Methods: We followed 44 787 HIV+ and 96 852 demographically matched uninfected persons during 1997–2012. We calculated age-, sex-, and race/ethnicity-standardized incidence rates and incidence rate ratios (IRR, HIV+ versus uninfected) over four calendar periods with incidence rate and IRR period trend P values for cancer groupings and specific cancer types.
Results: We observed 3714 incident cancer diagnoses in HIV+ and 5760 in uninfected persons. The HIV+ all-cancer crude incidence rate increased between 1997–2000 and 2009–2012 (P trend = 0.0019). However, after standardization, we observed highly significant HIV+ incidence rate declines for all cancer (25% decline; P trend <0.0001), AIDS-defining cancers (55% decline; P trend <0.0001), nonAIDS-defining cancers (NADC; 15% decline; P trend = 0.0003), and nonvirus-related NADC (20% decline; P trend <0.0001); significant IRR declines for all cancer (from 2.0 to 1.6; P trend <0.0001), AIDS-defining cancers (from 19 to 5.5; P trend <0.0001), and nonvirus-related NADC (from 1.4 to 1.2; P trend = 0.049); and borderline significant IRR declines for NADC (from 1.6 to 1.4; P trend = 0.078) and virus-related NADC (from 4.9 to 3.5; P trend = 0.071).
Conclusion: Improved HIV care resulting in improved immune function most likely contributed to the HIV+ incidence rate and the IRR declines. Further promotion of early and sustained ART, improved ART regimens, reduction of traditional cancer risk factor (e.g. smoking) prevalence, and evidence-based screening could contribute to future cancer incidence declines among HIV+ persons.
HIV disproportionately affects black men who have sex with men, and herpes simplex virus type 2 is known to increase acquisition of HIV. However, data on racial disparities in herpes simplex virus type 2 prevalence and risk factors are limited among men who have sex with men in the United States. InvolveMENt was a cohort study of black and white HIV-negative men who have sex with men in Atlanta, GA. Univariate and multivariate cross-sectional associations with herpes simplex virus type 2 seroprevalence were assessed among 455 HIV-negative men who have sex with men for demographic, behavioural and social determinant risk factors using logistic regression. Seroprevalence of herpes simplex virus type 2 was 23% (48/211) for black and 16% (38/244) for white men who have sex with men (p = 0.05). Education, poverty, drug/alcohol use, incarceration, circumcision, unprotected anal intercourse, and condom use were not associated with herpes simplex virus type 2. In multivariate analyses, black race for those ≤25 years, but not >25 years, and number of sexual partners were significantly associated. Young black men who have sex with men are disproportionately affected by herpes simplex virus type 2, which may contribute to disparities in HIV acquisition. An extensive assessment of risk factors did not explain this disparity in herpes simplex virus type 2 infection suggesting differences in susceptibility or partner characteristics.
Background. Variant influenza A(H3N2) viruses (H3N2v) have transmitted recently from pigs to humans in the United States. Vaccines strategies are needed. Methods. Healthy adults received 2 doses of subvirion H3N2v vaccine (15 μg of hemagglutinin/dose) 21 days apart in this open-label trial. Serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody (Ab) titers were measured before and 8 and 21 days after each dose. Memory B-cell (MBC) responses were assessed. Results. Vaccine was well tolerated. A total of 40% of subjects had an HAI Ab titer of ≥40 before vaccination. Eight-seven percent (95% confidence interval [CI], 79%-93%) and 73% (95% CI, 63%-81%) of subjects 18-64 years old (98 subjects) and ≥65 years old (90 subjects), respectively, had an HAI titer of ≥40 21 days after dose 1 (P =. 01); 51% (95% CI, 41%-61%) and 52% (95% CI, 41%-62%) of younger and older subjects, respectively, developed ≥4-fold rises in titer (P = not significant). Neut Ab response patterns were similar. Geometric mean titers were higher in younger subjects. Dose 2 provided no significant enhancement in responses. Cross-reactive MBCs were detected before vaccination and expanded after vaccination. Preexisting H3N2v-specific MBCs positively correlated with early increases in vaccine-induced Ab. Conclusions. In most healthy adults, one 15-μg dose of vaccine elicited levels of HAI Abs associated with protection. Studies in children and elderly individuals are indicated to define the immunization needs of these groups.
Objective We examined Vaccine Information Statements (VIS) dissemination practices and parental use and perceptions. Methods We conducted a national online panel survey of 2603 US parents of children aged <7. Primary outcomes included reported VIS receipt, delivery timing, reading experiences, and perceived utility. Results Most parents received a VIS (77.2%; [95% CI: 74.5–79.7%]), 59.7% [56.6–62.7%] before vaccination but 14.5% [12.5–16.8%] reported receiving it after their child's immunization; 15.1% [13.0–17.6%] were unsure of receipt status or timing; another 10.7% [9.0–12.6%] reported non-receipt of a VIS. Less than half who received a VIS before vaccination completed it before vaccination (46.2% [42.4, 50.0%]), but most who read at least some found the information useful (95.7% [93.8–97.0%]). Parents who delayed or refused at least one recommended non-influenza vaccine reported fewer opportunities to ask providers VIS questions. Conclusions Most parents report receiving VIS before vaccination as per federal guidelines. Continued effort is needed to enhance VIS distribution practice and parent-provider VIS content communication.
The liver is an organ in which antigen-specific T-cell responses manifest a bias toward immune tolerance. This is clearly seen in the rejection of allogeneic liver transplants, and multiple other phenomena suggest that this effect is more general. These include tolerance toward antigens introduced via the portal vein, immune failure to several hepatotropic viruses, the lack of natural liver-stage immunity to malaria parasites, and the frequent metastasis of cancers to the liver. Here we review the mechanisms by which T cells engage with hepatocellular antigens, the context in which such encounters occur, and the mechanisms that act to suppress a full T-cell response. While many mechanisms play a role, we will argue that two important processes are the constraints on the cross-presentation of hepatocellular antigens, and the induction of negative feedback inhibition driven by interferons. The constant exposure of the liver to microbial products from the intestine may drive innate immunity, rendering the local environment unfavorable for specific T-cell responses through this mechanism. Nevertheless, tolerance toward hepatocellular antigens is not monolithic and under specific circumstances allows both effective immunity and immunopathology.
by
NM Vora;
LA Orciari;
M Niezgoda;
G Selvaggi;
V Stosor;
George Lyon III;
GM Lyon;
RM Wallace;
J Gabel;
DR Stanek;
P Jenkins;
M Shiferaw;
P Yager;
F Jackson;
CA Hanlon;
I Damon;
JD Blanton;
S Recuenco;
R Franka
Background: The rabies virus causes a fatal encephalitis and can be transmitted through organ transplantation. In 2013, a man developed rabies 18 months after receiving a kidney from a donor with rabies, who was not known to have been infected when the organs were procured. Three additional persons who received organs from the same donor (liver, kidney, heart), all of whom were not vaccinated for rabies before transplantation, received rabies post-exposure prophylaxis (PEP) with rabies immune globulin and 5 doses of rabies vaccine as soon as the diagnosis of rabies was made in the donor (18 months after their transplant surgeries). We describe their clinical management.
Methods: As the 3 recipients were all on immunosuppressive medications, post-vaccination serologic testing was performed using the rapid fluorescent focus inhibition test to measure rabies virus neutralizing antibodies (RVNAs). An acceptable antibody response to administration of rabies vaccine was defined as detection of RVNAs at a concentration ≥0.1 IU/mL from a serum specimen collected ≥7 days after the fifth vaccine dose.
Results: All 3 recipients demonstrated an acceptable antibody response despite their immunosuppressed states. More than 36 months have passed since their transplant surgeries, and all 3 recipients have no evidence of rabies.
Conclusions: The survival of 3 previously unvaccinated recipients of solid organs from a donor with rabies is unexpected. Although the precise factors that led to their survival remain unclear, our data suggest that PEP can possibly enhance transplant safety in settings in which donors are retrospectively diagnosed with rabies.
Objective Understanding the current status of parents’ vaccine decision making is crucial to inform public policy. We sought to assess changes in vaccine decisions among parents of young children. Methods We conducted a web-based national poll of parents of children <7 years in 2012 and 2014. Participants reported vaccine decisions for their youngest child. We calculated survey-weighted population estimates of overall immunizations decisions, and delay/refusal rates for specific vaccines. Results In 2012, 89.2% (95% CI, 87.3–90.8%) reported accepting or planning to accept all recommended non-influenza childhood vaccines, 5.5% (4.5–6.6%) reported intentionally delaying one or more, and 5.4% (4.1–6.9%) reported refusing one or more vaccines. In 2014, the acceptance, delay, and refusal rates were 90.8% (89.3–92.1%), 5.6% (4.6–6.9%), and 3.6% (2.8–4.5%), respectively. Between 2012 and 2014, intentional vaccine refusal decreased slightly among parents of older children (2–6 years) but not younger children (0–1 years). The proportion of parents working to catch up on all vaccines increased while those refusing some but not all vaccines decreased. The South experienced a significant increase in estimated acceptance (90.1–94.1%) and a significant decrease in intentional ongoing refusal (5.0–2.1%). Vaccine delay increased in the Northeast (3.2–8.8%). Conclusions Nationally, acceptance and ongoing intentional delay of recommended non-influenza childhood vaccines were stable. These findings suggest that more effort is warranted to counter persistent vaccine hesitancy, particularly at the local level. Longitudinal monitoring of immunization attitudes is also warranted to evaluate temporal shifts over time and geographically.
by
Aaron S. Wallace;
Kathleen Wannemuehler;
George Bonsu;
Melissa Wardle;
Mawuli Nyaku;
Kwame Amponsah-Achiano;
John F. Dadzie;
Frederick O. Sarpong;
Walter Orenstein;
Eli Rosenberg;
Saad Omer
Background: Parents’ attitudes and beliefs in vaccination are important to understand for shaping vaccine acceptance and demand interventions. Little research has focused on developing a validated scale to measure parents’ attitudes towards vaccinations in low and middle-income countries; Ghana provided an opportunity develop a caregiver vaccination attitudes scale (CVAS) validated against childhood vaccine compliance.
Methods: We conducted a cluster survey of 373 households with children aged 12–35 months of age from Northern Region, Ghana. Caregivers responded to 22 vaccination behavior and belief survey items and provided the child's vaccination status. In exploratory factor analysis (EFA) to assess CVAS content validity, we used parallel analysis to guide the number of factors to extract and principal axis factor analysis for factor extraction. Reliability of the scale was assessed using McDonald's Omega coefficient. Criterion validity of scale and subscales was assessed against receipt of vaccinations by 12 months of age and vaccination delay, using number of days undervaccinated.
Results: EFA of CVAS responses resulted in removing 11 of 22 survey items due to loadings <0.30 and development of a 5-factor structure with subscales for Vaccine-Preventable Disease (VPD) Awareness, Vaccine Benefits, Past Behavior, Vaccine Efficacy and Safety, and Trust. The 5 factors accounted for 69% of the common variance and omega coefficients were >0.73 for all subscales. Validity analysis indicated that for every unit increase in the parent's scale score, the odds of the child being vaccinated decreased by 0.58 (95% confidence interval [CI]: 0.37, 0.68) and the number of days under-vaccinated increased by 86 (95%CI: 28, 143). The final 3-factor scale included Vaccine Benefits, Past Behavior, and Vaccine Efficacy and Safety.
Discussion: The final CVAS included three factors associated with vaccine compliance in Ghana, although several survey items suggested for use in vaccine acceptance scales were dropped. Replicating this study in several country settings will provide additional evidence to assist in refining a tool for use in routine vaccine acceptance and demand surveillance efforts.
Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system. In particular, NFATs are important regulators of inducible IL-4 gene expression. Interferon regulatory factor 4 (IRF4) is an immune system-restricted interferon regulatory factor that is required for lymphocyte activation, but its molecular functions in the T lineage remain to be elucidated. We demonstrate that IRF4 potently synergizes with NFATc2 to specifically enhance NFATc2-driven transcriptional activation of the IL-4 promoter. This function is dependent on the physical interaction of IRF4 with NFATc2. IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production. Furthermore, naïve T helper cells from mice lacking IRF4 are compromised severely for the production of IL-4 and other Th2 cytokines. The identification of IRF4 as a partner for NFATc2 in IL-4 gene regulation provides an important molecular function for IRF4 in T helper cell differentiation.
Background: Although modern combination antiretroviral therapy (cART) regimens are better tolerated and less complex than earlier treatments, regimen modification or discontinuation remains a concern.
Methods: We studied HIV Outpatient Study (HOPS) participants who initiated first or second cART regimens during: 1996–1999, 2000–2003, 2004–2007 and 2008–2011. We analyzed regimen durability (time to regimen modification) and success (achieving undetectable plasma HIV RNA) for first and second cART regimens using Kaplan-Meier curves and log-rank tests, and examined factors associated with durability and success of first cART regimen using proportional hazards models.
Results: Durability of cART was progressively longer for cART regimens initiated in more recent periods: median first cART regimen durations were 1.0, 1.1, 2.1 and 4.6 years in 1996–1999, 2000–2003, 2004–2007 and 2008–2011, and median second cART durations were 0.9, 1.2, 2.8 and 3.9 years, respectively (both p<0.001). Comparing 1996–1999 and 2008–2011, the percentage of patients who achieved an undetectable HIV RNA within 6 months of first cART initiation increased from 65% to 81%, and from 63% to 80% on second cART (both p<0.001). Among patients initiating first cART during 2008–2011, black non-Hispanic/Latino race/ethnicity and ≥twice daily dosing were significantly associated with higher rates of regimen modification (p<0.05), and higher baseline HIV RNA levels were associated with failure to achieve an undetectable HIV RNA (p<0.001).
Conclusions: Among HIV-infected U.S. adults in routine HIV care, durability of first and second cART regimens and the likelihood of prompt virologic suppression increased during 1996–2011, coincident with the availability of more tolerable, less complex cART options.