Loss of CD103+ DCs and Mucosal IL-17+ and IL-22+ Lymphocytes is Associated with Mucosal Damage in SIV Infection

HIV/SIV disease progression is associated with multifocal damage to the GI tract epithelial barrier that correlates with microbial translocation and persistent pathological immune activation but the underlying mechanisms remain unclear. Investigating alterations in mucosal immunity during SIV infection, we found that damage to the colonic epithelial barrier was associated with loss of multiple lineages of IL-17-producing lymphocytes, cells that microarray analysis showed express genes important for enterocyte homeostasis, including IL-22. IL-22-producing lymphocytes were also lost after SIV infection. Potentially explaining coordinate loss of these distinct populations, we also observed loss of CD103+ DCs after SIV infection which associated with loss of IL-17 and IL-22-producing lymphocytes. CD103+ DCs expressed genes associated with promotion of IL-17/IL-22+ cells, and co-culture of CD103+ DCs and naïve T-cells led to increased IL17A and RORc expression in differentiating T-cells. These results reveal complex interactions between mucosal immune cell subsets providing potential mechanistic insights into mechanisms of mucosal immune dysregulation during HIV/SIV infection, and offer hints for development of novel therapeutic strategies to address this aspect of AIDS virus pathogenesis

Mental health outcomes for individuals with chronic hepatitis C infection.

ObjectiveUsing data from the 2011–2015 IBM MarketScan® Commercial Claims and Encounters, we sought to assess the relationship between mental health outcomes and chronic hepatitis C infection after adjusting for important confounders. Persons with HCV antibody and RNA test results between 2011 and 2015 and continuous enrollment in fee-for-service plans were included in the analysisIntroductionHepatitis C virus (HCV) infection is a leading cause of liver disease-related morbidity and mortality in the United States and HCV incidence has been increasing. Mental illness may impact the likelihood of initial HCV infection, progress and adherence to treatment along the hepatitis C care cascade, and risk of subsequent reinfection for those cured of hepatitis C. The relationship between HCV infection and mental illness is not well understood and many studies have lacked sufficient sample size to adjust for important confounders. We sought to explore the association between chronic HCV infection and mental illness after adjusting for important confounders.MethodsWe obtained data from the 2011–2015 IBM MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. These data consist of inpatient and outpatient service claims for persons with employer-sponsored health insurance coverage and their dependents. Persons with HCV antibody and RNA test results between 2011 and 2015 and continuous enrollment in a fee-for-service plan were included in the analysis. Chronic HCV infection was defined by a positive HCV RNA test result. Controls without chronic HCV infection had a negative HCV antibody test result and no positive HCV antibody or RNA test result in the preceding or following year. The index date was defined by the date of the earliest positive HCV RNA or negative HCV antibody test. Demographic characteristics were obtained from the MarketScan® enrollment tables. All enrollees in the study population were at least 18 years old during the year of the index date. The analysis sample was restricted to persons who were identified as receiving outpatient prescription drug claims data feeds. We estimated adjusted odds ratios (OR) for the association between mental illness (ICD-9 code 295 or 296) and HCV RNA status. Multivariate models included age (18-44, 45-64, 65+ years), sex, region, and an adjusted Charlson Comorbidity Index which excluded liver disease and hepatocellular carcinoma.ResultsWe identified 2,847 individuals with chronic HCV infection (HCV RNA+) and 57,418 controls who were HCV antibody negative. With respect to age, 83% of HCV RNA+ individuals were aged 45-64 years while only 43% of the HCV antibody negative individuals were in the same age range. Similarly, for sex, 62% and 40% of HCV RNA+ individuals and controls, respectively, were male. For unadjusted analyses, age, sex, region, comorbid conditions, and mental illness (OR= 2.25 [95% CI; 1.52 - 3.34]) were all statistically associated with HCV RNA+. For the multivariate adjusted models, these same variables remained statistically significant. For the multivariate model, individuals with a mental illness were more likely to be HCV RNA+ relative to HCV antibody negative controls. (OR= 1.95 [95% CI; 1.30 - 2.93]).ConclusionsThis study demonstrated a strong association between mental illness and HCV chronic infection after adjusting for important confounders including other comorbid conditions. A growing body of research suggests that persons with mental illness are at increased risk for contracting and transmitting HCV due to high rates of substance use and high-risk sexual behavior among infected persons as well as high rates of sexual victimization. HCV prevention efforts should be directed toward individuals with mental illness or seeking treatment for mental illness.

Prevalence of Hepatitis C Testing Among Non-Institutionalized Individuals in the US, NHIS 2013-2017

ObjectiveUsing a large nationally representative dataset, we estimated the prevalence of self-reported hepatitis C testing among individuals who were recommended to be tested (i.e., baby boomer cohort born between 1945 and 1965) by the CDC and United States Preventive Services Task Force.IntroductionHepatitis C virus (HCV) infection is the most common blood-borne disease in the US and the leading cause of liver-related morbidity and mortality. Approximately 3.5 million individuals in the US were estimated to have been living with hepatitis C in 2010 and approximately half of them were unaware that they were infected. Among HCV infected individuals, those born between 1945 and 1965 (usually referred to as the baby boomer cohort) represents approximately 75% of current cases. Because of the substantial burden of disease among this age group, CDC expanded its existing hepatitis C risk-based testing recommendations to include a one-time HCV antibody test for all persons born between 1945 and 1965. The United States Preventive Services Task Force (USPSTF) subsequently made the same recommendation in June 2013.DescriptionMethodsThe following question "Have you ever had a blood test for hepatitis C?" has been administered annually from 2013 through 2017 on the National Health Interview Survey (NHIS). The NHIS is a nationally representative cross-sectional face-to-face household interview of civilian noninstitutionalized individuals in the U.S. The NHIS survey uses a complex multistage probability design that includes stratification, clustering, and oversampling. We estimated the prevalence of hepatitis C testing for adults in the US during the study period from 2013 to 2017. In addition, we carried out stratified analyses comparing those with private insurance to those who did not have private insurance. We reported weighted estimates taking into account the NHIS survey design. The R statistical software (R Core Team, 2018) was used to estimate weighted prevalence estimates for hepatitis C testing.ResultsDuring the study period from 2013-2017, there were 148,674 adults who responded to the ever tested for hepatitis C question. In addition, 33.56% of these individuals were born between 1945 and 1965; among all adults, the weighted percentage of individuals that responded yes they had received a hepatitis C screening test was 12.82% (95% CI: 12.54-13.10%) while for baby boomers the estimate was 13.93% (95% CI: 13.51-14.35%).Figure 1 presents the annual trend in the hepatitis C test prevalence over the study period by birth cohorts. For both cohorts, there were significant increases over time in hepatitis C testing prevalence. The two trend lines began to diverge in 2015 with the baby boomer cohort reporting higher rates of hepatitis C testing. For the baby boomer cohort, there was also a substantial increase in reported hepatitis C testing in 2017 relative to 2016. Similar trends were found for the samples when we restricted the sample to only those with private insurance. Compared to the people with private insurance, the baby boomers with 'Non-private’ insurance, including Medicaid, Medicare, or military- government sponsored insurances, reported higher rates of testing.ConclusionAcross the five-year period from 2013 through 2017, we found increasing rates of self-reported hepatitis C testing among non-institutionalized U.S. adults. For the baby boomer cohort, we saw a substantial increase in testing in 2017, which was likely due in part, to increased awareness among both physicians and patients of the CDC and USPSTF recommendation to have all baby boomers tested. Efforts to increase the awareness of these recommendations should continue. Additional targeted promotions among hard to reach populations should also be considered.How the Moderator Intends to Engage the Audience in Discussions on the TopicThis panel will discuss strengths and weaknesses for monitoring hepatitis C testing using alternative data sources including self-reported data, insurance claims data, and laboratory testing data.

Rate of AIDS progression is associated with gastrointestinal dysfunction in simian immunodeficiency virus-infected pigtail macaques

During HIV/SIV infection, mucosal immune system dysfunction and systemic immune activation are associated with progression to AIDS; however, it is unclear to what extent pre-existing gastrointestinal damage relates to disease progression postinfection. Pigtail macaques (PTM) are an excellent model in which to assess mucosal dysfunction in relation to HIV/SIV pathogenesis, as the majority of these animals have high levels of gastrointestinal damage, immune activation, and microbial translocation prior to infection, and rapidly progress to AIDS upon SIV infection. In this study, we characterized the mucosal immune environment prior to and throughout SIV infection in 13 uninfected PTM and 9 SIV-infected PTM, of which 3 were slow progressors. This small subset of slow progressors had limited innate immune activation in mucosal tissues in the periphery, which was associated with a more intact colonic epithelial barrier. Furthermore, we found that preinfection levels of microbial translocation, as measured by LPS-binding protein, in PTM correlated with the rate of progression to AIDS. These data suggest that pre-existing levels of microbial translocation and gastrointestinal tract dysfunction may influence the rate of HIV disease progression

Transitioning couple’s voluntary HIV counseling and testing (CVCT) from stand-alone weekend services into routine antenatal and VCT services in government clinics in Zambia’s two largest cities

Introduction: Most HIV infections in Africa are acquired by married/cohabiting adults and WHO recommends couple’s voluntary HIV counseling and testing (CVCT) for prevention. The handover from NGO-sponsored weekend CVCT to government-sponsored services in routine weekday antenatal care (ANC) and individual voluntary testing and counseling (VCT) services in Zambia’s two largest cities from 2009–2015 is described. Methods: Government clinic counselors were trained to provide CVCT, and along with community health workers they promoted CVCT services in their clinic and surrounding areas. When client volume exceeded the capacity of on-duty staff in ANC and VCT, non-governmental organization (NGO) subsidies were offered for overtime pay. Results: Implementation of routine CVCT services varied greatly by clinic and city. The 12 highest volume clinics were examined further, while 13 clinics had CVCT numbers that were too low to warrant further investigation. In Lusaka, the proportion of pregnant women whose partners were tested rose from 2.6% in 2009 to a peak of 26.2% in 2012 and 24.8% in 2015. Corresponding reports in Ndola were 2.0% in 2009, 17.0% in 2012 and 14.5% in 2015. Obstacles to CVCT included: limited space and staffing, competing priorities, record keeping not adapted for couples, and few resources for promotion and increasing male involvement. Conflicting training models for ‘partner testing’ with men and women separately vs. CVCT with joint post-test counseling led to confusion in reporting to district health authorities. Discussion: A focused and sustained effort will be required to reach a meaningful number of couples with CVCT to prevent heterosexual and perinatal HIV transmission. Establishing targets and timelines, funding for dedicated and appropriately trained staff, adoption of standardized data recording instruments with couple-level indicators, and expansion of community and clinic-based promotions using proven models are recommended

Dynamics of simian immunodeficiency virus SIVmac239 infection in pigtail macaques

Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P = 0.0018). However, increased SIV progression was not associated with increased viremia, as both peak and set-point plasma viremias were similar between PTM and RM (P = 0.7953 and P = 0.1006, respectively). Moreover, this increased disease progression was not associated with rapid CD4(+) T cell depletion, as CD4(+) T cell decline resembled other SIV/human immunodeficiency virus (HIV) models. Since immune activation is the best predictor of disease progression during HIV infection, we analyzed immune activation by turnover of T cells by BrdU decay and Ki67 expression. We found increased levels of turnover prior to SIV infection of PTM compared to that observed with RM, which may contribute to their increased disease progression rate. These data evaluate the kinetics of SIVmac239-induced disease progression and highlight PTM as a model for HIV infection and the importance of immune activation in SIV disease progression

Lusaka: Average number of couples per month that received weekday couples voluntary counseling and testing in clinics with a monthly average of ≥40 couples in at least one year.

<p>Blue bar represents CVCT provided by on-duty government counselors in the ANC clinics; orange bars represent CVCT provided by on duty government counselors in the VCT department; grey bar represents weekday CVCT provided by a ZEHRP-sponsored counselor. Grey stars indicate clinic-years when no ZEHRP-sponsored staff provided CVCT services. Blue and orange stars indicate clinics in which logbooks for data extraction were not available for that year.</p

Ndola: Average number of couples per month that received weekday couples voluntary counseling and testing in clinics with at least two years of data.

<p>Blue bar represents CVCT provided by on-duty government counselors in the ANC clinics; orange bars represent CVCT provided by on duty government counselors in the VCT department; grey bar represents weekday CVCT provided by a ZEHRP-sponsored counselor. Grey stars indicate clinic-years when no ZEHRP-sponsored staff provided CVCT services. Blue stars indicate clinics in which logbooks for data extraction were not available for that year.</p

Number and percent of first time ANC clients and partners tested 2009–2015, from HMIS reports to DHMT in Ndola.

<p>Blue represents women whose partners were not tested, orange represents women whose partners were tested. Percentage of ANC clients with male partner tested is shown above each bar.</p

Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques

HIV infection results in gastrointestinal (GI) tract damage, microbial translocation, and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, to enhance GI tract physiology, we treated SIV-infected pigtail macaques with ARVs, probiotics, and prebiotics or with ARVs alone. This synbiotic treatment resulted in increased frequency and functionality of GI tract APCs, enhanced reconstitution and functionality of CD4 + T cells, and reduced fibrosis of lymphoid follicles in the colon. Thus, ARV synbiotic supplementation in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis