HIV-1 Subtype C-Infected Individuals Maintaining High Viral Load as Potential Targets for the “Test-and-Treat” Approach to Reduce HIV Transmission

The first aim of the study is to assess the distribution of HIV-1 RNA levels in subtype C infection. Among 4,348 drug-naïve HIV-positive individuals participating in clinical studies in Botswana, the median baseline plasma HIV-1 RNA levels differed between the general population cohorts (4.1–4.2 log10) and cART-initiating cohorts (5.1–5.3 log10) by about one log10. The proportion of individuals with high (≥50,000 (4.7 log10) copies/ml) HIV-1 RNA levels ranged from 24%–28% in the general HIV-positive population cohorts to 65%–83% in cART-initiating cohorts. The second aim is to estimate the proportion of individuals who maintain high HIV-1 RNA levels for an extended time and the duration of this period. For this analysis, we estimate the proportion of individuals who could be identified by repeated 6- vs. 12-month-interval HIV testing, as well as the potential reduction of HIV transmission time that can be achieved by testing and ARV treating. Longitudinal analysis of 42 seroconverters revealed that 33% (95% CI: 20%–50%) of individuals maintain high HIV-1 RNA levels for at least 180 days post seroconversion (p/s) and the median duration of high viral load period was 350 (269; 428) days p/s. We found that it would be possible to identify all HIV-infected individuals with viral load ≥50,000 (4.7 log10) copies/ml using repeated six-month-interval HIV testing. Assuming individuals with high viral load initiate cART after being identified, the period of high transmissibility due to high viral load can potentially be reduced by 77% (95% CI: 71%–82%). Therefore, if HIV-infected individuals maintaining high levels of plasma HIV-1 RNA for extended period of time contribute disproportionally to HIV transmission, a modified “test-and-treat” strategy targeting such individuals by repeated HIV testing (followed by initiation of cART) might be a useful public health strategy for mitigating the HIV epidemic in some communities

Retrospective Surveillance of Perinatal Hepatitis C Virus Exposure – Tennessee, 2013-2017

Objective1. To quantify the burden of perinatal hepatitis C (HCV) exposure and examine the geographic variation in Tennessee (TN).2. Develop new surveillance strategies for retrospective tracking of perinatal HCV exposures.IntroductionHepatitis C virus (HCV) infections are increasing nationwide and are of particular concern in Tennessee, especially among individuals of reproductive age.1,2 Maternal HCV status reported on the birth certificate reveals that the rate of HCV among women giving birth in TN increased 163% from 2009-2014.3 Further, a 2017 TN Department of Health (TDH) study found that 30% of reproductive aged women with newly reported chronic HCV in TN were determined to be pregnant. While current treatment options are not recommended for children under 12, it is critical to identify an infant’s HCV status in order for him/her to receive proper care. Given the high rates of pregnancy reported among women with newly diagnosed HCV, we sought to expand viral hepatitis surveillance efforts to quantify the extent of the burden of HCV among women giving birth in TN, utilizing surveillance data in lieu of standalone birth certificate data.MethodsBirth certificate data, denoting all live births in TN from 2013 to 2017, were obtained from the TDH Birth Statistical File (n=404,694). Maternal HCV infection laboratory data were obtained from the TDH National Electronic Surveillance System (NEDSS) Based System (NBS). Maternal birth certificate and maternal HCV data were matched using a step-wise matching algorithm; records were required to match on one of the following criteria: (1) first name, last name, and date of birth (DOB); (2) first name, maiden name, and DOB; (3) phonetic first name, phonetic last name, DOB; (4) phonetic first name, phonetic maiden name, and DOB; or (5) social security number.For geographical variations, maternal county of residence was extracted from birth certificate data. As there is currently no case definition pertaining to HCV-positive pregnant women, laboratory data was used to determine perinatal exposure case status for each live birth as follows: (1) confirmed exposure, if a mother had at least 1 HCV RNA-positive lab during pregnancy, or in the absence of a pregnancy lab, at least one HCV RNA was conducted prior to pregnancy and the last HCV RNA prior to pregnancy was positive; (2) probable exposure, if a mother did not have an HCV RNA test, but had an HCV Ab-positive lab preceding or during pregnancy; or (3) no exposure, if a mother had a history of HCV, but only HCV RNA-negative labs during pregnancy, or in the absence of a pregnancy lab, at least one HCV RNA was conducted prior to pregnancy and the last RNA prior to pregnancy was negative. HCV infant exposure rates were calculated using the number of probable or confirmed HCV perinatal exposures divided by the total number of live births*1,000.ResultsFrom 2013 to 2017, there were 4,909 perinatal HCV exposures, with an average exposure rate of 12.1 per 1,000 live births. The exposure rate increased by 93.7%, from 7.9 in 2013 to 15.3 in 2017 (Table 1). Using an estimated 5.8% transmission rate, 285 infants acquired HCV infection perinatally over the past 5 years in TN.4Figure 1 depicts the rates of perinatal exposure per 1,000 live births in 2017, by county, and illustrates the large geographical variability of the perinatal HCV exposure rates. While the statewide average was 1.5%, this varied from 0% to 14.1% across TN. Eastern TN counties had higher rates; some signifying 5% to 14.1% of all infants born were vertically exposed to HCV.Limitations of our study included incomplete chronic HCV surveillance data, reporting bias, and external validity. Chronic HCV surveillance in TN was not routine until July 2015, and chronic HCV was not reportable until January 1, 2017. With respect to data included in our study prior to July 2015, only electronic laboratory reports were used, which could have resulted in under-reporting. Additionally, as pregnancy is not currently reportable in the context of HCV, we relied solely on birth certificate and NBS record matching to identify exposure. Lastly, our findings may not be generalizable to the rest of the US, as we only studied women of reproductive age in TN.Strengths to our study included the utilization of two reliable data sources, NBS and Birth Certificate data to determine perinatal HCV exposure. Analyzing data over a 5-year period allowed for a large sample size. Additionally, unlike previous studies, we analyzed laboratory data versus birth certificate data which is physician-reported and has been shown to underestimate the prevalence of maternal HCV infection.5ConclusionsHigh numbers of reported HCV cases among reproductive aged women translates into high rates of perinatal exposure to HCV among live born infants. As compared to maternal HCV status reported on birth certificates, matching birth records with HCV surveillance databases provides advantages to perinatal surveillance by: 1) detecting more cases, and 2) providing the ability to tease out current versus prior infection in mother and, therefore, actual exposure.This type of maternal surveillance provides unique opportunities to reach out and ensure that HCV infected mothers receive important information regarding appropriate infant testing, as indicated by the 2018 case definition, as well as disease prevention.6 Beginning in 2018, TDH has started to conduct surveillance on HCV exposed infants using these methods to track potential transmission in real-time, allowing us to evaluate testing outcomes among these exposed infants and determine if the infants are in appropriate care.References1. Zibbell JE, Asher AK, Patel RC, Kupronis B, Iqbal K, Ward JW, Holtzman D. Increases in Acute Hepatitis C Virus Infection Related to a Growing Opioid Epidemic and Associated Injection Drug Use, United States, 2004 to 2014. Am J Public Health. 2018 Feb; 108(2):175-181.2. Surveillance for Viral Hepatitis – United States, 2015. CDC.3. Patrick, Stephen W. et al. “Hepatitis C Virus Infection Among Women Giving Birth — Tennessee and United States, 2009–2014.” MMWR. Morbidity and Mortality Weekly Report 66.18 (2017): 470–473. PMC.4. Lenka Benova, Yousra A. Mohamoud, Clara Calvert, Laith J. Abu-Raddad; Vertical Transmission of Hepatitis C Virus: Systematic Review and Meta-analysis, Clinical Infectious Diseases, Volume 59, Issue 6, 15 September 2014, Pages 765–773.5. Snodgrass, Stephanie D., Tasha M. Poissant, and Ann R. Thomas. “Notes from the Field: Underreporting of Maternal Hepatitis C Virus Infection Status and the Need for Infant Testing — Oregon, 2015.” Morbidity and Mortality Weekly Report 67.6 (2018): 201–202. PMC.6. Hepatitis C, Perinatal Infection 2018 Case Definition. CDC

Infant morbidity, mortality, and breast milk immunologic profiles among breast-feeding HIV-infected and HIV-uninfected women in Botswana.

BACKGROUND: Infants of human immunodeficiency virus (HIV)-infected women have high mortality, but the immunologic integrity and protection afforded by the breast milk of HIV-infected women is unknown. METHODS: We determined morbidity and mortality by 24 months among breast-fed infants of 588 HIV-infected and 137 HIV-uninfected women followed-up in a clinical trial in Botswana. A matched case-control study compared clinical, behavioral, and breast milk immunologic parameters among 120 HIV-infected women by infant outcome. Breast milk factors were also compared between HIV-infected and HIV-uninfected women. RESULTS: Twenty-four-month mortality was 29.5% among HIV-infected infants, 6.7% among HIV-exposed uninfected infants, and 1.6% among HIV-unexposed infants. No differences were detected in breast milk immunologic profiles of HIV-infected women whose infants were either ill or well. Discontinuation of breast-feeding was the strongest predictor of illness (P<.001). Levels in breast milk of pathogen-specific immunoglobulin (Ig) G and IgA to Haemophilus influenzae, Campylobacter jejuni, Helicobacter pylori, Streptococcus pneumoniae, and innate immune factors were not lower among HIV-infected women than among HIV-uninfected women. CONCLUSIONS: Mortality was higher among HIV-infected and HIV-exposed infants than among HIV-unexposed infants. However, the immunologic profiles of breast milk among HIV-infected women were intact, and discontinuation of breast-feeding was the primary risk for infant morbidity. Thus, the breast milk of HIV-infected women may confer protection against common infant pathogens. TRIAL REGISTRATION: (ClinicalTrials.Gov) identifiers: NCT00197691 and NCT00197652

Response to antiretroviral therapy after a single, peripartum dose of nevirapine.

BACKGROUND: A single dose of nevirapine during labor reduces perinatal transmission of human immunodeficiency virus type 1 (HIV-1) but often leads to viral nevirapine resistance mutations in mothers and infants. METHODS: We studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana involving the prevention of the transmission of HIV-1 from mother to child. All women were treated with antenatal zidovudine. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment, estimated within groups by the Kaplan-Meier method. RESULTS: Of 218 women who started antiretroviral treatment, 112 had received a single dose of nevirapine and 106 had received placebo. By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine (P=0.002). Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure (P<0.001). In contrast, virologic failure rates did not differ significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively; P=0.39). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo (P<0.001). Maternal and infant findings did not change qualitatively by 12 and 24 months after the initiation of antiretroviral treatment. CONCLUSIONS: Women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine. However, this applied only when nevirapine-based antiretroviral therapy was initiated within 6 months after receipt of a single, peripartum dose of nevirapine. (ClinicalTrials.gov number, NCT00197587 [ClinicalTrials.gov].)

Low hepatitis C antibody screening rates among an insured population of Tennessean Baby Boomers.

Chronic Hepatitis C Virus (HCV) infection is common and can cause liver disease and death. Persons born from 1945 through 1965 ("Baby Boomers") have relatively high prevalence of chronic HCV infection, prompting recommendations that all Baby Boomers be screened for HCV. If chronic HCV is confirmed, evaluation for antiviral treatment should be performed. Direct-acting antivirals can cure more than 90% of people with chronic HCV. This sequence of services can be referred to as the HCV "cascade of cure" (CoC). The Tennessee (TN) Department of Health (TDH) and a health insurer with presence in TN aimed to determine the proportion of Baby Boomers who access HCV screening services and appropriately navigate the HCV CoC in TN.TDH surveillance data and insurance claim records were queried to identify the cohort of Baby Boomers eligible for HCV testing. Billing codes and pharmacy records from 2013 through 2015 were used to determine whether HCV screening and other HCV-related services were provided. The proportion of individuals accessing HCV screening and other steps along the HCV CoC was determined. Multivariable analyses were performed to identify factors associated with HCV screening and treatment.Among 501,388 insured Tennessean Baby Boomers, 7% were screened for HCV. Of the 40,019 who received any HCV-related service, 86% were screened with an HCV antibody test, 20% had a confirmatory HCV PCR, 9% were evaluated for treatment, and 4% were prescribed antivirals. Hispanics were more likely to be screened and treated for HCV than non-Hispanic whites. HCV screening was more likely to occur in the Nashville-Davidson region than in other regions of TN, but there were regional variations in HCV treatment.Many insured Tennessean Baby Boomers do not access HCV screening services, despite national recommendations. Demographic and regional differences in uptake along the HCV CoC should inform public health interventions aimed at mitigating the effects of chronic HCV

A new tool to quantify receptor recruitment to cell contact sites during host-pathogen interaction.

To understand the process of innate immune fungal recognition, we developed computational tools for the rigorous quantification and comparison of receptor recruitment and distribution at cell-cell contact sites. We used these tools to quantify pattern recognition receptor spatiotemporal distributions in contacts between primary human dendritic cells and the fungal pathogens C. albicans, C. parapsilosis and the environmental yeast S. cerevisiae, imaged using 3D multichannel laser scanning confocal microscopy. The detailed quantitative analysis of contact sites shows that, despite considerable biochemical similarity in the composition and structure of these species' cell walls, the receptor spatiotemporal distribution in host-microbe contact sites varies significantly between these yeasts. Our findings suggest a model where innate immune cells discriminate fungal microorganisms based on differential mobilization and coordination of receptor networks. Our analysis methods are also broadly applicable to a range of cell-cell interactions central to many biological problems

A Vector Force Model of Upper Eyelid Position in the Setting of a Trabeculectomy Bleb

A vector force model for the determination of upper eyelid position in the setting of a trabeculectomy bleb is presented. The model is used to explain the clinical courses of 5 patients with bleb-induced upper eyelid malposition and the efficacy of modalities previously described for the treatment of bleb-induced upper eyelid retraction. The novel use of botulinum toxin in the treatment of bleb-induced eyelid retraction and unique surgical considerations in patients with trabeculectomy blebs undergoing upper eyelid surgery are discussed. A vector force analysis was conducted and a force diagram constructed. The clinical and surgical courses of 5 patients with trabeculectomy blebs and upper eyelid malposition were reviewed. The vector force model was applied to these cases and the previously described treatment modalities for bleb-induced upper eyelid retraction. Vector force analysis demonstrates that in the case of trabeculectomy bleb-induced upper eyelid retraction, the net force vector, which represents the sum of all the individual forces acting on the eyelid, has a positive vertical component resulting in superior displacement of the eyelid. In contrast, bleb-induced ptosis results when the net force vector has a negative vertical component. In 3 patients, alterations in the bleb resulted in resolution of upper eyelid malposition. Botulinum toxin was used to achieve a normal upper eyelid position in 1 patient with lateral canthal tendon disinsertion and unilateral eyelid retraction and 1 patient with bilateral eyelid retraction. One patient developed unilateral ptosis in concert with the emergence of a large Tenon cyst that resolved with the treatment of the cyst via eyelid massage. One patient with unilateral ptosis and an ipsilateral bleb underwent external levator advancement but was unable to achieve the desired upper eyelid height as retraction over the bleb occurred with any attempt to elevate the eyelid above a marginal reflex distance of 1.5 mm. The efficacy of previously reported modalities for the treatment of trabeculectomy bleb-induced upper eyelid retraction can be explained by either a reduction in the positive vertical component of the net force vector or augmentation of the negative vertical component. A vector force model systematically accounts for the multiple determinants of upper eyelid position in the setting of a trabeculectomy bleb. This model provides a framework for the evaluation of bleb-induced upper eyelid malposition and offers a logical, mathematical explanation for the occurrence of bleb-induced upper eyelid retraction and the usefulness of previously reported treatment modalities for this clinical entity

Chronic hepatitis C cascade.

<p>Frequency and proportions of insured Tennessean Baby Boomers accessing various HCV-related services, among those eligible for HCV screening and among those who received any HCV-related service.</p

Map of Tennessee Department of Health regions.

<p>East Tennessee includes the Chattanooga-Hamilton, East, Knox, Northeast, Southeast, and Sullivan public health regions. Middle Tennessee includes the Mid-Cumberland, Nashville-Davidson, South Central, and Upper Cumberland public health regions. West Tennessee includes the Jackson-Madison, Memphis-Shelby, and West public health regions.</p