1 2 242 243 244 245
Africa

Strategic antiretroviral therapy and HIV testing for youth in rural Africa (SATURN) by UNIVERSITY OF CALIFORNIA, SAN FRANCISCO (The Research University TRU)

HAVLIR, DIANE V

 

SUMMARYDespite encouraging gains in HIV treatment outcomes among adults with HIV in Sub-Saharan Africa,adolescents and young adults(10-24 years of age) living with HIV (AYAH) are being left behind withyoung women disproportionately affected. AYAH have worse rates of HIV testing, linkage to care,retention in care, and dramatically lower rates of HIV viral suppression. Our goal is to evaluate astrategic ART combination intervention for AYAH (SATURN) in a cluster randomized controlled trial (RCT)of 1,400 AYAH in 28 clinics in rural Uganda and Kenya. SATURN is an innovative life-stage adaptedapproach to improve ART uptake, adherence, retention and virologic suppression among female and maleyouth. The life-stage adapted, combination SATURN intervention is based on premise that currentapproaches to engaging AYAH are challenged by lack of dynamic flexibility and care adaptation to thesignificant trajectories of cognitive, social, and life-stage developmental events that occur inadolescence and early adulthood. Our intervention is based on behavioral theory, implementationscience, youth/provider input, and process and outcome feasibility and pilot data from the region. InAIM 1, Phase-I (UG3), we will: a) Implement youth-led HIV testing and linkage programs using acommunity-based participatory research (CBPR) to reach AYAH who are undiagnosed or are not engaged incare b) Initiate the clustered RCT of SATURN intervention compared to standard of care among AYAH in 8of the planned 28 clinics in rural Uganda and Kenya. In AIM 2, Phase-2 (UH3) we will: Complete RCTenrollment of AYAH from 28 clinics and compare the rate of retention and virologic suppression at 2years in SATURN clinics vs control; and 2a) Identify the mechanisms of action, barriers and facilitators ofthe SATURN implementation at the community, clinic organization, provider, and patient levels using mixedmethods qualitative and quantitative assessments. 2b) Estimate the incremental costs and gains associatedwith SATURN through cost effectiveness analysis. Transition Milestones to move from UG3 to UH3: a)Enroll at least 400 youth from the first 8 clinics to the SATURN RCT; 2) Of those enrolled, 20% will be new orout-of-care diagnoses; 3) Achieve at least 70% retention with virologic suppression at 1 year in interventioncommunities. This research builds upon highly productive long-standing collaborations between Ministries ofHealth in Uganda and Kenya, African and US research organizations, and PEPFAR implementing partnerswith local community participation and substantial AYAH targeted formative work in Uganda and Kenya and isdirected at eventual dissemination and sustainability.

 

Africa

Simplified Isoniazid Preventive Therapy (SPIRIT) Strategy to Reduce TB Burden by UNIVERSITY OF CALIFORNIA, SAN FRANCISCO (The Research University TRU)

HAVLIR, DIANE V

 

ABSTRACTThe failure to use isoniazid (INH) preventative therapy (IPT) in persons living with HIV (PLHIV) in Sub-SaharanAfrica represents one of the single biggest implementation gaps between evidence and practice in today’sresponse to the HIV epidemic. In PLHIV, TB is a lead cause of death, and IPT reduces TB incidence by 40%.Yet in Africa, less than 2% of eligible individuals receive IPT. Given the existence of both country guidelinesrecommending IPT, as well as simple clinical algorithms to identify IPT eligible persons, a remaining criticalrequirement for scale-up is strengthening the link – mediated by middle management in most health systems -between health ministry policy and clinics. In Uganda, District Health Officers (DHOs) serve as key middlemanagers working at the nexus between policy and implementation. We propose to test a countrywide multi-component ?SPIRIT? (Simplified INH Preventive Therapy) intervention targeting DHOs ? whom we view ascritical dissemination agents. SPIRIT is based on the PRECEDE model of behavioral change that deployspredisposing (teaching collaborative); enabling (INH/B6/septrin single pill combination and SMS from DHO toprovider); and reinforcing (reporting collaborative) components. For this resubmission, we provide data to showfeasibility of SPIRT through a pilot study of 5 DHOs and their clinics. The DHOs engaged in the mini-collaborative and implemented key components of SPIRIT including bidirectional text messaging to front lineproviders. The number of HIV+ adults prescribed IPT increased from zero at baseline to 300 at 8 weeks.Aim 1: Determine if the SPIRIT intervention increases IPT initiation. We will form 20 groups of 5 DistrictHealth Officers and randomize 10 to the SPIRIT intervention and 10 to control (country standard) in a cluster-randomized trial. The primary outcome is proportion of IPT-eligible adults initiating IPT. For secondaryoutcomes, we will measure changes in knowledge, attitudes and practices regarding IPT among DHOs andfront line health workers to assess mechanisms through which the intervention achieves outcomes.Aim 2: Evaluate the effect of the SPIRIT intervention on IPT completion and TB incidence. Even if theintervention increases IPT use, quantifying actual use of IPT by patients and effects on population healthstatus (e.g. reduction in TB), provides an important impact measure that can enable policy makers to prioritizethis intervention more widely. A two-stage survey sampling approach will be used to identify a probabilitysample of patients eligible for IPT in which to measure adherence through hair levels of INH (direct measure ofpill consumption/adherence) and TB incidence (population health measure)Aim 3: Assess the cost and cost-effectiveness of SPIRIT. Using effectiveness measures obtained in Aims1 and 2, standard time and motion and costing methods, we will estimate the cost and cost-effectiveness ofSPIRIT vs standard of care in our sampled population from Aim 2. Outcomes of interest will include programcosts per: a) IPT initiation; b) IPT completion; and c) TB case averted.

 

Africa

Mechanisms and pilot intervention for addressing intimate partner violence and HIV in antenatal care by UNIV OF NORTH CAROLINA CHAPEL HILL (The Research University TRU)

HATCHER, ABIGAIL MAE

 

ABSTRACTThis application to the National Institutes of Mental Health will provide Dr. Abigail Hatcher with five years K01support for further training and mentored research. Dr. Hatcher is a social scientist at the University of NorthCarolina (UNC) with experience studying social drivers of HIV-related health. She has lived in South Africasince 2005, where she has established a solid career foundation for behavioral and social research around HIVand maternal health. The K01 award will provide essential training and professional scaffolding for a criticalcareer transition, during which Dr. Hatcher will return to Chapel Hill after considerable time abroad to be anindependent investigator and integral part of UNC Department of Health Behavior’s global health research.Prevention of mother-to-child transmission (PMTCT) programs are only effective if women take medicationregularly, yet many perinatal women in sub-Saharan Africa have sup-optimal adherence. Intimate partnerviolence (IPV) worsens women’s ability to adhere to antiretroviral therapy (ART), and leads to higher rates ofdepression. Dr. Hatcher proposes 3 aims, each linked to a robust career development plan advancinganalytical, adaptation, and implementation science skills. First, she will lead secondary analysis of longitudinalcohort data to determine mechanisms linking IPV to HIV-related health outcomes (ART adherence, viremia),exploring a hypothesized pathway of mental health. Coursework and mentorship in statistics and epidemiology(Drs. Levin, Turan, B, and Myer) will support her analyses. Second, qualitative research with perinatal womenand health workers will explore identified pathways and intervention ideas. Dr. Hatcher will systematicallyadapt evidence-based mental health programs, enhanced by site visits to Malawi and Zambia, and mentorshipfrom IPV and mental health experts (Drs. Maman, Christofides, and Pence). Third, she will conduct afeasibility study to assess acceptability of intervention content, measures, and study conditions. In a quasi-experimental design, she will assign 2 inner-city Johannesburg clinics to intervention or enhanced standard ofcare conditions. Following 80 women in a prospective cohort will allow for preliminarily assessment ofintervention effects on key pathways (perinatal depression and IPV) and refinement of HIV measures (ARTadherence using drug levels in hair samples). The feasibility study will be underpinned by coursework inimplementation research study design and intensive supervised practice from experts in implementationscience for PMTCT (Drs. Turan, J, Brahmbhatt, and Chi). Overall, the research will provide preliminary resultsto inform design of a future trial testing an optimized lay health worker strategy. By supporting didactic andfield-based learning and protected time for research, a K01 will advance Dr. Hatcher’s career progression asan independent HIV behavioral scientist, leading to better health and wellbeing among HIV-positive women.

 

Africa

Pre-fusion Arenavirus GP trimers: Structural template for functional analysis by LA JOLLA INSTITUTE FOR IMMUNOLOGY (The Research University TRU)

HASTIE, KATHRYN MARIE

 

Project Summary/AbstractThere are around 50 known viruses in the Arenavirus family. These include Lassa (LASV), Lujo(LUJV), Machupo (MACV), and Junín (JUNV), which cause hemorrhagic fever in Africa and SouthAmerica. The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), also causesencephalitis and birth defects in humans worldwide. Arenaviruses express one glycoprotein on theirsurface, termed GPC, which is responsible for receptor engagement, cell tropism, and entry.Understanding the structure of GPC, particularly in its trimeric, prefusion conformation, is key tounderstanding why the different arenaviruses recognize distinct receptors and in designingtherapeutics and vaccines against them. However, the GPC is metastable: it easily disassembles intoits component subunits and then springs into its more stable, post-fusion conformation. Thismetastability hindered structural biology efforts for years. Indeed, there has been no structure of anytrimeric, prefusion arenavirus GP until this year. A ten-year protein engineering effort in the labrecently culminated in the crystal structure of LASV GP in its trimeric, prefusion complex, the firstsuch structure for any arenavirus. This landmark structure illuminated new findings: that the properlyassembled prefusion trimer is essential for recognition by the most effective neutralizing antibodiesand for recognition by the LASV and LCMV cell surface receptor matriglycan. In the absence of stablyengineered prefusion GP, such potently protective antibodies would have been difficult to identify andcharacterize. There remains, however, no trimeric prefusion GP structure for any other arenavirus.Fortunately, the model built for LASV GP provides the blueprints we need to propel this effort forward.The premise of this proposal is that the correct quaternary assembly of GP can be engineeredfor other arenaviruses using the LASV GP structure as a template and the foundation ofknowledge laid by this structure. We will combine strong preliminary results and state-of the-artbiophysical techniques, with bio-layer interferometry and ELISA to analyze the interaction ofengineered MACV, JUNV, LCMV and LUJV GPs with their distinct receptors and with unique panelsof antibodies from human survivors (JUNV and LUJV) and mice (MACV and LCMV). In aim 1 we willdevelop the stable prefusion GPs necessary to determine if MACV and JUNV, like LASV, also elicitquaternary-epitope antibodies and the stoichiometry by which these viruses bind their TfR1 receptor.In aim 2 we will develop the GPs necessary to solve an LCMV-matriglycan complex, map theepitopes of LCMV-binding antibodies and identify and characterize LUJV GP antibodies and theLUJV GP structure involved in its atypical mechanism of entry. Multiple lines of inquiry will belaunched by the innovative research effort proposed here.

 

Africa

Development of RT-OLA-PCR assays for HIV drug resistance testing at Nigerian antenatal clinics by VANDERBILT UNIVERSITY (The Research University TRU)

HASELTON, FREDERICK R

 

Since 23% of children born with HIV are born in Nigeria, our collaborators have made prevention of motherto child HIV transmission one of their highest program priorities. It is essential for viremic pregnant women tomaintain durable viral suppression, so they do not transmit HIV to their unborn children. A major impediment tothis is the presence of drug resistance mutations that evade the HIV antiretroviral treatments resulting incontinued viremia. Currently at the Amino Kano Teaching Hospital antenatal care clinic viral load testing takes2-4 weeks to receive results, and it takes an additional 4-6 weeks to receive sequencing results from the nationallaboratory. This turnaround time significantly increases the duration of viral exposure to the unborn child. Wehypothesize that by providing a PCR-based test for drug resistance mutations, we will expedite determination ofthe most effective drug treatment regimens and reduce mother to child HIV transmission. In this R21, we proposeto develop and test reagents and magnetic bead sample processing for detecting drug resistance mutations. Wepropose to achieve this by converting highly variable HIV sequences surrounding a known drug resistancemutation into a single PCR reporter using three successive reactions ? reverse transcription (RT) to convert viralRNA to cDNA, an oligonucleotide ligation assay (OLA) reaction to create a unique PCR target in the presenceof drug resistance mutations, and PCR to amplify ligation products. Aim 1 optimizes a multiplex design for thisassay. A major challenge with this RT-OLA-PCR approach is that the ligation reaction is incompatible with boththe RT and PCR reaction conditions. To overcome incompatibility, in Aim 2, we propose to capitalize on ourexpertise using self-contained magnetic bead-based processing to maximize the limit of detection of the assay. The successful completion of this project will result in new drug resistance assays and benchtop processingmethods that could be used to detect the major genotypic mutations in a setting with access to standard PCR.A subsequent R01 with our partners in Nigeria will incorporate these reagents and methods to validate withclinical samples the RT-OLA-PCR assay and sample processing appropriate for the workflow, clinic personnel,and existing infrastructure in Nigerian clinics providing antenatal care.

 

Africa

A 100-fold more sensitive TB diagnostic based on magnetic concentration and ‘coffee ring’ formation by VANDERBILT UNIVERSITY (The Research University TRU)

HASELTON, FREDERICK R

 

The global burden of tuberculosis (TB) stands at ~9 million cases per year; and South Africa is the mostheavily TB-burdened country globally. TB is also the most common opportunistic infection in HIV-infectedpersons and it is responsible for 21% of deaths in South Africa. A program of active TB case finding and drugresistance typing in both urban and rural communities is needed to disrupt TB transmission, yet we currentlylack accessible point of care diagnostics to achieve this goal. Particularly in rural South Africa, where TB infection is widespread, microscopic examination of a sputumsmear is the most accessible method for detection of TB. Two major challenges are 1) the more accessiblemicroscopy methods have a current limit of detection of 10,000 bacilli per ml of sputum which prevents earlydetection and allows continued spread of infection, and 2) no methods using bright field microscopy are availablefor detecting drug resistant Mycobacterium tuberculosis genotypes. In this proposal Vanderbilt University and The University of Cape Town form a partnership to developand test bright field microscopy methods for diagnosing TB from sputum. We propose to develop simple methodsto improve the limit of detection of existing and more accessible bright field microscopy of sputum samples to100 bacilli/ml. Our approach is based on a magnetic concentration strategy and high density deposition onto astandard microscope slide using the coffee ring phenomenon (Aim 1). Secondly, we propose to develop adendrimer-genotyping probe followed by a silica condensation reaction to enable bright field identification of drugresistant phenotypes (Aim 2). These laboratory designs are then packaged into a simple kit format for initialclinical testing of retrospective sputum samples in a laboratory as well as in rural South Africa (Aim 3). When completed, these simple modifications to the current widely accessible microscopy methods willidentify individuals with low numbers of M. tuberculosis bacilli present in their sputum and enable much earliertreatment. In addition, enabling the identification of drug resistant bacilli by bright field microscopy will providean earlier means to begin more aggressive therapies and further prevent the spread of drug-resistant TB.

 

Africa

Understanding immune regulation in blood-stage malaria by UNIVERSITY OF IOWA (The Research University TRU)

HARTY, JOHN T

 

AbstractMalarial remains a global health burden that impacts >40% of humans. Although bed nets and antimalarialdrugs have reduced the incidence and severity of malaria, ~200,000,000 cases still occur annually with highmortality in children from sub-Saharan Africa. Additionally, front line drug therapies are now threatened byspread of resistant parasites. Thus, new approaches to effective vaccines and therapeutics are in need. Acritical limitation is our incomplete understanding of how the parasite manipulates host immune responses topermit chronic and recurring blood-stage infections. We used rodent malaria models to evaluate the cellulardynamics of the CD4 T cell and B cell responses generated during chronic blood-stage infection and thencompared these findings to humans living in endemic areas. These studies reveal that Tregs, which expand inboth humans and rodents during blood-stage malaria, interfere with conventional T helper (Th) responses andthe Follicular T helper (Tfh) cell:B cell partnership in germinal centers. Importantly, the negative impact ofTregs occurs in a previously unrecognized but critical temporal window after infection to impede protectiveimmunity, through CTLA-4. Precisely timed targeting of Tregs or CTLA-4 enhanced immune responses,accelerated clearance, and generated species-transcending immunity to blood-stage malaria. Thus, ourpreliminary data uncover a critical mechanism of immune-suppression associated with blood-stage malaria. Afull understanding of the cellular and molecular basis for compromised immunity in blood-stage malaria is thelong-term goal of this competitive renewal application. We will address these issues with the following specificaims: SA 1: Determine how precisely timed Treg-depletion and CTLA-4 blockade impacts malaria-specific Tcell and B cell responses to facilitate clearance of PRIMARY blood-stage infections. SA 2: Determine howprecisely timed Treg-depletion and/or CTLA-4 blockade impacts malaria-specific memory T cell and B cellresponses to facilitate species transcending control of SECONDARY blood-stage infections. SA 3: Dissecthow and when inhibitory pathways and cells limit clearance of PRIMARY infection and prevent development ofspecies transcending control of SECONDARY infections.

 

Africa

Memory CD8 T cell immunity to Plasmodium liver stage infec by UNIVERSITY OF IOWA (The Research University TRU)

HARTY, JOHN T

 

? DESCRIPTION (provided by applicant): Malarial disease, caused by Plasmodium species, remains an unresolved global health burden that impacts >40% of the world’s population. Although the availability of insecticide treated bed nets and antimalarial drugs has reduced the incidence and severity of malaria in some regions, ~200,000,000 cases still occur annually with ~850,000 fatalities in 2013. Thus, vaccines to prevent malaria remain an as yet unrealized but critical goal to combat this global threat. As shown in our preliminary data, only some of Plasmodium antigens that elicit CD8 T cell responses were targets of CD8 T cell mediated sterilizing immunity. Aim 1 will address the mechanisms that determine whether a specific Plasmodium antigen is the target of effective protection by memory CD8 T cells. Information generated from this aim will provide a practical basis to select new candidate antigens, from the expressed pool of ~5,000 ORF, for evaluation as subunit vaccines to protect against human malaria. Importantly, despite repeated exposures, sterilizing immunity (defined as prevention of blood-stage parasitemia after sporozoite infection) does not develop in individuals living in malaria endemic areas. Indeed our preliminary data reveal both numerical and functional impairment of memory CD8 T cells generated during malaria infection. In aim 2, we will use our newly developed tool-chest, including TCR-retrogenic mice specific for recently identified Plasmodium antigens, to determine how memory CD8 T cells generated after malaria infection are numerically and functionally impaired. Our long-term goal is to understand the mechanisms underlying protective CD8 T cell immunity to liver- stage Plasmodium infection in order to aid in the rational development of effective vaccines. SA 1. Determine why some, but not all Plasmodium antigens are targets of protective CD8 T cells. SA2. Determine the mechanism(s) by which Plasmodium infection results in compromised memory CD8 T cell populations.

 

Africa

Neuroprotective anti-inflammatory drugs as a novel combination therapy for neurological Rift Valley Fever by UNIVERSITY OF PITTSBURGH AT PITTSBURGH (The Research University TRU)

HARTMAN, AMY L

 

PROJECT SUMMARY/ABSTRACT Understanding the pathogenesis of neurological disorders caused by arboviruses is fundamental to thetreatment of viral encephalitis using drug or vaccine therapy. Rift Valley Fever (RVF) is a globally-importantemerging mosquito-transmitted disease that presents a significant risk to humans and livestock communities.The potential for global spread is high due to the pervasive mosquito vectors, and emergence would causeconsiderable economic damage (due to the agricultural impact) as well as fear and anxiety (due to humanillness). The most understudied clinical disease caused by RVFV is encephalitis, which causes long-termmorbidity in survivors as well as death in 50% of patients with neurological symptoms. This proposal is foundedupon 3 scientific findings from our preliminary data: 1) There are appropriate encephalitic disease animal modelsafter infection with a wild-type virulent strain of RVFV; 2) Overproduction of cytokines, chemokines, and matrixmetalloproteinases (MMPs) correlates with neurological disease onset; and 3) Treatment with the antiviraltherapeutic drug favipiravir is necessary but not sufficient to protect animals from lethal neurological disease.Taken together, the objective of this proposal is to understand the role of cytokine and MMP-mediated hostinflammatory response in RVF-induced neurological disease, with the ultimate goal of designing therapeuticinterventions to prevent neuropathology. We will address this objective using three complementary specific aims:In Aim 1, we will determine the kinetic mechanisms by which cytokines and MMPs modulate RVF CNSinflammation. Aim 2 will develop novel in vitro modeling systems to define RVFV-CNS cell interactions andscreen therapeutic candidates. Aim 3 will test novel therapeutic regimens in a relevant animal model. Thisproposal will result in an understanding of the contribution of immunopathology to RVF neurological disease.Importantly, we will have identified a post-exposure treatment regimen to protect from neurological RVF. Thisproposal represents a critical step in the event of an epidemic of this emerging pathogen.

 

Africa

Live-attenuated Rift Valley fever vaccines: comparative mechanisms of trans-placental transmission and vaccine efficacy for developing fetuses by UNIVERSITY OF PITTSBURGH AT PITTSBURGH (The Research University TRU)

HARTMAN, AMY L

 

PROJECT SUMMARY/ABSTRACT The World Health Organization warns of a pending public health emergency caused by mosquito-bornezoonotic pathogen Rift Valley fever virus (RVFV). The consequences of this emerging virus could beexacerbated by insufficient vaccines for prevention of infection and disease. RVF is an importantagroeconomic illness of domesticated livestock and is endemic in Africa and parts of the Middle East. Furtherspread is likely given that mosquito species capable of transmitting RVFV are found in Europe and theAmericas. The most striking feature of RVF disease in sheep is a wave of fetal loss (known as an ?abortionstorm?) that sweeps through herds of pregnant animals, where spontaneous abortion rates can reach as highas 90%. Vaccination of livestock protects animals while simultaneously reducing the spread of RVFV topeople. Obstacles in the successful development of RVFV livestock vaccines include: 1) vaccine strains oftencause fetal infection and death in pregnant animals, and 2) vaccines that protect adult animals from diseaseare not always effective at preventing vertical transmission during pregnancy. These hurdles represent a majorgap in the vaccine development field. The mechanisms by which live-attenuated vaccine strains of RVFV arevertically transmitted in utero, as well as the maternal immune response required for the protection ofdeveloping fetuses, are not known. No systematic evaluation of the vertical transmission potential of clinically-relevant live attenuated vaccines has been performed. To address this gap in the field, we propose to use anexperimental rodent model of RVFV vertical transmission and fetal death in late-gestation pregnant rats. RVFVdirectly infects the placenta in rats, causes hemorrhage and inflammation, and results in fetal malformationsincluding intrauterine fetal death even in pregnant dams without signs of disease. This proposal will use thepregnant rat model to test current RVF vaccine candidates for the mechanism(s) of vertical transmission, fetalprotection, and identification of maternal immune correlates of fetal protection. We will also conduct acomparative analysis of virulent and attenuated RVFV strains for permissivity of placental explants fromrelevant species to identify cellular and structural targets of infection. Our overall hypothesis is that infection ofpregnant rats with RVFV live-attenuated vaccines will provide pre-clinical quantitative data on vaccine safetyfor developing fetuses, efficacy for the fetuses, and critical maternal correlates of fetal protection. Completionof these studies will change the paradigm of RVFV vaccine development by providing, for the first time, amechanistic explanation for the vertical transmission potential of clinically relevant LAVs.

 

1 2 242 243 244 245 246 2,606 2,607
About Exponent

Exponent is a modern business theme, that lets you build stunning high performance websites using a fully visual interface. Start with any of the demos below or build one on your own.

Get Started
Privacy Settings
We use cookies to enhance your experience while using our website. If you are using our Services via a browser you can restrict, block or remove cookies through your web browser settings. We also use content and scripts from third parties that may use tracking technologies. You can selectively provide your consent below to allow such third party embeds. For complete information about the cookies we use, data we collect and how we process them, please check our Privacy Policy
Youtube
Consent to display content from Youtube
Vimeo
Consent to display content from Vimeo
Google Maps
Consent to display content from Google
Spotify
Consent to display content from Spotify
Sound Cloud
Consent to display content from Sound