Potential Impact of Antiretroviral Chemoprophylaxis on HIV-1 Transmission in Resource-Limited Settings

Background. The potential impact of pre-exposure chemoprophylaxis (PrEP) an heterosexual transmission of HIV-1 infection in resource-limited settings is uncertain. Methodology/Principle Findings. A deterministic mathematical model was used to simulate the effects of antiretroval PreP on an HIV-1 epidemic in sub-Saharan Africa under different scenarios (optimistic neutral and pessimistic) both with and without sexual disinhibition. Sensitivity analyses were used to evaluate the effect of uncertainty in input parameters on model output and included calculation of partial rank correlations and standardized rank regressions. In the scenario without sexual disinhibition after PrEP initiation, key parameters influencing infections prevented were effectiveness of PrEP (partial rank correlation coefficient (PRCC) = 0.94), PrEP discontinuation rate (PRCC=-0.94), level of coverage (PRCC=0.92), and time to achieve target coverage (PRCC=-082). In the scenario with sexual disinhibition, PrEP effectiveness and the extent of sexual disinhibition had the greatest impact on prevention. An optimistic scenario of PrEP with 90% effectiveness and 75% coverage of the general population predicted a 74% decline in cumulative HIV-1 infections after 10 years, and a 28.8% decline with PrEP targeted to the highest risk groups (16% of the population). Even With a 100% increase in at-risk behavior from sexual disinhibition, a beneficial effect (23.4%-62.7% decrease in infections) was seen with 90% effective PrEP across a broad range of coverage (25%-75%). Similar disinhibition led to a rise in infections with lower effectiveness of PrEP (≤50%). Conclusions/Significance. Mathematical modeling supports the potential public health benefit of PrEP. Approximately 2.7 to 3.2 million new HIV-1 infections could be averaged in southern sub-Saharan Africa over 10 years by targeting PrEP (having 90% effectiveness) to those at highest behavioral risk and by preventing sexual disinhibition. This benefit could be lost, however, by sexual disinhibition and by high PrEP discontinuation, especially with lower PrEP effectiveness (≤:50%). © 2007 Abbas et al

Audit of Antenatal Testing of Sexually Transmissible Infections and Blood Borne Viruses at Western Australian Hospitals

In August 2007, the Western Australian Department of Health (DOH) released updated recommendations for testing of sexually transmissible infections (STI) and blood-borne viruses (BBV) in antenates. Prior to this, the Royal Australian & New Zealand College of Obstetricians & Gynaecologists (RANZCOG) antenatal testing recommendations had been accepted practice in most antenatal settings. The RANZCOG recommends that testing for HIV, syphilis, hepatitis B and C be offered at the first antenatal visit. The DOH recommends that in addition, chlamydia testing be offered. We conducted a baseline audit of antenatal STI/BBV testing in women who delivered at selected public hospitals before the DOH recommendations. We examined the medical records of 200 women who had delivered before 1st July 2007 from each of the sevenWAhospitals included in the audit. STI and BBV testing information and demographic data were collected. Of the 1,409 women included, 1,205 (86%) were non-Aboriginal and 200 (14%) were Aboriginal. High proportions of women had been tested for HIV (76%), syphilis (86%), hepatitis C (87%) and hepatitis B (88%). Overall, 72% of women had undergone STI/BBV testing in accordance with RANZCOG recommendations. However, chlamydia testing was evident in only 18% of records. STI/BBV prevalence ranged from 3.9% (CI 1.5– 6.3%) for chlamydia, to 1.7% (CI 1–2.4%) for hepatitis C, 0.7% (CI 0.3–1.2) for hepatitis B and 0.6% (CI 0.2–1) for syphilis. Prior to the DOH recommendations, nearly three-quarters of antenates had undergone STI/BBV testing in accordance with RANZCOG recommendations, but less than one fifth had been tested for chlamydia. The DOH recommendations will be further promoted with the assistance of hospitals and other stakeholders. A future audit will be conducted to determine the proportion of women tested according to the DOH recommendations. The hand book from this conference is available for download Published in 2008 by the Australasian Society for HIV Medicine Inc © Australasian Society for HIV Medicine Inc 2008 ISBN: 978-1-920773-59-

Multi-scale immunoepidemiological modeling of within-host and between-host HIV dynamics: systematic review of mathematical models.

OBJECTIVE: The objective of this study is to conduct a systematic review of multi-scale HIV immunoepidemiological models to improve our understanding of the synergistic impact between the HIV viral-immune dynamics at the individual level and HIV transmission dynamics at the population level. BACKGROUND: While within-host and between-host models of HIV dynamics have been well studied at a single scale, connecting the immunological and epidemiological scales through multi-scale models is an emerging method to infer the synergistic dynamics of HIV at the individual and population levels. METHODS: We reviewed nine articles using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework that focused on the synergistic dynamics of HIV immunoepidemiological models at the individual and population levels. RESULTS: HIV immunoepidemiological models simulate viral immune dynamics at the within-host scale and the epidemiological transmission dynamics at the between-host scale. They account for longitudinal changes in the immune viral dynamics of HIV+ individuals, and their corresponding impact on the transmission dynamics in the population. They are useful to analyze the dynamics of HIV super-infection, co-infection, drug resistance, evolution, and treatment in HIV+ individuals, and their impact on the epidemic pathways in the population. We illustrate the coupling mechanisms of the within-host and between-host scales, their mathematical implementation, and the clinical and public health problems that are appropriate for analysis using HIV immunoepidemiological models. CONCLUSION: HIV immunoepidemiological models connect the within-host immune dynamics at the individual level and the epidemiological transmission dynamics at the population level. While multi-scale models add complexity over a single-scale model, they account for the time varying immune viral response of HIV+ individuals, and the corresponding impact on the time-varying risk of transmission of HIV+ individuals to other susceptibles in the population

Contributions to the Mathematical Systems Medicine of Antimicrobial Therapy and Genotype-Phenotype Inference.

The following summary of my publications describes the main ideas in the corresponding research articles and clarfifies my contribution in multi-author publications. I decided to apply for habilitation according to x2.I.1.(c) of the Habilitationsordnung (this path is usually referred as Kumulative Habilitation"). I selected 13 first- or last author publications for this habilitation that concern contributions to the mathematical systems medicine of antiviral therapy [tMH10, tMS+11, FtK+11, tMMS12, DSt12, DWSt15, Dt16, DSt16, DDKt18, DSD+19, DDKt19], as well as inference of genotype-phenotype associations [SDH+15, SSJ+18]. The selected publications represent my major contributions in this research eld since submitting my doctoral thesis in September 2009

Epidemiology Insights

This book represents an overview on the diverse threads of epidemiological research, brings together the expertise and enthusiasm of an international panel of leading researchers to provide a state-of-the art overview of the field. Topics include the epidemiology of dermatomycoses and Candida spp. infections, the epidemiology molecular of methicillin-resistant Staphylococcus aureus (MRSA) isolated from humans and animals, the epidemiology of varied manifestations neuro-psychiatric, virology and epidemiology, epidemiology of wildlife tuberculosis, epidemiologic approaches to the study of microbial quality of milk and milk products, Cox proportional hazards model, epidemiology of lymphoid malignancy, epidemiology of primary immunodeficiency diseases and genetic epidemiology family-based. Written by experts from around the globe, this book is reading for clinicians, researchers and students, who intend to address these issues

Understanding the links between agriculture and health:

CONTENTS: 1.Overview / Corinna Hawkes and Marie T. Ruel; 2. Agriculture, Food, and Health: Perspectives on a Long Relationship / Tim Lang; 3. Agricultural Technology and Health / Michael Lipton, Saurabh Sinha, and Rachel Blackman; 4. Agriculture and Nutrition Linkages: Old Lessons and New Paradigms / Corinna Hawkes and Marie T. Ruel; 5. Agriculture, Food Safety, and Foodborne Diseases / Ewen C. D. Todd and Clare Narrod; 6. Agriculture, Malaria, and Water-Associated Diseases / Clifford M. Mutero, Matthew McCartney, and Eline Boelee; 7. Agriculture and HIV/AIDS / Stuart Gillespie; 8. Occupational Health Hazards of Agriculture / Donald Cole; 9. Livestock and Health / Maria Angeles O. Catelo; 10. Fish and Health / Nanna Roos, Md. Abdul Wahab, Chhoun Chamnan, and Shakuntala Haraksingh Thilsted; 11. Agroforesty, Nutrition, and Health / Brent Swallow and Sophie Ochola; 12. Agrobiodiversity, Nutrition, and Health / Timothy Johns, Ifeyironwa Francisca Smith, and Pablo B. Eyzaguirre; 13. Urban Agriculture and Health / Diana Lee-Smith and Gordon Prain; 14. Agriculture, Environment, and Health: Toward Sustainable Solutions / Rachel Nugent and Axel Drescher; 15. Agriculture and Health in the Policymaking Process / Todd Benson; 16. Opportunities for Improving the Synergies between Agriculture and Health / Robert Bos.Agriculture, Agroforestry, Health and nutrition, Agricultural technology, Food safety, Malaria, Diseases, HIV/AIDS, Sustainability, Biodiversity, Agrobiodiversity, Environmental management,

Targeting Drug Resistance In HCV NS3/4A Protease: Mechanisms And Inhibitor Design Strategies

The Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs) have become a mainstay of newer all-oral combination therapies. Despite improvements in potency of this inhibitor class, drug resistance remains a problem with the rapid emergence of resistance-associated substitutions (RASs). In this thesis I elucidate the molecular mechanisms of drug resistance for PIs against a resistant variant and apply insights toward the design of inhibitors with improved resistance profiles using structural, biochemical and computational techniques. Newer generation PIs retain high potency against most single substitutions in the protease active site by stacking on the catalytic triad. I investigated the molecular mechanisms of resistance against the Y56H/D168A variant. My analysis revealed that the Y56H substitution disrupts these inhibitors’ favorable stacking interactions with the catalytic residue His57. To further address the impact of drug resistance, I designed new inhibitors that minimize contact with known drug resistance residues that are unessential in substrate recognition. The initially designed inhibitors exhibited flatter resistance profiles than the newer generation PIs but lost potency against the D168A variant. Finally, I designed inhibitors to extend into the substrate envelope (SE) and successfully regained potency against RAS variants maintaining a flat profile. These inhibitors both pack well in the enzyme and fit within the SE. Together these studies elucidate the molecular mechanisms of PI resistance and highlight the importance of substrate recognition in inhibitor design. The insights from this thesis provide strategies toward the development of diverse NS3/4A PIs that may one day lead to the eradication of HCV

Matrix assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF MS) proteomic profiling of mycobacteria.

M. Med. Sc. University of KwaZulu-Natal, Durban 2015.Mycobacterium tuberculosis still remains a major cause of tuberculosis(TB) and death. In addition, nontuberculous mycobacteria (NTM) play a significant role in the aetiology of tuberculosis-like syndromes. A diagnosis of M. tuberculosis as the causative agent of pulmonary TB using only clinical symptoms may be inadequate and inaccurate in some cases since M.bovis, M.avium, M.kansasii, and M.intracellulare may all produce a pulmonary disease in humans that may be indistinguishable from that caused by M.tuberculosis. For diagnostic purposes, current mycobacterial identification strategies to the species level primarily rely on phenotypic analysis, complex biochemical tests, cultivation on specific growth media and genotype analysis. However, the main disadvantages that are associated with these techniques include extensive processing times (6-12 weeks to confirm a positive identification) and misidentification. Both factors severely hinder the control and management of diseases associated with mycobacteria, particularly tuberculosis. Apart from an increased patient mortality, interpersonal transmission of mycobacterial infections may increase. This scenario will also result in the prescription of inappropriate anti-tubercular treatment regimes. The present study assesses the feasibility of using MALDI-TOF MS proteomic profiling as a rapid and precise technology to identify mycobacteria in Kwazulu-Natal, South Africa which is currently a global epicentre of mycobacterial-associated diseases. In this study a modified EFA protein extraction protocol that incorporates an initial cell envelope delipidation step was formulated and shown to produce mass spectra that were unique and highly reproducible. The spectra were used to create an independent main spectral profile reference library (CMEFAMSP) representing clinically relevant American Type Culture Collection (ATCC) mycobacterial strains. Interestingly, this proof of concept study clearly demonstrates that MALDI-TOF MS-based biotyping of mycobacteria using the CMEFA-MSP reference library correctly identified 11 blind-coded ATCC strains sourced from an autonomous facility to the genus and species level with 100% accuracy.In addition the CMEFA-MSP reference library was employed to differentiate 39 blind-coded clinical mycobacterial isolates. Importantly all CMEFA-derived samples of the 39 clinical mycobacterial isolates displayed log score values of ≥ 2.3 and were correctly identified to the species level. This strongly suggests that MALDITOF MS when used in conjunction with the CMEFA sample preparation protocol has potential as a simple and cost-effective alternative for the unambiguous identification of clinically important mycobacteria. Moreover, individual members of the MTBC and NTM groups used in this study were distinguished from each other