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(2016)ThesisThere is increasing recognition that gay and bisexual men may have unique health needs in addition to a higher incidence of HIV. This work aims to examine overall mortality and overall and cause-specific morbidity, particularly substance use- and mental health- related morbidity, in two cohorts of HIV-infected and –uninfected gay and bisexual men. These outcomes have been examined by linkage to their respective administrative health records. Subsequently this work aims to examine the sensitivity and specificity of current linkage methods and their utility in providing high quality data for assessment. All-cause mortality and hospitalisation rate was found to be significantly higher in the HIV-infected cohort compared with the –uninfected cohort and the general population. All-cause admissions were significantly lower in the –uninfected cohort when compared to the general population with no difference observed in terms of mortality. Illicit drug-related hospitalisation and hospitalisation for mood and anxiety disorders were significantly higher in both the -uninfected and –infected cohorts compared with the general population. Further, the odds of being admitted for either a mood and/or anxiety disorder or for substance abuse was significantly higher in HIV-infected compared with the –uninfected cohort. The examination of linkage methods found linkage without proven high sensitivity and specificity should be avoided as underestimation of outcomes may be considerable and threaten the scientific validity of the study. HIV-infected gay and bisexual men continue to experience morbidity in excess of -uninfected gay men and the general population. Morbidity due to both non-AIDS and AIDS-related diseases was apparent in the HIV-infected cohort. HIV-uninfected gay men had lower all-cause morbidity compared with the general male population suggesting that disparities related to sexual orientation may not impact health outcomes as had been anticipated. However, both substance use and mental health-related morbidity were evident in both the –uninfected and –infected cohorts. There is a need for better longitudinal health research differentiated by HIV status in gay and bisexual men. Future research should look at utilising robust record linkage methods to identify health outcomes in currently available large prospective cohorts of gay and bisexual men to further inform our current understanding of gay and bisexual men’s health.
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(2020)ThesisThe introduction of effective antiretroviral therapy (ART) has dramatically increased life expectancy of people living with HIV (PLHIV). However, due to lifestyle factors, side effects of ART, ongoing inflammation and immune activation, and ageing, non-communicable diseases (NCDs) are becoming more apparent in this population. This will prove challenging in some countries in the Asian region, where health systems are already strained by a high HIV burden and limited resources are available to provide optimal care for all PLHIV. The aim of this thesis was to investigate NCDs – primarily cardiovascular disease (CVD), diabetes and kidney disease – and related outcomes in PLHIV in the Asian region. All analyses were based on routinely collected data from the TREAT Asia cohorts, two large adult observational cohorts of PLHIV in 12 countries across the Asia-Pacific region. Similar to what is happening at the global level, ART uptake across this region has increased over time. Among those on ART in the TREAT Asia cohorts, there was a considerable burden of comorbid CVD, diabetes and kidney disease. Risk factors for CVD were primarily of modifiable nature, such as hypertension, unfavourable lipid levels and overweight. It was estimated that the CVD incidence might double in the next decade, although this could be largely addressed by implementing interventions that target CVD risk factors. Diabetes and prediabetes were strongly associated with mortality. When assessing risk factors of mortality after long-term exposure to ART, the findings showed that diabetes, kidney disease, and hepatitis were associated with increased mortality, while treatment continuity remained important to improve survival. Overall, the findings indicate that there was suboptimal monitoring for NCDs in the TREAT Asia cohorts. With the growing population of PLHIV who are on life-long ART, there is an urgent need for integrated NCD and HIV care. Timely interventions are key to reducing the unnecessary morbidity and mortality. Future efforts to improve NCD-related outcomes in PLHIV in the Asian region should thus have a clear focus on screening and monitoring for NCDs with appropriate diagnostic tools and access to affordable treatment options.
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(2021)ThesisGonorrhoea notifications have been increasing among young Australian heterosexuals since 2009 and the reasons for this are unclear. Gonorrhoea incidence has also increased in female sex workers (FSW) since 2009. Previous studies indicate that condom-use among FSW-clients declined from 2009-2017, mainly for oral sex and a high proportion of infections in heterosexual males arise from condomless oral sex with FSW. Thus, we hypothesise that an increase in condomless sex by FSW-clients may have contributed to the rising incidence of gonorrhoea among heterosexuals in Australia. In this thesis, mathematical modelling is used to provide insights to the role of the FSW-client interaction for heterosexual gonorrhoea transmission, to explore whether the increasing notifications can be explained, even partly, by decreasing condom-use among FSW-clients, and to evaluate the potential impact of providing gonorrhoea vaccination for FSW on gonorrhoea incidence/prevalence. A deterministic compartmental model was developed to address the stated objectives and was calibrated to reported female notifications and FSW incidence data for 2009. Using adaptations of the model that included/excluded FSW-client strata, we evaluated the role of FSW-client interactions in model dynamics and sensitivity of the reproduction number (Rt) in this population to changes in key parameters. We then estimated the annual percentage decline in condom-use between 2009 and 2017 that resulted in a model-produced notification rate that is consistent with the reported increase in heterosexual notifications using the model with FSW-client strata. Finally, the potential impact of a gonococcal vaccine for FSW on heterosexual gonorrhoea rates was assessed under different assumptions regarding the mode of vaccine conferred protection. Our results suggest that Rt and the heterosexual notification rate are highly sensitive to changes in parameters that govern transmission in the model that accommodates FSW-client interactions and infection rates are consequently highly sensitive to changes in condom-use by FSW-clients. An annual decline of only 0.26% in condom-use by FSW-clients is predicted to lead to an increase in heterosexual notifications that is consistent with the observed increase in notifications. Vaccinating FSW with a partially efficacious vaccine has the potential to substantially reduce gonorrhoea prevalence over time in the heterosexual population in Australia. These findings suggest that increasing condomless sex among FSW-clients can result in marked increases in heterosexual notifications. Therefore, promoting condom-use in commercial sex may help reduce the gonorrhoea burden in young heterosexuals. Additionally, targeted vaccination of FSW may be an effective means of controlling gonorrhoea in this population.
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(2020)ThesisMalaria still remains a major health problem across the globe and is responsible for more than 200 million cases and a half million deaths every year. Currently, artemisinin drugs are the recommended first line therapy for treating malaria, which have partly contributed to the overall reduction in mortality and morbidity caused by malaria infection. However, the rise of artemisinin resistant malaria parasites is stalling the progress in controlling this disease. Hence, there is a compelling need for new antimalarial drugs and an effective vaccine. Successful immunological and drug interventions must control infection, which could involve the direct removal of circulating parasites and/or blockage of new infections. In this thesis, I investigate the mechanisms of action of existing and novel antimalarial drugs and host responses in controlling of infection. I do this by developing mathematical models and combining them with data to directly measure the rate of parasite clearance, the rate of parasite replication and maturation through their life-cycle in malaria infection. I then utilise these approaches to explore how parasite clearance, maturation and replication are altered by various drugs, parasite gene knockdowns and host-immune interventions. Key insights from this work include, identifying that the rate of host removal of parasites cannot easily be increased from the basal rate. However, I identify two antimalarials (a novel and candidate agent), which induce rapid removal of parasites. However, most drugs and host responses control infection by directly killing or impairing parasites. Through this work I have also identified that a parasite protein, responsible for transporting other proteins to the surface of the red blood cell, is surprisingly not required for parasites to avoid host removal, but is important in parasite development. More generally, I observe that parasite maturation is perturbed by many interventions, suggesting delayed development is a generic parasite stress phenotype. Collectively, the work presented here greatly improves our understanding of host, parasite and drug interactions that govern parasite survival and control of infection by providing better tools to investigate host responses and the mechanisms of action of antimalarial drugs during infection.
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(2020)ThesisComprehensive, timely, and accurate health data are essential for the detection of outbreak-prone diseases. If these go unnoticed or are identified late, they pose significant risks to the health of a population. In the Pacific islands, a syndrome-based surveillance strategy, known as the Pacific Syndromic Surveillance System (PSSS), is employed for the early detection of outbreaks. The PSSS, implemented in 2010, has provided a mechanism by which resource-limited Pacific island governments have been able to perform routine surveillance activities and address many of their national and international health protection needs and obligations. Despite being a cornerstone of health protection for many Pacific islands, the surveillance system had not been comprehensively evaluated. Nor had behavioural, technical, or upstream health system factors that influence its performance been investigated. This thesis assesses whether the PSSS is meeting its stated objectives and produces evidence to augment technical and operational elements of the system. The thesis answers the following questions: (i) is the PSSS meeting its stated objectives? (ii) are algorithm-based approaches to outbreak detection appropriate in the Pacific island systems and context?; (iii) how can the PSSS be enhanced to meet information needs during public health emergencies?; and (iv) what factors enable and constrain surveillance nurses’data collection and reporting practice? The thesis found that the surveillance system is simple, well regarded, trusted, and context-relevant mechanism that Pacific island governments from across the development spectrum have been able to adopt and maintain with minimal external technical or financial support. Despite these positive findings, the research identified several statistical, procedural, and broader systems barriers to optimal performance, including chronic staffing and other resource constraints, insufficient data on which to base outbreak detection analysis, and poor integration of health information systems. Looking ahead, the thesis identifies practical opportunities for system improvement and highlights areas for further research.
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(2021)ThesisBACKGROUND South Africa has the highest HIV burden in the world. Clinical care guidelines for HIV testing, treatment, monitoring and infant feeding have evolved in recent years. However, there are gaps in guidelines implementation and quality of services, particularly in primary care. This thesis aims to investigate the impact and implementation of HIV care interventions on service quality. METHODS This research is based at nurse-led public sector primary care clinics in northern KwaZulu-Natal, South Africa. First, the impact of continuous quality improvement (CQI) on coverage of two key antenatal HIV care tests (VL monitoring among pregnant women living with HIV, and repeat HIV testing among pregnant women not living with HIV) at seven primary care clinics, is examined. These are the primary endpoints of the MONARCH stepped-wedge trial (www.clinicaltrials.gov NCT02626351). Second, the process by which CQI was implemented in the MONARCH trial and determinants of CQI practice and ‘normalisation’, are examined. Third, the association between maternal HIV status and infant feeding (i) knowledge and (ii) practice, among women recruited to the MONARCH trial, is examined. Finally, the impact of Universal Test and Treat (UTT) on mean CD4 count at ART initiation among men and women attending 17 primary care clinics, is examined. RESULTS CQI improved HIV VL monitoring among pregnant women living with HIV, but not repeat HIV testing among pregnant women not living with HIV, and coverage of both endpoints fell short of expected targets. Despite enthusiasm for CQI, staffing shortages, gaps in guidelines knowledge, poor data quality and poor clinical documentation hampered CQI uptake and ‘normalisation’. Although women living with HIV were more knowledgeable about correct infant feeding guidelines, they were less likely to breastfeed than women not living with HIV. Whilst CD4 count at ART initiation increased due to UTT, the long-term effect was modest and men initiated ART at lower CD4 counts than women. CONCLUSIONS Whilst CQI has potential to improve quality of care in resource-poor settings, concurrent health systems strengthening initiatives are necessary for maximum impact and sustainability. More efforts are needed to improve breastfeeding uptake, and to increase early ART initiation particularly among men.
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(2018)ThesisAn HIV-1 cure using gene therapy is presently proposed. Past and present inroads to genetically manipulate immune cells have specified the use of generalised gene therapy vectors, alongside extensive and prolonged cellular activation to impart vector compatibility with immune cells. Whilst these methods increase gene delivery outcomes, the harsh cellular conditioning regimen lowers cellular engraftment and proliferative potential. Given these consequences, perhaps optimising the viral vector, and not the target cell, could improve gene therapy outcomes. Two major challenges were firstly identified: overcoming a block at the viral membrane that inhibited particle delivery; and circumvention of a restriction factor, SAMHD1, that inhibited gene delivery post-entry. It was hypothesised the first barrier could be overcome by selecting an optimised pseudotype. Indeed, from many prospective pseudotypes, one lead candidate was identified. This pseudotype, consistently enabled cellular entry in greater than 80% of cellular targets. Whilst this solved the limitation of inefficient particle delivery, gene delivery was still inhibited by SAMHD1. By incorporating the lentiviral accessory protein Vpx into vectors, SAMHD1 could be depleted and this enabled achievement of gene delivery efficiencies approaching 40%. Importantly, these observed from the window of untouched resting CD4+ T cells. Further inroads into the characterisation of diverse Vpx variants yielded additional insights into how Vpx increases gene delivery. Firstly, several variants exist that enhance gene delivery greater than the canonical variant (SIVmac239). Secondly, T cell-tropic Vpx variants exist, that do not enhance gene delivery in macrophages. And finally, Vpx-mediated enhancements are mechanistically biphasic. Overall, this thesis described the development of a highly modular, custom gene therapy particle platform with broad- reaching applications encompassing efficient protein or gene delivery into multiple cell types. Given that the research community is headed into a gene editing Renaissance, the vector development platform described herein may favourably aid in the implementation of these latter applications into immune cells. A cure of HIV-1 proceed down a gene therapy may necessitate an efficient system to become viable in the clinic.
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(2017)ThesisBoth P. vivax and P. falciparum continue to be the leading causes of malaria morbidity and mortality. The work in this thesis seeks to use mathematical modelling to gain insights into the within-host dynamics of these infections and with the aim to infer better control methods for reducing their burdens. P. vivax infection involves hypnozoite formation. These hypnozoites remain dormant in the liver before they reactivate at varying time intervals. The relative contribution of a new P. vivax infection and hypnozoite reactivation to initiation of blood stage infection is unclear. Also, the mechanisms governing the duration of hypnozoite latency and frequency of reactivation of hypnozoites are not fully understood. This thesis investigates the contribution of new inoculations of P. vivax sporozoites to primary infection versus hypnozoite reactivation to total infection by combining both mathematical modelling and data from two clinical cohorts. I found that the majority of the blood stage infections arise from hypnozoite reactivation. The work on P. vivax infection is extended to determine how hypnozoites reactivate from latency using conceptual models of different hypnozoite reactivation mechanisms from the literature. Some of these mechanisms are complex explanations of the reactivation events including re-infection or without re-infection. Applying these models to published cohort data, I found that heterogeneity in exposure to infection can explain many of the features of hypnozoite reactivation without the need for inclusion of additional factors. In P. falciparum endemic regions the incidence of both infection and clinical malaria risk decreases with age. The mechanisms of how an individual controls parasites are not completely understood. Also, patients with parasites before the malaria season have a reduced risk of clinical malaria. Whether the presence of parasites contributes to this observation is unknown. By analysing cohort data from a seasonal transmission setting, I found that both infants and adults have a reduced risk of infection and clinical malaria and that the clearance of parasites before the malaria season does not decrease the risk of clinical malaria. Overall, the work in this thesis demonstrates how mathematical modelling can be used to develop intervention strategies for controlling and eliminating malaria.
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(2017)ThesisChlamydia trachomatis is the most common notifiable sexually transmissible infection in Australia with the highest prevalence in young people and men who have sex with men (MSM). Repeat detection of chlamydia is common following treatment, mainly as a result of reinfection. Retesting at three months to detect reinfections is important to prevent onward transmission and reproductive morbidity, but retesting rates are low. At the time this thesis commenced, there were a limited number of evaluations of interventions to improve retesting rates, with postal test kits and telephone reminders, found to be the most effective, but no assessment of SMS reminders. This thesis arises from a randomised controlled trial (RCT) to assess the effectiveness of postal test kits combined with short message service (SMS) reminders (intervention) to increase retesting after a chlamydia diagnosis among sexual health clinic patients, compared with SMS reminders and return to the clinic only. The RCT involved 600 participants (200 each of women, heterosexual men and MSM) with the study design described in Chapter 2. Chapter 3 shows the intervention was associated with substantial improvements in chlamydia retesting at 1-4 months in all risk groups and detection of more positive retests. Chapter 4 describes an acceptability survey which found the intervention was preferred by most participants over clinic-based retesting and preference was associated with being comfortable having a kit sent to their home, no previous chlamydia diagnosis, and living with friends, highlighting the importance of providing retesting options. In the same chapter, the cost of the intervention and infection detected were found to be lower than clinic-based retesting. Chapter 4 investigated behavioural and organism factors associated with positive retests. Treatment failure was more common in MSM with rectal chlamydia, reinforcing concerns about azithromycin treatment failure. In conclusion, this thesis demonstrated that the use of postal test kits combined with SMS reminders, was more effective at increasing retesting rates and detecting positive retests among sexual health clinic attendees than SMS reminders and returning to the clinic; the intervention was also acceptable to patients and cost saving. Extending the intervention to other primary care settings should be considered.
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(2017)ThesisThe introduction of antiretroviral treatment (ART) has allowed the once rapidly expanding HIV epidemic to slow. ART scale-up in Asia has doubled treatment coverage from 19% in 2010 to 41% in 2015. Yet, Asia is a diverse region where country differences may dictate the response to the HIV epidemic. The WHO guidelines aimed to provide universal recommendations to clinicians managing HIV-positive patients. Over time, advances in HIV research have altered these guidelines, subsequently, affecting patient outcomes. An Asian observational cohort was used to explore the patient sample and evaluate temporal trends in patient outcomes. HIV research has relied upon observational cohorts as a key epidemiological resource. However, patient sampling methods used are typically not random and may not be representative of the study population. The first empirical evidence, to my knowledge, is presented to suggest that a pseudo-random patient sample is representative of the larger study population and can reach similar conclusions for routinely ascertained endpoints. CD4 count monitoring is an integral component of HIV care, particularly in resource-limited settings where viral load monitoring is not routine. CD4 count restoration has been associated with decreased risk of death, AIDS and opportunistic infections. The findings suggested that the CD4 count response to ART was greater for those initiating ART recently, regardless of pre-ART CD4 count. Mortality trends in other regions have shown reductions over time, likely a result of newer ARV drugs and earlier ART initiation. The estimated survival probabilities were 2-3% higher for patients initiating ART in 2006-2013. Retention in care is a critical component of providing long-term HIV care, especially during ART scale-up. The findings suggest that LTFU rates have varied by the year of ART initiation, where those initiating in 2006-09 have the highest rate of LTFU compared to other time periods. Monitoring clinic population trends will be essential for identifying potential pitfalls for HIV programmes in coming years. Substantial increases in the number of patients initiating ART and attending care were found, as well as an increasing older population, greater proportions using second or third ART regimens and poor viral load monitoring.