Melbourne School of Population and Global Health - Theses
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ItemThe Epidemiology and Management of Rectal Chlamydia( 2021)Thesis Summary Introduction Chlamydia trachomatis (“chlamydia”) is the most commonly reported sexually transmitted infection (STI) in the world. Untreated, chlamydia is associated with serious reproductive sequelae in women including infertility. Rectal chlamydia is an important public health problem in Australia with rates rising dramatically among men who have sex with men (MSM), increasing evidence to suggest it is also an issue for women, and ongoing concern about rectal chlamydia treatment failure. This PhD program of research aims to investigate the epidemiology of rectal chlamydia with particular focus on treatment. It includes the first double-blind randomised control trial to identify the most efficacious treatment (azithromycin vs doxycycline), a cross-sectional study to further our understanding about the management of rectal chlamydia infection in men who have sex with men, and a systematic review and meta-analysis of the factors associated with rectal chlamydia positivity in women. Chapter outline The objectives of this thesis were: 1) To determine whether azithromycin or doxycycline is the most efficacious treatment for rectal chlamydia infection; 2) To examine the factors associated with the resumption of sexual activity following treatment for rectal chlamydia among MSM; and 3) To investigate the factors associated with rectal chlamydia in women with concurrent infection at other sites, and to compare these with those observed for rectal gonorrohoea. This thesis is comprised of three major components: 1) the protocol, statistical analysis plan, and results of a double-blind randomised controlled trial (RCT) comparing the efficacy of 1g azithromycin with 7-day 100mg doxycycline (twice a day) for the treatment of rectal chlamydia; 2) a cross-sectional study examining factors associated with resuming sexual activity following treatment for rectal chlamydia among MSM; and, 3) a systematic review and meta-analysis on the factors associated with rectal chlamydia positivity in women. Chapter 1 is a comprehensive literature review on what we know about the chlamydia and in particular, rectal chlamydia. The review discusses the factors for rectal chlamydia, its management, and the treatment concerns to provide context and rationale for this thesis. The literature review demonstrates that rectal Chlamydia trachomatis infection remains an important public health concern with increasing prevalence in both men and women and ongoing uncertainty in the efficacy differences for the treatments used. Several gaps remain in the epidemiology and control of rectal chlamydia including: 1) uncertainty about the most efficacious treatment for rectal chlamydia - azithromycin 1g single dose versus 7-day of doxycycline 100mg (twice a day); 2) the risk of onward transmission or reinfection following treatment among men who have sex with men, and the risk of selection pressure and resistance with continued use of azithromycin; 3) the factors associated with rectal chlamydia among women, in particular with concomitant infection at other sites. Chapters 2 to 4 presents the protocol, statistical analysis plan, and results of the RCT to compare the efficacy of 1g azithromycin to 100mg doxycycline twice daily for seven days for the treatment of rectal chlamydia – the first such trial in the world. The trial observed a microbiologic cure of 281/290 (96.9%; 95CI% 94.9, 98.9) for doxycycline and 227/297 (76.4%; 95%CI 73.8, 79.1) for azithromycin, with an adjusted risk difference of 19.9% (95%CI 14.6, 25.3; p<0.001) in favour of doxycycline. The trial found that the treatment efficacy of 1g azithromycin was even lower than predicted by previous meta-analysis (82.9%; 95%CI 76.0, 89.8%) and confirm that the efficacy this regimen to be far below the World Health Organization efficacy threshold of 95% for STI treatments. The trial provided unequivocal evidence that 1g azithromycin should be removed from international STI management guidelines. Chapter 5 is a cross-sectional study that utilised data from the RCT to investigate factors associated with resuming sexual activity following treatment for rectal chlamydia as a marker for risk of reinfection. This chapter also highlights the possibility of selective pressure of antimicrobial resistance for STIs such as Neisseria gonorrhoeae (NG) or Mycoplasma genitalium through the continued use of azithromycin for the treatment of rectal chlamydia. The study found that 9.5% of men resumed condomless receptive anal intercourse within a week of commencing treatment for rectal chlamydia and that this was independently associated with PrEP use (aRR=3.4; 95%CI 2.5, 4.8) or a man living with HIV (aRR=3.2; 95%CI 1.0, 9.9), relative to an HIV-negative man who did not use PrEP, and reporting 9 or more partners in the last three months (aRR=2.9; 95%CI 1.6, 5.0), relative to reporting 3 or fewer. In addition, 40% of men resumed condomless anal sex within 3 weeks. The study also found that 75% of men resumed any sexual activity within 3 weeks of commencing treatment for rectal chlamydia and that this was associated with reporting 4-8 (aRR=1.2; 95%CI 1.1, 1.5) or 9 or more sexual partners in the last three months (aRR=1.5; 95%CI 1.3, 1.7), relative to reporting 3 or fewer. This study illustrates the risk of induced antimicrobial resistance if azithromycin is continued to be used for rectal chlamydia in populations where reinfection is common and suggests that new health promotion messages may be required in some subgroups. Chapter 6 presents the findings of a systematic review and meta-analysis investigating the factors associated with anorectal chlamydia positivity in women. The review was novel in that it both: 1) quantified the relationship between anorectal chlamydia with concurrent chlamydia infection at the urogenital or oropharyngeal sites; and 2) compared to the same for anorectal gonorrhoea infection within the same study populations for a more comprehensive understanding. The review found that among the 25 studies eligible for inclusion, anorectal chlamydia positivity (summary estimate=8.0%; 95%CI 7.0, 9.1, I2=88.5%) was higher than anorectal gonorrhoea positivity (summary estimate=2.1%; 95%CI 1.6, 2.8, I2=92.7%). It found that urogenital chlamydia was strongly associated with rectal chlamydia (summary prevalence ratio [PR]=32.2; 95%CI 25.6, 40.7, I2=70.3%), but urogenital gonorrhoea was even more strongly associated with anorectal gonorrhoea (PR=89.3; 95%CI 53.1, 150.3, I2=80.1%). Similarly, the association between oropharyngeal and anorectal positivity was also stronger for gonorrhoea than chlamydia (PR=34.8; 95%CI 10.2, 118.2, I2=89.9% vs PR=8.8; 95%CI 6.8, 11.5, I2=58.1%). Finally, anal intercourse was associated with anorectal gonorrhoea (PR=4.3, 95%CI 2.2, 8.6, I2=0.0%) but not anorectal chlamydia (PR=1.0; 95%CI 0.7, 1.4; I2=0.0%). Conclusions This thesis found that azithromycin 1g was inferior to 7-day doxycycline in the treatment of anorectal chlamydia in men who have sex with men, providing unequivocal evidence that doxycycline must replace azithromycin as first line treatment for rectal chlamydia. It is essential that while azithromycin is still in use, there must be stronger health promotion messages following treatment encouraging condom use to minimize exposure to sub-inhibitory levels of the drug. Continued use of azithromycin 1g may contribute to selection pressure for antimicrobial resistance in other STIs that are highly prevalent in those diagnosed with rectal chlamydia. Finally, this thesis found that re-testing following treatment with azithromycin in women diagnosed with urogenital chlamydia is very important because of its strong association with concurrent rectal chlamydia and its potential to autoinoculate a subsequent urogenital infection if not effectively cured.
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ItemA study of the effect of adverse psychosocial work stressors on health and mortality( 2021)The working environment is central in the lives of individuals in employment, influencing health outcomes including psychological and physical well-being. Psychosocial work stressors are common exposures in the workplace and are important and modifiable determinants of health and health behaviours. There is broad agreement in the literature that exposure to adverse psychosocial work stressors, such as high job demands, low job control, low job security and high effort-reward imbalance are associated with poor health outcomes. All of these exposures are, in turn, associated with unhealthy behaviours such as smoking, alcohol consumption, poor diet and inactivity, and to the development of hypertension, cardiovascular disease, diabetes, musculoskeletal disorders and depressive disorders. Psychosocial work stressors have been identified as significant emerging risks linked to global changes in the structure, organisation and management of work during previous decades, presenting pressing challenges to occupational health and safety and workplace health, in general. Most of the literature in this area assesses disease incidence or other morbidity outcomes, with a growing number of studies focusing on mortality. However, whether exposure to these psychosocial work stressors associated with adverse health outcomes translates into increased mortality remains unclear, and barriers to making causal interpretations about the relationship between psychosocial work stressors and health persist, mostly due to inherent biases in the methodology across studies. In this thesis, the effect of exposures to psychosocial work stressors in the working environment such as job control, job demands, job strain, long working hours, job insecurity and shift work on health and mortality were investigated. A comprehensive systematic review including meta-analyses of the epidemiological research was conducted. Panel data from the Household, Income and Labour Dynamics in Australia survey was used to capture natural experiments of psychosocial work stressors associated changes in health and well-being, and mortality to investigate whether and how the effect of psychosocial work stressors on mortality differ in relation to demographic and socioeconomic characteristics. The initial focus of the research included establishing and quantifying the risks associated with adverse psychosocial work stressors, which workers are commonly exposed to in the workplace, on mortality. The final study in the PhD focused on understanding the exposure-outcome dynamics. The dynamics of the connexions between psychosocial work stressor perceived job control and general health, a strong predictor of future morbidity and mortality, were investigated for evidence of a causal relationship. The first study showed that improving the quality of work might contribute to better health and well-being and decrease the effect of psychosocial work stressors on all-cause mortality and cardiovascular disease mortality. If this observed association is causal, then policy and practice interventions to improve job control could contribute to reductions in mortality. Study II adds to the growing body of evidence showing an effect of adverse psychosocial work stressors on mortality. Study III showed that long-term exposure to low job control and job security was associated with increased risk of all-cause mortality. In Study IV, the dynamics of job control and general health were explored for evidence of a causal relationship using three complementary longitudinal modelling approaches. This study, using improved causal inference methods than previous research, showed that increased job control was strongly associated with increasing general health. Although the estimates for the single measures suggest modest increases in the risk of death and poor health, this translates to large population impacts because the exposures are relatively common across the working population. Thus, reducing exposure to psychosocial work stressors associated with mortality and poor health could have considerable public health benefit. Awareness by stakeholders, government and organisations of the implications of the adverse effects of psychosocial work stressors on health and mortality in workplaces; and the availability appropriate, evidence-based work stress interventions to reduce the exposure to work stressors might contribute to better health and well-being, reduce sickness absence and presenteeism to the benefit of workers, workplaces and society.