The Epidemiology and Management of Rectal Chlamydia
AffiliationMelbourne School of Population and Global Health
Document TypePhD thesis
Access StatusOpen Access
© 2021 Andrew Lau
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.
KeywordsChlamydia; Rectal; Azithromycin; Doxycycline; Epidemiology; Management
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