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Abstract
Objectives Recent outbreaks of anorectal lymphogranuloma venereum (LGV) among men who have sex with men (MSM) have been characterised by proctocolitis requiring extended antibiotic treatment compared with infections caused by other serovars of Chlamydia trachomatis (CT). We describe the prevalence and clinical features of LGV among Nigerian MSM diagnosed with anorectal CT.
Methods MSM were recruited for this observational cohort in Lagos, Nigeria, using respondent-driven sampling and screened for HIV and bacterial STIs every three months for up to 18 months. Nucleic acid amplification tests for CT were performed on rectal swab specimens. Prevalent and incident cases of anorectal CT underwent additional testing to identify LGV using novel real-time PCR assays specific for the L-serovars of CT.
Results From April 2014 to July 2016, 420 MSM underwent testing for rectal STIs, of whom 66 (15.7%) had prevalent anorectal CT. Among those without prevalent disease, 68 developed incident infections during 208 person-years of follow-up. Of 134 prevalent and incident cases of anorectal CT, 7 (5.2%) were identified as LGV. None of the seven participants with LGV reported any symptoms. Two of the participants with LGV were simultaneously coinfected with rectal gonorrhoea. HIV coinfection was common among participants with both LGV (n=5, 71%) and non-LGV (n=98, 77%) serovars of CT (P=0.66).
Conclusions Anorectal LGV was uncommon but present among Nigerian MSM in this study. Consistent screening for L-serovars of CT, or presumptive treatment for LGV in cases with a high suspicion for this diagnosis, could potentially improve patient outcomes and decrease transmission.
- chlamydia trachomatis
- lymphogranuloma venereum
- sexually transmitted infection
- HIV
- Africa
- men who have sex with men
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- chlamydia trachomatis
- lymphogranuloma venereum
- sexually transmitted infection
- HIV
- Africa
- men who have sex with men
Introduction
Lymphogranuloma venereum (LGV) is an STI caused by the L-serovars of Chlamydia trachomatis (CT) that has been associated with outbreaks of infectious proctitis and proctocolitis among men who have sex with men (MSM) in Europe and North America.1 Because of its invasive pathogenesis and long-term sequelae, such as fibrosis and stricture formation, an extended 21-day course of antibiotic therapy is recommended for treatment of LGV compared with the 7-day course for infections with other CT serovars.2 Identification of LGV requires advanced molecular testing that is often unavailable in resource-limited settings such as sub-Saharan Africa.
Nigeria is the most populous country in sub-Saharan Africa, and its population accounts for roughly 9% of people living with HIV globally.3 Moreover, stigma and criminalisation of same-sex practices limit STI and LGV case-finding among Nigerian MSM.4 We have previously reported prevalence of 44%–66% for HIV, 19%–26% for gonorrhoea and 17%–18% for CT among MSM in Abuja and Lagos, Nigeria.5
In this study, we describe the prevalence and clinical features of LGV among MSM diagnosed with anorectal CT in Lagos, Nigeria.
Methods
Study population
The Lagos site of the TRUST/RV368 cohort study enrolled MSM using respondent-driven sampling (RDS) as previously described.6 7 Seven initial ‘seed’ participants and each subsequent enrollee were given three coupons to distribute to other MSM. Eligible participants were 18 years or older, presented a valid RDS coupon and reported receptive or insertive anal intercourse with a male partner in the preceding 12 months. Participants who enrolled between 28 April 2014 and 19 July 2016 were included in these analyses.
STI testing and follow-up
Participants underwent testing for HIV and other STIs every three months for up to 18 months. Voided urine and self-collected or physician-collected rectal swabs were tested for Neisseria gonorrhoeae and CT using the Aptima Combo 2 assay (Hologic, Bedford, Massachusetts, USA). Fingerstick blood specimens were screened for HIV infection using a parallel algorithm of two rapid tests with Determine (Alere, Watham, Massachusetts, USA) and Uni-gold (Trinity Biotech, Wicklow, Ireland) kits. Testing was conducted according to package inserts. At each visit, medical history, clinical evaluation, STI-related symptoms and prescribed medications were recorded. Participants were notified of testing results as soon as they were available and were offered immediate treatment of any infection diagnosed.
LGV assay design
The polymorphic protein H gene for CT L-serovars (L1, L2, L2b and L3) was aligned against non-L-serovars using BioEdit (Tom Hall, Raleigh, North Carolina, USA) and ClustalW (European Bioinformatics Institute, Cambridge, UK). Areas unique to the L-serovars were used to design primers and probes (online supplementary table 1). Limit of detection was determined to be approximately 10 genomic copies/assay. Exclusivity testing was performed using known non-L CT serovars and three near-neighbour species (Chlamydophila abortus, Chlamydia muridarum and Chlamydia suis) at multiple concentrations. No cross-reactivity with the L-serovar-specific assays was observed.
Supplementary file 1
Testing for LGV serovars
Anal swabs from participants with prevalent anorectal CT underwent additional testing to identify LGV. Participants without prevalent anorectal CT were followed for incident infection and underwent LGV testing if anorectal CT was diagnosed. Only the first positive specimen for each participant underwent LGV testing.
Nucleic acid extraction was performed using the MagNA Pure LC robot DNA Isolation Kit I (Roche Diagnostics, Indianapolis, Indiana, USA) as per manufacturer instructions. Amplification reactions were performed as described in online supplementary table 1.
Statistical analyses
Characteristics of participants with LGV and non-LGV CT serovars were compared using Fisher’s exact test for categorical variables and Wilcoxon rank-sum test or t-test for continuous variables. Analyses were performed using Stata V.14.2 (Stata Corp LP, College Station, TX, USA). All participants provided written informed consent before enrolment.
Results
Study population
A total of 420 participants (128 HIV-uninfected, 292 HIV-infected) underwent testing for rectal STIs and 66 (15.7%) had prevalent anorectal CT at enrolment. Among those without prevalent disease, 68 developed incident anorectal CT during 208 person-years of observation. A total of 134 first-positive rectal swab specimens with CT underwent LGV identification. Seven (5.2%) cases of infection with LGV serovars were diagnosed.
Participants with anorectal LGV had a median age of 19 years (IQR 18–26), and participants with non-LGV anorectal CT had a median age of 23 years (IQR 21–26; P=0.06).
Symptoms
No participant with anorectal LGV reported symptoms. Among the 127 participants with non-LGV anorectal CT, five (3.9%) reported anorectal pain, three (2.4%) reported fever/sweats, two (1.6%) reported abdominal pain, two (1.6 %) reported anal discharge, and one (0.8%) reported nausea/vomiting.
Coinfections
In total, 5 (71.4%) participants with anorectal LGV were HIV-infected, as were 98 (77.2%) with non-LGV anorectal CT (P=0.66). Anorectal gonorrhoea was detected in 2 (28.6%) participants with LGV and 58 (45.7%) with non-LGV anorectal CT (P=0.46). Neither urogenital CT nor urogenital gonorrhoea was observed in participants with anorectal LGV. Among participants with non-LGV anorectal CT, these coinfections were found in 13 (10.2%; P>0.99) and 10 (7.9%; P>0.99), respectively.
Clinical outcomes
The clinical management and outcomes of participants with LGV are summarised in table 1. One participant was lost to follow-up before treatment could be administered, and one participant received treatment with 1 week of oral doxycycline but was lost to follow-up before repeat CT testing. All five remaining participants with LGV had documented clearance after therapy. Two participants cleared their infections after self-reported self-administration of antibiotics, which is common practice in Nigeria based on symptoms, exposure or a positive test. The antibiotics taken were not reported.
Characteristics and management of participants with anorectal lymphogranuloma venereum
Discussion
To our knowledge, this is the first study to identify anorectal LGV infection among MSM in sub-Saharan Africa. LGV is historically endemic to sub-Saharan Africa but typically associated with ulcerative genital disease.8 Few studies have evaluated the anorectal site for infection. One study of 43 HIV-uninfected MSM in Kilifi, Kenya, identified three cases of anorectal CT, but none with LGV.9 Healthcare providers should conduct anatomically appropriate screening for STIs based on patients’ sexual behaviours and should be aware of the risk of anorectal LGV among MSM.
In contrast to other reports, anorectal LGV was uniformly asymptomatic among Nigerian MSM in this study. In Europe and North America, reports suggest that only 5%–27% of cases have been asymptomatic.10 All cases of LGV in this study would have gone undiagnosed and untreated without universal screening of asymptomatic MSM. While there are financial and logistical barriers to implementation of universal screening, providers should consider additional testing or presumptive therapy for LGV in HIV-infected MSM with anorectal disease or who fail to clear anorectal CT after standard therapy.
In this study, LGV was diagnosed retrospectively and providers prescribed therapy based on CT results only. Still, most infections cleared even without LGV-specific therapy. Limited observational data of mostly symptomatic cases of anorectal LGV suggest that single-dose azithromycin and 7-day courses of doxycycline are less efficacious than a 21-day course of doxycycline, but clinical and microbiological cure has been observed with these regimens for some individuals.1 Further research is needed to clarify optimal regimens and duration, particularly in asymptomatic cases.
This study enrolled a highly marginalised population of MSM in Nigeria and conducted universal screening for anorectal STIs, including LGV, enabling novel characterisation of disease burden in this population. However, this study may have underestimated the burden of symptomatic disease due to factors such as recall bias or selection bias. For example, symptomatic individuals might have been more likely to seek treatment from providers outside of the study or through self-administration of antibiotics. Although STI treatment was available at no cost to participants throughout the study, including outside of regularly scheduled study visits, treatment was frequently delayed or undertaken through self-administration of antibiotics. Data regarding drugs and doses of self-administered antibiotics were not systematically collected. Outcomes of STI treatment were not available for all participants and may have been influenced by factors other than medications prescribed during study participation. Lastly, while the assay used for these analyses identified multiple CT serovars associated with LGV, it did not distinguish between these serovars.
Anorectal LGV was uncommon but present among MSM in Lagos, Nigeria. All cases were asymptomatic and would not have been captured without universal, anatomically appropriate screening. Syndromic management of anorectal STIs would not have been sufficient to diagnose either LGV or the vast majority of anorectal CT among participants in this study. Furthermore, it is imperative that healthcare providers discuss sexual practices with their patients in order to identify the appropriate anatomic sites to evaluate for STIs since infected patients may not present with specific complaints. In Nigeria and other settings where LGV testing is not widely available, healthcare providers may consider presumptive therapy for LGV in cases of anorectal CT that do not respond to the usual therapy. These data suggest that some cases of anorectal LGV can be cured with short courses of antibiotic therapy and further research is needed to define the optimal course of therapy for asymptomatic anorectal LGV.
Acknowledgments
The study team would like to thank the study participants for their valuable contributions to this research.
Footnotes
Handling editor Jackie A Cassell
Contributors TAC conceptualised these analyses, coordinated data collection and authored the first draft of the manuscript. JH performed LGV testing and assisted in the interpretation of results. KL, SO and AI coordinated and conducted other laboratory testing. ZP, AK, SeA and SyA oversaw the collection of clinical data. SDB, RGN, MEC and JA conceptualised the TRUST/RV368 study and assisted in the interpretation of results from these analyses. CAG oversaw development of the LGV assay and provided general oversight of these analyses. All authors reviewed this manuscript, provided feedback and approved the manuscript in its final form.
Funding This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (W81XWH-11-2-0174); the National Institutes of Health (R01 MH099001, R01 AI120913); Fogarty AITRP (D43TW01041); and the President’s Emergency Plan for AIDS Relief through a cooperative agreement between the Department of Health and Human Services/Centers for Disease Control and Prevention, Global AIDS Program and the Institute for Human Virology, Nigeria (U2G IPS000651).
Disclaimer The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense or the Department of Health and Human Services.
Competing interests TAC has received a speaker fee from Gilead Sciences. CAG has served as a consultant for BioFire and has received speaker fees from Cepheid and Becton Dickinson.
Patient consent Obtained.
Ethics approval This study was reviewed and approved by institutional review boards at the Walter Reed Army Institute of Research, Silver Spring, Maryland, USA; the University of Maryland, Baltimore, Maryland, USA; and the National HealthResearch Ethics Committee and Ministry of Defence, Abuja, Nigeria (approval #FHREC/2012/08//22/09-08-12). The investigators have adhered to the policies for protection of human subjects as prescribed in AR-70.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators The TRUST/RV368 Study Group includes Principal Investigators: William Blattner and Manhattan E Charurat (IHV, University of Maryland, Baltimore, MD, USA); Co-Investigators: Alash’le Abimiku, Sylvia Adebajo, Julie Ake, Akindiran Akintunde, Senate Amusu, Stefan D Baral, Trevor A Crowell, Charlotte A Gaydos, Hongjie Liu, Jennifer Malia, Nelson Michael, Helen Omuh, Ifeanyi Orazulike, Sheila Peel, Merlin Robb, Cristina Rodriguez-Hart, Sheree Schwartz; Institutions: Institute of Human Virology at the University of Maryland School of Medicine (IHV-UMB), Johns Hopkins Bloomberg School of Public Health (JHSPH), Walter Reed Army Institute of Research (WRAIR), U.S. Military HIV Research Program (MHRP), Department of Defense (DoD), Walter Reed Program - Nigeria (WRP-N), Institute of Human Virology Nigeria (IHVN), International Centre for Advocacy for the Right to Health (ICARH), The Initiative for Equal Rights (TIERS), Population Council (Pop Council).
Presented at This work was presented, in part, at IDWeek 2017 in San Diego, California, on 4–8 October 2017.