Rectal lymphogranuloma venereum (LGV), a sexually transmitted infection (STI) caused by the L-serovar of Chlamydia trachomatis (Ct), is in the western world typically seen in HIV-positive men who have sex with men (MSM).1 The infection is strongly associated with dense sociosexual networks and a high number of sexual partners.2,3 Furthermore, the implementation of pre-exposure prophylaxis (PrEP) to prevent HIV is associated with an increase in rectal STIs, and it has been suggested that the use of PrEP might be responsible for the increasing proportion of LGV cases among HIV-negative MSM.4,5
The number of cases of LGV continues to rise in Europe, and in 2019, an increase of 45% was seen in the UK (communication through Epidemic Intelligence Information System of European Centre for Disease Prevention and Control). Half of the LGV cases in the UK were found in HIV-negative MSM which may be due to changes in behavior or a more intensive testing strategy in MSM. A similar increase in LGV cases in HIV-negative MSM has been described in Belgium.6 Of note, this increase predates the roll-out of PrEP in Belgium in mid-2017 which could be explained by an increasing awareness of symptomatic LGV infection among health care providers and laboratory experts in 2014.7,8
In Belgium, LGV confirmation was added to the surveillance activities of the national reference centre (NRC) for STIs in 2011. Additional promotion of LGV by the Belgian government took place in 2014 and in 2018; national STI guidelines were issued which included the recommendation to further test positive anorectal Ct samples of MSM for LGV confirmation irrespective of their HIV status.9 Yet, this recommendation is not followed by all Belgian laboratories or physicians. The NRC-STI is affiliated to one of the largest Belgian HIV/STI clinics. In this clinic, positive anorectal Ct samples are routinely genotyped to distinguish non-L Ct strains versus LGV strains. We therefore aimed to describe the rectal LGV epidemic in Belgium including the PrEP-era until the end of 2019 and an exploration of the differences in epidemiological characteristics before and after the introduction of PrEP. Furthermore, this article focuses on the LGV epidemic among male patients attending our HIV/STI clinic to better understand the epidemiology of LGV in the HIV and PrEP cohorts of our clinic.
All male rectal LGV confirmed cases received by the Belgian NRC located at the Institute of Tropical Medicine (ITM) were used to explore the national LGV epidemic before and after the introduction of PrEP.
In addition, the HIV/STI clinic at ITM (Antwerp, Belgium), harbors a large aids reference centre which follows a large cohort of MSM in the framework of HIV treatment and HIV/STI prevention. In Belgium, the use of PrEP is reimbursed since July 2017 when prescribed by a physician specialist affiliated to an aids reference centre.7 We reviewed rectal Ct and LGV diagnoses in male patients in this HIV/STI clinic from 2011 until the end of 2019. Reinfections within 3 months of an initial diagnosis were removed from the database to exclude potential persistent infections and treatment failures.
Molecular testing of Ct was performed using the Abbott Real Time CT/NG molecular assay according to manufacturer's instructions. In case a positive result was obtained, further genotyping was performed by an in-house real time-molecular assay using previously published pmpH gene primers/probes to differentiate LGV (L genotypes) from non-LGV (A-K genotypes) strains.10
No ethical approval or informed consent was necessary because this retrospective study used coded data that was gathered for public health monitoring and infection control. According to ITM's policy, laboratory data of patients can be used for research if the patients' identity is not disclosed to third parties and the patient does not explicitly state his objection.
Overall Belgian Rectal LGV Epidemic
Segmented Poisson regression was performed to explore differences in the number of rectal LGV cases before and after the start of PrEP, for the whole data set and by the HIV status. The second semester (S2) of the year 2017 was used as the cut-off date of the intervention (introduction of PrEP). In addition, logistic regression was performed to check for associations between the absence of symptoms and HIV status on all received rectal LGV samples since 2011.
Ct and LGV Epidemic in the HIV/STI Clinic in Antwerp, Belgium
The overall rectal Ct and LGV prevalence was estimated among the male patients of the HIV/STI clinic as well as the male HIV cohort and male HIV negative individuals (HIV negative or HIV status unknown). Since S2 2017, the prevalence of LGV is also presented for PrEP users only. Prevalence per semester is defined as (the number of rectal positive results/the total number of rectal Ct tests performed per year) × 100.
Segmented logistic regression was performed to explore a change in trend in LGV prevalence in HIV positive individuals and HIV negative individuals.
The results of the regression models are presented as incidence rate ratios (IRR) with 95% confidence intervals (CI) in the case of the Poisson models and as odds ratios (OR) with 95% CI for the logistic regression models. For all analyses, estimates with P values below the 0.05 threshold are considered statistically significant. STATA v15.1 (StataCorp) was used for all statistical analyses.
Overall Belgian Rectal LGV Epidemic
In total, 572 male rectal LGV cases were identified from 2011 till the end of 2019 (Fig. 1). The demographic and epidemiologic data detailing the steady increase in cases until 2016 were previously published.6 Almost all LGV cases with known sexual behavior described themselves as MSM (98.9%; n = 429/434).
In 2017, 83 LGV cases were reported, and this number remained the same in 2018. An increase of 69% in LGV cases was noted in 2019 (n = 140).
The segmented regression model showed that the number of cases increases with 15% every semester (IRR: 1.15; 95% CI: 1.11 to 1.19; P < 0.0001) or approximately 30% per year. Right after 2017 (introduction of PrEP), there seems to be a significant drop in incidence, but the slope did not accelerate after 2017 (IRR: 1.18; 95% CI: 1.04 to 1.36).
Of the LGV cases with known HIV status (n = 505/572), the proportion that was HIV-negative increased from 0.0% in S1 of 2011 and 2012 to 24.3% in S1 of 2017 (n = 9/37; 95% CI: 11.2 to 41.2) just before the introduction of PrEP (Fig. 1). There was a strong increase in this trend over the semesters (IRR: 1.37; 95% CI: 1.22 to 1.53; P < 0.0001), but there was no difference in the magnitude of the trend after the introduction of PrEP (P > 0.05). In 2019, 56.2% of the LGV cases with known HIV status were HIV negative (n = 68/121; 95% CI: 46.9 to 65.2).
The increase of LGV cases in HIV-positive patients is smaller than in HIV-negative individuals (IRR: 1.13; 95% CI: 1.09 to 1.17). After the introduction of PrEP, no significant difference in magnitude of trend was documented (IRR: 1.05; 95% CI: 0.88 to 1.25; P > 0.05).
The presence of symptoms and HIV status of 373/572 (65.2%) rectal LGV cases was reported over the 9 years. The proportion of asymptomatic cases was higher in HIV-negative men (21.4%; 95% CI: 14.2 to 30.2; n = 24/112) than in HIV-positive men (7.3%; 95% CI: 4.4 to 11.1; n = 19/261; P < 0.0001), and subsequently, the odds of having an asymptomatic LGV infection was higher in HIV-negative individuals (OR: 3.47; 95% CI: 1.81 to 6.65; P < 0.0001). Poisson regression, however, did not show a statistically significant increase over the semesters in asymptomatic cases among HIV-positive nor among HIV-negative individuals.
Ct and LGV Epidemic in the HIV/STI Clinic in Antwerp, Belgium
The number of rectal Ct requests increased 10-fold over time: from less than 100 in the semesters of 2011–2013 to over 1000 requests in the semesters of 2019 (Fig. 2). The percentage of rectal swabs that were positive for all serovars of Ct fluctuated between 14.1% and 23.7% in the semesters of 2011–2014. Starting from 2015, the number of rectal Ct requests increased substantially, and subsequently, the prevalence of rectal Ct dropped from 15.1% (n = 23/152; 95% CI: 9.8 to 21.7) in the second semester of 2014 to 9.2% in the first semester of 2017 (n = 56/609; 95% CI: 7.0 to 11.8). After S1 2017, the prevalence of rectal Ct increased again and fluctuated between 10.8% and 13.6% between S2 2017 and S2 2019. Although that the prevalence of LGV followed the same trajectory as the prevalence of Ct (high prevalence in the years preceding 2015, followed by a drop in prevalence the next years), an increase in LGV prevalence was only reported in the semesters of 2019 (Fig. 2).
LGV Prevalence in the HIV and PrEP Cohort of ITM
Until the second semester of 2014, LGV infections were solely detected in HIV-positive men (Fig. 3). Men not belonging to the HIV cohort were also less frequently sampled (Fig. 2). Starting from the second semester of 2015, more Ct rectal requests were received from HIV-negative men (143 vs 120); and from 2016 until the end of 2019, 3 times more rectal Ct requests were received from HIV-negative men (Fig. 2). The LGV prevalence among HIV-positive individuals was mostly above 10% (11.1%–27.0%) until S2 2017. Starting from S2 2017, prevalence dropped below 10% and fluctuated in between 3.7% and 9.3% until the end of 2019.
LGV prevalence of HIV-negative men still remains below 5% (Fig. 3). Since S2 2017, PrEP became reimbursed in Belgium, and over the following semesters, more HIV-negative men visited the clinic in the framework of PrEP visits. Of all the cases of LGV diagnosed at ITM, PrEP users constituted 13.9% (n = 5/36) in 2017 and 46.2% (n = 36/78) in 2019. Among those known to be HIV positive, these figures were 80.6% (n = 29/36) in 2017 and 48.7% (n = 38/78) in 2019.
Segmented logistic regression, however, showed that there was no significant increase in LGV cases in HIV-negative individuals over the semesters before (OR: 1.03; 95% CI: 0.86 to 1.22; P > 0.05), but an increase was noted after the introduction of PrEP (OR: 1.40; 95% CI: 0.80 to 2.43; P = 0.032). Indeed, the prevalence of LGV in the PrEP cohort increased from 0.8% (n = 5/598; 95% CI: 0.3 to 1.9) in 2017 to 2.4% in 2019 (n = 36/1507; 95% CI: 1.7 to 3.3; P = 0.016). We could not document a change in trend among HIV-positive individuals.
Whereas the size of HIV-negative men who were tested at least once for rectal Ct doubled from 584 individuals in 2017 to 1181 in 2019; most of them were part of the PrEP cohort (360 in 2017 and 938 in 2019). The number HIV-positive patients tested for Ct increased from 221 to 370 over the same time period.
HIV positive patients were less frequently screened for rectal Ct compared with PrEP users. In 2019, 69% of the HIV cohort was only screened once, 24% twice, and only 7% was screened more than twice. The number of screening tests was considerably higher among the PrEP cohort. Hereby, 56% was screened once, around 31% twice, and 13% was screened more than twice for rectal Ct in 2019.
This study shows an increase in Belgian LGV cases of almost 70% in 2019 compared with 2018 which is in line with results reported in the United Kingdom (communication through Epidemic Intelligence Information System of European Centre for Disease Prevention and Control). In the United Kingdom and other European countries, a small decrease in LGV cases was noted in 2017, followed by an increase in 2018 which was possibly linked to a change in testing practice.11,12 In Belgium, the number of rectal LGV cases remained stable during 2016–2018 but increased noticeably in 2019. Belgium released new national STI guidelines in 2018 that included a recommendation to send Ct positive anorectal samples of MSM to the NRC for LGV genotype determination. This guidance likely increased awareness among health care providers and could, therefore, explain the rise in number of LGV cases in 2019.8 Furthermore, the increasing proportion of LGV attributed to HIV-negative MSM (56.2% of the LGV cases in 2019) in Belgium, may be related to the more frequent screening for asymptomatic STIs, which remain otherwise undiagnosed, in PrEP recipients compared with HIV-positive individuals. Indeed, our study showed that asymptomatic LGV cases were more likely to be found among HIV-negative (21.0%) than HIV-positive MSM (7.3%) and complements other studies documenting a high asymptomatic LGV rate in HIV-negative MSM (30%–50%).5,13 Unfortunately, because of underreporting of the presence of symptoms, a change in asymptomatic rate over the years could not be analyzed. We can however not exclude that these asymptomatic infections would become symptomatically over time.
In this article, we tried to explore trends in the Belgian LGV epidemic after the introduction of PrEP. Although we found that the number of LGV cases increased among HIV negative individuals over the years, there was no acceleration in this trend after the introduction of PrEP.
To assess a difference in trends of Ct and LGV prevalence over time among HIV-positive and HIV-negative men, we investigated the prevalence in our HIV/STI clinic. Overall, rectal Ct and LGV prevalence among men in our HIV/STI clinic was high in the years before 2015 (mean prevalence Ct: 17.4% and LGV: 10.6%), subsequently dropped until 2018, but increased again in 2019 (Ct: 12.7% and LGV: 3.4%). Importantly, the data showed an increase in the number of LGV diagnoses and the proportion of tests positive among HIV-negative individuals and in particularly PrEP users (from 0.8% in 2017 to 2.4% in 2019). Interestingly, a Dutch study investigating LGV positivity in rectal samples among HIV-positive and HIV-negative MSM, reported a much lower rectal LGV prevalence in both cohorts (2.5% in HIV positive MSM and 0.3% in HIV negative MSM in 2017) than our study (10.2% and 0.7%) which is probably because of the implementation of universal rectal chlamydia and LGV testing for all MSM since 2015 in the Netherlands.5 Importantly, they also documented a doubling in LGV prevalence in HIV negatives over time from 0.12% in 2011 to 0.33% in 2017.5 They, however, could not assess the proportion of LGV among PrEP users, as PrEP was not widely implemented in the Netherlands until 2019.
Although we found an increasing LGV prevalence among PrEP users in our STI clinic, we previously documented that HIV-negative persons constituted an increasing proportion of LGV in Belgium.6 The current findings suggest that as of 2019, more than half of the LGV infections were found in HIV-negative individuals. In the ITM cohort, 46.2% of LGV diagnoses were in individuals enrolled in our PrEP cohort, and 48.7% were part of the HIV cohort. These findings may reflect less serosorting or simply the dense sexual network that certain MSM are part of, irrespective of the use of PrEP.11
Our study has some important limitations. First, the epidemiological data were missing for many cases including the lack of information on the presence of symptoms. Therefore, we could not explore changes of asymptomatic cases by the HIV status over time. Second, every patient given PrEP at least once was categorized as such, regardless of the date of Ct and LGV testing being before, during, or after using PrEP. This may have resulted in overestimation of the number of PrEP users. Furthermore, PrEP users must exhibit high risk behavior before they are eligible for PrEP acquisition. They are therefore a population already at high risk for STI acquisition. Hence, we cannot generalize the results to HIV-negative MSM that are not taking PrEP. Finally, all rectal male samples of patients not belonging to our HIV cohort were categorized as HIV negative or unknown. Consequently, a few cases might have been erroneously categorized as being not HIV positive.
To conclude, this study showed that the increase in LGV cases among HIV negative men in Belgium started before the introduction of PrEP and that this trend did not increase after the introduction of PrEP in Belgium. LGV prevalence among PrEP users is however increasing in our STI clinic. Therefore, continued surveillance in MSM irrespective of their HIV status and PrEP use is required for the management and control of the LGV epidemic.
The authors thank all laboratory staff of the National Reference Centre of STIs in Belgium including Wendy Thys for the data entry.
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