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Treatment Outcomes for Rectal Lymphogranuloma Venereum in Men Who Have Sex with Men Using Doxycycline, Azithromycin, or Both: A Review of Clinical Cases

Leeyaphan, Charussri MD; Ong, Jason J. PhD; Chow, Eric P.F. PhD; Dimovski, Karolina MSc; Kong, Fabian Y.S. PhD; Hocking, Jane S. PhD; Howden, Ben PhD; Bissessor, Melanie MD; Fairley, Christopher K. PhD; Bradshaw, Catriona PhD; Read, Timothy PhD; Chen, Marcus PhD

Sexually Transmitted Diseases: April 2017 - Volume 44 - Issue 4 - p 245–248
doi: 10.1097/OLQ.0000000000000578
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Background: Treatment for rectal lymphogranuloma venereum where doxycycline 100 mg twice daily for 21 days was used—either alone or together with azithromycin 1 g single dose—resulted in microbiological cure of 97%. These data support doxycycline 100 mg twice daily for 21 days as the preferred treatment for rectal lymphogranuloma venereum.

This study supports the continued recommendation of doxycycline 100 mg twice daily for 21 days as preferred treatment for rectal lymphogranuloma venereum in men who have sex with men.

From the *Melbourne Sexual Health Centre, Alfred Health, Carlton, Melbourne, Victoria, Australia; †Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ‡Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne; §Microbiological Diagnostic Unit Public Health Laboratory, University of Melbourne, Parkville; and ¶Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia

Conflict of interest: None declared.

Correspondence: Charussri Leeyaphan, MD, Department of Dermatology, Faculty of Medicine Siriraj Hospital Mahidol University, 2 Prannok Bangkoknoi, Bangkok 10700, Thailand. E-mail: charussrilee@gmail.com or charussri.lee@mahidol.ac.th.

Received for publication September 19, 2016, and accepted December 9, 2016.

Lymphogranuloma venereum (LGV) has been a reemergent sexually transmitted infection among men who have sex with men (MSM) since initial reports in the early 2000s.1,2 These have predominantly involved the rectum causing symptomatic or asymptomatic proctitis.3–7 Most have been attributable to specific L2 and L2b serovars of Chlamydia trachomatis.8

Published studies on treatment outcomes for rectal LGV in MSM have been limited in number and by the number of cases in those studies.9–13 Several guidelines recommend doxycycline 100 mg twice daily for 21 days as first-line therapy for rectal LGV.14–16 Azithromycin 1 g weekly for 3 weeks has been proposed as an alternative; however, this is based on very limited data.10,17,18

To expand the evidence base for rectal LGV treatment, we undertook a retrospective study that examined outcomes after the treatment with doxycycline or azithromycin or a combination of these.

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METHODS

This was a retrospective study of MSM attending the Melbourne Sexual Health Centre between 2005 and 2015 who had genotype confirmed rectal LGV infection and who received doxycycline and/or azithromycin treatment followed by repeat anal swab testing for C. trachomatis. The study was approved by Alfred Hospital Research Ethics Committee.

An anal swab for rectal chlamydia testing was routinely obtained for screening of MSM attending the clinic and for MSM who presented with symptoms of proctitis. Testing for C. trachomatis was performed using strand displacement amplification (BD Probetec) before March 2015 or by APTIMA Combo 2 assay (GenProbe Diagnostics) after March 2015. Genotyping of positive rectal chlamydial specimens was undertaken selectively in MSM presenting with symptoms of proctitis (rectal pain, bleeding, and/or discharge) or HIV-positive MSM using previously published methods with minor modifications.19 The equivalent serovar was identified by finding the closest matching nucleotide sequence of L2 and L2b from Genebank no. M14738 and AY586530 (Fig. 1).

Figure 1

Figure 1

Over the study period, clinic guidelines recommended doxycycline 100 mg orally twice daily for 21 days (henceforth “doxycycline”) for suspected or genotype confirmed rectal LGV (Fig. 2.1). Azithromycin 1 g weekly for 3 weeks was an alternative (Fig. 2.2), where doxycycline was contraindicated. From June 2012, MSM presenting with symptoms of proctitis were treated for rectal chlamydia including LGV, gonorrhoea, Mycoplasma genitalium, and herpes simplex virus using a combination of doxycycline, azithromycin, ceftriaxone 500 mg single dose, and valaciclovir (Fig. 2.3).20,21 Thus, some men with rectal LGV were treated with doxycycline and azithromycin concurrently. Treatment of rectal chlamydia was with azithromycin 1-g single dose (henceforth “azithromycin”). Because of a 2- to 3-week delay between detection of rectal chlamydia and genotype results, some men were initially treated with azithromycin for rectal chlamydia with doxycycline later added for LGV (Fig. 2.4).

Figure 2

Figure 2

Men treated for chlamydia or rectal LGV were advised to return in 3 months for a repeat anal chlamydia test to establish microbiological cure. This outcome was examined for 5 groups: (1) azithromycin 1 g, (2) azithromycin 1 g weekly for 3 weeks, (3) doxycycline alone, (4) doxycycline with concurrent azithromycin 1 g, and (5) doxycycline after previous administration of azithromycin 1 g.

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RESULTS

There were 57,730 rectal chlamydia tests undertaken in MSM: 3670 (6%) were positive for rectal chlamydia and 1029 of these were genotyped. Genotype L2b was detected in 68 (7%) of specimens from 64 men (Fig. 1). There were 51 cases of rectal LGV where repeat testing was undertaken after a median interval of 82 (interquartile range [IQR], 49–142) days. Four cases were excluded because doxycycline for periods other than 21 days were administered. The remaining 47 cases from 45 men were included. Two men experienced 2 separate episodes of rectal LGV 3 and 5 years later.

Median age among men was 40 years, and 39 (83%) were HIV positive (median CD4, 598). Concurrent gonorrhoea or early syphilis were detected in 6 (13%) and 4 (9%). Twelve (25%) men reported intravenous drug use and 4 (9%) had hepatitis C infection.

Eight (17%) men had asymptomatic LGV. The clinical characteristics among symptomatic men included: rectal pain (70%), rectal bleeding (49%), anal discharge (40%), anorectal ulceration (26%), and/or inguinal lymphadenopathy (9%). The median duration of rectal symptoms was 10 (IQR, 6–21) days.

The characteristics of LGV cases and treatment outcomes are shown in Tables 1 and 2 by treatment group. The median time between commencement of treatment and repeat testing was 77 (IQR, 48–133) days. The proportion of men who were negative on retesting was: 5 (71%) of 7 (95% CI, 36–92%) for azithromycin 1 g; 9 (100%) of 9 (95% CI, 70–100%) for doxycycline; 14 (100%) of 14 (95% CI, 78–100%) for doxycycline with concurrent azithromycin 1 g; and 14 (93%) of 15 (95% CI, 70–99%) for doxycycline after azithromycin 1 g given a median of 16 days previously. Azithromycin 1 g was less effective than doxycycline 100 mg twice daily for 21 days among men with proctitis symptoms (3/5, 60% vs. 32/33, 97%, P = 0.04). Both men treated with azithromycin 1 g weekly for 3 weeks tested negative after treatment 2 (100%) of 2 (95% CI, 34–100%).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

Three men had positive repeat tests: 2 with L2b genotype and 1 positive for C. trachomatis with insufficient material for genotyping. Two of the men were treated with azithromycin 1 g and the other received azithromycin 1 g followed by doxycycline. All 3 men reported condomless anal sex between treatment and repeat testing therefore reinfection cannot be excluded.

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DISCUSSION

In this study treatment for rectal LGV in MSM where doxycycline 100 mg twice daily for 21 days was used—either alone or together with azithromycin 1 g single dose—resulted in microbiological cure in 37 (97%) of 38 cases (95% CI, 87–100%). The study also suggests that this also applies when azithromycin 1 g is given at the same time doxycycline is commenced, or before it. Fourteen men were treated with doxycycline with concurrent azithromycin 1 g as clinic guidelines recommended presumptive combination treatment for MSM presenting with symptomatic proctitis for—chlamydia, LGV, gonorrhoea, and M. genitalium based on pathogens detected in previous studies from our clinic.20,21 All men treated using this combination treatment achieved microbiological cure. A further 15 men received azithromycin 1 g initially followed by doxycycline a median of 16 days later. All of these men achieved microbiological cure except one who had rectal LGV detected on repeat testing. He reported condomless anal sex between treatment and repeat testing therefore reinfection was possible. Azithromycin, when added to doxycycline, may have an additive effect in terms of LGV cure; however, the extent of this is uncertain.

One previous study of 32 MSM with rectal LGV receiving azithromycin 1 g weekly for 3 weeks demonstrated a microbiological cure rate of 29 (97%) of 30.10 There were 2 patients treated with azithromycin 1 g weekly for 3 weeks in our study, and both achieved microbiological cure.

There are limited data on the efficacy of azithromycin 1 g single dose for rectal LGV. Observational studies suggest it may be less effective than doxycycline for rectal chlamydia. Previous LGV case reports treated with azithromycin 1 g have had variable outcomes.22,23 In our study, 5 of 7 men with rectal LGV achieved microbiological cure after azithromycin 1 g. Six of 7 men received a test of cure before starting doxycycline as there was a delay in follow-up, and 1 man declined to take doxycycline. The 2 men with positive repeat chlamydial tests following single dose azithromycin both reported condomless anal sex between treatment and repeat testing; therefore, it is possible that these may have reflected reinfection or treatment failure. Microbiological cure using azithromycin 1 g was lower than that for doxycycline when used alone or in combination with azithromycin 1 g among men with symptoms of proctitis. We speculate that this could reflect higher organism loads in clinically severe proctitis, which are more difficult to cure.24

There are a number of limitations in this study. This was a retrospective study with a relatively small sample size with different treatment combinations reflecting changes in clinical practice over time. Microbiological cure was based on a single test which could miss persistent chlamydial infection if shedding was intermittent.24 Asymptomatic LGV cases are likely to have been excluded due to selective chlamydial genotyping with potential bias toward symptomatic cases. For cases where doxycycline followed previous administration of azithromycin 1 g, it is not clear whether the addition of doxycycline contributed to the microbiological cure as there was no test of cure between these two drugs administrations. Data on whether or not shorter courses of doxycycline are sufficient to cure asymptomatic or clinically less severe cases of rectal LGV would be of interest. Our data add support for the continued recommendation for doxycycline 100 mg twice daily for 21 days as first-line therapy for rectal LGV in MSM.

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