The lymphogranuloma venereum (LGV) biovars of Chlamydia trachomatis (CT) have been recognized as a cause of proctitis in men who have sex with men (MSM) since the 1960s,1 and over the last decade, LGV has reestablished itself as an endemic sexually transmitted infection in MSM in the United Kingdom, Europe, and the United States.2–4 Recent Public Health England data showed a sharp increase in UK infections since 2012, with diagnoses rising by 40% from 2014 to 2015. In 2015, 946 LGV cases (both symptomatic and asymptomatic) were reported to Public Health England,5 the highest ever number of annual cases despite routine rectal chlamydia testing in the United Kingdom in MSM for over a decade. Most LGV in MSM manifests as symptomatic proctitis, but more recently, a large, multicenter case finding study showed higher rates (27%) of asymptomatic LGV in the United Kingdom than previously reported.6 This may, in part, be due to recent guidance, which suggests that in addition to MSM with proctitis, all HIV+ MSM with rectal chlamydia should be tested for LGV regardless of symptoms, that is, whether or not lymphoid or granulomatous pathology is present.7
A recent systematic review and meta-analysis including 9 prospective and retrospective studies showed a pooled treatment efficacy for rectal LGV in MSM of 98.5% with 21 days of doxycycline.8 Shorter treatment courses were not considered. There is no biological reason why nonbubonic LGV should require a longer course of doxycycline than other uncomplicated chlamydial infection, provided the antibiotic is able to reach the organism at the required concentration. Division times of CT LGV and non-LGV biovars have not been shown to be different in vitro, and thus, one might expect that sufficient drug exposure to effect microbiological cure might be achieved with similar regimens of doxycycline to that for non-LGV CT infections. Standard treatment of rectal CT diagnosed in our clinics is doxycycline 100 mg twice a day for 1 week; routine testing of such specimens for LGV DNA gave us an opportunity to observe treatment responses to this shorter regimen when the specimen was confirmed subsequently to be LGV. Such results might help to guide future treatment recommendations and dosing schedules for any controlled trial assessing LGV treatment efficacy.
We conducted a retrospective case note review in 2 central London genitourinary medicine clinics seeing a high number of MSM between November 2012 and November 2016. All MSM who tested positive for LGV DNA by LGV-specific DNA polymerase chain reaction (PCR) were identified, and we then selected any patients where less than 21 days of doxycycline was used for initial treatment. Routine testing for CT on rectal swab specimens was performed using the Gen-Probe/Hologic Aptima Combo2 assay (Hologic, San Diego, CA). If positive for CT and LGV testing was indicated, the specimens were sent to the Sexually Transmitted Bacteria Reference Unit at Colindale, United Kingdom, for LGV-specific DNA PCR according to a previously published technique.9 Testing was indicated when a patient had symptoms or were a contact of LGV, or for HIV+ MSM as per British Association for Sexual Health and HIV guidelines.7 Since July 2016, in 1 of the 2 clinics, an in-house LGV PCR test was used deploying identical targets to the STBRU assay. Data on demographics, HIV status, clinical presentation, duration of doxycycline treatment, other concurrent treatment provided, and test of cure (TOC) results were collected. All patient data were anonymized. Patients in whom no TOC was performed or those given 21 days of doxycycline for initial treatment were excluded.
We found 60 MSM who were treated initially with less than 21 days of doxycycline for rectal CT that was subsequently confirmed as LGV infection. Median age was 38 years (range, 25–57 years); 26 (44%) were white British, 23 (38%) were white other, 2 (3%) were black Caribbean, 2 (3%) were black other, 1 (2%) were black African, and 6 (10%) were of “other” ethnicity. Fifty-six (93%) of 60 patients were HIV positive. Fifty-percent of the patients were asymptomatic (30/60); 27 patients (45%) had one or more anorectal symptoms and 5 (8%) of patients presented with other genitourinary symptoms, most commonly urethral discharge in 4 of 5 patients. Anorectal symptoms included anal discharge/mucus, pain, tenesmus, constipation, diarrhea, and bleeding. Symptoms suggestive of severe proctitis such as tenesmus and constipation were present in 7 patients. Four of 7 were treated initially with 7 days of doxycycline, and 3 of 7 received 14 days of doxycycline. In addition, 6 of 7 received ceftriaxone and 1 of 7 received 1 g of azithromycin. All 7 patients had negative TOC and symptom resolution at the time of TOC. Of 14 patients who had a proctoscopy, 7 (50%) had clinical proctitis on examination. Several declined proctoscopy due to severe pain. Nine patients had confirmed gonococcal infection (6/9 rectal). Fourteen patients had attended as a result of being a known contact of a sexually transmitted infection, with 8 contacts of CT, 8 of Neisseria gonorrhoeae, and 1 of Shigella.
Duration of Treatment and Comedication
Fifty (83%) of 60 had been prescribed 7-day courses of doxycycline initially, and 10 (17%) were treated initially with 14 days of doxycycline. The comedications given to patients are described in Table 1. Eleven (18%) of 60 patients received azithromycin in addition to doxycycline.
After confirmation of LGV, all patients were invited back to the clinic to be offered further medication to complete a 3-week course, and at this visit, a TOC rectal swab for CT was obtained to evaluate possible clearance of the infection. In the non azithromycin group, the median time to TOC from the start of initial doxycycline course was 28 days (range, 7–200 days); 47 (96%) of 49 had a negative TOC for CT. Of the 2 positive TOC results, one was positive for CT but negative for LGV; the TOC was done after 114 days and this was likely reinfection with a non-LGV serovar. The other positive TOC result had CT and LGV DNA detected. The time to TOC for the second patient was 28 days, and he had received 7 days of doxycycline with no comedication. There was no documentation regarding his adherence. This patient was also documented as having more than 50 partners in 3 months, including at least 2 in the time between treatment and TOC, raising the possibility of reinfection.
A second TOC was completed in 23 (47%) of 49 patients. These were not specifically intended to be a TOC but were carried out because patients presented either for repeat asymptomatic screening or due to new symptoms. Twenty (87%) of 23 tested negative for CT; the median duration between the first and second TOCs was 65 days (range, 7–658 days). One patient's second TOC was positive for CT but LGV negative, and 2 further patients had positive LGV at second TOC. The durations between the first and second TOCs in these patients were 55 and 168 days, and again reinfection was considered likely because multiple sexual partners were documented during this period.
Eleven (18%) of 60 patients were coadministered azithromycin. Ten (91%) of these 11 patients received a stat dose of 1 g, and 1 patient received a 3-day course for a respiratory infection. All 11 patients given azithromycin were given 7 days of doxycycline, and 11 (100%) of 11 had a negative TOC result at a median of 37 days (range, 13–162 days). Seven (100%) of those 7 patients who had a second TOC at a median of 139 days later (range, 37–638 days) remained negative.
The main reasons for initial use of less than the recommended 21 days of doxycycline were a positive CT result from the rectum where patients were asymptomatic, patients being treated as a contact of infection, or patients being treated empirically for urethral or rectal gonorrhea with ceftriaxone and 7 days of doxycycline. For patients with proctitis, 14 days of doxycycline was given to some patients with a planned review at 2 weeks, although patients did not always return for review at this time point.
As far as we know, this is the only published case series describing outcomes in MSM treated with less than the recommended 21 days of doxycycline for confirmed LGV. Our data show that 7 to 14 days of doxycycline is effective in most cases with initial negative TOC results in 59 of 60 patients. A significant proportion of the cohort was asymptomatic; however, even in patients with clinical proctitis, shorter treatment duration was effective.
British, European, and Centers for Disease Control and Prevention guidelines suggest that first-line treatment of LGV should be with oral doxycycline 100 mg twice daily for 21 days.10–12 The evidence base for LGV treatment, including its duration, is very limited with no published randomized controlled trials. One of the rationales for prolonged treatment of LGV is the invasive and systemic nature of the infection,13 though historically, it was likely based on the observational responses to treatment and time taken until symptomatic resolution, primarily in bubonic disease. The anorectal syndrome seen as a complication of primarily heterosexual infection is likely a different disease entity to the primary proctitis seen in MSM, where symptom response to antibiotic treatment is generally prompt.14 Delayed microbial clearance of LGV was noted in one study where CT RNA persisted in the rectum for up to 16 days in one MSM with rectal LGV,15 where 15 of 20 patients were chlamydia DNA negative after 7 days of doxycycline and 18 of 20 by 14 days. It is well established that detectable nonviable nucleic acid might persist for days in the absence of ongoing infection, and thus, inference that 21-day treatment is always necessary is not justified by these data. For non-LGV chlamydia, a shorter duration of treatment with 7 days of doxycycline is recommended because of higher rates of treatment failure seen with azithromycin 1 g stat at the rectal site7; observed treatment responses to 7 days of doxycycline for non-LGV or untyped asymptomatic rectal CT have been consistently greater than 95%.16 Case reports of LGV lymphadenitis requiring prolonged antibiotic therapy17 reinforce the established literature that buboes often require repeated drainage and extended antibiotic coverage due to loculated disease and poor drug penetration.
Reflecting previously reported data,18 most of our patients were HIV positive, and this is likely to reflect sexual networks, sexual risk behavior, and possible biological synergy.
One of the 2 participating clinics does not use azithromycin in the routine treatment of gonorrhea (using doxycycline instead in addition to ceftriaxone). As a result, a relatively low proportion (11/60; 18%) of patients had received azithromycin in addition to doxycycline. We were not able to determine if azithromycin alone had cleared LGV infection, but the addition of 1/52 of doxycycline instead of 3/52 as usually indicated achieved cure in all 11 patients. The evidence for azithromycin efficacy against LGV is limited; however, a recent case series showed efficacy with stat dosing in 5 (71% cases) of 7.19 When used as an alternative to doxycycline in the treatment of LGV, weekly dosing with 1 g for 3 weeks is recommended.7 Only one patient in our cohort received 3 doses of azithromycin, and this was a course of 500 mg daily for 3 consecutive days for concomitant sinusitis.
Reducing the duration of doxycycline might mitigate the issue of gastrointestinal adverse effects such as dyspepsia and nausea as well as photosensitivity for some patients; a modest cost saving could also be achieved. Reducing the duration for the course would reduce the administration of unnecessary antibiotics and improve antimicrobial stewardship.
There are certain limitations to this study. This was a retrospective review of cases and was not systematic. A higher proportion of asymptomatic patients were seen in this analysis than would be expected overall in all individuals testing positive for LGV, because these patients were less likely to have received 21 days of doxycycline. It is likely that these cases are skewed toward less severe infections. The case review was only carried out in 2 central London clinics, reducing its generalizability, although the majority of LGV in the United Kingdom is seen in London MSM.4 Several patients were prescribed comedication such as azithromycin, and this might have affected interpretation of doxycycline activity, because anti-LGV activity of azithromycin would be expected. Establishing cure with a single TOC at any time point from 3 to 8 weeks after treatment of chlamydial infection has some limitations,20 although nearly half the present cases had at least one further TOC, with all but 2 showing negative results.
A recent meta-analysis and case series by Leeyaphan et al.8,19 concluded that their data added support for the continued use of 21 days of doxycycline as first-line therapy for rectal LGV; however, we suggest that our results do not necessarily support this conclusion. Contrary to what is advised in the current British Association for Sexual Health and HIV CT guidelines, the clinical scenario of finding asymptomatic rectal CT in an HIV+ MSM does not necessarily warrant a 3-week course of doxycycline. A 1-week course followed by a TOC if LGV is subsequently detected should be sufficient based on our experience. This might also remove the clinical imperative to perform costly LGV testing routinely in such a frequently detected infection as asymptomatic rectal CT in MSM, although such results are still important for LGV surveillance and partner notification. There is clearly a case for a multicenter randomized controlled trial comparing different durations of doxycycline treatment to determine the shortest optimal duration of therapy in all patients with LGV regardless of severity. We suggest that one arm of such a trial should be treatment with 7 days of doxycycline 100 mg twice a day.
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