The association between Lymphogranuloma venereum and HIV among men who have sex with men: systematic review and meta-analysis

Lymphogranuloma venereum (LGV) is a sexually transmitted infection (STI) which largely disappeared from the Western world after the introduction of antibiotics. LGV is caused by the species Chlamydia trachomatis (CT) which produces infection in humans and includes three biovars [1]; serovars A-C cause trachoma, an eye infection that mainly spreads via child-to-child transmission and is the leading cause of preventable blindness, while the second biovar (serovars D-K, and occasionally also B [2]) is transmitted sexually [3]. Serovars A-K have a limited host-cell range, they infect mainly squamocolumnar epithelial cells and are incapable of infecting deeper tissues. The third biovar, LGV, is formed by serovars L1, L2 and L3 and it causes a more invasive disease due to its ability to infect macrophages and consequently it can spread to lymphatic tissue at the site of infection leading to a systemic disease [4]. LGV is classified as a genital ulcer disease (GUD) without clear tissue tropism for mucosa contrary to non-LGV chlamydia, and it has been considered endemic in the tropics although LGV epidemiology in these areas has not been systematically described. In 2003 a cluster of LGV cases was reported in Rotterdam, the Netherlands [5] and, following an international alert, case reports were published of similar outbreaks in large European cities [6–10]. Reports of LGV from the United States [11], Canada [12] and Australia [13] followed.

The clinical features of LGV have historically been divided into three stages: the primary stage involves the site of inoculation where a small papule, ulcer, herpetiform lesion or nonspecific urethritis appears after incubation period of 3-30 days [4]. During the secondary stage, which emerges after 10-30 days or even months later, local lymph nodes draining the site of primary infection enlarge and necrotic areas develop following an inflammatory process which results in chronic oedema and formation of ulcers and sclerosing fibrosis. Without adequate treatment a tertiary phase with chronic inflammatory response will follow. This is characterized by genital ulcers, fistulas, rectal strictures and genital elephantiasis. The scarring and formation of fibrotic tissue often requires surgical repair [4]. The classical manifestation in men is characterised by inguinal lymphadenopathy. During the recent emergence of LGV, the clinical manifestation has been different. Acute ulcerative proctitis or proctocolitis is often seen as the primary manifestation [4, 14] (approximately 96% of the cases in the United Kingdom [15]) while inguinal lymphadenopathy alone has been observed in only a few cases [16]. Rectal discharge, pain, bleeding [14] and systemic symptoms such as malaise [17] and high white blood cell count (>10/high power field) in gram stained rectal smears [18] have been reported as indicators of LGV. It is not clear why inguinal symptoms, indicating urethral acquisition of LGV, have been so rare and it has been suggested that different modes of transmission, such as sexual practices of fisting and use of sex toys and other fomites, are contributing to the spread of LGV. Traumatic practices to the mucosa have been previously associated with the acquisition of other rare STIs such as sexually acquired hepatitis C virus [19].

In response to the outbreak surveillance systems were established in several affected countries. These have produced a consistent picture of cases among men who have sex with men (MSM), many of whom are co-infected with HIV (for example 74% co-infection rates in the UK [20] and over 70% reported in other European countries [21]). On average, affected patients have also been older (mean age above 35 [21]) than MSM presenting to STI clinics for other reasons, and with a high rate of concurrent STIs and hepatitis C (14% of cases in the UK [20]). In 2009 a case-finding study in genitourinary medicine (GUM) clinics in London found a prevalence estimate of LGV among MSM to be 1.2% (36 out of 3076 men) [22] while another case-finding exercise conducted in four GUM clinics in London and Brighton found LGV positivity among rectal samples from MSM to be 0.9% (61 of 6778 rectal samples tested for LGV) [23].

As LGV seems to be circulating mainly among HIV-positive MSM it is important to consider the effect these STIs have on each other [24]. STIs may contribute to transmission of HIV and concurrent HIV infection may alter the epidemiology of an STI: both STI and HIV can become more infectious in a co-infected individual. HIV may also increase the susceptibility of an HIV-positive individual to other STIs and HIV may be transmitted more easily in discordant couple if the HIV-negative partner has a concurrent STI [25]. In meta-analysis by Rottingen et al. (2001) [25] both GUD and CT were found to increase susceptibility to HIV-infection in heterosexual transmission and it would seem plausible that LGV may increase HIV transmission also in homosexual partnerships. The aim of this study is to quantify the association between HIV infection and LGV among MSM in the context of the current emergence of LGV.

We found consistent evidence of a strong association between HIV and LGV across the literature. In thirteen descriptive studies at least two-thirds of MSM with LGV were co-infected with HIV. In a meta-analysis, MSM with LGV were over eight times more likely to have HIV (OR 8.19, 95% CI 4.68-14.33) than those who had non-LGV chlamydia infection. This association is stronger than for other sexually transmitted infections which have also re-emerged in MSM over the past decade [50]. As the descriptive studies presented results mainly in aggregate form, it was not possible to further investigate the effect of LGV genotype or rectal and non-rectal infection on the association between HIV and LGV. However, in the majority of studies rectal symptoms and proctitis were the dominant manifestation of LGV, as shown by results from the three largest studies: in the UK 90% of confirmed cases had proctitis [20], in France only rectal swabs were included in the surveillance system [47], and 91% of cases in Netherlands had proctitis [49]. Similarly only aggregate information was available for LGV genotype, but Canada [12], France [47] and the Netherlands [46] found only L2b genotype in the samples that were sequenced. Other descriptive studies selected for this study found mainly L2 serotype with predominantly L2b variant in the sequenced samples (such as 426/470 of samples in UK surveillance that were confirmed L2b [20]). Primary data sources would be needed to analyse differences between HIV positive and HIV negative LGV cases.

A number of detailed reviews have been published on the emergence of LGV [14, 51]. However to our knowledge this review is the first to systematically identify and quantitatively analyse the association between HIV and LGV in the re-emergence of LGV, and includes data from 17 reports. However, it is limited by the inclusion of a number of surveillance reports. Surveillance of LGV is said to suffer from the lack of consistency between countries giving rise to different case-definitions and surveillance methods, some of which are based on voluntary and potentially partial reporting [52]. Surveillance reports formed a large proportion of publications used for the HIV-prevalence estimates, but the studies in this review all defined detection of LGV serovars as a requirement for confirmed cases. Nevertheless it is possible that cases have been identified with different accuracy between countries and the international data may not be comparable. Previous literature has noted that the variation in the structure of surveillance systems limits cross-country comparison [53]. The geographical differences may be a result of variation in sexual partnerships, differential sexual behaviours (such as seroadaptive behaviour), testing and case finding policies, time of introduction of LGV into the network and the impact of local public health interventions [50].

In this review we did not apply strict quality criteria. This is due to the relatively small number of published studies and our desire to be inclusive in order to increase sample size. This means that we cannot exclude the possibility that sampling and measurement differences may account for some of the heterogeneity. Outcome-level assessment for LGV was performed by including only confirmed cases (identification of LGV serovars required for a confirmed case) which assures the validity of the data for the main outcome. Due to the small number of studies conducted to date and the recent emergence of LGV, publication bias was not thought to be relevant in this analysis. The search and article retrieval was conducted by the first author alone, but the analysis and interpretation was done by both authors.

The strong association between LGV and HIV in an unadjusted model is interesting, and some association would be expected to remain after adjusting for confounders, especially since the association is strong even though the control group represents another high risk group of MSM with a non-LGV CT infection. It is possible that there may be a biological interaction between HIV-infection and LGV. HIV-infection has been reported to cause abnormalities in the structure and function of the gastrointestinal tract as well as abnormal lymphocyte trafficking [54] that may facilitate LGV acquisition. In a South African cohort of patients with GUD, LGV infection was diagnosed more often among the HIV-infected participants compared to HIV-negative participants with relative risk 1.3 (95% CI 1.2-1.4) [55]. Also in the Bahamas, an LGV epidemic was associated with crack cocaine use and HIV infection [56]. Two of the case-control studies included in this review compared median CD4 count between cases and controls, but neither found a significant difference [57, 58]. van der Bij et al. [18] also hypothesised that immunorestoration inflammatory syndrome could explain the emergence of this highly symptomatic LGV. They analysed the association between having symptomatic LGV and start of highly active antiretroviral therapy (HAART) but no association was found. Time-series analysis may be a more effective way to measure the potential interaction between HIV and LGV.

The strongest confounder for this hypothesis is high-risk sexual behaviour. There have been behavioural changes in MSM communities as a response to HIV epidemic, and serosorting may make HIV-positivity an intermediating factor: individuals participate in certain type of practices partly because of their HIV-infection [59]. Seroadaptive behaviour can reduce the number of new HIV infections but it also facilitates the spread of other STIs and can create dense sexual networks where disease propagation is fast [53]. Exploring this further was not possible in this review because of the lack of comparable data on sexual behaviour.

The findings from HIV prevalence estimates and case-control studies reveal that HIV-infected MSM are disproportionately affected by the emergence of LGV. LGV prevention efforts should be targeted towards HIV-infected sexually active MSM. Although the majority of LGV infected individuals are HIV-positive, a proportion of diagnosed LGV cases are HIV-negative and this group would benefit from primary HIV prevention as they belong to sexual networks where HIV-seropositivity is common and subsequently they are at high risk of HIV-infection.

The strong association between LGV and HIV co-infection identified from case control studies may indicate a biological synergy between LGV and HIV, but further research is required to explore the relationship between HIV-infection, behaviour and acquisition of LGV.