Minttu Rönn

Contribution of sexually transmitted infections to the sexual transmission of HIV.

Purpose of reviewWe review recent evidence about the link between sexually transmitted infections (STI) and HIV transmission and consider implications for control programmes. Recent findingsNew studies and meta-analyses confirm the association of HIV acquisition and transmission with recent STIs, although there is considerable heterogeneity between organisms and populations. Much of the recent evidence relates to herpes simplex virus type 2 (HSV-2), for which the population-attributable risk percentage (PAR%) for HSV-2 is between 25 and 35 in Africa. Mathematical models show how transmission attributable to STI varies with HIV epidemic phase, and HSV-2 becomes increasingly important as the epidemic matures. HSV-2 suppressive therapy reduces HIV concentrations in plasma and the genital tract in people coinfected with HSV-2, in part due to direct inhibition of HIV reverse transcriptase. Recent trials of HSV-2 suppressive therapy have not shown an impact on the risk of HIV acquisition, nor in controlling transmission from dually infected people to their serodiscordant heterosexual partners. SummaryAlthough there is a plausible link between STI and HIV risk, intervention studies continue to be disappointing. This fact does not disprove a causal link, but mechanisms of action and the design and implementation of interventions need to be better understood.

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

BackgroundLymphogranuloma venereum (LGV) is an important re-emerging sexually transmitted infection which is reported to affect particularly HIV-positive men who have sex with men (MSM). The aim of this study is to quantify the association between LGV and HIV in the context of the current emergence of LGV.MethodsA systematic review was performed on the emergence of LGV among MSM since 2000. We report the prevalence of HIV infection from descriptive studies of MSM with LGV, and conduct a meta-analysis to produce a summary estimate of the association between LGV and HIV from case-control studies where cases were MSM with LGV and controls were MSM with rectal chlamydia caused by non-LGV serovars.ResultsThe prevalence of HIV among LGV cases ranges from 67% to 100% in 13 descriptive studies. There is a significant association between HIV and LGV (odds ratio 8.19, 95% CI 4.68-14.33).ConclusionsHIV-positive MSM are disproportionately affected by LGV highlighting the importance of prevention efforts to be targeted to this group. Further research is needed to determine whether the association is due to biological or behavioural factors.

Developing a Conceptual Framework of Seroadaptive Behaviors in HIV-Diagnosed Men Who Have Sex With Men

Background. Seroadaptive behaviors are strategies employed by men who have sex with men (MSM) to reduce the transmission risk for human immunodeficiency virus (HIV). It has been suggested that they contribute to the increasing diagnoses of sexually transmitted infections in HIV-diagnosed MSM. To understand the context in which the reemerging sexually transmitted infections appear, we developed a social epidemiological model incorporating the multiple factors influencing seroadaptive behaviors. Methods. A literature review of seroadaptive behaviors in HIV-diagnosed MSM was conducted. The literature was synthesized using a social epidemiological perspective. Results. Seroadaptive behaviors are adopted by MSM in high-income countries and are a way for HIV-diagnosed men to manage and enjoy their sexual lives. Influences are apparent at structural, community, interpersonal, and intrapersonal levels. There is little evidence of whether and when the behavior forms part of a premeditated strategy; it seems dependent on the social context and on time since HIV diagnosis. Social rules of HIV disclosure and perception of risk depend on the setting where partners are encountered. Conclusions. Seroadaptive behaviors are strongly context dependent and can reduce or increase transmission risk for different infectious diseases. Further data collection and mathematical modeling can help us explore the specific conditions in more detail.

Characteristics of LGV repeaters: analysis of LGV surveillance data

Objectives A number of individuals have acquired lymphogranuloma venereum (LGV) infection multiple times since its re-emergence. We describe the characteristics of reinfections and those who acquire them. Methods The LGV Enhanced Surveillance system collected detailed information on LGV episodes in the UK from 2004 to 2010. Using logistic regression we compared the baseline characteristics of men who have sex with men (MSM) who had a repeat LGV episode (‘repeaters’) to MSM with a single reported episode (‘non-repeaters’). Results There were 66 individuals among the 1281 MSM (5.2%) with LGV episode who had a recorded reinfection during the data collection period. Those who acquired LGV reinfection were more likely to be HIV positive (97% vs 79%), visit a clinic in London (OR 2.0, 95% CI 1.1 to 3.8), and have hepatitis C (OR 2.2, 95% CI 1.1 to 4.6) or concurrent gonorrhoea (OR 2.2, 95% CI 1.2 to 3.8) on their first recorded LGV episode. Repeaters reported higher levels of unprotected sex, but behavioural variables were not significantly different between repeaters and non-repeaters. Conclusions Among LGV repeaters, risk behaviour alone did not explain subsequent reinfection. LGV repeaters have a high level of other sexually transmitted infections (STIs) which may be linked to their central position in the sexual network that contributes to their heightened risk of STI acquisition. Given the low prevalence of LGV in the general MSM population, momentary increases in incidence in subsets of the population may be an important factor for LGV risk where the overall level of sexual risk behaviour is higher. Validating this would require research into sexual network structures.

The Use of Mathematical Models of Chlamydia Transmission to Address Public Health Policy Questions: A Systematic Review

Background Mathematical models of chlamydia transmission can help inform disease control policy decisions when direct empirical evaluation of alternatives is impractical. We reviewed published chlamydia models to understand the range of approaches used for policy analyses and how the studies have responded to developments in the field. Methods We performed a literature review by searching Medline and Google Scholar (up to October 2015) to identify publications describing dynamic chlamydia transmission models used to address public health policy questions. We extracted information on modeling methodology, interventions, and key findings. Results We identified 47 publications (including two model comparison studies), which reported collectively on 29 distinct mathematical models. Nine models were individual-based, and 20 were deterministic compartmental models. The earliest studies evaluated the benefits of national-level screening programs and predicted potentially large benefits from increased screening. Subsequent trials and further modeling analyses suggested the impact might have been overestimated. Partner notification has been increasingly evaluated in mathematical modeling, whereas behavioral interventions have received relatively limited attention. Conclusions Our review provides an overview of chlamydia transmission models and gives a perspective on how mathematical modeling has responded to increasing empirical evidence and addressed policy questions related to prevention of chlamydia infection and sequelae.

Lymphogranuloma venereum in men who have sex in men: are we missing a reservoir of infection?

Over the past decade, lymphogranuloma venereum (LGV) has become endemic among men who have sex with men (MSM) in many European countries, primarily affecting men with HIV, and there have been reports of increasing numbers of cases over recent years in the UK, Amsterdam, Barcelona, and Madrid. The reemergence and persistence of this invasive form of Chlamydia trachomatis have occurred despite the implementation of control measures such as diagnostic testing, case finding, surveillance, and prevention campaigns. Diagnosed and reported infections have been mainly rectal, with few reports of urogenital (from urethral swabs, urine, ulcers, or buboes) or pharyngeal sites. This could indicate an undiagnosed reservoir of infection in the urethra or pharynx, or in the rectum of asymptomatic men. In this issue, de Vrieze and colleagues report results of a study to test whether there is a reservoir of urethral infection. They measured the prevalence of urethral LGV among patients with rectal LGV and their contacts; 2.1% of patients with rectal LGV and 6.8% of their 59 contacts had urethral LGV, and only 1 of the 11 cases had inguinal lymphadenopathy. They conclude that we are missing such cases that may be the hidden link in transmission. The existence of such a reservoir of urethral infection has been suggested before, but there is sparse evidence. Urogenital infections have formed small minority of cases in surveillance data and research reports. This may reflect the lack of diagnostic testing for urethral LGV and, therefore, more systematic case finding has been undertaken, but this, too, has identified few cases of urogenital LGV. In a separate report from the Amsterdam group, positivity of LGV in anorectal samples tested for chlamydia was 1.2% compared with 0.6% for inguinal LGV (from genital ulcer swabs). In an earlier study of unselected MSM attending clinics in the UK, urethral LGV prevalence was estimated at 0.04% compared with 0.9% for rectal LGV. A more recent study from Germany included screening of 1883 MSM; chlamydia-positive specimens from the rectum, pharynx, and urethra or urine were genotyped. Lymphogranuloma venereum was identified in 17 of 103 chlamydiapositive rectal specimens, 2 of 13 pharyngeal specimens, and none of 8 urethral/urine specimens. In Madrid, 2.6% (10/338) of urethral chlamydia-positive samples were found to be LGV, all symptomatic, although 4 of these were in heterosexual men. The overall positivity of urethral LGV was 0.4% (10/2420). There was no urogenital LGV in Finland among the MSM who had rectal LGV. It is possible that there is transient urethral infection in MSM and that screening studies are missing this. There is indication for tissue tropism in other C. trachomatis serovars, and although LGV distribution is highly concentrated in rectal infection, it might be partially explained by LGV serovars’ higher affinity to rectal mucosa compared with urethral epithelia. Without further evidence building on that presented by de Vrieze and colleagues, it is therefore difficult to conclude that there is a substantial urethral, or pharyngeal, reservoir, although it may of course be important in the dense networks within which LGV and HIV are circulating. The other potential reservoir is the rectum, with the possibility that some form of rectal-to-rectal transmission occurs and that infection might be sustained by asymptomatic rectal cases. There is certainly evidence of a higher prevalence in the rectum. In Madrid, 19.6% (82/419) of rectal chlamydia cases were typed as LGV, an overall LGV rectal positivity of 2.6% (82/3185). In the German study, the authors estimated the overall LGV prevalence to be 1.7% (11/632) among HIV-positive men and 0.6% (8/1251) among HIV-negative men, the majority being rectal cases, half of which (8/15) reported no recent rectal symptoms. EDITORIAL

Challenges presented by re-emerging sexually transmitted infections in HIV positive men who have sex with men: an observational study of lymphogranuloma venereum in the UK.

Background United Kingdom has reported the largest documented outbreak of lymphogranuloma venereum (LGV), a re-emerging sexually transmitted infection (STI) which is primarily seen in HIV-positive men who have sex with men (MSM). A diagnostic service was established in response to the outbreak linked to a voluntary LGV Enhanced Surveillance system. We examined the performance of this novel surveillance system to identify utility in tracking a re-emerging infection. Methods We described laboratory data on samples and surveillance data from case reports for LGV from 2004-2010. We performed a cross-sectional analysis comparing clinical and behavioural characteristics of HIV-positive and HIV-negative/unknown LGV cases diagnosed in MSM using multivariable logistic regression models with generalised estimating equations to control for repeat infections. Results LGV Surveillance data were available for 87% (1,370/1,581) of LGV cases (after de-duplication). There were 1,342 episodes in 1,281 MSM, most of whom were known to be HIV-positive (1,028/1,281, 80.2%,). HIV-positive men reported a shorter duration of symptoms (aOR 0.5; 95%CI 0.3, 0.8 for reporting more than a week compared to a week or less) in comparison to HIV-negative/unknown MSM, and were more likely to report unprotected receptive anal intercourse (aOR 2.7; 95% CI 1.3, 5.8). Conclusion The surveillance identified the population at greater risk of infection based on higher levels of risk behaviour in HIV-positive LGV cases. However, there was diagnostic bias towards HIV-positive LGV cases who presented with a shorter duration of symptoms when compared to HIV-negative/unknown LGV cases.

Challenges presented by re-emerging sexually transmitted infections: an observational study of lymphogranuloma venereum in the UK

Abstract Background Lymphogranuloma venereum (LGV) is a rare sexually transmitted infection (STI), a biovar of Chlamydia trachomatis , which re-emerged in 2003 and mainly affects HIV-positive men who have sex with men (MSM). A diagnostic service at the National Reference Laboratory was established in response to the LGV outbreak in the UK, which has been the largest documented in Europe. Surveillance protocol operates through testing patients with symptoms indicative of the infection and their sexual contacts. Additionally, a voluntary enhanced surveillance system was ongoing in 2004–10 in the UK. We assess the utility of the novel surveillance system in light of its strengths and limitations. Methods We described data on samples tested for LGV in 2004–10 in the diagnostic service. These data were analysed together with the LGV enhanced surveillance dataset and we undertook a cross-sectional analysis of clinical and behavioural characteristics between HIV-positive and HIV-negative or unknown cases diagnosed in MSM in 2004–10. We used multivariable logistic regression models with generalised estimating equations to control for repeat infections. The final model was adjusted for clinical and behavioural variables chosen through selection of variables based on a-priori hypotheses and statistical associations. Findings Overall, 11 196 C trachomatis -positive samples were tested for LGV, most of which were from men (10 035 of 11 196 [89·6%]), and most of these were from rectal sites (9138 of 10 035 [91·1%]); 1523 (15·2%) of 10 035 samples in men and four (0·8%) of 531 samples in women were confirmed as LGV. Of those confirmed to have the disease, 1370 (86·7%) of 1581 had a LGV enhanced surveillance form. The enhanced surveillance included 1342 episodes of infection in 1281 MSM and most were known to be HIV positive (1028 of 1281 [80·2%]). In comparison with HIV-negative and unknown cases, HIV-positive men were more likely to report unprotected receptive anal intercourse in the preceding 3 months (adjusted odds ratio [aOR] 2·7, 95% CI 1·3–5·8). However, HIV-positive men were also more likely to report a shorter duration of symptoms before clinic presentation (aOR 0·5, 95% CI 0·3–0·8 for reporting more than a week compared with a week or less), and the recorded information on the clinical variables was more complete for HIV-positive MSM. Interpretation There has been good coverage with the enhanced surveillance data, probably because of its link to a centralised diagnostic capacity. The surveillance was able to focus on the subpopulation at greater risk of infection because risk behaviour was more common in HIV-positive than in HIV-negative or unknown LGV cases. Furthermore, the surveillance has shown a stable epidemiological profile of cases over time, and LGV seems to remain confined to a small subpopulation of HIV-positive MSM. However, diagnostic bias was suggested in favour of HIV-positive cases with LGV who presented with a shorter duration of symptoms than HIV-negative or unknown cases. This factor is probably a result of the protocol used for testing together with clinical requests for tests. Surveillance for LGV may be systematically missing asymptomatic cases as well as there being a delay in recognising cases in HIV-negative men. Control of the disease needs targeted prevention messages that are suitable for the key population affected, including outreach and direct contact to key venues and networks via the internet. Because LGV has established itself in the UK and is present at low levels, surveillance might benefit from supplemented periodic case finding and collection of detailed information of patients to monitor the epidemiology of the disease. Funding The work was produced as part of the PhD study of MR, who was funded by the Osk Huttunen Foundation (Finland) and by the Wellcome Trust (090285/Z/09/Z). HW has received funding for research on LGV from the UK Medical Research Council and support from the National Institute for Health Research Imperial Biomedical Research Centre. PW thanks the Medical Research Council for centre funding.

Evidence of synergistic relationships between HIV and human papillomavirus (HPV): systematic reviews and meta-analyses of longitudinal studies of HPV acquisition and clearance by HIV status, and of HIV acquisition by HPV status

Observational studies suggest HIV and human papillomavirus (HPV) infections may have multiple interactions. We reviewed the strength of the evidence for the influence of HIV on HPV acquisition and clearance, and the influence of HPV on HIV acquisition.

O01.6 Evaluating chlamydia trends in the united states 2000–2015 using a pair formation transmission model

Introduction In the United States reported cases of chlamydia have increased since reporting began, due in part to increased screening. However, the implication of these trends for the population prevalence remains unclear. We aimed to understand and reconcile the epidemiological trends, and examine counterfactuals. Methods We developed a deterministic heterosexual pair formation model to simulate chlamydia epidemiology in the US heterosexual population aged 15-54y. The pair formation model accounts explicitly for sexual partnership dynamics, such as re-infection within the partnership, and the model is stratified by age, risk and relationship type (long-term v. casual). We used a Bayesian approach to calibrate model parameters (including time-varying screening, reporting and test sensitivity) to age- and sex-specific national case report rates from 2000–2015 (ages 15-54y), lab-measured population prevalence estimates from NHANES 1999–2014 (15-39y), and sexual behaviour data from the Youth Risk Behaviour Survey (15-18y). Results Model estimates were able to reproduce both chlamydia prevalence and reported case rates. Results indicate an increase in chlamydia screening in women. Conclusion This analysis is the first to fit a chlamydia transmission model to national sex- and age- specific prevalence and case report time trends. The results suggest screening would have to achieve a higher coverage, or we should investigate novel strategies to reduce chlamydia prevalence further. This model could be used to investigate the impact of novel prevention interventions, such as improved partner notification strategies and targeted screening programs.