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Chlamydia trachomatis (Ct) and human papilloma virus (HPV) are common infections in sexually active young women. The risk factors for acquiring each of these sexually transmitted infections (STIs) are similar. Although each infection causes a distinct disease entity, the consequences of having Ct infection in the context of HPV infection may be even more significant. Specifically, Ct infection may increase a woman's risk of cervical dysplasia, which could progress to cervical cancer.
Does chlamydial infection increase the risk of cervical dysplasia, otherwise known as cervical intraepithelial neoplasia (CIN)? On the surface, this research question seems straightforward. In reality, addressing this question is complex and requires careful consideration of the study population, study design and, importantly, the underlying theoretical causal model for the relationship. In this issue of Sexually Transmitted Infections, Lehtinen et al present an interesting and suggestive study of the relationship between chlamydial infection and CIN based on a retrospective cohort analysis of the placebo arms of the FUTURE (Females United to Unilaterally Reduce Endo/ Ectocervical Disease) trials.1 This secondary analysis is not the first to suggest an association between chlamydial infection and CIN and/or cervical cancer.2–7 But each of these studies, like the Lehtinen et al study, has significant methodological issues, which cloud interpretation of the results. Using the placebo arms of the FUTURE trials is opportunistic, but this approach also has major limitations, including concerns regarding temporality, uncertainty of Ct infection status prior to enrolment, limited behavioural information and inconsistent results between Ct and high-grade dysplasia (CIN-2 vs CIN-3). Consequently, we must be cautious not to overinterpret the observed association as evidence for causality. Studies addressing this issue are methodologically challenging. Considering these challenges provides important lessons for STI researchers regarding the design of aetiological epidemiological research.
Aetiology of cervical cancer
The aetiology and natural history of cervical cancer is complex. Infection with HPV, especially HPV-16 or HPV-18, is a necessary component cause of cervical cancer.8–10 However, infection with HPV alone is insufficient to cause cervical cancer. Women with HPV may spontaneously clear infection, and women with CIN may revert to normal at later points in time.11–14 Development of CIN, that is, dysplasia, requires HPV persistence and progression of epithelial cell changes.8 9
Simplistic causal model of the aetiology of cervical cancer
Using a simplistic causal model, we can consider the aetiological pathway for HPV to cause cervical cancer. This pathway is shown simply below:
Exposure to HPV→Infection with HPV→Dysplasia/early neoplasia(CIN)→Cervical cancer.
Within this framework, we can consider how chlamydial infection could affect the incidence of cervical cancer. First, chlamydial infection could affect HPV acquisition. Second, chlamydial infection could increase the rate of transformation to dysplasia or early dysplasia (CIN). Finally, chlamydial infection could also increase the likelihood that cervical dysplasia leads to cervical cancer. With this framework in mind, we can consider possible biological mechanisms underlying the potential effect of chlamydial infection on CIN and cervical cancer and appropriate study designs to evaluate the mechanisms.
Potential biological mechanisms of the effect of chlamydial infection on cervical cancer
Biologically, chlamydial infection could increase the risk of HPV infection by altering the cervical milieu. HPV infects the basal keratinocytes of the mucosal epithelium, which requires the presence of microabrasions or disrupted epithelium.10 15 Binding of HPV prior to entry in the keratinocytes appears to involve both specific and non-specific receptors.15 Chlamydial infection could plausibly lead to epithelial disruption, facilitating exposure to the basal keratinocytes, or possibly increase the receptor density on the target cells. Alternatively, chlamydial infection could affect non-specific immune mechanisms there by reducing the likelihood of establishing HPV infection.
Chlamydial infection might also affect the progression from HPV infection to dysplasia and cervical cancer. HPV infection is cleared by about 90% of women, typically within 6–24 months.8 9 Persistence for longer durations substantially increases the risk of cervical cancer. A plausible mechanism for chlamydial infection to increase cervical cancer risk in HPV-infected women is increasing HPV persistence, presumably by disturbing the immune response necessary to clear the virus. Women with a history of chlamydial infection appear to have an increased risk of HPV persistence, supporting the plausibility of this relationship.5
Chlamydial infection and HPV acquisition risk
Given the biological plausibility, how would we study the effect of chlamydial infection on HPV acquisition (Exposure to HPV→Infection with HPV)? First, we must engage a cohort of women without HPV infection. Next, we must consider the temporality and duration of chlamydial infection within the context of the temporality of HPV infection and development of CIN. This design would require frequently spaced biological samples to assess incident Ct infection and HPV infection. A traditional cohort design assessing chlamydial infection at baseline and HPV acquisition or development of CIN during follow-up would be inadequate. The retrospective analysis of the FUTURE trials could only provide limited data.
The complexity in assessing other risk factors, potential confounders and intermediaries must also be considered. As both Ct and HPV are STIs, many of the causal risk factors that affect the first component of the simplistic causal pathway (exposure to HPV) are shared between the two infections. Consider, for example, the number of sexual partners. This risk factor is essentially an indicator of the probability that someone will be exposed to the particular STI. Increasing the number of partners increases the risk that one of them is infected with that STI. If we conduct a traditional cohort study in which we assess chlamydial infection at baseline in women who are HPV naïve and measure HPV acquisition after Ct treatment, increased HPV acquisition in women with baseline Ct infection will probably be due to increased exposure to HPV (due to similar behavioural risk factors), rather than Ct infection directly affecting HPV acquisition. Adjusting for the number of sexual partners, while necessary, may not be sufficient to account for the increased exposure to HPV, due to measurement error. Other potential confounding variables, such as condom use, are also difficult to measure, and researchers' approaches to capturing this and similar information must be carefully considered in the design phase.
Chlamydial infection and progression from HPV infection to dysplasia and cervical cancer
Similar to using an incident infection study design to better assess the relationship between Ct and HPV acquisition, the same design will allow for assessment of progression of disease from infection to dysplasia and cancer. In addition, biological specimens must be used to evaluate the duration of HPV presence. Ideally, such a study would start with a sexually naïve cohort, with assessment for chlamydial infection and HPV infection (using serology and baseline nucleic acid amplification tests). Concurrently, patients would be assessed for the most pertinent and measurable outcome, development of CIN and progression of CIN. HPV infection and duration would be an important intermediate. If chlamydial infection increases HPV persistence, the hypothesis that chlamydial infection increases the risk of CIN among HPV-infected women would be supported.
Practical challenges and recommendations
One significant challenge to the design of any study relating chlamydial infection to cervical cancer (or other reproductive outcomes) is the ethical obligation to treat women with chlamydial infection and certain stages of CIN. If a study is designed with frequent evaluation and treatment for chlamydial infection, then the duration of any infection may not be sufficient to affect the development of cervical cancer. However, if infrequent observations are used, a woman may experience chlamydial infection and clear it without detection, even though the duration may have been sufficient to affect the causal chain. Consequently, study designs using frequent specimen collection, specimen storage and batch testing after study completion may be necessary. Investigators using this design would be ethically obligated to ensure that public health recommendations regarding chlamydial screening frequency are met.
Similar issues arise with regard to the treatment of CIN-2 and CIN-3. Current recommendations are that all women with CIN-3 be treated.16 Similarly, treatment of CIN-2 is recommended in older women, but observation is acceptable in young women and adolescents.16 The ethical obligation to treat women with later-stage CIN limits the investigator's ability to examine the link between chlamydial infection and cervical cancer, per se.
Carefully designed, methodologically sound studies of the relationship between chlamydial infection and HPV infection are needed, despite the challenges in their design and conduct. These studies are feasible and important, but must be designed prospectively and must consider the potential biological, behavioural or social mechanisms underlying the relationship. With appropriate planning and implementation, these studies will inform the recommendations for screening and counselling of young women at risk for these prevalent infections.
Linked article 044354.
Correction notice This article has been corrected since it was published Online First. The title has been amended.
Competing interests None.
Provenance and peer review Commissioned; not externally peer reviewed.
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