The effect of ART on cervical cancer precursor lesions

In the Lancet HIV, Helen Kelly and colleagues1Kelly H Weiss H Benavente Moreno Y et al.Antiretroviral therapy, high-risk human papillomavirus and cervical intraepithelial neoplasia: a systematic review and meta-analysis.Lancet HIV. 2017; (published online Oct 22.)http://dx.doi.org/10.1016/S2352-3018(17)30149-2Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar present a meta-analysis of the effect of antiretroviral therapy (ART) on high-risk human papillomavirus (HPV)-induced cervical lesions in women living with HIV.1Kelly H Weiss H Benavente Moreno Y et al.Antiretroviral therapy, high-risk human papillomavirus and cervical intraepithelial neoplasia: a systematic review and meta-analysis.Lancet HIV. 2017; (published online Oct 22.)http://dx.doi.org/10.1016/S2352-3018(17)30149-2Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar As the authors note, cervical cancer is the most common cancer affecting women in low-income and middle-income countries (LMIC)2Bosch FX Broker TR Forman D et al.Comprehensive control of human papillomavirus infections and related diseases.Vaccine. 2013; 31: H1-H31Crossref PubMed Scopus (35) Google Scholar and the most common cancer in women living with HIV.3Control CfDa1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.MMWR Recomm Rep. 1992; 41: 1-19Google Scholar For this reason, most HIV management guidelines recommend frequent colposcopy for this population,4WHOConsolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations— 2016 update.http://www.who.int/hiv/pub/guidelines/keypopulations-2016/en/Date: 2016Google Scholar an unpleasant procedure for patients and a resource burden on many health systems. Cervical cancer is caused by a persistent high-risk HPV infection and develops through a series of well defined precursor lesions, named cervical intraepithelial neoplasia (CIN). CIN lesions are graded 1–3 according to the degree of epithelial atypia. Low-grade CIN (CIN1/2) mainly result from a productive HPV infection and are likely to regress after virus clearance. High-grade CIN lesions (CIN2+) harbour a so-called transforming HPV infection and can develop within 3 years after a persistent high-risk HPV infection. Progression to cervical cancer might take another 10–30 years.5Steenbergen RDM Snijders PJ Heideman DA Meijer CJ Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions.Nat Rev Cancer. 2014; 14: 395-405Crossref PubMed Scopus (267) Google Scholar Infection with HIV is an important risk factor for a persistent high-risk HPV infection and the development of CIN2+ and cervical cancer.6Chaturvedi AK Madeleine MM Biggar RJ Engels EA Risk of human papillomavirus-associated cancers among persons with AIDS.J Natl Cancer Inst. 2009; 101: 1120-1130Crossref PubMed Scopus (383) Google Scholar The high prevalence of high-risk HPV in women living with HIV and the assumed increased cancer risk indicate that a better understanding of the associations between viral infections, treatment, and cervical pathogenesis is needed to allow for effective cancer prevention strategies in this population. In their meta-analysis, Kelly and colleagues aimed to review and summarise the evidence on the association of ART with high-risk HPV prevalence, and with CIN2+ prevalence, incidence, progression, and regression. Secondly the role of HIV-related cofactors that might modify these associations, such as duration and timing of ART, initiation of ART, immune suppression, and recovery were investigated. The researchers unveiled some findings one might expect on the basis of the ART attributed immune restoration effect. Women living with HIV on ART have a lower prevalence of both high-risk HPV and CIN2+ lesions. Furthermore and as expected, a reduction in the incidence and progression of CIN2+ lesions were seen in women on ART, and an increase in regression of CIN2+ lesions. Notably, these effects remained after adjusting for immune restoration indicators such as CD4 cell count and duration of ART use. Strong points of this study are the subanalysis on the level of timeperiod and geographical location of the included studies. Some striking discrepancies caused by study heterogeneity were brought to light. On the one hand, studies from Africa, Europe, and North America overall found a preventive effect of ART on cervical lesion incidence and progression and promotion of regression. On the other hand, studies from Latin America and Asia reported an overall increased risk of high-risk HPV and CIN2+ lesions among women on ART compared with treatment-naive women. The latter is counterintuitive if one assumes that ART induced immune restoration would reduce high-risk HPV-associated morbidity. The authors propose the explanation that the Latin American and Asian studies involved a generation of women who might have started ART under older guidelines at lower CD4 cell count thresholds and therefore might not have fully recovered their HPV-specific mucosal immune response. Kelly and colleagues mention that there were fewer studies available from Asia and Latin America and most were cross-sectional in design. Still, these heterogeneous findings again indicate that ART initiation irrespective of CD4 cell count in combination with sustained adherence are important for immune recovery and reduce high-risk HPV-associated morbidity. Kelly and colleagues1Kelly H Weiss H Benavente Moreno Y et al.Antiretroviral therapy, high-risk human papillomavirus and cervical intraepithelial neoplasia: a systematic review and meta-analysis.Lancet HIV. 2017; (published online Oct 22.)http://dx.doi.org/10.1016/S2352-3018(17)30149-2Summary Full Text Full Text PDF PubMed Scopus (128) Google Scholar also offer some practical lessons. Apart from the importance of commencing ART as soon as possible, women with low or unknown nadir CD4 counts should be screened more frequently. Future studies will have to elucidate which women can be screened less frequently on the basis of markers indicating successful immune restoration. Triaging women for colposcopy would relieve overburdened health systems and might reduce unnecessary procedures. Particularly in LMIC with high prevalence of high-risk HPV and HIV, implementation of effective cytology-based or HPV-based screening programmes has proven difficult. Research shows7De Vuyst H Franceschi S Plummer M et al.Methylation levels of CADM1, MAL, and MIR124–2 in cervical scrapes for triage of HIV-infected, high-risk HPV-positive women in Kenya.J Acquir Immune Defic Syndr. 2015; 70: 311-318Crossref PubMed Scopus (26) Google Scholar, 8Van Zummeren M Kremer WW Van Aardt MC et al.Selection of women at risk for cervical cancer in an HIV-infected South African population.AIDS. 2017; 31: 1945-1953Crossref PubMed Scopus (11) Google Scholar that molecular methylation tests aimed at the detection of lesions resulting from a transforming high-risk HPV infection (high-grade CIN and cancer), might provide an interesting selection method for women living with HIV in LMIC. Further development of rapid point-of-care tests would allow women to be (self) screened and depending on local facilities potentially treated in one day, thereby preventing loss to follow-up. Furthermore, future research in the line of Kelly and colleagues' could be applied to anal cancer screening in HIV-positive men who have sex with men. Triaging men for high resolution anoscopy to screen for anal precursor lesions would be welcomed for the same reasons.9van Heukelom MLS Marra E de Vries HJC van der Loeff MFS Prins JM Risk factors for anal HSIL in HIV-positive MSM: is targeted screening possible?.AIDS. 2017; (published online Sept 18.)DOI:10.1097/QAD.0000000000001639PubMed Google Scholar HJCdV has received grants from MSD. RDMS holds minority shares in Self-screen BV and has a patent for Methylation markers for cervical cancer detection. Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysisEarly ART initiation and sustained adherence is likely to reduce incidence and progression of SIL and CIN and ultimately incidence of invasive cervical cancer. Future cohort studies should aim to confirm this possible effect. Full-Text PDF Open Access

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