Ablative therapy for premalignant lesions of the cervix in women living with HIV - PowerPoint Presentation

1. Ablative therapy for premalignant lesions of the cervix in women living with HIV Prevention and management of concomitant infections in people living with HIV Sebitloane HM, Department of Obstetrics and Gynaecology; Nelson R Mandela School of MedicineUniversity of KwaZulu Natal, Durban, South Africa

2. What is your main question?Are locally ablative therapies sufficient as management of preinvasive cervical lesions in women living with HIVWhat did you find?Evidence suggests ablative therapies may be sufficient to treat preinvasive lesions of the cervix in well selected WLHIV particularly in LMIC, and may accelerate the 90/70/90 goal - proper follow up of women is essentialWhy is it important?Large number of women living with HIV are in hard to reach regions of the world, where surgical excision not only has higher morbidity but may not be accessible, Summary

3. - Women living with HIV (WLHIV) have a higher risk of acquiring HPV infection, developing persistence of HPV with subsequent CIN, or even for cervical cancer. - Consequently, women living with HIV (WLHIV) have on average a 3x higher incidence of cervical lesions than those not living with HIV - Adequate screening followed by treatment of cervical precancer, specifically cervical intraepithelial neoplasia grade 2 and higher (CIN2+), can prevent the development of malignant lesions. - HPV test has a high sensitivity, however, treatment of all HPV positive (without evidence of a lesion) will result in overtreatment, whereas a VIA triage test is provider-dependant and specificity and sensitivity vary widely. Introduction

4. - WHO recommends 2 strategies after an HPV-test: *either to treat the women when HPV positive or *to proceed to a VIA triage test and treat those who test positive . **The new recommendation does not recommend direct ablative treatment without triage for WLWH - Excisional procedures such as large loop excision of the transformation zone (LLETZ) and cold knife conization often are unavailable in low-resource settings, and women are treated most often by ablation therapy is some settings - robust evidence for WLHIV needed Introduction (cont)

5. - Ablative therapies include: **cryotherapy - freezing and thawing to cause tissue necrosis **thermal ablation - heat to cause tissue inflammation and necrosis**carbon dioxide (CO2) laser ablation - removes tissue by vaporization - Main disadvantage of ablation is that, unlike excisional methods of treatment, it does not yield a pathology specimen for confirmatory diagnosis. Various modalities of ablation therapies

6. Cost comparison of ablative methods

7. - Eligibility for treatment requires a visual assessment (visual assessment for treatment - VAT) which includes: colposcopy (ifavailable) or naked eye examination of cervix after applying 3–5% acetic acid for 1 minute. - women who screen positive are eligible for ablative therapy if there is no suspicion of invasive or glandular disease, and if: • the TZ is fully visible, the whole lesion is visible and it does not extend into the endocervix; or • the lesion is type 1 TZ; or • the lesion is type 2 TZ where the probe tip will achieve complete ablation of the SCJ epithelium, i.e., where it can reach the upper limit of the TZ. (Sometimes the SCJ can be seen high in the canal but a probe tip would not reach it) - Ablation therapy is appropriate for lesions that involve less than 75% of the cervix, do not extend into the endocervical canal or onto the vagina, and are not suggestive of invasive cancer. Indications / Eligibility for Thermal ablation or Cryotherapy

8. - Now compared equally with Cryo in 2019 recommendations - there may be little to no difference between the proportion of women who are cured when treated with thermal ablation (91%) or cryotherapy (90%). - Evidence shows that more women may be cured with a 2-probe method (95%; 95%CI, 93–98%) than a one-probe method (85%; 95%CI, 80–90%)CryotherapyThermal ablation - Until 2019 - gas-based cryotherapy was the only ablative treatment endorsed by the WHO for the treatment of CIN2+ in LMICs - Cure rates range from 77% to 93%, which is similar to cure rates for excisional methods like LEEPOutstanding issuesSingle versus double freeze / NO2 vs CO2Newer agents eg Cryopen / Cryopop

9. Recommendation 1.aWHO suggests either LLETZ, or cryotherapy or thermal ablation to treat all women who have histologically confirmed CIN2+ disease and who are eligible for thermal ablation or cryotherapy.This recommendation applies to all women, including women livingwith HIV.

10. Recommendation 1.bWHO suggests thermal ablation be provided at a minimum of 100 °C for 20–30seconds using as many applications as needed to cover the entire transformation zonein overlapping fields.

11. Ablation therapy in women living with HIV

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13. Should the management of high grade cervical squamous intraepithelial lesion (HSIL) be different in HIV‑positive women?Gilles et al. AIDS Res Ther (2021) 18:44 https://doi.org/10.1186/s12981-021-00371Retrospective, controlled study included 146 HIV-positive women, matched for HSIL, age and year of diagnosis, with 146 HIV-negative women.Persistence of cervical disease was more frequently observed in HIV-positive women (41.8%, of which 47.5% had a HSIL lesion) than in HIV negative ones (16.5%, of which 41.6% had a HSIL; p < 0.001). At cone biopsy - The margins of the specimens were more frequently positive in HIV-positive women than in HIV negative ones (37 versus 16%; p < 0.05).Treatment failure was associated with HIV-positive women with detectable VL at the time of dysplasia had 3.5 times increased risk (95% IC: 1.5–8.3)Being treated through ablative therapy was associated with a 7.4 (95% IC: 3.2–17.3) cf consization among WLHIV

14. CErvical cancer Screening and Treatment Algorithms study using HPV testing in Africa (CESTA) manuscript in preparation

15. - 108/188 women were evaluable for VIA, 90 of them were positive (VIA positivity 83%) – out of the 90 VIA +ve, 42% CIN 2+ - Unable to evaluate for ablative treatment (ineligible) - n=82/188 (44%) in the VIA triage Arm - 14/45 (31%) in the no-triage Arm, p=0.13 - (82 eventually had colposcopy, 33/82 being CIN2+ = 40% - in the no triage arm 2=3/14 (21%) – - 55/90 (65%) had lesions less than CIN2, and were treated with either ablative treatment or colposcopy / LLETZ - 30/90 were correctly identified at VIA, 5 did not histology result. - among the 34 CIN2+ diagnosis, VIA was able to identify 30 (88%) and missed 4 (12%) (p=0.348). VIA-triage Arm (CESTA)

16. VIA performance- CESTA

17. CESTA – 1 year reviewComparable rates of HPV regardless of treatment given - ?reinfection / persistence, p=0.712

18. - In this cohort of WLHIV, there was a high rate of HR-HPV infections – 61% - Most HPV +ve women were deemed VIA +ve – 83% (poor discriminator - 65% of the women with positive VIA had <CIN2+) - VIA was able to identify 30 of the 34 of CIN2+ needing treatment, - Among lesions not suitable for LAT, 40% with CIN 2+ - At 1 year, LAT was comparable in terms of clearance of lesions p=0.712 More studies needed evaluate VIA as a form of triage in WLHIV as well as more evidence for local ablative therapy – [VIA sensitivity was found to be high (85%) in women <50yrs – ESTAMPA – ?women not living with HIV] CESTA conclusion

19. - There are no comparative studies evaluating the benefits and harms of thermal ablation compared to other treatment methods or no treatment in WLHIV with histologically confirmed CIN 2-3. - There are very few studies evaluating cure or other outcomes with thermal ablation in WLHIV. - From the few studies, the proportion of cures in WLHIV who were treated with thermal ablation was within the range of cures in women not living with HIV. - The GDG agreed that given the benefits and harms are similar between thermal ablation and cryotherapy in WLHIV, then the benefits and harms between the two treatments in WLHIV are likely similar. - However, since cure is typically lower in WLHIV compared to women not living with HIV, follow-up is important, especially after ablative treatment.Recommendations for ablative therapy in WLHIV

20. Evidence suggests ablative therapies may be sufficient to treat preinvasive lesions of the cervix in well selected WLHIV particularly in LMIC, and may accelerate the 90/70/90 goal - proper follow up of women is essential

21. Bibliography - Ablative Therapies for Cervical Intraepithelial Neoplasia in Low-Resource Settings: Findings and Key Questions Miriam L. Cremer, Gabriel Conzuelo-Rodriguez, William Cherniak, and Thomas Randall Journal of Global Oncology 2018 :4, 1-10 - Effect of Cryotherapy vs Loop Electrosurgical Excision Procedure on Cervical Disease Recurrence Among Women With HIV and High-Grade Cervical Lesions in Kenya: A Randomized Clinical Trial. JAMA. Greene SA, De Vuyst H, John-Stewart GC, Richardson BA, McGrath CJ, Marson KG, Trinh TT, Yatich N, Kiptinness C, Cagle A, Nyongesa-Malava E, Sakr SR, Mugo NR, Chung MH. 2019 Oct 22;322(16):1570-1579. doi: 10.1001/jama.2019.14969. PMID: 31638680; PMCID: PMC6806442. - WHO guidelines for the use of thermal ablation for cervical pre-cancer lesions. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO. - Should the management of high grade cervical squamous intraepithelial lesion (HSIL) be different in HIV‑positive women?Gilles et al. AIDS Res Ther (2021) 18:44 https://doi.org/10.1186/s12981-021-00371Greene SA, De Vuyst H, John-Stewart GC, Richardson BA, McGrath CJ, Marson KG, Trinh TT, Yatich N, Kiptinness C, Cagle A, Nyongesa-Malava E, Sakr SR, Mugo NR, Chung MH. Effect of Cryotherapy vs Loop Electrosurgical Excision Procedure on Cervical Disease Recurrence Among Women With HIV and High-Grade Cervical Lesions in Kenya: A Randomized Clinical Trial. JAMA. 2019 Oct 22;322(16):1570-1579. doi: 10.1001/jama.2019.14969. PMID: 31638680; PMCID: PMC6806442. - Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen-positive women: results from the ESTAMPA study. Baena A, Mesher D, Salgado Y, Martínez S, Villalba GR, Amarilla ML, Salgado B, et al., ESTAMPA study group. Int J Cancer. 2023 Apr 15;152(8):1581-1592. doi: 10.1002/ijc.34384. Epub 2022 Dec 7. PMID: 36451311; PMCID: PMC10107773.Acknowledgements – CESTA sponsored by IARC/ HRP / WHOThank You, Ke a leboga