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Original Investigation
August 5, 2021

Human Papillomavirus Persistence and Association With Recurrent Cervical Intraepithelial Neoplasia After Cryotherapy vs Loop Electrosurgical Excision Procedure Among HIV-Positive Women: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine, Emory University, Atlanta, Georgia
  • 2Department of Global Health, University of Washington, Seattle
  • 3Department of Public Health and Primary Care, Ghent University, Ghent, Belgium
  • 4Early Detection, Prevention, and Infections Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France
  • 5Kenya Medical Research Institute, Nairobi, Kenya
  • 6Chronic Viral Diseases Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia
  • 7Coptic Hospital, Nairobi, Kenya
  • 8Department of Population Health, Aga Khan University, Nairobi, Kenya
  • 9Department of Obstetrics and Gynecology, Aga Khan University, Nairobi, Kenya
JAMA Oncol. Published online August 5, 2021. doi:10.1001/jamaoncol.2021.2683
Key Points

Question  Among HIV-positive women, is cryotherapy or loop electrosurgical excision procedure (LEEP) more effective at clearing cervical high-risk human papillomavirus (hrHPV) infection, and is persistent hrHPV detection associated with recurrent cervical intraepithelial neoplasia (CIN)?

Findings  In this secondary analysis of a randomized clinical trial that included 354 HIV-positive women in Kenya, LEEP was 40% more likely to clear hrHPV infection compared with cryotherapy, and persistent hrHPV detection was 5 times more likely to be associated with recurrent CIN than no HPV.

Meaning  LEEP may be more likely to clear hrHPV infection than cryotherapy, and persistent detection of hrHPV was associated with recurrent CIN among HIV-positive women.


Importance  Persistence of cervical high-risk human papillomavirus (hrHPV) after treatment for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) has not been compared between cryotherapy and loop electrosurgical excision procedure (LEEP) among HIV-positive women.

Objective  To evaluate whether cryotherapy or LEEP is more effective at clearing hrHPV and whether persistent hrHPV is associated with CIN2+ recurrence among HIV-positive women.

Design, Setting, and Participants  This is a secondary analysis of a randomized clinical trial conducted among women with HIV, hrHPV, and CIN2+ in Nairobi, Kenya. From June 2011 to September 2016, 354 HIV-positive women with CIN2+ disease had hrHPV cervical samples collected before and after treatment with cryotherapy or LEEP. Data were analyzed from September 2018 to January 2021.

Interventions  Women were randomized 1:1 to receive cryotherapy or LEEP and were followed up every 6 months for 24 months with hrHPV cervical swab and Papanicolaou test with confirmatory biopsy.

Main Outcomes and Measures  The main outcomes of this analysis were hrHPV positivity defined as having 1 of 12 hrHPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) and disease recurrence defined as CIN grade 2 or higher as determined with cervical biopsy.

Results  A total of 354 HIV-positive women with CIN2+ were included in the study; mean (SD) age was 37 (8) years in the cryotherapy arm and 38 (9) years in the LEEP arm. Baseline hrHPV prevalence was 90% (160 of 177) in the cryotherapy arm and 94% (166 of 177) in the LEEP arm (P = .24), and the most common hrHPV types detected were 16 (87 of 326 [27%]), 58 (87 of 326 [27%]), 35 (86 of 326 [26%]), 52 (66 of 326 [20%]), and 18 (56 of 325 [17%]). Over 24 months, clearance of hrHPV was significantly higher among those who underwent LEEP compared with cryotherapy (hazard ratio, 1.40; 95% CI, 1.03-1.90; P = .03). In multivariable analysis, hrHPV type-specific persistence at 12-month follow-up was significantly associated with CIN2+ recurrence from 12 months to 24 months (adjusted hazard ratio, 4.70; 95% CI, 2.47-8.95; P < .001). Performance of hrHPV testing at 12 months for recurrent CIN2+ was 93% sensitivity, 46% specificity, 38% positive predictive value, and 95% negative predictive value.

Conclusions and Relevance  In this secondary analysis of a randomized clinical trial, HIV-positive women who received LEEP were more likely to clear hrHPV infection compared with those undergoing cryotherapy, reinforcing the efficacy of LEEP in this population. Persistent hrHPV was significantly associated with recurrent CIN2+, suggesting that LEEP’s benefits may be related in part to its ability to clear hrHPV infection. Screening for hrHPV infection after treatment among HIV-positive women may be used to rule out recurrent CIN disease given its high sensitivity and negative predictive value.

Trial Registration  ClinicalTrials.gov Identifier: NCT01298596

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