A randomized clinical trial comparing cervical dysplasia treatment with cryotherapy vs loop electrosurgical excision procedure in HIV-seropositive women from Johannesburg, South Africa

Published:March 30, 2017DOI:


      Mortality associated with cervical cancer is a public health concern for women, particularly in HIV–seropositive women in resource-limited countries. HIV-seropositive women are at a higher risk of high-grade cervical precancer, which can eventually progress to invasive carcinoma as compared to HIV-seronegative women. It is imperative to identify effective treatment methods for high-grade cervical precursors among HIV-seropositive women.


      Randomized controlled trial data are needed comparing cryotherapy vs loop electrosurgical excision procedure treatment efficacy in HIV-seropositive women. Our primary aim was to compare the difference in the efficacy of loop electrosurgical excision procedure vs cryotherapy for the treatment of high-grade cervical intraepithelial neoplasia (grade ≥2) among HIV-seropositive women by conducting a randomized clinical trial.

      Study Design

      HIV-seropositive women (n = 166) aged 18-65 years with histology-proven cervical intraepithelial neoplasia grade ≥2 were randomized (1:1) to cryotherapy or loop electrosurgical excision procedure treatment at a government hospital in Johannesburg. Treatment efficacy was compared using 6- and 12-month cumulative incidence posttreatment of: (1) cervical intraepithelial neoplasia grade ≥2; (2) secondary endpoints of histologic cervical intraepithelial neoplasia grade ≥3 and grade ≥1; and (3) high-grade and low-grade cervical cytology. The study was registered ( NCT01723956).


      From January 2010 through August 2014, 166 participants were randomized (86 loop electrosurgical excision procedure; 80 cryotherapy). Cumulative cervical intraepithelial neoplasia grade ≥2 incidence was higher for cryotherapy (24.3%; 95% confidence interval, 16.1–35.8) than loop electrosurgical excision procedure at 6 months (10.8%; 95% confidence interval, 5.7–19.8) (P = .02), although by 12 months, the difference was not significant (27.2%; 95% confidence interval, 18.5–38.9 vs 18.5%; 95% confidence interval, 11.6–28.8, P = .21). Cumulative cervical intraepithelial neoplasia grade ≥1 incidence for cryotherapy (89.2%; 95% confidence interval, 80.9–94.9) did not differ from loop electrosurgical excision procedure (78.3%; 95% confidence interval, 68.9–86.4) at 6 months (P = .06); cumulative cervical intraepithelial neoplasia grade ≥1 incidence by 12 months was higher for cryotherapy (98.5%; 95% confidence interval, 92.7–99.8) than loop electrosurgical excision procedure (89.8%; 95% confidence interval, 82.1–95.2) (P = .02). Cumulative high-grade cytology incidence was higher for cryotherapy (41.9%) than loop electrosurgical excision procedure at 6 months (18.1%, P < .01) and 12 months (44.8% vs 19.4%, P < .001). Cumulative incidence of low-grade cytology or greater in cryotherapy (90.5%) did not differ from loop electrosurgical excision procedure at 6 months (80.7%, P = .08); by 12 months, cumulative incidence of low-grade cytology or greater was higher in cryotherapy (100%) than loop electrosurgical excision procedure (94.8%, P = .03). No serious adverse effects were recorded.


      Although rates of cumulative cervical intraepithelial neoplasia grade ≥2 were lower after loop electrosurgical excision procedure than cryotherapy treatment at 6 months, both treatments appeared effective in reducing cervical intraepithelial neoplasia grade ≥2 by >70% by 12 months. The difference in cumulative cervical intraepithelial neoplasia grade ≥2 incidence between the 2 treatment methods by 12 months was not statistically significant. Relatively high cervical intraepithelial neoplasia grade ≥2 recurrence rates, indicating treatment failure, were observed in both treatment arms by 12 months. A different treatment protocol should be considered to optimally treat cervical intraepithelial neoplasia grade ≥2 in HIV-seropositive women.

      Key words

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        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-E386
      1. Chibwesha C, Goeieman B, Mulongo M, et al. Increasing access to cervical cancer screening and prevention for South African women infected with HIV. Poster presented at: South African AIDS Conference; June 9-12, 2015; Durban, South Africa.

      2. UNAIDS. How AIDS changed everything. Geneva. Available at: Accessed Sept. 15, 2015.

        • UNAIDS
        2008 Report on the global AIDS epidemic.
        World Health Organization, Geneva2008 (Available at:) (Accessed Sept. 20, 2015)
        • De Vuyst H.
        • Lillo F.
        • Broutet N.
        • Smith J.S.
        HIV, human papillomavirus and cervical neoplasia, and cancer in the era of highly active antiretroviral therapy.
        Eur J Cancer Prev. 2008; 17: 545-554
        • Massad L.S.
        • Riester K.A.
        • Anastos K.M.
        • et al.
        Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with human immunodeficiency virus-1.
        J Acquir Immune Defic Syndr. 1999; 21: 33-41
        • Abraham A.G.
        • Strickler H.D.
        • Jing Y.
        • et al.
        Invasive cervical cancer risk among HIV-infected women: a North American multi-cohort collaboration prospective study.
        J Acquir Immune Defic Syndr. 2013; 62: 405-413
        • Heard I.
        • Tassie J.M.
        • Schmitz V.
        • Mandelbrot L.
        • Kazatchkine M.D.
        • Orth G.
        Increased risk of cervical disease among human immunodeficiency virus-infected women with severe immunosuppression and high human papillomavirus load 200.
        Obstet Gynaecol. 2000; 96: 403-409
        • Firnhaber C.
        • Van Le H.
        • Pettifor A.
        • et al.
        Association between cervical dysplasia and human papillomavirus in HIV seropositive women from Johannesburg South Africa.
        Cancer Causes Control. 2010; 21: 433-443
        • Palefsky J.
        Human papillomavirus-related disease in people with HIV.
        Curr Opin HIV AIDS. 2009; 4: 52-56
        • Mocroft A.
        • Ledergerber B.
        • Katlama C.
        • et al.
        Decline in the AIDS and death rates in the EuroSIDA study: an observational study.
        Lancet. 2003; 362: 22-29
        • Antiretroviral Therapy Cohort Collaboration
        Life expectance of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies.
        Lancet. 2008; 372: 293-299
        • Memiah P.
        • Mbuthia W.
        • Kiiru G.
        • et al.
        Prevalence and risk factors associated with precancerous cervical cancer lesions among HIV-infected women in resource-limited settings.
        AIDS Res Treat. 2012; 2012: 953743
        • Firnhaber C.
        • Nomtha M.
        • Lu M.
        • et al.
        Validation of cervical cancer screening methods in HIV positive women from Johannesburg South Africa.
        PLoS One. 2013; 8: e53494
        • Echelman D.
        • Feldman S.
        Management of cervical precancers: a global perspective.
        Hematol Oncol Clin North Am. 2012; 26: 31-34
        • Saslow D.
        • Runowicz C.D.
        • Solomon D.
        • et al.
        American Cancer Society guideline for the early detection of cervical neoplasia and cancer.
        CA Cancer J Clin. 2002; 52: 342-362
        • Chamot E.
        • Kristensen S.
        • Stringer J.
        • Mwanahamuntu M.
        Are treatments for cervical precancerous lesions in less-developed countries safe enough to promote scaling-up of cervical screening programs? A systematic review.
        BMC Womens Health. 2010; 10: 11
        • Pfaendler K.S.
        • Mwanahamuntu M.H.
        • Sahasrabuddhe V.V.
        • Mudenda V.
        • Stringer J.S.
        • Parham G.P.
        Management of cryotherapy-ineligible women in a “screen-and-treat” cervical cancer prevention program targeting HIV-infected women in Zambia: lessons from the field.
        Gynecol Oncol. 2008; 110: 402-407
        • Mwanahamuntu M.
        • Sahasrabuddhe V.
        • Pfaendler K.
        • et al.
        Implementation of “see and treat” cervical cancer prevention services linked to HIV care in Zambia.
        AIDS. 2009; 23: N1-N5
        • Chirenje Z.
        • Rusakaniko S.
        • Akino V.
        • Mlingo M.
        A randomized clinical trial of loop electrosurgical excision procedure (LEEP) versus cryotherapy in the treatment of cervical intraepithelial neoplasia.
        J Obstet Gynaecol. 2001; 21: 617-621
        • Singh A.
        • Arthur B.
        • Agarwal V.
        LEEP versus cryotherapy in CIN.
        Obstet Gynaecol. 2011; 61: 431-435
        • Sellors J.
        • Sankaranarayanan R.
        Colposcopy and treatment of cervical intraepithelial neoplasia: a beginners’ manual. Chapters 12–13.
        International Agency for Research on Cancer, Lyon (France)2003
        • Yasmin A.
        • Cyril J.
        • Guy de B.
        • James M.
        • Diane T.
        • Neil M.
        Predictors of persistent cytologic abnormalities after treatment of cervical intraepithelial neoplasia in Soweto, South Africa: a cohort study in a HIV high prevalence population.
        BMC Cancer. 2008; 8: 211
        • Russomano F.
        • Reis A.
        • Camargo M.J.
        • Grinsztejn B.
        • Tristão M.A.
        Recurrence of cervical intraepithelial neoplasia grades 2 or 3 in HIV-infected women treated by large loop excision of the transformation zone (LLETZ).
        Sao Paulo Med J. 2008; 126: 17-22
        • Stang A.
        Randomized controlled trials–an indispensable part of clinical research.
        Dtsch Arztebl Int. 2011; 108: 661-662
        • Jacob M.
        • Broekhuizen F.F.
        • Castro W.
        • Sellos J.
        Experience using cryotherapy for treatment of cervical precancerous lesions in low-resource settings.
        Int J Gynecol Obstet. 2005; 89: S13-S20
        • Soler M.E.
        • Gaffikin L.
        • Blumenthal P.D.
        Cervical cancer screening in developing countries.
        Prim Care Update Obstet Gynecol. 2000; 7: 118-123
        • Rahangdale L.
        • Lippmann Q.K.
        • Garcia K.
        • Budwit D.
        • Smith J.S.
        • van Le L.
        Topical 5-fluorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial.
        Am J Obstet Gynecol. 2014; 210: 314.e1-314.e8
        • Yang A.
        • Jeang J.
        • Cheng K.
        • et al.
        Current state in the development of candidate therapeutic HPV vaccines.
        Expert Rev Vaccines. 2016; 15: 1-19

      Linked Article

      • Recurrence of CIN 2 and 3 after treatment in HIV positive patients
        American Journal of Obstetrics & GynecologyVol. 219Issue 2
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          A randomized controlled trial of 166 HIV-positive patients comparing treatment for cervical intraepithelial neoplasia (CIN) 2 and 3 by loop electrosurgical excision (LEEP) (n = 86) and cryotherapy (n = 80) in a tertiary government hospital in South Africa, published in the August edition of this journal,1 highlights the high recurrence rates after treatment.
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