Kuhn L, Wang C, Tsai WY, Wright TC, Denny L . Efficacy of human papillomavirus-based screen-and-treat for cervical cancer prevention among HIV-infected women. AIDS. 2010; 24:(16), 2553-61.
HIV-infected women have higher incidence, prevalence, and persistence of human papillomavirus infections (HPV) and are at higher risk of developing high-grade cervical cancer precursors and invasive cervical cancer.(1) With the scale-up of HIV care and treatment programs in sub-Saharan Africa, HIV-positive women are able to live longer and it is likely that more of these women will develop cervical cancer unless effective prevention programs can be established. Conventional cytology-based cervical cancer screening programs have been difficult to establish in low resource settings due to the infrastructure requirements, including adequately equipped laboratories, highly trained personnel, and clinical expertise needed for cytology, pathology, and colposcopy.(2) Simpler, screen and treat approaches, which use noncytology based screening methods, including HPV DNA testing or visual inspection with acetic acid (VIA) and immediate treatment of women with positive screening tests with cryotherapy have been shown to be safe and effective.(3) However, little is known about the safety and efficacy of these screen and treat approaches when used in HIV-infected women.
To evaluate the safety and efficacy of two screen-and-treat strategies: HPV-DNA testing based screen and treat and VIA-based screen-and-treat for cervical cancer prevention among HIV-positive women.
Ambulatory women's health clinics in Cape Town, South Africa.
A three-arm randomized clinical trial.
Women aged 35-65, who were not previously screened for cervical cancer, and who were not pregnant. After visual inspection, eligible participants did not have cervical lesions that were suspected of being cancerous or large acetowhite lesions extending over 70% of the cervix or into the endocervical canal or were not considered by clinicians to be inappropriate for cryotherapy.
The primary endpoint was cervical intraepithelial neoplasia grade 2 or higher (CIN2+), confirmed by biopsy or endocervical curettage ECC through 36 months.
This study was conducted from January 2000 to December 2002. Eligible women were randomly assigned to one of three study arms: HPV-and-treat, where women with a positive HPV test underwent cryotherapy; VIA-and-treat, where women with positive VIA tests underwent cryotherapy; or a control group in which evaluation or treatment was delayed for 6 months. All women were followed at six months with colposcopy and biopsy to determine CIN2 or higher. All women had an endocervical curettage collected. All women were screened at enrollment using an HPV DNA test (Hybrid Capture 2) that detects 13 HPV types considered high risk for development of cervical cancer, on cervical samples and had VIA examination done by specially trained nurses. Data on sociodemographic characteristics and sexual history was obtained by questionnaire. Samples were also collected for cervical cytology, Neisseria gonorrhea, Chlamydia trachomatis, and Trichomonas infection. Women were asked to return in 2-6 days to obtain their screening tests results and randomization was done at that visit. Cryotherapy was performed, where indicated, at this follow-up visit by nurses using nitrous oxide and a commercially available cryosurgical unit. Women were advised to refrain from sexual intercourse for one month and were provided with condoms if intercourse did occur. Side effects were documented at time of cryotherapy, and data were also collected on sexual behaviors and symptoms by questionnaire at one month after randomization. A systematic sample of women was selected for extended follow-up at 12, 24, and 36 months with additional colposcopy and biopsy. This sample included all women who were HPV-positive or VIA positive at enrollment and one third of women who tested negative for both HPV and VIA at enrollment. Women with documented CIN2+ at 6 months or later were treated with large loop electrosurgical excision.
Voluntary HIV counseling and testing services were included as part of the study and women were strongly encouraged to learn their HIV test results and be referred to HIV services in the community. Anonymous HIV tests were performed as part of the study at baseline, 6, 12, 24, and 36 months. HIV-positive and HIV-negative women were not distinguished during the study and all were randomized as part of the larger group. At the time of the study antiretroviral treatment was not routinely available in the public sector. Women ever testing HIV-positive were compared with women who were negative throughout follow-up.
Data were analyzed using an intention-to-treat approach, stratified by HIV status.
Of the 6552 women enrolled, 956 were HIV positive and 5596 were HIV negative. At enrollment, HIV-positive women were more likely to test positive for HPV DNA (46%) than HIV-negative women (17%), to have a positive VIA test (30% HIV-positive vs. 20% HIV-negative), and to have a cytological diagnosis of ASCUS+ (23% vs. 11%). Baseline characteristics between randomized group assignments did not differ among HIV positive women or among HIV-negative women examined separately. Retention at 6 months was 85% of HIV-positive and 87% of HIV-negative women, but dropped to 63% and 69.5%, respectively, by 36 months. Among controls, HIV-positive women had significantly higher rates of CIN2+ (14.9%) compared to HIV- negative women (4.6%) at 36 months. Screen-and-treat with HPV DNA testing significantly reduced the risk of CIN2+ by 36 months in both HIV-positive (RR=0.20, 95%CI 0.06-0.69) and HIV-negative women (RR=0.31, 95%CI 0.20-0.50). Screen-and-treat with VIA reduced the risk of CIN2+ in HIV-positive women (RR=0.51, 95%CI 0.29-0.89), but did not reach statistical significance in HIV-negative women (RR=0.76, 95%CI 0.52-1.1). For every 100 women screened, HPV screen-and-treat could prevent 11.9 CIN2+ cases in HIV-positive women and 3.1 CIN2+ cases in HIV-negative women, whereas VIA screen-and-treat could prevent 7.4 cases in HIV-positive women and 1.1 cases in HIV-negative women. Cumulative CIN2+ rates increased steadily during the 36 month follow-up in HIV-negative women in all three groups, but the increase was greater between 12 and 36 months among HIV-positive women in the HPV and VIA screen-and-treat arms compared to HIV-negative women in those arms.
In the control group, the sensitivity of HPV DNA testing to detect CIN2 at 36 months was 87% in HIV negative women and 94% among HIV-positive women; sensitivity of VIA was 48% in HIV-negative women and 64% in HIV-positive women. Specificity of HPV DNA testing was 87% in HIV negative women and 64% among HIV-positive women; specificity of VIA was 80% in HIV-negative women and 74% in HIV-positive women.
Among those who underwent cryotherapy, there were no significant differences between HIV-positive and HIV-negative women in rates of complications and side effects. For both HIV-positive and HIV-negative women who underwent cryotherapy, rates of vaginal discharge (>80%), abdominal pain (30-33%), abnormal bleeding (13-15%), and unscheduled clinic visits (9-10%) were higher than among non-treated women. There was one serious complication of severe bleeding one week after cryotherapy among an HIV-positive patient which required transfusion. CIN2+ failure rates after cryotherapy in the HPV screen-and-treat group were slightly lower among HIV-positive (2.8%) than HIV negative (7.1%) women (p=0.05); among the VIA screen- and- treat group failure rates were similar among HIV-positive (4.8%) and HIV-negative (2.8%) women.
HPV DNA testing followed by cryotherapy as a screen-and-treat strategy is safe and effective in HIV-positive women, and reduced high grade cervical cancer precursors (CIN2+) by 80% at 36 months. VIA screen-and treat was also effective among HIV- positive women, reducing CIN2+ by 50% at 36 months, although less effective compared to HPV DNA testing. These screening approaches have the potential to expand access to cervical cancer prevention in low resource settings.
This study met the criteria for a well designed clinical trial. However, the trial was not designed to address the efficacy of screen and treat in HIV-positive women; the analysis was done among the subgroup of HIV+ women enrolled in the trial. Retention at the 36 month endpoint was only 63% among HIV- positive women.
Screen and treat cervical-cancer screening strategies with VIA or HPV DNA testing conducted in 1 to 2 visits have been demonstrated to be cost-effective in low resource settings compared to conventional three-visit cytology.(4) New rapid HPV tests, which are less expensive and easier to use than the hybrid capture 2 test, may potentially be the more feasible strategy in low resource settings.(5) This trial suggests that both the HPV-DNA and VIA screen-and-treat strategy were safe and effective and could substantially reduce high grade cervical cancer precursors among HIV-positive women. These types of screening programs are currently being piloted in HIV care and treatment programs in Africa.(6) HIV care and treatment programs could provide an important platform for implementation of effective cervical cancer prevention programs. More data are needed on the impact of these strategies among HIV-infected women, particularly among those on antiretroviral therapy, and on the rate of recurrence after treatment in HIV-positive women.
- De Vuyst H, Lillo F, Broutet N, Smith JS. HIV, human papillomavirus, and cervical neoplasia and cancer in the era of highly active antiretroviral therapy. Eur J Cancer Prev. 2008 Nov;17(6):545-5.
- Denny L. The prevention of cervical cancer in developing countries. BJOG. 2005 Sep;112(9):1204-12.
- Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC Jr. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial. JAMA. 2005 Nov 2;294(17):2173-81.
- Goldie SJ, Gaffikin L, Goldhaber-Fiebert JD, Gordillo-Tobar A, Levin C, Mahé C, Wright TC; Alliance for Cervical Cancer Prevention Cost Working Group. Cost-effectiveness of cervical-cancer screening in five developing countries. N Engl J Med. 2005 Nov 17;353(20):2158-68.
- Levin CE, Sellors J, Shi JF, Ma L, Qiao YL, Ortendahl J, O'Shea MK, Goldie SJ. Cost-effectiveness analysis of cervical cancer prevention based on a rapid human papillomavirus screening test in a high-risk region of China. Int J Cancer. 2010 Sep 1;127(6):1404-11.
- Mwanahamuntu MH, Sahasrabuddhe VV, Pfaendler KS, Mudenda V, Hicks ML, Vermund SH, Stringer JS, Parham GP. Implementation of 'see-and-treat' cervical cancer prevention services linked to HIV care in Zambia. AIDS. 2009 Mar 27;23(6):N1-5.