World Health Organization Guidelines for treatment of cervical intraepithelial neoplasia 2-3 and screen-and-treat strategies to prevent cervical cancer

"BACKGROUND: It is estimated that 1%-2% of women develop cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) annually worldwide. The prevalence among women living with HIV is higher, at 10%. If left untreated, CIN 2-3 can progress to cervical cancer. WHO has previously published guidelines for strategies to screen and treat precancerous cervical lesions and for treatment of histologically confirmed CIN 2-3. METHODS: Guidelines were developed using the WHO Handbook for Guideline Development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. A multidisciplinary guideline panel was created. Systematic reviews of randomized controlled trials and observational studies were conducted. Evidence tables and Evidence to Recommendations Tables were prepared and presented to the panel. RESULTS: There are nine recommendations for screen-and-treat strategies to prevent cervical cancer, including the HPV test, cytology, and visual inspection with acetic acid. There are seven for treatment of CIN with cryotherapy, loop electrosurgical excision procedure, and cold knife conization. CONCLUSION: Recommendations have been produced on the basis of the best available evidence. However, high-quality evidence was not available. Such evidence is needed, in particular for screen-and-treat strategies that are relevant to low- and middle-income countries."

Prevalence and determinants of human papillomavirus infection and cervical lesions in HIV-positive women in Kenya.

BACKGROUND: We assessed the association of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) with various characteristics, CD4 count and use of combination antiretroviral therapy (cART) among HIV-positive women. METHODS: Cross-sectional study of 498 HIV-positive women who underwent HPV PCR-based testing, cytology, and systematic cervical biopsy. RESULTS: In all, 68.7% of women were HPV-positive, 52.6% had high-risk (hr) HPV, and 40.2% multiple type infections. High-risk human papillomavirus-positivity did not vary significantly by age but it was negatively associated with education level. The most frequent types in 113 CIN2/3 were HPV16 (26.5%), HPV35 (19.5%), and HPV58 (12.4%). CD4 count was negatively associated with prevalence of hrHPV (P<0.001) and CIN2/3 among non-users of cART (P=0.013). Combination antiretroviral therapies users (≥2 year) had lower hrHPV prevalence (prevalence ratio (PR) vs non-users=0.77, 95% confidence interval (CI): 0.61-0.96) and multiple infections (PR=0.68, 95% CI: 0.53-0.88), but not fewer CIN2/3. The positive predictive value of hrHPV-positivity for CIN2/3 increased from 28.9% at age <35 years to 53.3% in ≥45 years. CONCLUSION: The burden of hrHPV and CIN2/3 was high and it was related to immunosuppression level. Combination antiretroviral therapies ( ≥2 year) use had a favourable effect on hrHPV prevalence but cART in our population may have been started too late to prevent CIN2/3.

Different cervical cancer screening approaches in a Chinese multicentre study.

To evaluate alternative cervical cancer screening methods, digital colposcopy and collection of cervical exfoliated cells for liquid-based cytology (LBC) and hybrid capture 2 (HC2) testing were performed among 2562 women aged 15-59 years in three study sites in the People's Republic of China (rural Shanxi province, Shenyang city in Liaoning province and Shenzhen city in Guangdong province). Visual inspection with acetic acid (VIA) was also evaluated independently from colposcopy. A total of 74 cases of histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) were identified, and 16 CIN2+ cases were imputed among unbiopsied women to correct for verification bias. Corrected sensitivity for CIN2+ was 37% for VIA, 54% for colposcopy, 87% for LBC with a threshold of atypical cells of undetermined significance (LBC>or=ASCUS), 90% for HC2, 84% for LBC using HC2 to triage ASCUS and 96% for positivity to LBC>or=ASCUS or HC2. For VIA, sensitivity was much lower among women >or=40 years (12%) than those aged or=ASCUS or HC2, up to 94% for LBC using HC2 to triage ASCUS. In conclusion, LBC, HC2 and their combinations performed well, whereas VIA missed a majority of CIN2+, particularly in older women. Digital colposcopy performed better than VIA, but still missed nearly half of CIN2+ in this study.

The Pap smear for detection of bacterial vaginosis.

OBJECTIVE: To assess validity of Pap smears in diagnosing bacterial vaginosis. METHOD: A prospective diagnostic accuracy study with 533 women in Mombasa, Kenya. Diagnosis of bacterial vaginosis using clinical observations scored with simplified Amsel's criteria and Bethesda system for Pap smears was compared with a reference standard (Nugent criteria for gram stains). Both laboratory tests were interpreted blindly. RESULT: Bacterial vaginosis prevalence was 36.7% (191/521) with Nugent criteria. Pap smear sensitivity and specificity were 59.4% (111/187) and 83.3% (270/324), with corresponding figures for simplified Amsel's criteria of 44.8% (81/181) and 84.8% (263/310). For Pap smear and simplified Amsel's criteria, positive predictive values were 67.3 and 63.3%, and negative predictive values 78.0% and 72.5%. CONCLUSION: In diagnosing bacterial vaginosis, Pap smears have moderate sensitivity (though higher than simplified Amsel's criteria). Specificity of Pap smears is adequate. Including bacterial vaginosis assessment as a standard component of Pap smears warrants consideration.

Comparison of pap smear, visual inspection with acetic acid, human papillomavirus DNA-PCR testing and cervicography.

OBJECTIVE: To assess the test qualities of four screening methods to detect cervical intra-epithelial neoplasia in an urban African setting. METHOD: Six hundred fifty-three women, attending a family planning clinic in Nairobi (Kenya), underwent four concurrent screening methods: pap smear, visual inspection with acetic acid (VIA), PCR for high risk human papillomavirus (HR HPV) and cervicography. The presence of cervical intra-epithelial neoplasia (CIN) was verified by colposcopy or biopsy. RESULT: Sensitivity (for CIN2 or higher) and specificity (to exclude any CIN or cancer) were 83.3% (95% CI [73.6, 93.0]) and 94.6% (95% CI [92.6, 96.5]), respectively, for pap smear; 73.3% (95% CI [61.8, 84.9]) and 80.0% (95% CI [76.6, 83.4]) for VIA; 94.4% (95% CI [84.6, 98.8]) and 73.9% (95% CI [69.7, 78.2]) for HR HPV; and 72.3% (95% CI [59.1, 85.6]) and 93.2% (95% CI [90.8, 95.7]) for cervicography. CONCLUSION: The pap smear had the highest specificity (94.6%) and HPV testing the highest sensitivity (94.4%). The visual methods, VIA and cervicography, were similar and showed an accuracy in between the former two tests.

Performance of the acetic acid test when used in field conditions as a screening test for cervical cancer.

OBJECTIVE: To assess if visual inspection with acetic acid (VIA) is a useful alternative screening test for cervical cancer, when used in a resource-poor setting with an existing cytology-based screening programme. METHODS: Women living in Rivas district (Nicaragua), who attended the programme, were concurrently screened with VIA and Papanicolau (PAP) smear. Screening was performed by health providers who had received training in VIA and a refresher course in cytology. Women testing positive for either of the results were referred for colposcopy and biopsy when indicated. The performance of VIA was compared with PAP smear, calculating the relative true and false positive rate (RELTPR and RELFPR) and for a high threshold on biopsy (cervical intraepithelial neoplasia grade 2 or a higher grade). We determined the trade-off between both tests by calculating the ratio of extra false positives detected through extra true positives (EFP:ETP ratio). RESULTS: A total of 1076 patients were screened. Nearly 33% had a positive screening test. On biopsy, 7.6% had a low-grade intraepithelial lesion, 4.5% a high-grade intraepithelial lesion (HSIL) and 0.5% invasive cancer. The RELTPR (VIA to PAP) was 1.96, the RELFPR 5.02 and the EFP:ETP ratio 8.04. VIA detected twice as much HSIL and invasive cancers as the PAP smear. Yet, for every extra diagnosis, eight extra false positives had to be examined at the referral level. CONCLUSIONS: The VIA spectacularly increases the number of HSIL and invasive cancers detected. The high FPR is a concern for the organization of the referral level. There is a need to establish uniform criteria on test positivity and to further improve the performance in field conditions.

Integration of cervical screening in family planning clinics.

OBJECTIVES: To assess the suitability of cervical cancer screening in family planning (FP) clinics and the relevance for women's health. METHODS: A survey was done on clients visiting the clinics of the Family Planning Association of Kenya (FPAK). Client characteristics, age, screening status and PAP smear results were registered. In-depth interviews were held with a limited number of staff and clients. RESULTS: In 1999, 38052 clients visited FPAK clinics, 43.5% were younger than 30 years old. More than 10000 cervical smears were taken. A total of 4.5% of the smears were abnormal, including 1.5% high-grade squamous intraepithelial lesions (HSIL) and 0.2% invasive cancers. The clinics were well prepared to provide high quality screening services. Patients and staff had a positive view on screening. CONCLUSIONS: Providing cervical cancer screening in FP clinics is beneficial for the clients but is unlikely to have an impact on the epidemiology of cervical cancer morbidity as FP services reach only a small percentage of the women who are most at risk. Measures to reach more and older women could assure a larger impact.

HIV and cervical cancer in Kenya.

OBJECTIVES: To determine the effect of the HIV epidemic on invasive cervical cancer in Kenya. METHODS: Of the 3902 women who were diagnosed with reproductive tract malignancies at Kenyatta National Hospital (KNH) from 1989 to 1998, 85% had invasive cervical cancer. Age at presentation and severity of cervical cancer were studied for a 9-year period when national HIV prevalence went from 5% to 5-10%, to 10-15%. RESULTS: There was no significant change in either age at presentation or severity of cervical cancer. Of the 118 (5%) women who were tested for HIV, 36 (31%) were seropositive. These women were 5 years younger at presentation than HIV-negative women. CONCLUSIONS: A two- to three-fold increase in HIV prevalence in Kenya did not seem to have a proportional effect on the incidence of cervical cancer. Yet, HIV-positive women who presented with cervical cancer were significantly younger than HIV-negative women.

CD8+ cells and not CD4+ T cells are hyporesponsive to CD28- and CD40L-mediated activation in HIV-infected subjects.

T cell dysfunction in HIV-infected subjects could be the consequence of altered sensitivity of CD4+ or CD8+ T cells to various costimulatory signals. Therefore, we studied proliferation and cytokine production in highly purified CD8+ and CD4+ T cells from HIV-infected and HIV- subjects, induced by co-activation via cell-bound CD80, CD86 and CD40 or by allo-activation. Regardless of the nature of the first and the costimulatory signal, CD8+ T cells from patients proliferated consistently less than controls, while responses from CD4+ T cells were similar in patients and controls. This phenomenon was observed after ligation of CD28 combined with anti-CD3 or phorbol myristate acetate (PMA), but also after allogeneic stimulation and after activation by CD40 and anti-CD3. Anti-CD3 combined with CD80 or CD86 induced a mixed Th1/Th2-type cytokine profile in both CD4+ and CD8+ T cells from controls, whereas anti-CD3 plus CD40 induced only low levels of Th2-type cytokines and no interferon-gamma (IFN-gamma) in CD4+ T cells. Compared with controls, CD4+ T cells from patients produced slightly lower levels of IL-10 but equal amounts of IFN-gamma, IL-4 and IL-5, while CD8+ T cells from patients produced less of all cytokines tested. In conclusion, responses of purified CD4+ T cells from HIV+ subjects to various costimulatory pathways are relatively intact, whereas CD8+ T cells are hyporesponsive at the level of proliferation and cytokine production. A generalized intrinsic CD8+ T cell failure might contribute to viral and neoplastic complications of HIV infection.