Age-specific burden of cervical cancer associated with HIV: A global analysis with a focus on sub-Saharan Africa.

HIV substantially worsens human papillomavirus (HPV) carcinogenicity and contributes to an important population excess of cervical cancer, particularly in sub-Saharan Africa (SSA). We estimated HIV- and age-stratified cervical cancer burden at a country, regional and global level in 2020. Proportions of cervical cancer (a) diagnosed in women living with HIV (WLHIV), and (b) attributable to HIV, were calculated using age-specific estimates of HIV prevalence (UNAIDS) and relative risk. These proportions were validated against empirical data and applied to age-specific cervical cancer incidence (GLOBOCAN 2020). HIV was most important in SSA, where 24.9% of cervical cancers were diagnosed in WLHIV, and 20.4% were attributable to HIV (vs 1.3% and 1.1%, respectively, in the rest of the world). In all world regions, contribution of HIV to cervical cancer was far higher in younger women (as seen also in empirical series). For example, in Southern Africa, where more than half of cervical cancers were diagnosed in WLHIV, the HIV-attributable fraction decreased from 86% in women ≤34 years to only 12% in women ≥55 years. The absolute burden of HIV-attributable cervical cancer (approximately 28 000 cases globally) also shifted toward younger women: in Southern Africa, 63% of 5341 HIV-attributable cervical cancer occurred in women <45 years old, compared to only 17% of 6901 non-HIV-attributable cervical cancer. Improved quantification of cervical cancer burden by age and HIV status can inform cervical cancer prevention efforts in SSA, including prediction of the impact of WLHIV-targeted vs general population approaches to cervical screening, and impact of HIV prevention.

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.

Importance: The World Health Organization recommends cryotherapy or loop electrosurgical excision procedure (LEEP) for histologically confirmed cervical intraepithelial neoplasia (CIN) grade 2 or higher regardless of HIV status. Cryotherapy is more feasible in resource-limited settings but may be less effective for women living with HIV. Objective: To evaluate whether cryotherapy or LEEP is a more effective treatment for high-grade cervical lesions among women with HIV. Design, Setting, and Participants: Single-center randomized trial conducted among women with HIV and CIN grade 2 or 3. From June 2011 to September 2016, women with HIV in Kenya underwent cervical screening with Papanicolaou testing and confirmatory biopsy. The final date on which a study procedure was administered was September 7, 2016. Interventions: Women with HIV infection and CIN grade 2 or 3 were randomized 1:1 to receive cryotherapy (n = 200) or LEEP (n = 200) and were followed up every 6 months for 24 months with a Papanicolaou test and confirmatory biopsy. Main Outcome and Measures: The primary outcome was disease recurrence, defined as CIN grade 2 or higher on cervical biopsy, during the 24-month follow-up period. Results: Among 400 women who were randomized (median age, 37.4 [interquartile range, 31.9-43.8] years), 339 (85%) completed the trial. Over 2 years, 60 women (30%) randomized to cryotherapy had recurrent CIN grade 2 or higher vs 37 (19%) in the LEEP group (relative risk, 1.71 [95% CI, 1.12-2.65]; risk difference, 7.9% [95% CI, 1.9%-14.0%]; P = .01). Adverse events occurred in 40 women (45 events, including change in pathology and death due to other causes) in the cryotherapy group and in 30 women (38 events, including change in pathology and unrelated gynecological complications) in the LEEP group. Conclusions and Relevance: In this single-center study of women with HIV infection and CIN grade 2 or 3, treatment with LEEP compared with cryotherapy resulted in a significantly lower rate of cervical neoplasia recurrence over 24 months. Cost-effectiveness analysis is necessary to determine whether the additional benefit of LEEP represents an efficient use of the additional resources that would be required. Trial Registration: ClinicalTrials.gov Identifier: NCT01298596.

Increased Cervical Human Immunodeficiency Virus (HIV) RNA Shedding Among HIV-Infected Women Randomized to Loop Electrosurgical Excision Procedure Compared to Cryotherapy for Cervical Intraepithelial Neoplasia 2/3.

Background: Treatment of human immunodeficiency virus (HIV)-infected women to prevent cervical cancer may stimulate HIV RNA cervical shedding and risk HIV transmission. Methods: From 2011 to 2014, 400 HIV-infected women diagnosed with cervical intraepithelial neoplasia 2/3 in Kenya were randomized to loop electrosurgical excision procedure (LEEP) or cryotherapy. Cervical samples were collected at baseline and 3 weekly intervals. Samples were tested for HIV RNA using the Gen-Probe Aptima HIV assay with a minimum detection level of 60 copies/swab and analyzed using generalized estimating equations. Results: Women who received LEEP had significantly higher cervical HIV RNA levels than those who received cryotherapy at weeks 2 (adjusted incident rate ratio [aIRR], 1.07; P = .038) and 3 (aIRR, 1.08; P = .046). Within LEEP, significantly higher cervical shedding was found at weeks 2 (2.03 log10 copies/swab; P < .001) and 3 (2.04 log10 copies/swab; P < .001) compared to baseline (1.80 log10 copies/swab). Cervical HIV RNA was significantly higher following LEEP for up to 3 weeks among women on antiretroviral treatment (ART) (0.18 log10 copies/swab increase; P = .003) and in ART-naive women (1.13 log10 copies/swab increase; P < .001) compared to baseline. Within cryotherapy, cervical shedding increased in ART-naive women (0.72 log10 copies/swab increase; P = 0.004) but did not increase in women on ART. Conclusions: Women randomized to LEEP had a larger increase in post-procedural cervical HIV shedding than cryotherapy. Benefits of cervical cancer prevention outweigh the risk of HIV sexual transmission; our findings underscore the importance of risk-reduction counseling. Clinical Trials Registration: NCT01298596.

Socio-demographic and reproductive determinants of cervical neoplasia in seven sub-Sahara African countries.

BACKGROUND: Since most human papilloma virus (HPV) infections regress without any intervention, HPV is a necessary but may not be a solely sufficient cause of cervical intraepithelial neoplasia (CIN) and cervical cancer. Hence, the influence of cofactors on progression from cervical HPV infection to high-grade CIN and invasive cervical cancer has been a subject of intensive research. OBJECTIVE: We assessed the effect of socio-demographic and sexual reproductive factors on the prevalence of invasive cervical cancer and CIN diagnosed in cross-sectional cervical cancer screening projects carried out in seven sites of different sub-Saharan countries. METHODS: Between January 2000 and August 2007, healthy women aged 25-59 who participated in the screening projects were interviewed for socio-demographic, reproductive, and behavioral characteristics, investigated for disease confirmation with colposcopy, and had biopsies directed from colposcopically abnormal areas by trained local physicians. Odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analyses were used to assess the effect of women characteristics on CIN 1, CIN 2-3, CIN 3, and invasive cancer outcome measures. RESULTS: Among 47,361 women screened and investigated for disease confirmation, CIN 1 was diagnosed in 1,069 (2.3%), CIN 2 in 517 (1.1%), CIN 3 in 175 (0.5%), and invasive cancer in 485 (1.0%). The site-specific prevalence of CIN 2-3 lesions ranged from 0.3 to 5.1% and from 0.2 to 1.9% for invasive cancers. Risk factors for CIN 2-3 were being widowed or separated versus currently married (OR 1.3, 95% CI 1.0-1.7 a); and having had at least four pregnancies versus zero or one pregnancy (OR at least 1.4-fold, 95% CI 1.1-1.8). Risk factors for invasive cancer were being widowed or separated versus currently married (OR 2.0, 95% CI 1.3-3.1); and having had at least three pregnancies versus zero or one pregnancy (OR at least 3.0-fold, 95% CI 2.1-4.2). Additionally, cervical cancer risk increased with increasing age, age at menarche, and age at marriage, while the risk decreased with increasing level of education and in those with some form of employment compared to housewives. CONCLUSION: The exposure of the exocervix and/or the increased levels of estrogen and progesterone for more prolonged periods during pregnancy in multiparous women and the vulnerability of widowed/separated women in society might result in increased risk of cervical neoplasia more so among women exposed to HPV infection. High parity probably explains the persistently high rates of cervical cancer in sub-Saharan Africa.

Comparison of HPV DNA testing in cervical exfoliated cells and tissue biopsies among HIV-positive women in Kenya.

HIV-positive women are infected with human papillomavirus (HPV) (especially with multiple types), and develop cervical intraepithelial neoplasia (CIN) and cervical cancer more frequently than HIV-negative women. We compared HPV DNA prevalence obtained using a GP5+/6+ PCR assay in cervical exfoliated cells to that in biopsies among 468 HIV-positive women from Nairobi, Kenya. HPV prevalence was higher in cells than biopsies and the difference was greatest in 94 women with a combination normal cytology/normal biopsy (prevalence ratio, PR = 3.7; 95% confidence interval, CI: 2.4-5.7). PR diminished with the increase in lesion severity (PR in 58 women with high-grade squamous intraepithelial lesions (HSIL)/CIN2-3 = 1.1; 95% CI: 1.0-1.2). When HPV-positive, cells contained 2.0- to 4.6-fold more multiple infections than biopsies. Complete or partial agreement between cells and biopsies in the detection of individual HPV types was found in 91% of double HPV-positive pairs. The attribution of CIN2/3 to HPV16 and/or 18 would decrease from 37.6%, when the presence of these types in either cells or biopsies was counted, to 20.2% when it was based on the presence of HPV16 and/or 18 (and no other types) in biopsies. In conclusion, testing HPV on biopsies instead of cells results in decreased detection but not elimination of multiple infections in HIV-positive women. The proportion of CIN2/3 attributable to HPV16 and/or 18 among HIV-positive women, which already appeared to be lower than that in HIV-negative, would then further decrease. The meaning of HPV detection in cells and random biopsy from HIV-positive women with no cervical abnormalities remains unclear.

Cervical Cancer Screening and Treatment algorithms using Human Papillomavirus testing - lessons learnt from a South African pilot randomized controlled trial.

BACKGROUND: To report quantitative and qualitative results on cervical cancer (CC) HPV-based screening and treatment algorithms, with/out triage with visual inspection after acetic acid (VIA), followed by ablative treatment (AT). METHODS: Women 30-54 years-old from Durban, South Africa were recruited, regardless of HIV status, randomized into one of two study arms and screened for HPV. VIA-triage arm: HPV-positive women were triaged using VIA, biopsied and received AT if VIA-positive and eligible; no-triage arm: eligible HPV-positive women received AT. Women ineligible for AT were referred to colposcopy. Women were asked about side effects immediately and one week after AT. Retention to screening and treatment algorithms was compared between arms. RESULTS: 350 women (275 HIV-uninfected and 75 women living with HIV, (WLWH)) were allocated to receive HPV testing with VIA-triage (n=175) or no-triage (n=175). HPV prevalence was 28% (95%CI=23-33); WLWH: 52% (95%CI=40-64) vs HIV-uninfected: 21% (95%CI=17-27) (p<0.05). Among women who underwent VIA triage with histological diagnosis, 3/17 were VIA negative with CIN2+; 14/18 were VIA positive with

Prevalence of human papillomavirus in women with invasive cervical carcinoma by HIV status in Kenya and South Africa.

Data on the prevalence of human papillomavirus (HPV) types in cervical carcinoma in women with HIV are scarce but are essential to elucidate the influence of immunity on the carcinogenicity of different HPV types, and the potential impact of prophylactic HPV vaccines in populations with high HIV prevalence. We conducted a multicentre case-case study in Kenya and South Africa. During 2007-2009, frozen tissue biopsies from women with cervical carcinoma were tested for HPV DNA using GP5+/6+-PCR assay. One hundred and six HIV-positive (mean age 40.8 years) and 129 HIV-negative women (mean age 45.7) with squamous cell carcinoma were included. Among HIV-positive women, the mean CD4 count was 334 cells/µL and 48.1% were on combined antiretroviral therapy. HIV-positive women had many more multiple HPV infections (21.6% of HPV-positive carcinomas) compared with HIV-negative women (3.3%) (p < 0.001) and the proportion of multiple infections was inversely related to CD4 level. An excess of HPV18 of borderline statistical significance was found in HIV-positive compared with HIV-negative cases (Prevalence ratio (PR) = 1.9, 95% confidence interval (CI): 1.0-3.7, adjusted for study centre, age and multiplicity of infection). HPV16 and/or 18 prevalence combined, however, was similar in HIV-positive (66.7%) and HIV-negative cases (69.1%) (PR = 1.0, 95% CI: 0.9-1.2). No significant difference was found for other HPV types. Our data suggest that current prophylactic HPV vaccines against HPV16 and 18 may prevent similar proportions of cervical SCC in HIV-positive as in HIV-negative women provided that vaccine-related protection is sustained after HIV infection.

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.

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.

Loop electrosurgical excision procedure (LEEP) plus top hat for HIV-infected women with endocervical intraepithelial neoplasia in Kenya.

OBJECTIVE: To determine the utility of detecting endocervical cervical intraepithelial neoplasia (CIN) 2+ with endocervical curettage (ECC) and treating with loop electrosurgical excision procedure (LEEP) plus top hat (+TH) among women with HIV. METHODS: Cytology was followed by coloscopy-directed biopsy if participants had HSIL or ASC-H and biopsy plus ECC if there were glandular cells present. CIN2/3 on ECC and/or inadequate colposcopy (ENL) was treated with LEEP+TH, while CIN2/3 on ectocervix (ECL) received LEEP alone. Recurrent CIN2+ were compared over a 2-year follow-up. RESULTS: Of 5330 participants, 160 underwent ECC, 98 were CIN2/3 on ECC, and 77 received LEEP+TH. ECC detected 15 (9%) more women with CIN2/3 than biopsy alone. Women were more likely to have ENL if they were older (≥45 vs <35 years) (adjusted relative risk [aRR] 2.14; P = 0.009) and on antiretroviral treatment longer (≥2 vs <2 years) (aRR 3.97; P < 0.001). Over the 2-year follow-up, 35 (29%) ENL had recurrent CIN2+ after TH compared to 19 (24%) ECL after LEEP (hazard ratio 1.32; 95% confidence interval 0.75-2.31; P = 0.338). CONCLUSION: Among HIV-infected women, adding ECC did not increase detection of pre-cancerous disease significantly and treatment with LEEP+TH for ENL was comparable to treatment with LEEP for ECL.

The prevalence of human papillomavirus infection in Mombasa, Kenya.

OBJECTIVES: A human papillomavirus (HPV) prevalence survey was done in Mombasa, Kenya, to improve the knowledge of HPV prevalence and genotype distribution in sub-Saharan African countries overall, and in women of different ages. METHODS: HPV prevalence was assessed using PCR in women older than 15 years attending family planning and mother-child care services. RESULTS: Among 496 women, HPV prevalence was high (42.3%; 95% CI: 37.9-46.8; world age-standardized). Moreover, 46% of HPV-positive women harbored multiple-type infections. The most common types were HPV58 (10.5% of women), HPV16 (7.7%), HPV53 (6.7%), HPV18 (4.6%), and HPV6 (4.4%), and the prevalence of any high-risk HPV type was 28.8%. HPV prevalence was elevated among all age-groups (range 36.4-45.7%). Independent associations with HPV positivity were found for being in a polygamous marriage (OR = 1.7) and lifetime number of sexual partners (OR for ≥ 3 vs. 1 = 1.5), although they were of only borderline statistical significance. CONCLUSIONS: These findings differ from other world regions, showing a high HPV burden in all age-groups with a high proportion of multiple-type infections. Our data strengthen the urgency of HPV vaccination in Kenya but also highlight the elevated number of women who would have positive results in an HPV-based screening program in the country.

The impact of scaling up cervical cancer screening and treatment services among women living with HIV in Kenya: a modelling study.

Introduction: We aimed to quantify health outcomes and programmatic implications of scaling up cervical cancer (CC) screening and treatment options for women living with HIV in care aged 18-65 in Kenya. Methods: Mathematical model comparing from 2020 to 2040: (1) visual inspection with acetic acid (VIA) and cryotherapy (Cryo); (2) VIA and Cryo or loop excision electrical procedure (LEEP), as indicated; (3) human papillomavirus (HPV)-DNA testing and Cryo or LEEP; and (4) enhanced screening technologies (either same-day HPV-DNA testing or digitally enhanced VIA) and Cryo or LEEP. Outcomes measured were annual number of CC cases, deaths, screening and treatment interventions, and engaged in care (numbers screened, treated and cured) and five yearly age-standardised incidence. Results: All options will reduce CC cases and deaths compared with no scale-up. Options 1-3 will perform similarly, averting approximately 28 000 (33%) CC cases and 7700 (27%) deaths. That is, VIA screening would yield minimal losses to follow-up (LTFU). Conversely, LTFU associated with HPV-DNA testing will yield a lower care engagement, despite better diagnostic performance. In contrast, option 4 would maximise health outcomes, averting 43 200 (50%) CC cases and 11 800 (40%) deaths, given greater care engagement. Yearly rescreening with either option will impose a substantial burden on the health system, which could be reduced by spacing out frequency to three yearly without undermining health gains. Conclusions: Beyond the specific choice of technologies to scale up, efficiently using available options will drive programmatic success. Addressing practical constraints around diagnostics' performance and LTFU will be key to effectively avert CC cases and deaths.

Reproducibility of a Rapid Human Papillomavirus Test at Different Levels of the Healthcare System in Tanzania: The AISHA Study.

BACKGROUND: To inform policy makers in Tanzania if and how best to implement rapid HPV testing, we assessed the interobserver reproducibility of careHPV test at three different levels of the healthcare system in an urban and a rural region of Tanzania. METHODS: Women aged 30 to 50 years were screened by careHPV testing in two primary healthcare centers (PHC), two district hospitals (DiH), and two regional hospitals (ReH). Aliquots were retested at regional (ReH) and national referral laboratories (NRL). Reproducibility was evaluated using agreement and kappa index measures. Intralaboratory reproducibility was also evaluated in a set of 10 positive and 10 negative samples. RESULTS: Samples from 1,134 women were locally tested and retested at ReH and/or NRL. Test results from Dar es Salaam ReH and Kilimanjaro PHC showed clear quality problems including suspicion of contamination during testing or aliquoting. After excluding these samples, 18.8% of 743 women were HPV positive at clinic level. The resulting careHPV reproducibility at different levels of the healthcare system was very good [agreement 95.7%, 95% confidence interval (CI), 94.0-96.9; kappa, 0.86, 95% CI, 0.81-0.91]. Intralaboratory agreement was also very good across four different experiments, with Fleiss' kappa between 0.87 (95% CI, 0.61-1.00) and 1.00 (0.75-1.00). CONCLUSIONS: Rapid HPV testing was highly reproducible between lower and higher levels of the healthcare system in Tanzania; however, performance seems to be operator dependent. IMPACT: The careHPV test seems to be a feasible option for cervical cancer screening in an organized, decentralized system and in limited-resource settings if quality assurance measures are in place.

Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis.

This meta-analysis investigated human papillomavirus (HPV) prevalence in vulvar, vaginal and anal intraepithelial neoplasia (VIN, VAIN, AIN) grades 1-3 and carcinoma from 93 studies conducted in 4 continents and using PCR assays. Overall HPV prevalence was 67.8%, 85.3% and 40.4% among 90 VIN1, 1,061 VIN2/3 and 1,873 vulvar carcinomas; 100%, 90.1% and 69.9% among 107 VAIN1, 191 VAIN2/3 and 136 vaginal carcinomas; and 91.5%, 93.9% and 84.3% among 671 AIN1, 609 AIN2/3 and 955 anal carcinomas, respectively. HPV16 was found more frequently (>75%) and HPV18 less frequently (<10%) in HPV-positive vulvar, vaginal and anal carcinomas than in cervical carcinoma. HPV6 and 11 were common in VIN1 and AIN1, but not in VAIN1. HPV prevalence in vulvar carcinoma varied most by histological type (69.4% in warty-basaloid and 13.2% in keratinized type) and was also higher in women 60 years or younger and in studies carried out in North America. HPV prevalence in anal carcinoma was higher among women (90.8%) than men (74.9%), but no difference by gender emerged in North America. The majority of AIN2/3 derived from studies of HIV-positive individuals and/or men who have sex with men. Among AIN2/3, HIV infection was associated with higher HPV prevalence, more multiple-type infections and a relative under-representation of HPV16. In conclusion, approximately 40% of vulvar, 60% of vaginal and 80% of anal carcinoma may be avoided by prophylactic vaccines against HPV16/18. This proportion would be similar for the corresponding high-grade lesions of the vagina and anus, but higher for VIN2/3 (75%) than for vulvar carcinoma.

Self-sampling for human papillomavirus (HPV) testing: a systematic review and meta-analysis.

INTRODUCTION: Human papillomavirus (HPV) self-sampling test kits may increase screening for and early detection of cervical cancer and reduce its burden globally. To inform WHO self-care guidelines, we conducted a systematic review and meta-analysis of HPV self-sampling among adult women on cervical (pre-)cancer screening uptake, screening frequency, social harms/adverse events and linkage to clinical assessment/treatment. METHODS: The included studies compared women using cervical cancer screening services with HPV self-sampling with women using standard of care, measured at least one outcome, and were published in a peer-reviewed journal. We searched PubMed, the Cumulative Index to Nursing and Allied Health Literature (CNIAHL), Latin American and Caribbean Health Sciences Literature (LILACS) and Embase through October 2018. Risk of bias was assessed using the Cochrane tool for randomised controlled trials (RCTs) and the Evidence Project tool for non-randomised studies. Meta-analysis was conducted using random-effects models to generate pooled estimates of relative risk (RR). RESULTS: 33 studies in 34 articles with 369 017 total participants met the inclusion criteria: 29 RCTs and 4 observational studies. All studies examined HPV self-sampling; comparison groups were standard of care (eg, Pap smear, visual inspection with acetic acid, clinician-collected HPV testing). 93% of participants were from high-income countries. All 33 studies measured cervical cancer screening uptake. Meta-analysis found greater screening uptake among HPV self-sampling participants compared with control (RR: 2.13, 95% CI 1.89 to 2.40). Effect size varied by HPV test kit dissemination method, whether mailed directly to home (RR: 2.27, 95% CI 1.89 to 2.71), offered door-to-door (RR: 2.37, 95% CI 1.12 to 5.03) or requested on demand (RR: 1.28, 95% CI 0.90 to 1.82). Meta-analysis showed no statistically significant difference in linkage to clinical assessment/treatment between arms (RR: 1.12, 95% CI 0.80 to 1.57). No studies measured screening frequency or social harms/adverse events. CONCLUSION: A growing evidence base, mainly from high-income countries and with significant heterogeneity, suggests HPV self-sampling can increase cervical cancer screening uptake compared with standard of care, with a marginal effect on linkage to clinical assessment/treatment. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42018114871.

Human papillomavirus types in women with invasive cervical carcinoma by HIV status in Kenya.

To evaluate the fraction of invasive cervical carcinoma (ICC) that could be prevented in HIV-infected women by vaccines currently available against human papillomavirus (HPV)16 and 18, we conducted a cross-sectional study in women with ICC in Nairobi, Kenya. Fifty-one HIV-positive women were frequency-matched by age to 153 HIV-negative women. Cervical cells were tested for HPV DNA using polymerase chain reaction-based assays (SPF10-INNO-LiPA). Comparisons were adjusted for multiplicity of HPV types. As expected, multiple-type infections were much more frequent in HIV-positive (37.2%) than in HIV-negative (13.7%) women, but the distribution of HPV types was similar. HPV16 was detected in 41.2% versus 43.8% and HPV16 and/or 18 in 64.7% versus 60.1% of HIV-positive versus HIV-negative women, respectively. The only differences of borderline statistical significance were an excess of HPV52 (19.6% versus 5.2%) and a lack of HPV45 (7.8% versus 17.0%) in HIV-positive women compared to HIV-negative women, respectively. We have been able to assess an unprecedented number of ICCs in HIV-positive women, but as we did not know the age of HIV acquisition, we cannot exclude that it had occurred too late in life to affect the type of HPV involved in cervical carcinogenesis. However, if our findings were confirmed, they would suggest that the efficacy of current vaccines against HPV16 and 18 to prevent ICC is similar in HIV-positive and HIV-negative women, provided vaccination is administered before sexual debut, as recommended.

Role of p16 testing in cervical cancer screening among HIV-infected women.

BACKGROUND: p16 immunohistochemistry is used to evaluate for HPV-associated cervical intraepithelial neoplasia. The diagnostic performance of p16 in HIV infection is unclear. METHODS: Between June-December 2009, HIV-infected women underwent Papanicolaou (Pap) smear, human papillomavirus (HPV) testing, visual inspection with acetic acid (VIA), and colposcopy-directed biopsy as the disease gold standard at a HIV clinic in Kenya. Pap smears were evaluated for p16 expression. Sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC) of p16 to detect CIN2/3 on histology and the impact of immunosuppression and ART was assessed. RESULTS: Of 331 cervical samples with p16 expression, p16 sensitivity and specificity to detect CIN2/3 was 54.1% and 72.4% respectively, which was lower than Pap and HPV in sensitivity, but higher in specificity than Pap, HPV, and VIA. Combining tests and p16 reduced sensitivity and increased specificity of Pap from 90.5% to 48.7% and 51.4% to 81.7%; of VIA from 59.5% to 37.8% and 67.6% to 89.9%; and of HPV from 82.4% to 50.0% and 55.3% to 84.8%. Combination p16 increased the PPV of Pap from 34.9% to 43.4%; of HPV from 34.7% to 48.7%; and VIA from 34.9% to 51.9%. Adjunctive p16 did not change AUC (P>0.05). P16 performance was not altered by immunosuppression or ART use. Combining p16 with HPV and VIA reduced the variation in HPV and VIA performance associated with CD4 and ART. CONCLUSION: As an adjunctive test in HIV-infected women, p16 immunohistochemistry increased specificity and PPV of HPV and VIA for CIN2/3, and was not altered in performance by immunosuppression, ART, or age.

A Smartphone-Based Approach for Triage of Human Papillomavirus-Positive Sub-Saharan African Women: A Prospective Study.

BACKGROUND: Sub-Saharan African countries are marked by a high incidence of cervical cancer. Madagascar ranks 11th among the countries with the highest cervical cancer incidence worldwide. OBJECTIVE: The aim of the study was to evaluate the performances of digital smartphone-based visual inspection with acetic acid (D-VIA) and Lugol's iodine (D-VILI) for diagnosing cervical precancer and cancer. METHODS: Human papillomavirus (HPV)-positive women recruited through a cervical screening campaign had D-VIA and D-VILI examinations with endocervical curettage (ECC) and cervical biopsy. Three images were captured for each woman (native, D-VIA, D-VILI) using a smartphone camera. The images were randomly coded and distributed on 2 online databases (Google Forms). The D-VIA form included native and D-VIA images, and the D-VILI form included native and D-VILI images. Pathological cases were defined as cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Physicians rated the images as non-pathological or pathological. Using the ECC and cervical biopsy results as references, the sensitivity and specificity of D-VIA and D-VILI examinations for each and all physicians were calculated. RESULTS: Altogether, 15 clinicians assessed 240 images. Sensitivity was higher for the D-VIA interpretations (94.1%; 95% CI 81.6-98.3) than for the D-VILI interpretations (78.8%; 95% CI 54.1-92.1; P=.009). In contrast, the specificity was higher for the D-VILI interpretations (56.4%; 95% CI 38.3-72.9) than for the D-VIA interpretations (50.4%; 95% CI 35.9-64.8; P=.005). CONCLUSION: Smartphone-based image for triage of HPV-positive women is more accurate for detecting CIN2+ lesions with D-VIA than D-VILI, although with a small loss of specificity.

Effect of HIV Infection on Human Papillomavirus Types Causing Invasive Cervical Cancer in Africa.

OBJECTIVES: HIV infection is known to worsen the outcome of cervical human papillomavirus (HPV) infection and may do so differentially by HPV type. DESIGN: Twenty-one studies were included in a meta-analysis of invasive cervical cancers (ICC) among women infected with HIV in Africa. METHOD: Type-specific HPV DNA prevalence was compared with data from a similar meta-analysis of HIV-negative ICC using prevalence ratios (PR). RESULTS: HPV detection was similar in 770 HIV-positive (91.2%) and 3846 HIV-negative (89.6%) ICC, but HIV-positive ICC harbored significantly more multiple HPV infections (PR = 1.75, 95% confidence intervals: 1.18 to 2.58), which were significantly more prevalent in ICC tested from cells than from biopsies. HPV16 was the most frequently detected type in HIV-positive ICC (42.5%), followed by HPV18 (22.2%), HPV45 (14.4%), and HPV35 (7.1%). Nevertheless, HIV-positive ICC were significantly less frequently infected with HPV16 than HIV-negative ICC (PR = 0.88, 95% confidence intervals: 0.79 to 0.99). Other high-risk types were significantly more prevalent in HIV-positive ICC, but only for HPV18 was there a significantly higher prevalence of both single and multiple infections in HIV-positive ICC. Increases for other high-risk types were primarily accounted for by multiple infections. The proportion of HPV-positive ICC estimated attributable to HPV16/18 (71.8% in HIV positive, 73.4% in HIV negative) or HPV16/18/31/33/45/52/58 (88.8%, 89.5%) was not affected by HIV. CONCLUSIONS: HIV alters the relative carcinogenicity of HPV types, but prophylactic HPV16/18 vaccines may nevertheless prevent a similar proportion of ICC, irrespective of HIV infection.

Web-based instrument to assess skills in visual inspection of the cervix among healthcare providers.

OBJECTIVE: To validate a web-based instrument for assessing healthcare providers' skills in visual inspection with acetic acid or Lugol iodine (VIA/VILI) for the diagnosis and management of cervical intraepithelial neoplasia. METHODS: An observational cross-sectional study enrolled healthcare providers in a web-based assessment of VIA/VILI skills between August and November 2014. Participants participated in a four-module training course, followed by a multiple-choice test with 70 questions based on cervical photographs of HPV-positive women participating in cervical screening. Logistic regression was used to identify relationships between independent variables and success on the test. RESULTS: Overall, 255 participants completed the test and 99 (38.8%) passed. No correlation was found between age or sex and test performance. Compared with other healthcare workers, physicians (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.01-3.63; P=0.048), and participants with more colposcopy experience (OR 3.62, 95% CI 1.91-6.85; P<0.001) and postgraduate VIA/VILI training (OR 1.95, 95% CI 1.16-3.29; P=0.012) were more likely to pass the test. Participants who repeated the test (31/255 [12.2%]) were five times more likely to succeed on their second repeat (OR 5.89, 95% CI 1.46-23.73; P=0.013). CONCLUSION: Web-based training for VIA/VILI is feasible and can identify healthcare workers who are proficient in this technique.

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.