High-risk human papillomavirus distribution according to human immunodeficiency virus status among women with cervical cancer in Abidjan, Côte d'Ivoire, 2018 to 2020.

As human papillomavirus (HPV) immunisation and HPV-based cervical cancer (CC) screening programmes expand across sub-Saharan Africa, we investigated the potential impact of human immunodeficiency virus (HIV) status on high-risk (HR)-HPV distribution among women with CC in Côte d'Ivoire. From July 2018 to June 2020, paraffin-embedded CC specimens diagnosed in Abidjan, Côte d'Ivoire were systematically collected and tested for HR-HPV DNA. Type-specific HR-HPV prevalence was compared according to HIV status. Of the 170 CC specimens analysed (median age 52 years, interquartile range: [43.0-60.0]), 43 (25.3%) were from women living with HIV (WLHIV) with a median CD4 count of 526 [373-833] cells/mm3 and 86% were on antiretroviral therapy (ART). The overall HR-HPV prevalence was 89.4% [95% CI: 84.7-94.1]. All were single HR-HPV infections with no differences according to HIV status (P = .8). Among HR-HPV-positive CC specimens, the most prevalent HR-HPV types were HPV16 (57.2%), HPV18 (19.7%), HPV45 (8.6%) and HPV35 (4.6%), with no significant differences according to HIV status. Altogether, infection with HPV16/18 accounted for 71.1% [95% CI: 55.9-86.2] of CC cases in WLHIV vs 78.9% [95% CI: 71.3-86.5] in women without HIV (P = .3). The study confirms the major role of HPV16/18 in CC in Côte d'Ivoire and should support a regional scale-up of HPV16/18 vaccination programmes regardless of HIV status. However, vaccines targeting additional HR-HPV types, including HPV45 and HPV35, could further decrease future CC incidence in Côte d'Ivoire, both for WLHIV and women without HIV.

Impact of Human Papillomavirus Vaccination, Rwanda and Bhutan.

Rwanda and Bhutan, 2 low- and middle-income countries, implemented primarily school-based national human papillomavirus (HPV) vaccination in 2011 (Rwanda) and 2010 (Bhutan). We estimated vaccination effectiveness through urine-based HPV prevalence surveys in schools in 2013-2014 and 2017. In Rwanda, 912 participants from baseline surveys and 1,087 from repeat surveys were included, and in Bhutan, 973 participants from baseline surveys and 909 from repeat surveys were included. The overall effectiveness against vaccine-targeted HPV types (i.e., HPV-6/11/16/18) was 78% (95% CI 51%-90%) in Rwanda, and 88% (6%-99%) in Bhutan and against other α-9 types was 58% (21-78) in Rwanda and 63% (27-82) in Bhutan. No effect against other HPV types was detectable. Prevalence of vaccine-targeted HPV types decreased significantly, as well as that of other α-9 types, suggesting cross-protection. These findings provide direct evidence from low- and middle-income countries of the marked effectiveness of high-coverage school-based, national HPV vaccination programs.

Prevalence of Human Papillomavirus and Estimation of Human Papillomavirus Vaccine Effectiveness in Thimphu, Bhutan, in 2011-2012 and 2018 : A Cross-sectional Study.

BACKGROUND: Bhutan implemented a national program for human papillomavirus (HPV) vaccination in 2010 involving girls aged 12 to 18 years and achieving nearly 90% coverage. OBJECTIVE: To estimate HPV vaccine effectiveness in a city in Bhutan. DESIGN: 2 cross-sectional surveys, 2011-2012 and 2018. SETTING: 2 hospitals in Thimphu, capital of Bhutan. PARTICIPANTS: Sexually active women aged 17 to 29 years: 1445 participants from the baseline survey and 1595 from the repeated survey. INTERVENTION: National HPV vaccination program. MEASUREMENTS: HPV was assessed in cervical cell samples by using general primer GP5+/GP6+-mediated polymerase chain reaction. Human papillomavirus types were stratified as vaccine types (HPV6/11/16/18) and nonvaccine types. Age- and sexual behavior-adjusted overall, total, and indirect (herd immunity) vaccine effectiveness (VE) was computed as (1 - HPV prevalence ratio) for HPV among all women and among unvaccinated women. RESULTS: Between the 2 surveys, the prevalence of HPV vaccine types decreased from 8.3% to 1.4%, whereas the prevalence of nonvaccine types increased from 25.8% to 31.4%. The overall and indirect adjusted VE against vaccine-targeted HPV types was 88% (95% CI, 80% to 92%) and 78% (CI, 61% to 88%), respectively. Among women younger than 27 years, who were targeted by the vaccination program, the overall and indirect adjusted VE was 93% (CI, 87% to 97%) and 88% (CI, 69% to 95%), respectively. No impact on nonvaccine HPV types was detectable. LIMITATION: Hospital-based recruitment; self-reported vaccination status. CONCLUSION: In Bhutan, the prevalence of vaccine-targeted HPV types has decreased sharply, providing the first evidence of the effectiveness of a high-coverage national HPV vaccination program in a lower-middle-income country. PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

Human papillomavirus genotypes in cervical and other HPV-related anogenital cancer in Rwanda, according to HIV status.

The study aim was to describe human papillomavirus (HPV)-attributable cancer burden in Rwanda, according to anogenital cancer site, HPV type, age and HIV status. Tissue specimens of cervical, vulvar, vaginal, penile and anal cancer diagnosed in 2012-2018 were retrieved from three cancer referral hospitals and tested for high-risk (HR) HPV DNA. Cervical cancer represented the majority of cases (598 of 738), of which 96.0% were HR-HPV positive. HPV-attributable fractions in other cancer sites varied from 53.1% in 81 penile, through 76.7% in 30 vulvar, 83.3% in 24 vaginal, up to 100% in 5 anal cases. HPV16 was the predominant HR-HPV type in cervical cancer (55.0%), followed by HPV18 (16.6%) and HPV45 (13.4%). HPV16 also predominated in other cancer sites (60-80% of HR-HPV-attributable fraction). For cervical cancer, type-specific prevalence varied significantly by histology (higher alpha-9 type prevalence in 509 squamous cell carcinoma vs. higher alpha-7 type prevalence in 80 adenocarcinoma), but not between 501 HIV-negative and 97 HIV-positive cases. With respect to types targeted, and/or cross-protected, by HPV vaccines, HPV16/18 accounted for 73%, HPV31/33/45/52/58 for an additional 22% and other HR-HPV types for 5%, of HPV-attributable cancer burden, with no significant difference by HIV status nor age. These data highlight the preventive potential of the ongoing national HPV vaccination program in Rwanda, and in sub-Saharan Africa as a whole. Importantly for this region, the impact of HIV on the distribution of causal HPV types was relatively minor, confirming type-specific relevance of HPV vaccines, irrespective of HIV status.

Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention.

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.

Evaluation of human-papillomavirus testing and visual inspection for cervical cancer screening in Rwanda.

BACKGROUND: A pilot screening campaign in Rwanda, based on careHPV-testing followed by visual inspection with acetic acid triage (careHPV+VIA triage), was evaluated against other WHO-recommended screening options, namely HPV screen-and-treat and VIA screen-and-treat. METHODS: 764 women aged 30-69 underwent at visit 1: i) VIA, and cervical cell collection for ii) careHPV in Rwanda, and iii) liquid-based cytology and GP5+/6+ HR-HPV PCR in The Netherlands. All 177 women positive by VIA, careHPV and/or PCR were recalled, of whom 84% attended. At visit 2, VIA was again used to triage screen-positive women for treatment and to obtain biopsies from all women either from visible lesions or at 12 o'clock of the squamocolumnar junction. Cross-sectional screening indices were estimated primarily against histological high-grade squamous intraepithelial lesions or worse (hHSIL+), after imputation of missing histology data, based on 1-visit or 2-visit approaches. RESULTS: In a 1-visit screen-and-treat approach, VIA had sensitivity and specificity of 41% and 96%, respectively, versus 71% and 88% for careHPV, and 88% and 86% for PCR. In a 2-visit approach (in which hHSIL+ imputed among women without visit 2 were considered untreated) careHPV sensitivity dropped to 59% due to loss of 13% of hHSIL+. For careHPV+VIA triage, sensitivity dropped further to 35%, as another 24% of hHSIL+ were triaged to no treatment. CONCLUSIONS: CareHPV was not as sensitive as gold-standard PCR, but detected considerably more hHSIL+ than VIA. However, due to careHPV-positive hHSIL+ women being lost to follow-up and/or triaged to no treatment, 2-visit careHPV+VIA triage did not perform better than VIA screen-and-treat.

Evaluation of the performance of Human Papillomavirus testing in paired urine and clinician-collected cervical samples among women aged over 30 years in Bhutan.

BACKGROUND: Urine sampling may offer a less invasive solution than cervical sampling to test for human papillomavirus (HPV) for HPV vaccine impact monitoring. METHODS: Paired samples of urine and exfoliated cervical cells were obtained for 89 women with history of high-risk (HR) HPV-positive normal cytology in Bhutan. Urine sampling protocol included self-collection of first-void urine immediately into a conservation medium and procedures to optimize DNA yield. Colposcopical abnormalities were biopsied. Two HPV assays were used: a multiplex type-specific PCR (E7-MPG) and a less analytically sensitive GP5+/6+ PCR followed by reverse line blot. RESULTS: HPV positivity for 21 types common to both assays was similar in urine and cells by E7-MPG (62.9% and 57.3%, respectively, p = 0.32) but lower in urine by GP5+/6+ (30.3% and 40.4%, p = 0.05). HPV6/11/16/18 positivity did not significantly differ between urine and cells by either assay. Sensitivity of urine (using cells as gold standard) to detect 21 HPV types was 80% and 58% for E7-MPG and GP5+/6+, respectively, with specificity 61% and 89%. HPV type distribution in urine and cells was similar, regardless of assay. The 5 detected CIN3+ were HR-HPV positive in cells by both assays, compared to 4 and 3 by E7-MPG and GP5+/6+, respectively, in urine samples. CONCLUSION: For the monitoring of vaccine impact, we demonstrate validity of a urine sampling protocol to obtain HPV prevalence data that are broadly comparable to that from cervical cells. However, detection of HPV in urine varies according to assay sensitivity, presumably because low level infections are frequent.

Urine testing to monitor the impact of HPV vaccination in Bhutan and Rwanda.

Bhutan (2010) and Rwanda (2011) were the first countries in Asia and Africa to introduce national, primarily school-based, human papillomavirus (HPV) vaccination programmes. These target 12 year-old girls and initially included catch-up campaigns (13-18 year-olds in Bhutan and ninth school grade in Rwanda). In 2013, to obtain the earliest indicators of vaccine effectiveness, we performed two school-based HPV urine surveys; 973 female students (median age: 19 years, 5th-95th percentile: 18-22) were recruited in Bhutan and 912 (19 years, 17-20) in Rwanda. Participants self-collected a first-void urine sample using a validated protocol. HPV prevalence was obtained using two PCR assays that differ in sensitivity and type spectrum, namely GP5+/GP6+ and E7-MPG. 92% students in Bhutan and 43% in Rwanda reported to have been vaccinated (median vaccination age = 16, 5th-95th: 14-18). HPV positivity in urine was significantly associated with sexual activity measures. In Rwanda, HPV6/11/16/18 prevalence was lower in vaccinated than in unvaccinated students (prevalence ratio, PR = 0.12, 95% confidence interval, CI: 0.03-0.51 by GP5+/GP6+, and 0.45, CI: 0.23-0.90 by E7-MPG). For E7-MPG, cross-protection against 10 high-risk types phylogenetically related to HPV16 or 18 was of borderline significance (PR = 0.68; 95% CI: 0.45-1.01). In Bhutan, HPV6/11/16/18 prevalence by GP5+/GP6+ was lower in vaccinated than in unvaccinated students but CIs were broad. In conclusion, our study supports the feasibility of urine surveys to monitor HPV vaccination and quantifies the effectiveness of the quadrivalent vaccine in women vaccinated after pre-adolescence. Future similar surveys should detect increases in vaccine effectiveness if vaccination of 12 year-olds continues.

Comparison of Two Widely Used Human Papillomavirus Detection and Genotyping Methods, GP5+/6+-Based PCR Followed by Reverse Line Blot Hybridization and Multiplex Type-Specific E7-Based PCR.

GP5+/6+-based PCR followed by reverse line blot hybridization (GP5+/6+RLB) and multiplex type-specific PCR (E7-MPG) are two human papillomavirus (HPV) genotyping methodologies widely applied in epidemiological research. We investigated their relative analytical performance in 4,662 samples derived from five studies in Bhutan, Rwanda, and Mongolia coordinated by the International Agency for Research on Cancer (IARC). A total of 630 samples were positive by E7-MPG only (13.5%), 24 were positive by GP5+/6+RLB only (0.5%), and 1,014 were positive (21.8%) by both methods. Ratios of HPV type-specific positivity of the two tests (E7-MPG:GP5+/6+RLB ratio) were calculated among 1,668 samples that were HPV positive by one or both tests. E7-MPG:GP5+/6+RLB ratios were >1 for all types and highly reproducible across populations and sample types. E7-MPG:GP5+/6+RLB ratios were highest for HPV53 (7.5) and HPV68 (7.1). HPV16 (1.6) and HPV18 (1.7) had lower than average E7-MPG:GP5+/6+RLB ratios. Among E7-MPG positive infections, median mean fluorescence intensity (MFI; a semiquantitative measure of viral load) tended to be higher among samples positive for the same virus type by GP5+/6+RLB than for those negative for the same type by GP5+/6+RLB. Exceptions, however, included HPV53, -59, and -82, for which the chances of being undetected by GP5+/6+RLB appeared to be MFI independent. Furthermore, the probability of detecting an additional type by E7-MPG was higher when another type was already detected by GP5+/6+RLB, suggesting the existence of masking effects due to competition for GP5+/6+ PCR primers. In conclusion, this analysis is not an evaluation of clinical performance but may inform choices for HPV genotyping methods in epidemiological studies, when the relative merits and dangers of sensitivity versus specificity for individual types should be considered, as well as the potential to unmask nonvaccine types following HPV vaccination.

Human papillomavirus infection in Rwanda at the moment of implementation of a national HPV vaccination programme.

BACKGROUND: Cervical cancer is the most common female cancer in Rwanda that, in 2011, became the first African country to implement a national vaccination programme against human papillomavirus (HPV). METHODS: To provide a robust baseline for future evaluations of vaccine effectiveness, cervical cell specimens were obtained from 2508 women aged 18-69 years from the general population in Kigali, Rwanda, during 2013/14. 20 % of women were HIV-positive. Samples were used for liquid-based cytology and HPV testing (44 types) with GP5+/6+ PCR. RESULTS: HPV prevalence was 34 %, being highest (54 %) in women ≤19 years and decreasing to 20 % at age ≥50. Prevalence of high risk (HR) HPV and cytological abnormalities was 22 and 11 % respectively (including 2 % with high-grade squamous intraepithelial lesions, HSIL) decreasing with age. Age-standardised prevalence of HR HPV was 22 % (or 19 % among HIV-negative women), and HPV16 was the most common type. Prevalence of HPV and cytological abnormalities were significantly higher in HIV-positive than HIV-negative women, and the difference increased with age. Other significant risk factors for HPV positivity in multivariate analyses were high lifetime number of sexual partners, receiving cash for sex, and being a farmer. 40 % of women with HSIL were infected with HPV16/18 and there was no significant difference between HIV-positive and HIV-negative women. CONCLUSIONS: This study confirms Rwanda to be a setting of high prevalence of HPV and cervical disease that is worsened by HIV. These data will serve as a robust baseline for future evaluations of HPV vaccine programme effectiveness.

Contribution of ATM and FOXE1 (TTF2) to risk of papillary thyroid carcinoma in Belarusian children exposed to radiation.

A dramatic increase in the incidence of papillary thyroid carcinoma (PTC) after childhood exposure to ionizing radiation from the Chernobyl nuclear accident has been described as the largest number of tumors of one type due to one cause that have ever occurred. inter-individual variations in response to radiation have been documented and the role of genetics in sporadic PTC is well established, suggesting that genetic factors may also affect the risk of radiation-related PTC. To investigate how environmental and host factors interplay to modify PTC risk, we genotyped 83 cases and 324 matched controls sampled from children living in the area contaminated by fallout from the Chernobyl power plant accident for 19 polymorphisms previously associated with PTC, thyroid biology or radiation-induced second primary tumors. Significant association with PTC was found for rs1801516 (D1853N) in ATM (odds ratio (OR) = 0.34, 95% confidence interval (CI) 0.16, 0.73) and rs1867277 in the promoter region of FOXE1 (OR = 1.55, 95% CI 1.03, 2.34). Analysis of additional polymorphisms confirmed the association between these two genes and PTC. Our findings suggest that both DNA double-strand break repair pathway and thyroid morphogenesis pathway or dysregulation of thyroid differentiated state maintenance are involved in the etiology of PTC, and that the studied genetic polymorphisms and radiation dose appear to act as independent multiplicative risk factors for PTC.

Human papillomavirus infection in Bhutan at the moment of implementation of a national HPV vaccination programme.

BACKGROUND: Cervical cancer is the most common female cancer in Bhutan, the first low/middle-income country to implement a national human papillomavirus (HPV) vaccination programme. METHODS: To provide a robust baseline for future evaluations of vaccine effectiveness, cervical cell specimens were obtained from 2,505 women aged 18-69 years from the general population, and biopsies from 211 cervical intraepithelial neoplasia grade 3 (CIN3) and 112 invasive cervical cancer (ICC) cases. Samples were tested for HPV using GP5+/6+ PCR. RESULTS: Among the general population, HPV prevalence was 26%, being highest (33%) in women ≤24 years, but remaining above 15% in all age-groups. Determinants of HPV included age, marital status, and number of sexual partners. Among the eight percent with cytological abnormalities, 24 CIN3 and 4 ICC were histologically confirmed. Even after additional testing with a sensitive E7 PCR, no infections with vaccine-targeted HPV types were detected in the few vaccinated women (n = 34) compared to 6% prevalence in unvaccinated women of similar age (p = 0 · 215). CONCLUSION: Based upon type-specific prevalence among biopsies, at least 70% of ICC in Bhutan are theoretically preventable by HPV16/18 vaccination, but screening programmes should be expanded among older women, who have an important underlying burden of CIN3 and ICC.

Cervical cancer screening program in Thimphu, Bhutan: population coverage and characteristics associated with screening attendance.

BACKGROUND: Bhutan has been engaged in good-quality cytology-based cervical screening since 2000 and has vaccinated >90% girls against human papillomavirus (HPV) since 2010. We explored the characteristics associated with lack of previous screening and screening coverage in women age ≥25 years. METHODS: Women were invited at home or during their attendance at 2 outpatient clinics, in the capital, Thimphu, and nearby Lungthenphu. Age-adjusted odds ratios for lack of previous screening by selected characteristics were computed among 1,620 participating women. In Thimphu an invitation registry allowed to estimate screening history not only among participating women but also among additional 500 women who did not accept to join our study. RESULTS: Among women who had a Pap smear, lack of previous screening was associated with age <35 or ≥45 years. It was also associated with some occupations; being single, or widowed/separated; and presence of HPV infection. Multiparity and use of contraceptive methods were associated with having been screened. In women invited at home in Thimphu screening history substantially differed by participation. Past screening attendance was 59% among women recruited in the 2 clinics, 53% in women who were invited from home and accepted the invitation, but only 25% in those who refused it. Based on all women recruited from home the estimate of population-based coverage in Thimphu is 34% (95% CI: 31-37). CONCLUSIONS: Transition from an opportunistic screening to an all-reaching population-based screening is yet to be achieved in Bhutan, even in the capital. Better ways to target never-screened women are needed.

Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection.

Human Papillomavirus (HPV) type variants have been classified into lineages and sublineages based upon their whole genome sequence. Here we have examined the specificity of antibodies generated following natural infection with lineage variants of oncogenic types (HPV16, 18, 31, 33, 45, 52 and 58) by testing serum samples assembled from existing archives from women residing in Africa, The Americas, Asia or Europe against representative lineage-specific pseudoviruses for each genotype. We have subjected the resulting neutralizing antibody data to antigenic clustering methods and created relational antigenic profiles for each genotype to inform the delineation of lineage-specific serotypes. For most genotypes, there was evidence of differential recognition of lineage-specific antigens and in some cases of a sufficient magnitude to suggest that some lineages should be considered antigenically distinct within their respective genotypes. These data provide compelling evidence for a degree of lineage specificity within the humoral immune response following natural infection with oncogenic HPV.

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.

Human papillomavirus vaccine effect against human papillomavirus infection in Rwanda: evidence from repeated cross-sectional cervical-cell-based surveys.

BACKGROUND: Rwanda was the first African country to implement national human papillomavirus (HPV) vaccination (against types HPV6, 11, 16, and 18). In 2011, a school-based catch-up programme was initiated to vaccinate girls aged younger than 15 years but it also reached older girls in schools. We aimed to estimate the population-level effect of HPV vaccination on HPV prevalence. METHODS: Cross-sectional surveys were done between July, 2013, and April, 2014 (baseline), and between March, 2019, and December, 2020 (repeat), in sexually active women aged 17-29 years at health centres in the Nyarugenge District of Kigali, Rwanda. HPV prevalence was assessed in cervical cell samples collected by a health-care worker in PreservCyt solution (Cytyc, Boxbourough, MA, USA) and tested using a general primer (GP5+ or GP6+)-mediated PCR. Adjusted overall, total, and indirect (herd immunity) vaccine effectiveness was computed as the percentage of HPV detection among all women and among unvaccinated women. FINDINGS: 1501 participants completed the baseline survey and 1639 completed the repeat survey. HPV vaccine-type prevalence in participants aged 17-29 years decreased from 12% (173 of 1501) in the baseline survey to 5% (89 of 1639) in the repeat survey, with an adjusted overall vaccine effectiveness of 47% (95% CI 31 to 60) and an adjusted indirect vaccine effectiveness of 32% (9 to 49). Among participants aged 17-23 years, who were eligible for catch-up vaccination, the adjusted overall vaccine effectiveness was 52% (35 to 65) and the adjusted indirect vaccine effectiveness was 36% (8 to 55), with important heterogeneity according to education (overall vaccine effectiveness was 68% [51 to 79] in participants with ≥6 years of school completed and 16% [-34 to 47] in those with <6 years) and HIV status (overall vaccine effectiveness was 55% [36 to 69] for HIV-negative participants and 24% [-62 to 64] for HIV-positive participants). INTERPRETATION: In Rwanda, the prevalence of vaccine-targeted HPV types has been significantly decreased by the HPV vaccine programme, most notably in women who were attending school during the catch-up programme in 2011. HPV vaccine coverage and population-level impact is expected to increase in future cohorts who are eligible for routine HPV vaccination at age 12 years. FUNDING: Bill & Melinda Gates Foundation.

Human papillomavirus testing on self-collected samples to detect high-grade cervical lesions in rural Bhutan: The REACH-Bhutan study.

BACKGROUND: "REACH-Bhutan" aimed to evaluate the feasibility and clinical performance of a community-based screening program for cervical cancer in rural Bhutan using self-collected samples for high-risk human papillomavirus (HR-HPV) testing. METHODS: In April/May 2016, 2590 women aged 30-60 years were screened across rural Bhutan by providing a self-collected sample for careHPV testing. All careHPV-positive women, plus a random sample of careHPV-negative women, were recalled for colposcopy and biopsy. Self-samples also underwent GP5+/6+ polymerase chain reaction (PCR)-based HR-HPV DNA detection and genotyping. Cross-sectional screening indices were estimated against histological high-grade squamous intraepithelial lesions or worse (hHSIL+), including imputation of hHSIL+ in women without colposcopy. RESULTS: HR-HPV positivity was 10.2% by careHPV and 14.8% by GP5+/6+ PCR. Twenty-two cases of hHSIL+ were histologically diagnosed, including one invasive cancer; an additional 7 hHSIL+ were imputed in women without colposcopy. HR-HPV testing by GP5+/6+ showed higher sensitivity for hHSIL+ (89.7%, 95% CI 72.6-97.8) than careHPV (75.9%, 95% CI 56.5-89.7). Negative predictive value was also slightly higher for GP5+/6+ (99.9%, 95% CI 99.6-100) than careHPV (99.7%, 95% CI 99.4-99.9). Specificity, however, was lower for GP5+/6+ (86.1%, 95% CI 84.6-87.4) than careHPV (90.6%, 95% CI 89.4-91.7), as was positive predictive value (6.9%, 95% CI 4.5-9.9 vs. 8.5%, 95% CI 5.4-12.6). Of 377 HR-HPV-positive women by GP5+/6+, 173 (45.9%) were careHPV-positive, including 54.7% HPV16-positive and 30.2% HPV18-positive women. CONCLUSIONS: The final REACH-Bhutan results show that screening for cervical cancer with self-collection of samples and HR-HPV testing, in addition to our previous report of achieving high participation, can also perform well to detect women with hHSIL+.

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.

Prevalence of human papillomavirus types in cervical lesions from women in rural Western India.

Cervical cancer is the most common cancer among women in many areas of India which contributes for a fifth of the global burden of disease. Persistent infection with one of the high-risk human papillomaviruses (HPV) has been established as the cause for cervical cancer and the documentation of the prevalence of HPV types in cervical cancer in different regions of India is useful for a prevention program combining both screening and vaccination. In this study, the HPV type distribution and the frequency of p16(INK4a) immunoexpression have been determined in 125 cases of inflammatory lesions or grade 1 cervical intraepithelial neoplasia, 74 cases of grade 2, 72 cases of grade 3, and 113 cervical cancer cases diagnosed among women from rural Solapur and Osmanabad districts, Maharashtra. The overall prevalence of high-risk HPV was 37.6% in inflammatory lesions or grade 1 cervical intraepithelial neoplasia, 63.5% in grade 2, 97.2% in grade 3 and 92% in cervical cancer cases. HPV 16 and HPV 18 were detected in 80.6% of grade 3 cervical intraepithelial neoplasia and 86.5% of cervical cancer cases. 94.7% of the cervical cancer and 84.4% of the high grade lesions with a strong and full thickness staining for p16(INK4a) were positive for HPV infection; p16(INK4a) immunoexpression increased with worsening grade of cervical intraepithelial neoplasia. The HPV genotyping data showing a high HPV 16 and 18 prevalence in cancer specimens indicate that prophylactic HPV 16/18 vaccination would have a significant impact on the prevention of cervical cancer in India.

Phylogenomic Analysis of Human Papillomavirus Type 31 and Cervical Carcinogenesis: A Study of 2093 Viral Genomes.

Human papillomavirus (HPV) type 31 (HPV31) is closely related to the most carcinogenic type, HPV16, but only accounts for 4% of cervical cancer cases worldwide. Viral genetic and epigenetic variations have been associated with carcinogenesis for other high-risk HPV types, but little is known about HPV31. We sequenced 2093 HPV31 viral whole genomes from two large studies, one from the U.S. and one international. In addition, we investigated CpG methylation in a subset of 175 samples. We evaluated the association of HPV31 lineages/sublineages, single nucleotide polymorphisms (SNPs) and viral methylation with cervical carcinogenesis. HPV31 A/B clade was >1.8-fold more associated with cervical intraepithelial neoplasia grade 3 and cancer (CIN3+) compared to the most common C lineage. Lineage/sublineage distribution varied by race/ethnicity and geographic region. A viral genome-wide association analysis identified SNPs within the A/B clade associated with CIN3+, including H23Y (C626T) (odds ratio = 1.60, confidence intervals = 1.17-2.19) located in the pRb CR2 binding-site within the E7 oncogene. Viral CpG methylation was higher in lineage B, compared to the other lineages, and was most elevated in CIN3+. In conclusion, these data support the increased oncogenicity of the A/B lineages and suggest variation of E7 as a contributing risk factor.