Association of naturally acquired type-specific HPV antibodies and subsequent HPV re-detection: systematic review and meta-analysis.

BACKGROUND: Understanding the role of naturally acquired (i.e., infection-induced) human papillomavirus (HPV) antibodies against reinfection is important given the high incidence of this sexually transmitted infection. However, the protective effect of naturally acquired antibodies in terms of the level of protection, duration, and differential effect by sex remains incompletely understood. We conducted a systematic review and a meta-analysis to (1) strengthen the evidence on the association between HPV antibodies acquired through past infection and subsequent type-specific HPV detection, (2) investigate the potential influence of type-specific HPV antibody levels, and (3) assess differential effects by HIV status. METHODS: We searched Embase and Medline databases to identify studies which prospectively assessed the risk of type-specific HPV detection by baseline homologous HPV serostatus among unvaccinated individuals. Random-effect models were used to pool the measures of association of naturally acquired HPV antibodies against subsequent incident detection and persistent HPV positivity. Sources of heterogeneity for each type were assessed through subgroup analyses stratified by sex, anatomical site of infection, male sexual orientation, age group, and length of follow-up period. Evidence of a dose-response relationship of the association between levels of baseline HPV antibodies and type-specific HPV detection was assessed. Finally, we pooled estimates from publications reporting associations between HPV serostatus and type-specific HPV detection by baseline HIV status. RESULTS: We identified 26 publications (16 independent studies, with 62,363 participants) reporting associations between baseline HPV serostatus and incident HPV detection, mainly for HPV-16 and HPV-18, the most detected HPV type. We found evidence of protective effects of baseline HPV seropositivity and subsequent detection of HPV DNA (0.70, 95% CI 0.61-0.80, NE = 11) and persistent HPV positivity (0.65, 95% CI 0.42-1.01, NE = 5) mainly for HPV-16 among females, but not among males, nor for HPV-18. Estimates from 8 studies suggested a negative dose-response relationship between HPV antibody level and subsequent detection among females. Finally, we did not observe any differential effect by baseline HIV status due to the limited number of studies available. CONCLUSION: We did not find evidence that naturally acquired HPV antibodies protect against subsequent HPV positivity in males and provide only modest protection among females for HPV-16. One potential limitation to the interpretation of these findings is potential misclassification biases due to different causes.

Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence.

Pre-exposure prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate and emtricitabine administered orally daily is effective in preventing human immunodeficiency virus (HIV) acquisition in both men and women with sufficient adherence; however, the adherence-efficacy relationship in cisgender women has not been well established. We calculated the adherence-efficacy curve for cisgender women by using HIV incidence and plasma TFV concentration data from three trials (FEM-PrEP, VOICE and Partners PrEP). We imputed TFV diphosphate (TFV-DP) concentrations, a measure of long-term adherence, from TFV quantification by using data from the HIV Prevention Trials Network 082 study, which measured both TFV-DP and TFV concentrations. Two, four and seven pills per week reduced HIV incidence by 59.3% (95% credible interval (CrI) 29.9-95.8%), 83.8% (95% CI 51.7-99.8%) and 95.9% (95% CI 72.6-100%), respectively. Our adherence-efficacy curve can be validated and updated by HIV prevention studies that directly measure TFV-DP concentrations. The curve suggests that high adherence confers high protection in cisgender women. However, the lower efficacy with partial adherence highlights the need for new PrEP products and interventions to increase adherence.

Development of a tool to assess HIV prevention readiness of adolescent girls and young women in HPTN 082 study.

BACKGROUND: African adolescent girls and young women (AGYW) represent a large proportion of new HIV infections, a priority population for pre-exposure prophylaxis (PrEP), but adherence remains a challenge. A reliable, valid readiness tool would help identify AGYW motivated to take PrEP who need adherence support. METHODS: In the HPTN 082 open-label PrEP study (2016-2019), South African and Zimbabwean women ages 16-25 were administered an HIV prevention readiness measure (HPRM). The 25 items in the HPRM included medication beliefs, connection with care, disclosure of PrEP use, social support, and housing stability using a 5-point Likert scale. Exploratory factor analysis (EFA) using polychoric correlations, scale reliability, and predictive validity were performed on data from 315 participants who responded to all items. We assessed the predictive value of HPRM scores with PrEP adherence, defined as tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots, as a continuous measure and dichotomized as high PrEP adherence (≥700 fmol/punch). RESULTS: EFA yielded 23 items with three subscales: self-efficacy (16 items), PrEP disclosure (4 items), and social support (3 items). Cronbach's α ranged from 0.71 to 0.92 for the overall scale and the subscales. The average overall scale and the subscales were predictive of 3-month PrEP adherence for TFV-DP concentrations: for each unit increase of the HPRM score, TFV-DP concentration increased by 103 fmol/punch (95% CI: 16, 189, p = 0.02); the highest HPRM score equated with 608 fmol/punch on average. For the self-efficacy subscale, TFV-DP increased by 90 fmol/punch (95% CI: 7, 172, p = 0.03); PrEP disclosure, 68 fmol/punch (95% CI: 19, 117 p = 0.01); and social support, 58fmol/punch (95% CI: 2, 113, p = 0.04). Higher PrEP disclosure suggests high adherence (OR 1.36, 95% CI: 1.00, 1.86, p = 0.05) and predicted persistent high adherence at both months three and six (OR: 1.50, 95% CI: 1.03, 2.21, p = 0.04). CONCLUSIONS: The HPRM scale overall and the subscales individually demonstrated good internal consistency among African young women. PrEP disclosure subscale exhibiting significant association with persistent high PrEP adherence is an important finding for PrEP adherence support programs. Future work will assess replicability and expand self-efficacy and social-support subscales after item revision. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

Regional and country-level trends in cervical cancer screening coverage in sub-Saharan Africa: A systematic analysis of population-based surveys (2000-2020).

BACKGROUND: Sub-Saharan Africa (SSA) has the highest cervical cancer (CC) burden globally-worsened by its HIV epidemics. In 2020, the World Health Organization (WHO) introduced a CC elimination strategy with goals for vaccination, screening, and treatment. To benchmark progress, we examined temporal trends in screening coverage, percent screened at least twice by the age of 45, screening coverage among women living with HIV (WLHIV), and pre-cancer treatment coverage in SSA. METHODS AND FINDINGS: We conducted a systematic analysis of cross-sectional population-based surveys. It included 52 surveys from 28 countries (2000 to 2020) with information on CC screening among women aged 25 to 49 years (N = 151,338 women). We estimated lifetime and past 3-year screening coverage by age, year, country, and HIV serostatus using a Bayesian multilevel model. Post-stratification and imputations were done to obtain aggregate national, regional, and SSA-level estimates. To measure re-screening by age 45, a life table model was developed. Finally, self-reported pre-cancer treatment coverage was pooled across surveys using a Bayesian meta-analysis. Overall, an estimated 14% (95% credible intervals [95% CrI]: 11% to 21%) of women aged 30 to 49 years had ever been screened for CC in 2020, with important regional and country-level differences. In Eastern and Western/Central Africa, regional screening coverages remained constant from 2000 to 2020 and WLHIV had greater odds of being screened compared to women without HIV. In Southern Africa, however, screening coverages increased and WLHIV had equal odds of screening. Notably this region was found to have higher screening coverage in comparison to other African regions. Rescreening rates were high among women who have already been screened; however, it was estimated that only 12% (95% CrI: 10% to 18%) of women had been screened twice or more by age 45 in 2020. Finally, treatment coverage among 4 countries with data was 84% (95% CrI: 70% to 95%). Limitations of our analyses include the paucity of data on screening modality and the few countries that had multiple surveys. CONCLUSION: Overall, CC screening coverage remains sub-optimal and did not improve much over the last 2 decades, outside of Southern Africa. Action is needed to increase screening coverage if CC elimination is to be achieved.

Understanding the public health value and defining preferred product characteristics for therapeutic human papillomavirus (HPV) vaccines: World Health Organization consultations, October 2021-March 2022.

The World Health Organization (WHO) global strategy to eliminate cervical cancer (CxCa) could result in >62 million lives saved by 2120 if strategy targets are reached and maintained: 90% of adolescent girls receiving prophylactic human papillomavirus (HPV) vaccine, 70% of women receiving twice-lifetime cervical cancer screening, and 90% of cervical pre-cancer lesions and invasive CxCa treated. However, the cost and complexity of CxCa screening and treatment approaches has hampered scale-up, particularly in low- and middle-income countries (LMICs), and new approaches are needed. Therapeutic HPV vaccines (TxV), which could clear persistent high-risk HPV infection and/or cause regression of pre-cancerous lesions, are in early clinical development and might offer one such approach. During October 2021 to March 2022, WHO, in collaboration with the Bill and Melinda Gates Foundation, convened a series of global expert consultations to lay the groundwork for understanding the potential value of TxV in the context of current CxCa prevention efforts and for defining WHO preferred product characteristics (PPCs) for TxV. WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper reports on the main discussion points and findings from the expert consultations. Experts identified several ways in which TxV might address challenges in current CxCa prevention programmes, but emphasized that the potential value of TxV will depend on their degree of efficacy and how quickly they can be developed and implemented relative to ongoing scale-up of existing interventions. Consultation participants also discussed potential use-cases for TxV, important PPC considerations (e.g., vaccine indications, target populations, and delivery strategies), and critical modelling needs for predicting TxV impact and cost-effectiveness.

Characterization of Human Immunodeficiency Virus (HIV) Infections in Women Who Received Injectable Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention: HPTN 084.

BACKGROUND: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding. METHODS: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V. CONCLUSIONS: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.

Impact of one and two human papillomavirus (HPV) vaccine doses on community-level HPV prevalence in South African adolescent girls: study protocol and rationale for a pragmatic before-after design.

INTRODUCTION: Vaccines against human papillomavirus (HPV) are the key to controlling cervical cancer in low/middle-income countries (LMICs) where incidence is highest, but there have been limited data from these settings on programme impact on HPV prevalence, and none in a population with endemic HIV infection. Furthermore, for many LMICs, the currently recommended two-dose schedule is difficult to deliver at scale, so there is mounting interest in a single-dose schedule. METHODS AND ANALYSIS: The Human Papillomavirus One and Two-Dose Population Effectiveness Study is a hybrid impact evaluation of the national South African HPV vaccination programme, which has targeted grade 4 girls aged at least 9 years in public schools with two doses of vaccine since 2014, and a single-dose vaccine 'catch-up' programme delivered in one district in 2019. Impacts of both schedules on the prevalence of type-specific HPV infection will be measured using repeat cross-sectional surveys in adolescent girls and young women aged 17-18 years recruited at primary healthcare clinics in the four provinces. A baseline survey in 2019 measured HPV prevalence in the cohort who were ineligible for vaccination because they were already above the target age or grade under either the national programme or the single-dose programme in the selected district. HPV prevalence surveys are repeated in 2021 in the selected district, and in 2023 in all four provinces. We will calculate prevalence ratios to compare the prevalence of HPV types 16 and 18 in the single-dose (2021) and two-dose (2023) cohorts, with the vaccine-ineligible (2019) cohort. ETHICS AND DISSEMINATION: The project was approved by the University of the Witwatersrand Human Research Ethics Committee (HREC #181005), and the University of New South Wales HREC (#181-005). Findings will be disseminated through peer-reviewed journals, scientific meetings, reports and community forums.

Diagnostic accuracy of cervical cancer screening and screening-triage strategies among women living with HIV-1 in Burkina Faso and South Africa: A cohort study.

BACKGROUND: Cervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen-triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa. METHODS AND FINDINGS: WLHIV aged 25-50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol's iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%-52.7%) and CIN3+ (56.1%, 95% CI 43.3%-68.3%) in both countries, with specificity for ≤CIN1 of 78.7% (95% CI 76.0%-81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%-93.2%) for CIN2+ and 86.4% (95% CI 75.7%-93.6%) for CIN3+. Specificity for ≤CIN1 was 55.4% (95% CI 52.2%-58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%-76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%-86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28-2.32; CIN3+: 1.18, 95% CI 0.94-1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%-77.9%; CIN3+: 80.8%, 95% CI 67.5%-90.4%) and specificity (81.6%, 95% CI 77.6%-85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%-91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%-47.1%; relative specificity = 0.57, 95% CI 0.52-0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%-3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%-3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%-1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today. CONCLUSIONS: In this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone.

Performance of the Swede score to predict cervical intraepithelial neoplasia in women with HIV-1 in Johannesburg, South Africa.

OBJECTIVE: To evaluate the performance of the Swede score to detect cervical intraepithelial neoplasia (CIN) in women with HIV-1 in Johannesburg, South Africa. METHODS: A cross-sectional study using secondary data analysis from the HPV in Africa Research Partnership (HARP) study that compared the performance of three different screening tests to detect CIN. Colposcopy was performed on any woman who screened positive and findings were recorded using the Swede score. A biopsy of any lesion and a four-quadrant biopsy was taken. The score was evaluated against a histological diagnosis of >CIN1. The sensistivity, specificity, PPV and NPV for each score was calculated. RESULTS: Median age and CD4+ count of the 576 women eligible from the Johannesburg cohort was 34 years (IQR, 30-39) and 427 cells/mm3 (IQR, 323-579), respectively. Almost two-thirds (64%) were on ART and about 21% had CIN 2+ on histology. A Swede score of 5 or greater had the best combination of sensitivity and specificity for CIN 2+ with an AUC of 0.72 (95% CI, 0.68-0.76) corresponding to a sensitivity of 72.1 (95% CI, 63.5-79.6) and specificity of 71.8 (95% CI, 67.4-75.9). CONCLUSION: The Swede score can assist in determining whether women with HIV/AIDS should have treatment at the first colposcopy visit versus those who may be followed up, thereby individualizing treatment.

Human Papillomavirus Seroprevalence and Seroconversion Among Men Living With HIV: Cohort Study in South Africa.

BACKGROUND: Men living with HIV (MLHIV) have a high burden of human papillomavirus (HPV)-related cancer. Understanding serological dynamics of HPV in men can guide decisions on introducing HPV vaccination and monitoring impact. We determined HPV seroprevalence and evaluated factors associated with HPV seroconversion among MLHIV in Johannesburg, South Africa. METHODS: We enrolled 304 sexually active MLHIV 18 years and older and collected sociobehavioral data, blood samples (CD4 counts, HIV-1 plasma viral load, and HPV serology), and genital and anal swabs [HPV DNA and HPV viral load (VL)] at enrollment and 6-monthly for up to 18 months. Antibodies to 15 HPV types were measured using HPV pseudovirions. Generalized estimating equations were used to evaluate correlates of HPV seroconversion. RESULTS: Median age at enrollment was 38 years (IQR: 22-59), 25% reported >1 sexual partner in the past 3 months, and 5% reported ever having sex with other men. Most participants (65%) were on antiretroviral therapy (ART), with median CD4 count of 445 cells/µL (IQR: 328-567). Seroprevalence for any HPV type was 66% (199/303). Baseline seropositivity for any bivalent (16/18), quadrivalent (6/11/16/18), and nonavalent (6/11/16/18/31/33/45/52/58) vaccine types was 19%, 37%, and 60%, respectively. At 18 months, type-specific seroconversion among 59 men whose genital samples were HPV DNA positive but seronegative for the same type at enrollment was 22% (13/59). Type-specific seroconversion was higher among men with detectable HIV plasma viral load (adjusted odds ratio = 2.78, 95% CI: 1.12 to 6.77) and high HPV VL (adjusted odds ratio = 3.32, 95% CI: 1.42 to 7.74). CONCLUSIONS: Seropositivity and exposure to nonavalent HPV types were high among MLHIV. HPV vaccination of boys before they become sexually active could reduce the burden of HPV infection among this at-risk population.

Human papillomavirus infection and cervical dysplasia in HIV-positive women: potential role of the vaginal microbiota.

OBJECTIVES: To assess the associations between microbiological markers of vaginal dysbiosis and incident/cleared/type-swap/persistent high-risk human papillomavirus (hrHPV) infection; and incident/cured/cleared/persistent high-grade cervical intraepithelial neoplasia (CIN2+) while controlling for persistent hrHPV infection. DESIGN: Two nested case-control studies (N = 304 and 236) within a prospective cohort of HIV-positive women in Johannesburg, South Africa. METHODS: Participants were examined for hrHPV type (INNO-LiPA), cervical dysplasia (histology), and vaginal microbiota (VMB) composition (V3-V4 Illumina HiSeq 2x300 bp) at baseline and endline, a median of 16 months later. RESULTS: Women with incident hrHPV compared to those who remained hrHPV-negative were less likely to have an optimal Lactobacillus crispatus or jensenii-dominated VMB type at end-line [relative risk ratio (RRR) 0.125, P = 0.019], but not at baseline. Having different hrHPV types at both visits was associated with multiple anaerobic dysbiosis markers at baseline (e.g. increased bacterial vaginosis-associated anaerobes relative abundance: RRR 3.246, P = 0.026). Compared to women without CIN2+, but with hrHPV at both visits, women with incident CIN2+ had increased Simpson diversity (RRR 7.352, P = 0.028) and nonsignificant trends in other anaerobic dysbiosis markers at end-line but not baseline. These associations persisted after controlling for age, hormonal contraception, and CD4 cell count. Current hormonal contraceptive use (predominantly progestin-only injectables) was associated with increased CIN2+ risk over-and-above persistent hrHPV infection and independent of VMB composition. CONCLUSIONS: hrHPV infection (and/or increased sexual risk-taking) may cause anaerobic vaginal dysbiosis, but a bidirectional relationship is also possible. In this population, dysbiosis did not increase CIN2+ risk, but CIN2+ increased dysbiosis risk. The CIN2+ risk associated with progestin-only injectable use requires further evaluation.

Prevalent, persistent anal HPV infection and squamous intraepithelial lesions: Findings from a cohort of men living with HIV in South Africa.

OBJECTIVE: To estimate the prevalence, incidence and persistence of anal HPV infection and squamous intra-epithelial lesions (SILs) among men living with HIV (MLHIV), and determine their risk factors. METHODS: We enrolled MLHIV ≥18 years, who attended 6-monthly visits for 18 months. Socio-behavioural data were collected by questionnaire. Clinicians collected blood sample (CD4+ count and HIV plasma viral load), anal swabs (HPV DNA testing) and anal smears (Bethesda classification) at each visit. HPV DNA testing and classification of smears were done at enrolment and last follow-up visit (two time points). Factors associated with persistent anal HPV infection and SILs were evaluated with generalized estimating equations logistic regression and standard logistic regression respectively. RESULTS: Mean age of 304 participants was 38 (Standard Deviation, 8) years; 25% reported >1 sexual partner in the past 3 months. Only 5% reported ever having sex with other men. Most (65%) participants were taking antiretroviral treatment (ART), with a median CD4+ count of 445 cells/µL (IQR, 328-567). Prevalence of any-HPV infection at enrolment was 39% (88/227). In total, 226 men had anal HPV DNA results at both enrolment and final visits. Persistence of any-anal HPV infection among 80 men who had infection at enrolment was 26% (21/80). Any persistent anal HPV infection was more frequent among MLHIV with low CD4+ count (<200 vs. >500 cells/µL; aOR = 6.58; 95%CI: 2.41-17.94). Prevalence of anal SILs at enrolment was 49% (118/242) while incidence of SILs among MLHIV who had no anal dysplasia at enrolment was 27% (34/124). Of the 118 men who had anal dysplasia at enrolment, 15% had regressed and 38% persisted by month 18. Persistent anal HPV infection was associated with persistent SILs (aOR = 2.95; 95%CI: 1.08-10.89). ART status or duration at enrolment were not associated with persistent anal HPV infection or persistent SILs during follow-up. CONCLUSION: In spite of a high prevalence of anal HPV, HIV-positive heterosexual men have a low burden of anal HPV related disease. HPV vaccine and effective ART with immunological reconstitution could reduce this burden of infection.

Incidence, Persistence, Clearance, and Correlates of Genital Human Papillomavirus Infection and Anogenital Warts in a Cohort of Men Living With Human Immunodeficiency Virus in South Africa.

OBJECTIVE: To estimate the incidence; persistence and correlates of human papillomavirus (HPV) infection and anogenital warts (AGW) among men living with human immunodeficiency virus (MLHIV). METHODS: Overall, 304 MLHIV 18 years or older were enrolled and attended follow-up visits at 6, 12, and 18 months. Clinicians examined for AGW, collected blood, and penile swabs for HPV testing (Roche Linear Array) at each visit. Time to AGW incidence or clearance was estimated by Kaplan-Meier method. Factors associated with persistent HPV infection and AGW clearance were evaluated with generalized estimating equations and Cox regression, respectively. RESULTS: Mean age of participants was 38 years (standard deviation, 8 years); 25% reported more than 1 sexual partner in the past 3 months. Most (65%) participants were on antiretroviral treatment (ART) with a median CD4 count of 445 cells/µL (interquartile range, 328-567). Prevalence of HPV infection and AGW at enrolment were 79% (224 of 283) and 12% (36 of 304), respectively. Two hundred fifty-nine men were followed up for a median (interquartile range) 1.4 years (0.5-1.7 years). Incidence of any-genital HPV infection was 2.9 (95% confidence interval, 1.5-5.5) per 100 person-years. Persistence of any-genital HPV infection was 35% (68 of 192) and was higher among MLHIV with low CD4 count (adjusted odds ratio, 3.54; 95% confidence interval, 2.07-6.05). Incidence of AGW was 1.4 per 100 person-years. Men living with human immunodeficiency virus with high CD4 count were more likely to clear AGW than those with low CD4 count (adjusted hazard ratio, 3.69; 95% confidence interval, 1.44-9.47). No associations were observed between persistent genital HPV infection, AGW clearance with enrolment ART status or duration. CONCLUSIONS: Human immunodeficiency virus-positive men have a high burden of genital HPV infection and AGW. The ART and HPV vaccine could reduce this burden.

Patterns and trends of HPV-related cancers other than cervix in South Africa from 1994-2013.

BACKGROUND: HPV infection causes several cancers which include cervical, vaginal, vulval, penile and oropharyngeal cancer (OPC). Understanding the burden of HPV-related cancers is important for guiding cancer prevention and treatment interventions. METHODS: To inform policy, we analysed trends of age-standardised incidence (ASIR) and mortality (ASMR) rates for HPV-related head and neck (HNC) and anogenital cancers (AGC) in South Africa between 1994 and 2013. RESULTS: A total of 1 028 330 incident cancers and 617 044 cancer-related deaths were reported during the study period. The overall ASIR (-5.5%) and ASMR (-2.2%) for HNC declined, in part related to the anti-smoking legislation. In contrast, incidence (2.9%) and mortality (0.8%) rates for AGC increased with the rising HIV prevalence. ASIR for oral cavity cancer (OCC: -6.3%) and laryngeal cancer (LC: -11.3%) declined, including mortality associated with these cancers (OCC:-1.9%, and LC:-2.6%). However, oropharyngeal cancer showed a slower rate of decline in ASIR (-4.4%) and ASMR did not change. Compared to women, ASIR and ASMR for HNC were 3-fold higher among men. ASIR for both anal (7.5%) and vulval cancer (16.1%) increased. Median age at diagnosis of vulval cancer declined by 18 years (p-value = 0.01). Mortality rates for anal (3.9%) and vulval (2.6%) cancer increased. ASIR (-3.2%) and ASMR (-2.0%) for penile cancer declined. Rates for vaginal cancer did not change. CONCLUSIONS: Anal and vulval cancers have increased over the reporting period. There is need to continuously monitor trends of these cancers. Implementation of HPV vaccination could significantly reduce the burden of HPV-related cancers.

Collateral benefits: how the practical application of Good Participatory Practice can strengthen HIV research in sub-Saharan Africa.

INTRODUCTION: The Good Participatory Practice (GPP): Guidelines for Biomedical HIV Prevention Trials, second edition (2011) were developed to provide clinical trial sponsors and implementers with a formal stakeholder engagement framework. As one of the largest African research institutes, Wits Reproductive Health and HIV Institute (Wits RHI) became an early adopter of GPP by implementing its principles within large-scale national and regional clinical trials. This article examines Wits RHI's lessons learned from implementing GPP, its ongoing efforts to institutionalize GPP, and the yet to be realized potential in creating fully sustainable structures for meaningful stakeholder engagement in HIV prevention research, implementation science and beyond. DISCUSSION: For the past seven years, Wits RHI has undertaken both centralized leadership roles in implementing GPP across multi-party regional research consortia as well as overseeing GPP for smaller investigator-driven trials. Through this iterative roll-out of GPP, key lessons have emerged. Obtaining upfront funding to support GPP activities throughout and between the research life cycle, and a trained multi-disciplinary team of GPP practitioners have helped facilitate an enabling environment for GPP implementation. We further recommend formally integrating stakeholder engagement into study documents, including monitoring and evaluation plans with indicators and performance metrics, to assist teams to track and refine their GPP strategies. Finally, institutionalizing resources and supporting organization-wide GPP along with ongoing support can help build efficiencies and maximize economies of scale toward a pragmatic and innovative application of the GPP Guidelines. CONCLUSIONS: Thanks to a growing global network of GPP practitioners and a burgeoning GPP Community of Practice, there has been substantive progress in making GPP an integral component of clinical HIV prevention research. The Wits RHI experience highlights the possibilities and the challenges to translating the GPP principles into concrete practices within specific clinical trials and across a research institute. Realizing the full potential of GPP, including direct and indirect - 'collateral benefits' will require the collective buy-in and support from sponsors, implementers and community stakeholders across the research field. As the HIV prevention research field expands, however, a more conscious and systematic implementation of GPP is timely.

Human Papillomavirus Vaccine Introduction in South Africa: Implementation Lessons From an Evaluation of the National School-Based Vaccination Campaign.

BACKGROUND: In April 2014, a national school-based human papillomavirus (HPV) vaccination program was rolled out in South Africa, targeting Grade 4 girls aged ≥9 years. A bivalent HPV vaccine with a 2-dose (6 months apart) schedule was used. At the request of the National Department of Health (NDoH), we conducted an external assessment of the first-dose phase of the vaccination program to evaluate program coverage and vaccine safety and identify factors that influenced implementation. METHODS: We based our cross-sectional and mixed-methods approach on a process evaluation framework, which included a review of key planning and implementation documents and monitoring data; observation at vaccination sites; key informant interviews (N=34); and an assessment of media coverage and content related to the campaign.Findings: There was overall success in key measures of coverage and safety. Over 350,000 Grade 4 girls were vaccinated in more than 16,000 public schools across South Africa, which translated to 94.6% of schools reached and 86.6% of age-eligible learners vaccinated. No major adverse events following immunization were detected. We attributed the campaign's successes to careful planning and coordination and strong leadership from the NDoH. The primary challenges we identified were related to obtaining informed consent, vulnerabilities in cold chain capacity, and onsite management of minor adverse events. While campaign planners anticipated and prepared for some negative media coverage, they did not expect the use of social media for spreading misinformation about HPV vaccination. CONCLUSIONS: The first phase of the national school-based HPV vaccination campaign was successfully implemented at scale in this setting. Future implementation will require improvement in the storage and monitoring of vaccine doses, better communication of role expectations to all stakeholders, and streamlined consent processes to ensure program sustainability.

Associations of human gene EPB41L3 DNA methylation and cervical intraepithelial neoplasia in women living with HIV-1 in Africa.

OBJECTIVES: To evaluate associations of DNA methylation of the human tumour suppressor gene EPB41L3 with high-grade cervical intraepithelial neoplasia (CIN2+) and HIV-related factors among women living with HIV-1 (WLHIV) in Burkina Faso and South Africa. DESIGN: Case-control study of WLHIV aged 25-50 with histology-determined CIN2+ (cases, N = 152) and ≤CIN1 (controls, N = 210). METHODS: EPB41L3 methylation was measured by pyrosequencing of bisulphite converted DNA from exfoliated cervical specimens at baseline and 16 months later. Median methylation levels were compared across CIN grades using the Mann-Whitney test and Cuzick test for trend. EPB41L3 methylation levels were dichotomized into 'high' and 'low' using the 66.7 percentile point of the distribution in the controls. Associations of EPB41L3 methylation with HIV-related factors were estimated by logistic regression. RESULTS: Among 94 WLHIV in Burkina Faso and 268 in South Africa, median methylation levels at baseline for EPB41L3 increased with increasing CIN grade in both countries (P-trend <0.001).'High' methylation was more frequent among women with a longer time since HIV diagnosis in Burkina Faso [>5 years vs. ≤5 years; adjusted odds ratio (aOR) = 4.15, 95% CI 1.09-15.83, adjusted for age, CD4 count, high-risk HPV and CIN status], with low CD4 count in both countries (CD4 ≤200 vs. ≥350 cells/µl: aOR = 7.14, 95% CI 1.44-35.37 in Burkina Faso; aOR = 2.55, 95% CI 1.07-6.07 in South Africa), and with prolonged ART use in South Africa (ART >2 years vs. ART-naïve: aOR = 2.40, 95% CI: 1.23-4.69). CONCLUSION: Methylation of EPB41L3 DNA is elevated among WLHIV with CIN2+ and independently associated with lower CD4 count and ART use.

Human Papillomavirus Serology Among Women Living With HIV: Type-Specific Seroprevalence, Seroconversion, and Risk of Cervical Reinfection.

Background: Human papillomavirus (HPV) serodynamics following infection has never been evaluated prospectively among women living with HIV (WLHIV). We determined HPV seroprevalence, seroconversion, and cervical HPV-DNA acquisition among WLHIV. Methods: Prospective study of 604 WLHIV in Johannesburg, South Africa aged 25-50 years. At baseline and 16 months (endline), HPV type-specific antibodies (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) were measured using HPV-pseudovirions and cervical HPV-DNA genotypes using INNO-LiPA. Results: Seroprevalence of any-HPV was 93.2% and simultaneous seropositivity for HPV types of the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18), and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines were 21.4%, 10.9%, and 2.8%. Among 219 women with cervical HPV-DNA, same-type seronegative and without high-grade cervical intraepithelial neoplasia at baseline, 51 (23.3%) had type-specific seroconversion at endline. Risk of type-specific seroconversion was higher among recent antiretroviral therapy users (ART ≤2 years vs ART naive: adjusted OR [aOR] = 2.39; 95% CI, 1.02-5.62), and lower among women with low CD4+ at endline (≤350 vs >350 cells/mm3: aOR = 0.51; 95% CI, 0.24-1.07). Risk of cervical HPV-DNA acquisition was lower in women seropositive for HPV18, 35, and 58 at baseline. Conclusion: WLHIV have evidence of seroconversion in response to baseline HPV-DNA, dependent on CD4+ count and ART. Baseline HPV seropositivity confers limited protection against some HPV types.

Prevalence, incidence and correlates of low risk HPV infection and anogenital warts in a cohort of women living with HIV in Burkina Faso and South Africa.

OBJECTIVE: To report the prevalence and incidence of low-risk human papillomavirus infection (LR-HPV) and anogenital warts (AGW) among women living with HIV (WLHIV) in Burkina Faso (BF) and South Africa (SA), and to explore HIV-related factors associated with these outcomes. METHODS: We enrolled 1238 WLHIV (BF = 615; SA = 623) aged 25-50 years and followed them at three time points (6, 12 and 16 months) after enrolment. Presence of AGW was assessed during gynaecological examination. Cervico-vaginal swabs for enrolment and month 16 follow-up visits were tested for HPV infection by Inno-LiPA® genotyping. Logistic regression was used to assess risk factors for prevalent infection or AGW. Cox regression was used to assess risk factors for incident AGW. RESULTS: Women in SA were more likely than those in BF to have prevalent LR-HPV infection (BF: 27.1% vs. SA: 40.9%; p<0.001) and incident LR-HPV infection (BF: 25.8% vs. SA: 31.6%, p = 0.05). Prevalence of persistent LR-HPV was similar in the two countries (BF: 33.3% vs. SA: 30.4%; p = 0.54), as were prevalence and incidence of AGW (Prevalence: BF: 7.5% vs. SA: 5.7%; p = 0.21; Incidence: BF: 2.47 vs. SA: 2.33 per 100 person-years; p = 0.41). HPV6 was associated with incident AGW (BF: adjusted Hazard Ratio (aHR) = 4.88; 95%CI: 1.36-17.45; SA: aHR = 5.02; 95%CI: 1.40-17.99). Prevalent LR-HPV (BF: adjusted Odds Ratio [aOR = 1.86]; 95%CI: 1.01-3.41; SA: aOR = 1.75; 95%CI: 0.88-3.48); persistent LR-HPV (BF: aOR = 1.92; 95%CI: 0.44-8.44; SA: aOR = 2.81; 95%CI: 1.07-7.41) and prevalent AGW (BF: aOR = 1.53; 95%CI: 0.61-3.87; SA: aOR = 4.11; 95%CI: 1.20-14.10) were each associated with low CD4+ counts (i.e. <200 vs. >500 cells/µL). Duration of ART and HIV plasma viral load were not associated with any LR-HPV infection or AGW outcomes. CONCLUSION: LR-HPV infection and AGW are common in WLHIV in sub-Saharan Africa. Type-specific HPV vaccines and effective ART with immunological reconstitution could reduce the burden of AGW in this population.