Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

Global Type-Specific Genital Human Papillomavirus Prevalence in Men, by Sexual Orientation: A Systematic Review and Meta-Analysis.

BACKGROUND: Knowledge on genital type-specific human papillomavirus (HPV) prevalence among men is important for prevention of HPV-related cancers and other diseases. Men who have sex with men (MSM) have higher anal prevalence than men who have sex with women only (MSW) but for genital HPV this is unclear. We performed a systematic review and meta-analysis of type-specific genital HPV prevalence among men, by sexual orientation. METHODS: MEDLINE and Embase were used for searching publications reporting on male genital HPV prevalence with data from November 2011 onwards. A random-effects meta-analysis was conducted estimating pooled type-specific and grouped external genital and urethral HPV prevalence. Subgroup analyses were conducted for sexual orientation. RESULTS: Twenty-nine studies were eligible. Of those, 13 studies reported prevalence among MSM, 5 among MSW, and 13 studies did not stratify by sexual orientation. The most common genotypes were HPV-6 and HPV-16 for both anatomical locations, although heterogeneity was high. HPV prevalence was similar among studies reporting on MSW, MSM, and men with unknown sexual orientation. CONCLUSIONS: Genital HPV is common among men, with HPV-6 and HPV-16 being the most common genotypes. Type-specific HPV genital prevalence appears to be similar among MSM and MSW, which contrasts with earlier findings on anal HPV.

Long-term evolution of comorbidities and their disease burden in individuals with and without HIV as they age: analysis of the prospective AGEhIV cohort study.

BACKGROUND: People with HIV generally have more ageing-associated comorbidities than those without HIV. We aimed to establish whether the difference in comorbidities and their disease burden changes with ageing. METHODS: In this prospective, longitudinal cohort study, we assessed comorbidities commonly associated with ageing every 2 years in 596 HIV-positive and 550 HIV-negative participants. HIV-positive participants were recruited from the HIV outpatient clinic of the Amsterdam University Medical Centres (Amsterdam, Netherlands). HIV-negative participants were recruited from the sexual health clinic and the Amsterdam Cohort Studies at the Public Health Service of Amsterdam (Amsterdam, Netherlands). Inclusion criteria were participants aged 45 years or older and, for HIV-negative participants, a documented HIV-negative antibody test. The mean number of comorbidities present over time was compared between groups by use of Poisson regression, accounting for dropout and death through joint survival models. Mean disability-adjusted life-years (DALYs) accrued during 2-year intervals were compared between groups by use of an exponential hurdle model. FINDINGS: Between Oct 29, 2010, and Oct 9, 2012, participants were enrolled and then prospectively followed up until their last visit before Oct 1, 2018. 1146 participants were followed up for a median 5·9 years (IQR 5·7-6·0), during which 231 participants (20·2%) dropped out: 145 (24·3%) of 596 HIV-positive and 86 (15·6%) of 550 HIV-negative. 38 (3·3%) of 1146 participants died: 31 (5·2%) of 596 HIV-positive and seven (1·3%) of 550 HIV-negative. 24 HIV-positive and two HIV-negative participants died from ageing-associated comorbidities. 15 HIV-positive participants versus one HIV-negative participant died from non-AIDS malignancies. At inclusion, mean number of comorbidities was higher in HIV-positive participants (0·65) than in HIV-negative participants (0·32; p<0·0001). Mean number of comorbidities increased at similar rates over time: rate ratio (RR) per year for HIV-positive participants 1·04 (95% CI 1·00-1·08), RR per year for HIV-negative participants 1·05 (1·01-1·08; pinteraction=0·78). Number of comorbidities was associated with an increased risk of death (hazard ratio 3·33 per additional comorbidity, 95% CI 2·27-4·88; p<0·0001). HIV-positive participants had higher increases in mean DALYs than HIV-negative participants (0·209 per year, 95% CI 0·162-0·256 vs 0·091 per year, 0·025-0·157; pinteraction=0·0045). This difference was reduced when deaths were excluded in establishing DALYs (0·127, 0·083-0·171 vs 0·066, 0·005-0·127; pinteraction =0·11). INTERPRETATION: The larger comorbidity prevalence in HIV-positive participants aged 50-55 years on effective antiretroviral treatment than in HIV-negative participants increased similarly as participants aged and was associated with an increased risk of death, particularly of non-AIDS malignancies. Our findings reinforce the need for strategies to optimise prevention, screening, and early intervention. FUNDING: Netherlands Organization for Health Research and Development, Aidsfonds, Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, and Merck & Co. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Incidence and Clearance of Anal Human Papillomavirus Infection in 16 164 Individuals, According to Human Immunodeficiency Virus Status, Sex, and Male Sexuality: An International Pooled Analysis of 34 Longitudinal Studies.

BACKGROUND: Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized. METHODS: We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their determinants. RESULTS: Human papillomavirus (HPV) 16 had the highest incidence-clearance ratio of the hrHPV types. MSMWH had the highest hrHPV incidence (eg, 15.5% newly HPV-16 infected within 2 years), followed by HIV-negative MSM (7.5%), WWH (6.6%), HIV-negative women (2.9%), MSWWH (1.7%), and HIV-negative MSW (0.7%). Determinants of HPV-16 incidence included HIV status and number of sexual partners for MSM, women, and MSW, and anal sex behavior for MSM only. HPV-16 clearance was lower for people with HIV (PWH) and lower for prevalent than incident infection. Among MSM, increasing age was associated with lower clearance of prevalent, but not incident, HPV-16 infection. CONCLUSIONS: This robust and unifying analysis of anal hrHPV natural history is essential to designing and predicting the impact of HPV vaccination and HPV-based screening programs on anal cancer prevention, particularly in MSM and PWH. Importantly, it demonstrates the higher carcinogenic potential of longstanding anal prevalent hrHPV infection than more recent incident infection.

Approaches to Estimating Clearance Rates for Human Papillomavirus Groupings: A Systematic Review and Real Data Examples.

INTRODUCTION: Approaches to estimating clearance rates, an important metric of human papillomavirus (HPV) clearance, for HPV groupings differ between studies. We aimed to identify the approaches used in the literature for estimating grouped HPV clearance rates. We investigated whether these approaches resulted in different estimations, using data from existing studies. METHODS: In this systematic review, we included articles that reported clearance rates of HPV groupings. We identified approaches to data in the HAVANA cohort, comprising adolescent girls, and the H2M cohort, comprising men who have sex with men. We estimated clearance rates for six HPV groupings (bivalent-, quadrivalent- and nonavalent vaccine-related, and low-risk, high-risk, and any HPV). RESULTS: From 26 articles, we identified 54 theoretically possible approaches to estimating clearance rates. These approaches varied regarding definitions of clearance events and person-time, and prevalence or incidence of infections included in the analysis. Applying the nine most-used approaches to the HAVANA ( n = 1,394) and H2M ( n = 745) cohorts demonstrated strong variation in clearance rate estimates depending on the approach used. For example, for grouped high-risk HPV in the H2M cohort, clearance rates ranged from 52.4 to 120.0 clearances/1000 person-months. Clearance rates also varied in the HAVANA cohort, but differences were less pronounced, ranging from 24.1 to 57.7 clearances/1000 person-months. CONCLUSIONS: Varied approaches from the literature for estimating clearance rates of HPV groupings yielded different clearance rate estimates in our data examples. Estimates also varied between study populations. We advise clear reporting of methodology and urge caution in comparing clearance rates between studies.

Change in Substance Use and the Effects of Social Distancing on Health-Related Quality of Life and Depressive Symptoms During the COVID-19 Pandemic in People Living With and Without HIV.

BACKGROUND: Little is known about the impact of social distancing on health-related quality of life and depressive symptoms in older people with HIV during the COVID-19 pandemic. SETTING: HIV-positive and HIV-negative AGEhIV Cohort Study participants. METHOD: In September-November 2020, participants completed questionnaires on social distancing, change in substance use, health-related quality of life (EQ-6D, including EQ-VAS), and depressive symptoms (PHQ-9). Associations between social distancing and (1) EQ-VAS or (2) PHQ-9 score ≥10 (clinically relevant depressive symptoms) were analyzed using fractional and binomial logistic regression, respectively. RESULTS: Two hundred fourteen HIV-positive and 285 HIV-negative participants were analyzed. 77.4% found social distancing important and 66.9% reported good adherence to these measures, without significant differences between HIV-positive and HIV-negative participants. In both groups, &lt;5% reported increased smoking or recreational drug use, but more HIV-positive (12.2%) than HIV-negative (4.9%) participants (P = 0.005) reported increased/more frequent alcohol use. Median EQ-VAS was slightly lower in HIV-positive (80 IQR = 73-90) than HIV-negative (84 IQR = 75-90) participants (P = 0.041). The prevalence of clinically relevant depressive symptoms was similar (HIV-positive, 8.4% and HIV-negative, 8.8%). Worrying about contracting COVID-19 and having ≥3 (vs no) comorbidities were associated with lower EQ-VAS and finding social distancing easy with higher EQ-VAS. Worrying about contracting COVID-19 and younger than 60 years (vs ≥65) were associated with higher odds of clinically relevant depressive symptoms. HIV status was associated with neither outcome. CONCLUSIONS: Initially during the COVID-19 pandemic in the Netherlands, a similar majority of HIV-positive and HIV-negative participants reported adhering to social distancing. Irrespective of HIV status, concerns about contracting COVID-19 negatively affected participants' perceived current health and increased risk of depressive symptoms.

Improving indicator-condition guided testing for HIV in the hospital setting (PROTEST 2·0): A multicenter, interrupted time-series analysis.

Background: Indicator-condition (IC) guided HIV testing is a feasible and cost-effective strategy to identify undiagnosed people living with HIV (PLHIV), but remains insufficiently implemented. We aimed to promote IC-guided HIV testing in seven ICs. Methods: Relevant departments in five hospitals of the Amsterdam region participated. HIV testing among adult patients without known HIV infection but with an IC was assessed using electronic health records during pre-intervention (January 2015-June 2020) and intervention (July 2020-June 2021) periods. The multifaceted intervention included audit and feedback. The primary endpoint was HIV testing ≤3 months before or after IC diagnosis and the effect of the intervention was evaluated using segmented Poisson regression. Findings: Data from 7986 patients were included, of whom 6730 (84·3%) were diagnosed with an IC in the pre-intervention period and 1256 (15·7%) in the intervention period. The proportion HIV tested ≤3 months before or after IC diagnosis increased from 36.8% to 47.0% (adjusted risk ratio [RR]= 1.16, 95% CI=1.03-1.30, p=0.02). For individual ICs, we observed significant increases in HIV testing among patients with cervical cancer or intraepithelial neoplasia grade 3 (adjusted RR=3.62, 95% CI=1.93-6.79) and peripheral neuropathy (adjusted RR=2.27 95% CI=1.48-3.49), but not the other ICs. Eighteen of 3068 tested patients were HIV positive (0.6%). Interpretation: Overall IC-guided testing improved after the intervention, but not for all ICs. Variations in effect by IC may have been due to variations in implemented developments, but the effect of separate elements could not be assessed. Funding: HIV Transmission Elimination Amsterdam (H-TEAM) initiative, Aidsfonds (grant number: P-42702).

DNA Methylation Analysis to predict Regression of high-grade anal Intraepithelial Neoplasia in HIV+ men (MARINE): a cohort study protocol.

INTRODUCTION: Anal cancer precursors, or high-grade anal intraepithelial neoplasia (HGAIN), are highly prevalent in HIV-seropositive (HIV+) men who have sex with men (MSM). Around 30% of lesions regress within 1 year, but current histopathological assessment is unable to distinguish between HGAIN likely to regress and HGAIN likely to persist or progress to cancer. We aim to assess if host cell DNA methylation markers can predict regression of HGAIN, thus determining the need for immediate treatment or active surveillance. This could reduce overtreatment and the associated anal and psycho-sexual morbidity. METHODS AND ANALYSIS: This is an active surveillance cohort study in three centres located in Amsterdam, the Netherlands, in 200 HIV+ MSM diagnosed with HGAIN. Participants will not be treated, but closely monitored during 24 months of follow-up with 6 monthly visits including cytology, and high-resolution anoscopy with biopsies. The primary study endpoint is histopathological regression of each baseline HGAIN lesion at the end of the study. Regression is defined as ≤low grade anal intraepithelial neoplasia in the exit biopsy at 24 months. Regression proportions in lesions with low versus high methylation levels (ASCL1, ZNF582), other biomarkers (HPV genotype, HPV-E4, p16INK4A, Ki-67) and immunological markers at baseline will be compared. Main secondary endpoints are the histological and clinical outcome (ie, the number of octants affected by HGAIN) of each baseline HGAIN lesion and overall HGAIN disease (i.e., all lesions combined) after each visit. The health-related quality of life of the study group will be compared with that of a control group of 50 HIV+ MSM receiving regular HGAIN treatment. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Board of the Academic Medical Center (Amsterdam, The Netherlands; reference no. 2021_099). Participants are required to provide written informed consent. Findings will be disseminated through publication in peer-reviewed scientific journals and presentations at international scientific conferences; dissemination to policy makers and the target patient group will be achieved through our (inter-)national network, professional associations and collaboration with a patient representative organisation. TRIAL REGISTRATION NUMBER: NL9664.

Type-specific concurrent anogenital HPV detection among young women and MSM attending Dutch sexual health clinics.

OBJECTIVES: This study aimed to investigate type-specific concurrent anogenital human papillomavirus (HPV) detection and examine associations with concurrent detection. METHODS: Data from a Dutch repeated cross-sectional study among young sexual health clinic visitors (Papillomavirus Surveillance among STI clinic Youngsters in the Netherlands) between 2009 and 2019 were used. Cohen's kappa was used to assess the degree of type-specific concordance of HPV detection between anal and genital sites for 25 HPV genotypes for women and men who have sex with men (MSM) separately. Associations with type-specific concurrent HPV were identified. Receptive anal intercourse (RAI) was forced into the model to investigate its influence. RESULTS: Among women (n=1492), type-specific concurrent anogenital detection was common; kappa was above 0.4 for 20 genotypes. Among MSM (n=614), kappa was <0.4 for all genotypes. The only significant association with type-specific concurrent anogenital detection among women was genital chlamydia (adjusted OR 1.5, 95% CI 1.1 to 2.2). RAI was not associated. CONCLUSIONS: Type-specific concurrent anogenital HPV detection was common among young women, and uncommon among MSM. For women, concurrent HPV detection was associated with genital chlamydia. Our results are suggestive of autoinoculation of HPV among women.

Trends in Sexual Behavior and Sexually Transmitted Infections After Initiating Human Immunodeficiency Virus Pre-Exposure Prophylaxis in Men Who Have Sex with Men from Amsterdam, the Netherlands: A Longitudinal Exposure-Matched Study.

Men who have sex with men (MSM) initiating human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) may increase condomless anal sex (CAS) and number of partners, and, consequently, more often acquire sexually transmitted infections (STIs). Using data from the Amsterdam Cohort Studies, we compared sexual behavior and STI among MSM after PrEP-initiation with controls not initiating PrEP. The MSM reported on sexual behavior and were tested for HIV, chlamydia, gonorrhea, and syphilis semi-annually. We matched MSM who initiated PrEP between January 1, 2015 and December 31, 2019 1:1 to MSM who did not use time-dependent propensity scores based on age, sexual behavior, and STI. Primary end-points were number of casual partners, and proportion with CAS and receptive CAS (rCAS) with casual partners, sexualized drug use (SDU), any STI, and anal STI. We modeled end-points during the 4 years before and 2 years after PrEP-initiation or matched PrEP-initiation timepoint by using logistic regression (dichotomous end-points) or negative binomial regression (count end-point), adjusted for calendar year. Two hundred twenty-eight out of the 858 (26.6%) MSM initiated PrEP. We matched 198 out of 228 (86.8%) to a control. Before PrEP-initiation, end-points increased over time in both groups, with no statistically significant difference. The odds of CAS, rCAS, and anal STI were on average higher after than before PrEP-initiation in PrEP initiators, whereas after versus before differences were not observed in controls. After PrEP-initiation, PrEP initiators had statistically significantly more casual partners, and higher odds of CAS, rCAS, SDU, any STI, and anal STI than controls. These findings support frequent STI screening and counseling in MSM using PrEP.

Similar Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Similar Nucleocapsid Antibody Levels in People With Well-Controlled Human Immunodeficiency Virus (HIV) and a Comparable Cohort of People Without HIV.

BACKGROUND: Within the ongoing AGEhIV Cohort Study in Amsterdam, we prospectively compared the incidence of and risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between human immunodeficiency virus (HIV)-positive and HIV-negative participants. Moreover, we compared SARS-CoV-2 nucleocapsid antibody levels between participants with incident infection from both groups. METHODS: Starting in September 2020, consenting HIV-positive and HIV-negative participants were assessed every 6 months for incident SARS-CoV-2 infection, using combined immunoglobulin (Ig) A/IgM/IgG SARS-CoV-2 nucleocapsid antibody assay. Cumulative incidence of SARS-CoV-2 infection and associated risk factors were assessed from 27 February 2020 through 30 April 2021, using complementary log-log regression. In those with incident SARS-CoV-2 infection, nucleocapsid (N) antibody levels were compared between groups using linear regression. RESULTS: The study included 241 HIV-positive (99.2% virally suppressed) and 326 HIV-negative AGEhIV participants. The cumulative SARS-CoV-2 incidence by April 2021 was 13.4% and 11.6% in HIV-positive and HIV-negative participants, respectively (P = .61). Younger age and African origin were independently associated with incident infection. In those with incident infection, only self-reported fever, but not HIV status, was associated with higher N antibody levels. CONCLUSIONS: HIV-positive individuals with suppressed viremia and adequate CD4 cell counts had similar risk of SARS-CoV-2 acquisition and similar SARS-CoV-2 N antibody levels after infection compared with a comparable HIV-negative cohort. CLINICAL TRIAL REGISTRATION: NCT01466582.

Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies.

BACKGROUND: Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality. METHODS: We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models. FINDINGS: The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15-18 years and 28·8% (141 of 490) among those age 23-24 years (ptrend=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25-34 years and 22·8% (451 of 1979) among those age 55 and older (ptrend<0·0001). HPV16 prevalence in HIV-negative MSM was 6·7% (15 of 223) among those age 15-18 and 13·9% (166 of 1192) among those age 23-24 years (ptrend=0·0076); the prevalence plateaued thereafter (ptrend=0·72). Similar age-specific patterns were observed for HR-HPV. No significant differences for HPV16 or HR-HPV were found by age for either HIV-positive or HIV-negative MSW. HSIL+ detection ranged from 7·5% (12 of 160) to 54·5% (61 of 112) in HIV-positive MSM; after adjustment for heterogeneity, HIV was a significant predictor of HSIL+ (aPR 1·54, 95% CI 1·36-1·73), HPV16-positive HSIL+ (1·66, 1·36-2·03), and HSIL+ in HPV16-positive MSM (1·19, 1·04-1·37). Among HPV16-positive MSM, HSIL+ prevalence increased with age. INTERPRETATION: High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+. FUNDING: International Agency for Research on Cancer.

Human papillomavirus vaccination in adults: impact, opportunities and challenges - a meeting report.

For more than a decade human papillomavirus (HPV) vaccine have been implemented in most high-income countries, and more recently also in several low- and middle-income countries. The vaccines are safe and their impact and effectiveness in preventing HPV vaccine type infection and associated diseases has been thoroughly established. Currently, the primary recommended cohorts for immunisation are adolescents, 9-15 years of age but HPV is an ubiquitous infection that is mainly (but not exclusively) sexually transmitted. Sexually active adults remain susceptible to infection and continued transmission of the virus, representing a reservoir of infection in the population. A recent meeting, conducted by the HPV Prevention and Control Board (HPV-PCB), reviewed the current status of HPV vaccination of adults, discussed limitations, challenges and benefits of HPV vaccination of adults, evaluated the effectiveness of HPV vaccination after treatment of post cervical cancer and precancerous lesions, and discussed the potential impact of adult vaccination on cervical cancer elimination strategies in light of the current and future HPV vaccine shortage. HPV-PCB is an independent multidisciplinary board of international experts that disseminates relevant information on HPV to a broad array of stakeholders and provides guidance on strategic, technical and policy issues in the implementation of HPV prevention and control programs. The HPV-PCB concluded that, given the current data available on adult HPV vaccination and the ongoing vaccine supply constraints, it is too early to implement routine vaccination of adults. Many research gaps need to be filled before we have a better understanding of the efficacy and broader public health impact of HPV vaccination in adult women.

Promoting HIV indicator condition-guided testing in hospital settings (PROTEST 2.0): study protocol for a multicentre interventional study.

BACKGROUND: Late presentation remains a key barrier towards controlling the HIV epidemic. Indicator conditions (ICs) are those that are AIDS-defining, associated with a prevalence of undiagnosed HIV > 0.1%, or whose clinical management would be impeded if an HIV infection were undiagnosed. IC-guided HIV testing is an effective strategy in identifying undiagnosed HIV, but opportunities for earlier HIV diagnosis through IC-guided testing are being missed. We present a protocol for an interventional study to improve awareness of IC-guided testing and increase HIV testing in patients presenting with ICs in a hospital setting. METHODS: We designed a multicentre interventional study to be implemented at five hospitals in the region of Amsterdam, the Netherlands. Seven ICs were selected for which HIV test ratios (proportion of patients with an IC tested for HIV) will be measured: tuberculosis, cervical/vulvar cancer or high-grade cervical/vulvar dysplasia, malignant lymphoma, hepatitis B and C, and peripheral neuropathy. Prior to the intervention, a baseline assessment of HIV test ratios across ICs will be performed in eligible patients (IC diagnosed January 2015 through May 2020, ≥18 years, not known HIV positive) and an assessment of barriers and facilitators for HIV testing amongst relevant specialties will be conducted using qualitative (interviews) and quantitative methods (questionnaires). The intervention phase will consist of an educational intervention, including presentation of baseline results as competitive graphical audit and feedback combined with discussion on implementation and opportunities for improvement. The effect of the intervention will be assessed by comparing HIV test ratios of the pre-intervention and post-intervention periods. The primary endpoint is the HIV test ratio within ±3 months of IC diagnosis. Secondary endpoints are the HIV test ratio within ±6 months of diagnosis, ratio ever tested for HIV, HIV positivity percentage, proportion of late presenters and proportion with known HIV status prior to initiating treatment for their IC. DISCUSSION: This protocol presents a strategy aimed at increasing awareness of the benefits of IC-guided testing and increasing HIV testing in patients presenting with ICs in hospital settings to identify undiagnosed HIV in Amsterdam, the Netherlands. TRIAL REGISTRATION: Dutch trial registry: NL7521 . Registered 14 February 2019.

Incidence and Clearance of Penile High-Risk Human Papillomavirus Infection and Their Determinants Among HIV-Negative Men Who Have Sex With Men.

BACKGROUND: Men who have sex with men (MSM) are at increased risk of anogenital human papillomavirus (HPV) infections. We aimed to assess the incidence and clearance of penile high-risk HPV (hrHPV) infections and their determinants among HIV-negative MSM living in the Netherlands. METHODS: Between 2010 and 2015, HIV-negative MSM were semiannually tested for penile HPV and completed detailed questionnaires on health and sexual behavior. Self-collected penile swabs were tested for HPV DNA using SPF10-PCR DEIA/LiPA25 system. Type-specific hrHPV incidence (IR) and clearance rates (CR) were calculated for 12 hrHPV types (HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, and HPV-59). Determinants of incidence and clearance of HPV-16 and HPV-18, separately, and combined 7 hrHPV types covered by the nonavalent vaccine were assessed by Poisson regression using generalized estimating equations for combined hrHPV types. RESULTS: We included 638 HIV-negative MSM, with a median age of 38 (interquartile range, 33-43) years. HPV-16 had an IR of 4.9/1000 person-months of observation at risk (PMO; 95% confidence interval [95% CI], 3.8-6.3) and CR of 90.6/1000 PMO (95% CI, 60.7-135.1). The IR and CR of HPV-18 were 3.4/1000 PMO (95% CI, 2.5-4.5) and 119.2/1000 PMO (95% CI, 76.9-184.8), respectively. Age and condom use during insertive anal sex were not associated with hrHPV incidence, whereas high number of recent sex partners was. CONCLUSIONS: The relatively high IR and low CR of penile HPV-16 and HPV-18 among HIV-negative MSM correlates with their high prevalence and oncogenic potential. Incident HPV infections were associated with recent sexual risk behavior.

Incidence and risk factors of C. trachomatis and N. gonorrhoeae among young women from the Western Cape, South Africa: The EVRI study.

OBJECTIVE: Young women in South Africa are highly affected by sexually transmitted infections (STI), like C. trachomatis (CT) and N. gonorrhoeae (NG). We aimed to estimate the incidence of CT and NG, and its determinants, among young women from the Western Cape, South Africa, participating in an HPV vaccine trial (the EVRI study). METHODS: HIV-negative women aged 16-24 years were enrolled between October 2012 and July 2013. At enrolment and month 6 participants were screened for CT and NG (Anyplex CT/NG real-time detection method). A questionnaire on demographic and sexual history characteristics was completed at enrolment and month 7. Treatment for CT and/or NG was offered to infected participants. Incidence rates (IR) of CT and NG were estimated. Determinants of incident CT and NG infections were assessed using Poisson regression. RESULTS: 365 women were tested for CT and/or NG at least twice. Prevalence of CT and NG at baseline was 33.7% and 10.4%, respectively. Prevalence of co-infection with CT and NG was 7.1%. During 113.3 person-years (py), 48 incident CT infections were diagnosed (IR = 42.4 per 100 py, 95% confidence interval (CI) 31.9-56.2). Twenty-nine incident NG were diagnosed during 139.3 py (IR = 20.8 per 100 py, 95%CI 14.5-29.9). Prevalent CT infection at baseline was associated with incident CT (adjusted incidence rate ratio (aIRR) 5.8, 95%CI 3.0-11.23. More than three lifetime sex partners increased the risk for incident NG (3-4 partners aIRR = 7.3, 95%CI 2.1-26.0; ≥5 partners aIRR = 4.3, 95%CI 1.1-17.5). CONCLUSIONS: The IR of bacterial STIs among young women in the Western Cape is very high. Besides being previously infected and a higher lifetime number of sex partners, no other risk factors were found for CT and NG, suggesting that the majority of these women were at risk. This indicates the need for intensified prevention of STIs as well as screening and treatment programs to increase sexual health in this region.

Cost-effectiveness of two screening strategies for Chlamydia trachomatis and Neisseria gonorrhoeae as part of the PrEP programme in the Netherlands: a modelling study.

OBJECTIVES: Pre-exposure prophylaxis (PrEP) users are routinely tested four times a year (3 monthly) for asymptomatic Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections on three anatomical locations. Given the high costs of this testing to the PrEP programme, we assessed the impact of 3 monthly screening(current practice), compared with 6 monthly on the disease burden. We quantified the difference in impact of these two testing frequencies on the prevalence of CT and NG among all men who have sex with men (MSM) who are at risk of an STI, and explored the cost-effectiveness of 3-monthly screening compared with a baseline scenario of 6-monthly screening. METHODS: A dynamic infection model was developed to simulate the transmission of CT and NG among sexually active MSM (6500 MSM on PrEP and 29 531 MSM not on PrEP), and the impact of two different test frequencies over a 10-year period. The difference in number of averted infections was used to calculate incremental costs and quality-adjusted life-years (QALY) as well as an incremental cost-effectiveness ratio (ICER) from a societal perspective. RESULTS: Compared with 6-monthly screening, 3-monthly screening of PrEP users for CT and NG cost an additional €46.8 million over a period of 10 years. Both screening frequencies would significantly reduce the prevalence of CT and NG, but 3-monthly screening would avert and extra ~18 250 CT and NG infections compared with 6-monthly screening, resulting in a gain of ~81 QALYs. The corresponding ICER was ~€430 000 per QALY gained, which exceeded the cost-effectiveness threshold of €20 000 per QALY. CONCLUSIONS: Three-monthly screening for CT and NG among MSM on PrEP is not cost-effective compared with 6-monthly screening. The ICER becomes more favourable when a smaller fraction of all MSM at risk for an STI are screened. Reducing the screening frequency could be considered when the PrEP programme is established and the prevalence of CT and NG decline.

Changes in lung function among treated HIV-positive and HIV-negative individuals: analysis of the prospective AGEhIV cohort study.

BACKGROUND: The AGEhIV cohort study is a prospective cohort study evaluating the occurrence of age-related comorbidities in people living with and without HIV. We previously reported a lower forced vital capacity (FVC) in HIV-positive compared with HIV-negative participants in those without heavy smoking exposure at time of enrolment in the AGEhIV cohort study. In this study we evaluate longitudinal changes in spirometry indices in the same AGEhIV cohort accounting for smoking behaviour and other risk factors. METHODS: We obtained pre-bronchodilator spirometry measurements in AGEhIV cohort participants during biennial visits over a median of 5·9 years (IQR 5·7-6·0). Adjusted declines in forced expiratory volume in 1 s (FEV1), FVC, and FEV1/FVC ratio were modelled using linear mixed-effects models and compared by HIV status and smoking status. To evaluate whether changes in spirometry measurements could be driven by increased levels of chronic inflammation, we assessed associations between rates of FEV1 and FVC decline and CD4 and CD8 T-cell counts, and plasma concentrations of C-reactive protein (CRP), interleukin 6, soluble CD14, soluble CD163, and intestinal fatty-acid-binding protein in separate models. The study is registered at ClinicalTrials.gov, NCT01466582. FINDINGS: 500 HIV-positive and 481 HIV-negative participants were included with spirometry data from Oct 29, 2010, to Aug 14, 2018. HIV-positive participants were virally suppressed (<40 copies per mL) during 1627 (95%) study visits, and 159 (32%) HIV-positive and 183 (38%) HIV-negative participants had never smoked. Adjusted declines in FEV1 were 10·0 mL per year faster in HIV-positive non-smokers (95% CI 4·2 to 15·7, p=0·00066) compared with HIV-negative non-smokers, and 11·1 mL per year faster in HIV-positive smokers (95% CI 0·7 to 21·4, p=0·036) compared with HIV-negative smokers. In comparison, smoking was associated with a 16·4 mL per year steeper decline in FEV1 among HIV-positive participants (95% CI 8·0 to 24·7, p=0·00012), and 15·3 mL per year steeper decline among HIV-negative participants (95% CI 6·7-24·0, p=0·00052) compared with not smoking. Adjusted yearly declines in FEV1 and FVC, but not FEV1/FVC, were significantly greater in HIV-positive than HIV-negative participants overall (additional decline in HIV-positive participants, FEV1 10·5 mL per year [95% CI 4·7 to 16·3], p=0·00040; FVC 11·5 mL per year [2·8 to 20·3], p=0·0096; FEV1/FVC 0·07% per year [-0·05 to 0·19], p=0·26), with a similar observation for never-smokers (FEV1 6·0 mL per year [-1·8 to 13·7], p=0·13; FVC 9·1 mL per year [-3·0 to 21·1], p=0·14; FEV1/FVC ratio 0·00% per year [-0·18 to -0·18], p=0·97). Higher CRP concentrations during follow-up were associated with accelerated declines in FEV1 and FVC among HIV-positive participants but not among HIV-negative participants. INTERPRETATION: Treated HIV infection was associated with faster declines in both FEV1 and FVC, but not in the FEV1/FVC ratio. These changes were independent of smoking and might have been driven by ongoing interstitial or small airway damage, potentially related to increased inflammation. FUNDING: ZonMW, Aidsfonds, Gilead Sciences, ViiV Healthcare, Janssen Pharmaceuticals, Merck.

Human Immunodeficiency Virus (HIV)-Negative Men Who Have Sex With Men Have Higher CD8+ T-Cell Counts and Lower CD4+/CD8+ T-Cell Ratios Compared With HIV-Negative Heterosexual Men.

BACKGROUND: We previously reported T-cell senescence to be similar in people with human immunodeficiency virus (PWH) with suppressed viremia (predominantly men who have sex with men [MSM]) and human immunodeficiency virus (HIV)-negative otherwise comparable controls but greater than in healthy blood donors. This led us to compare CD4+ and CD8+ T-cell counts and CD4+/CD8+ ratios between HIV-negative MSM and men who only have sex with women (MSW) and relate observed differences in behavioral factors and infectious exposures, including cytomegalovirus (CMV) infection. METHODS: In 368 HIV-negative MSM and 72 HIV-negative MSW, T lymphocyte phenotyping was performed 3 times biennially. Baseline CMV serology and sexually transmitted infection (STI) incidence and/or STI seroprevalence, sexual, and substance-use behavior data were collected during study visits. RESULTS: Men who have sex with men, compared with MSW, had higher CD8+ counts (551 vs 437 cells/mm3, P < .001), similar CD4+ counts (864 vs 880 cells/mm3, P = .5), and lower CD4+/CD8+ ratios (1.84 vs 2.47, P < .001). Differences were most pronounced for MSM with >10 recent sex partners and partly explained by higher CMV seroprevalence in MSM. CONCLUSIONS: These findings suggest that factors other than HIV may, in both PWH and certain HIV-negative MSM, contribute to a low CD4+/CD8+ ratio. Whether this, like in PWH, contributes to comorbidity risk in HIV-negative MSM requires further study.