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Objectives: Evidence on the optimal frequency of laboratory testing during outpatient parenteral antimicrobial therapy (OPAT) is lacking. Therefore, we investigated how often and when laboratory abnormalities occur during OPAT and which factors are associated with these abnormalities., Methods: We performed a multicenter cohort study in four Dutch hospitals among adult patients receiving OPAT and collected routinely obtained laboratory test results. Incidence and incidence rates were calculated for various laboratory abnormalities. Survival analysis was performed to visualize the time to the first occurrence of laboratory abnormalities and Poisson regression analysis to compare the number of abnormalities in the first and second 30 OPAT days among patients receiving OPAT for ≥60 days. Predictors were identified using a multivariable Cox proportional hazard regression model., Results: 45.1% of 1152 included patients developed laboratory abnormalities, but only 2% led to OPAT discontinuation. Hepatotoxicity was most common (33.9 events/1000 OPAT days), with a time-dependent decrease in the occurrence of the first hepatotoxic event, while hypokalemia was rare (1.7 events/1000 OPAT days). In the subgroup of patients receiving ≥60 days of OPAT, nephrotoxicity was more common in days 31-60. We observed partly toxicity-specific associations between antibiotic type, concomitant medication, baseline laboratory values, patient characteristics, and the occurrence of laboratory abnormalities., Conclusions: While laboratory abnormalities are frequently observed during OPAT, they rarely lead to discontinuation of OPAT. Specific patient, treatment and laboratory characteristics were associated with the occurrence of laboratory abnormalities. Based on our results, we recommend a more personalized laboratory monitoring policy with less blood sampling., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Obesity is rising among people with HIV (PLWH), sparking interest in bariatric surgery (BS) for this group. Yet, large-scale comparative research on BS outcomes in PLWH is lacking., Methods: We performed a retrospective, matched cohort analysis in PLWH and HIV uninfected controls. Subjects were retrieved from the Dutch Audit for Treatment of Obesity (DATO) registry. Matching (1:7 ratio) included age (± 5-years), sex, body-mass index (BMI) of ± 3 kg/m 2 , surgery type, and associated health problems (AHPs) at baseline. The primary endpoint was total weight loss percentage (%TWL) ≥ 20% achieved at 1-year post-BS. Secondary endpoints were cumulative %TWL achieved at 2-years post-BS, a reported remission or improvement in AHPs post-BS, and surgical complications, both at 1-year post-BS. Comparisons were performed using conditional logistic regression., Results: Twenty-seven PLWH and 168 controls were included. At 1-year post-BS, 89% PLWH achieved ≥ 20%TWL, compared to 94% of controls (p = 0.4). Cumulative %TWL at 2-years post-BS were 82% and 92% in PLWH and controls, respectively (p = 0.2). Improvement rates in hypertension and type 2 diabetes mellitus were 50% and 86% in PLWH, versus 87% and 87% in controls. Full remission occurred in 20% and 71% of PLHIV, versus 49% and 44% of controls, respectively. No improvement or remission was observed for dyslipidaemia in PLHIV compared to 54% improvement and 29% remission in controls. Surgical complications were 0% in PLHIV and 13% (n = 21) in controls., Conclusion: Efficacy and safety outcomes of BS were similar between PLWH and controls except for the lack of improvement in dyslipidaemia in PLWH., (© 2024. The Author(s).)

Background: The implications of bariatric surgery (BS) on virologic and metabolic outcomes in people with human immunodeficiency virus (HIV; PWH) on antiretroviral therapy (ART) are unknown., Methods: Here, we report a retrospective analysis up to 18 months post-BS in PWH from the AIDS Therapy evaluation in The Netherlands (ATHENA) cohort with data from all dutch HIV treating Centers. Primary end points were a confirmed virologic failure (2 consecutive HIV-RNA measurements >200 copies/mL) and the percentage of patients who achieved >20% total body weight loss up to 18 months post-BS. Switches from baseline ART and trough plasma concentrations of antiretrovirals were also reported post-BS. Metabolic parameters and medication usage were compared pre- and post-BS., Results: Fifty-one patients were included. One case of confirmed virologic failure and 3 cases with viral blips were detected in this cohort up to 18 months post-BS. Eighty-five percent of patients achieved >20% total body weight loss at 18 months post-BS, with a mean difference from baseline (95% confidence interval) of -33.5% (-37.7% to -29.3%). Trough plasma concentrations of measured antiretroviral agents were all above minimum effective concentrations, except for 1 sample of darunavir. Lipid profiles, but not serum creatinine and blood pressure, improved significantly (P < .01) post-BS. Total medications and obesity-related comedications declined from 203 to 103 and from 62 to 25, respectively, at 18 months post-BS., Conclusions: BS was an effective intervention for weight loss and lipid control in PWH using ART in this cohort with no clear link to poor virologic outcomes., Competing Interests: Potential conflicts of interest . The following authors report grants and/or honoraria: D. M. B. and A. C. from Janssen, MSD, AbbVie, Bristol-Myers Squibb Company (BMS), Gilead, and ViiV Healthcare; C. R. from AIDSfonds, ZonMW, Dutch Federation Medical Specialists, Health Holland, Merck, Janssen-Cilag, Gilead, and ViiV Healthcare. C. R. also reports payment or honoraria for speaking engagements or presentations from Virology Education, Academic Medical Education (AME), and ViiV; travel support from ViiV and Gilead; and participation on data and safety monitoring boards (DSMBs) or advisory boards for The European treatment network of HIV, hepatitis and global infectious diseases (neat-id), ViiV, and Gilead. A. C. also reports participation on an advisory board for Gilead (paid to institution). J. G. dH. reports consulting fees from ViiV and Gilead. M. vd. V. reports grants or contracts and consulting fees from ViiV, Gilead, and MSD (paid to institution). O. R. reports board membership and role of treasurer of the Dutch Society of HIV Treating Physicians. F. W. reports consulting fees from ViiV Healthcare for advisory board participation and unpaid participation on the Data Safety Monitoring Board (DSMB) for an IAVI HIV vaccine study. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: Anal cancer is increasing in HIV+ men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I to II dose-finding study, we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01) in HIV+ MSM with HPV16-positive HGAIN., Patients and Methods: Four dosage schedules (1-5-10; 5-10-20; 10-20-40; and 40-40-40-40 μg) of SLP-HPV-01 were administered intradermally with a 3-week interval in 10 patients per dose level (DL). In each dose group, 5 patients also received 1 μg/kg pegylated IFNα-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3, 6, and 12 months., Results: Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFNα groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histologic response and one had a partial response (in total 9/38, 23.7%). At the highest dosage level, the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders., Conclusions: The highest DL is safe, immunogenic, and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN., (©2023 American Association for Cancer Research.)

Background and Objectives: Obesity trends and metabolic dysregulation are rising in people living with HIV using antiretrovirals (ARVs). Underlying causes and preventive strategies are being investigated. Two glucagon like-peptide 1 (GLP-1) agonists, liraglutide and semaglutide, were formerly approved as glucose-lowering drugs and have been recently approved for long-term weight loss in people with obesity. Due to the lack of therapeutic guidelines or clinical trials in people with HIV, we discuss the potential benefits, safety aspects and pharmacological considerations of prescribing liraglutide and semaglutide in people with HIV., Results: Clinical experience is limited to two clinical cases of diabetic people with HIV using liraglutide after which a successful weight loss and glycaemic control were observed. None of the adverse events associated with liraglutide and semaglutide usage indicate an additional risk for people with HIV. Extra caution showed be warranted when initiating GLP-1 agonist therapy in people with HIV taking protease inhibitors who have pre-existing risk factors for heart rate variability to reduce the incidence of RP interval prolongation. GLP-1 agonists are metabolized by endopeptidases, and thus do not generate major drug-drug interactions with most drugs, including ARVs. GLP-s agonists are known to inhibit gastric acid secretion, which warrants caution and close monitoring when combined with atazanavir and oral rilpivirine, two ARVs that require low gastric pH for an optimal absorption., Conclusion: Theoretical considerations and a few available clinical observations support semaglutide and liraglutide prescription in people with HIV, with, thus far, no indications of concern regarding efficacy, safety or pharmacological interactions with ARVs., (© 2023 British HIV Association.)

Objective: Lower urinary tract symptoms (LUTS) are becoming more prevalent in the ageing population of males living with HIV. Drugs to treat LUTS are known for both their potential role as victims in drug-drug interactions (DDIs) and their side effects. We aimed to evaluate the current use of drugs to treat LUTS and to assess potential DDIs in our cohort of adult males living with HIV., Design: This was a retrospective review of pharmacy records., Methods: We recorded the combination antiretroviral therapy (cART) regimen and any use of drugs to treat LUTS (anatomical therapeutic chemical codes G04CA/CB/CX and G04BD). Potential DDIs were assessed using the interaction checker developed by the University of Liverpool (https://www.hiv-druginteractions.org/checker)., Results: A total of 411 adult males living with HIV were included in this analysis. The median (interquartile range [IQR]) age was 53 (41-62) years. Nineteen (4.6%) patients used one or more drugs to treat LUTS. As expected, older patients were more likely to be receiving treatment for LUTS: Q1 (20-40 years) = 0%; Q2 (41-52 years) = 2%; Q3 (53-61 years) = 7%; Q4 (62-79 years) = 10%. Seven potential DDIs between cART and LUTS treatment were noted in six of the 19 (32%) patients. Following medication reviews of these six patients, the following interventions were proposed: evaluate safe use of alpha-blocker (n = 4), change in cART (n = 2), and dose reduction of the anticholinergic agent (n = 1)., Conclusion: Treatment for LUTS coincided with cART in 7%-10% of patients aged above the median age of 53 years in our cohort. Improvements in DDI management appeared to be possible in this growing cohort of males living with HIV and with LUTS., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Incidence of anal cancer is high in people living with HIV, particularly in men who have sex with men (MSM). Screening for and treatment of precursor lesions might prevent progression to anal cancer in people living with HIV. We examined trends in incidence of and mortality after anal cancer diagnosis in people living with HIV, including the effect of screening from 2007 onwards, in the Netherlands., Methods: In this observational cohort study, we analysed data from the ongoing open nationwide Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. We included all consenting adults living with HIV and identified all primary anal squamous cell carcinoma. We reported temporal trends in incident anal cancer cases from Jan 1, 1996, to Dec 31, 2020, and all-cause and anal cancer-related mortality in individuals diagnosed with anal cancer. Multivariable Poisson regression was used to explore risk factors for incident anal cancer and multivariable Cox regression was used to explore risk factors for anal cancer-related mortality., Findings: Among 28 175 individuals in HIV care (59·7% MSM), 227 primary anal cancer cases were diagnosed. Despite the increasing average age of the cohort, crude incidence rates of anal cancer in MSM declined slowly over time, from 107·0 (95% CI 75·7-147·0) per 100 000 person-years in 1996-2005 to 93·7 (75·3-115·0) per 100 000 person-years in 2013-20 (p=0·49). Crude incidence rates in men who do not have sex with men (non-MSM) and women were generally lower than in MSM, but increased slightly over time, from 51·08 (95% CI 20·54-105·25) to 67·82 (40·83-105·91; p=0·52) per 100 000 person-years in non-MSM and from 8·09 (0·20-45·06) to 24·95 (10·03-51·40; p=0·29) per 100 000 person-years in women. The age-adjusted incidence rate in MSM in 2013-20 was significantly lower (rate ratio 0·62 [95% CI 0·41-0·92]) compared with in 1996-2005. Changes in risk factors (less smoking, cumulative exposure to CD4 count of <200 cells per μL, and plasma HIV-1 RNA of >1000 copies per mL) mostly explained the decrease in anal cancer risk over time in MSM. 3866 (23·0%) of 16 819 MSM participated in anal cancer screening at least once. TNM tumour staging was more favourable (Cochrane-Armitage test for trend p=0·033) in individuals diagnosed during screening. Crude anal cancer-associated 5-year mortality in people living with HIV decreased from 30·4% (1996-2005) to 18·3% (2013-20; odds ratio 0·48; p=0·070). Anal cancer-related mortality was 3·7% (95% CI 0·5-23·5) in all men who had been screened and 24·0% (95% CI 18·1-31·3) in men who had not been screened (p=0·023). In men, screening participation (hazard ratio [HR] 0·31, p=0·051) and cumulative exposure to CD4 counts of less than 200 cells per μL (HR 1·11 per year; p=0·0022) were independently associated with anal cancer-related mortality., Interpretation: As anal cancer incidence is slowly declining in MSM but not in non-MSM and women, health-care professionals should not focus only on MSM for anal cancer prevention. Men diagnosed with anal cancer during screening had improved survival, probably because they were diagnosed at an earlier disease stage. Next to preventing anal cancer, these data are an important justification to screen those most at risk of anal cancer., Funding: None., Competing Interests: Declaration of interests FWNMW has received consultancy fees from ViiV. MvdV has received grants and consultancy fees from ViiV, Gilead, and MSD, all paid to his institution. HJCdV received financial compensation or goods for research from Gilead; financial compensation for presentations from Abbott, AbbVie, and Janssen; and financial compensation for advice to Abbott. PR through his institution has received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals, Merck & Co, and ViiV Healthcare, and has served on scientific advisory boards for Gilead Sciences, ViiV Healthcare, and Merck & Co, which were all paid to his institution. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with human immunodeficiency virus (HIV), but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe., Methods: Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF area under the curve (AUClast) below the target of 53.1 ng∗h/mL was determined. Clinical efficacy and safety outcome parameters were reported., Results: In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30%, and 34%, respectively. The proportion of women with a TAF AUClast < 53.1 ng∗h/mL was 6% at third trimester and 0% postpartum. One out of 20 women had a viral load > 50 copies/mL at third trimester and no mother-to-child transmission occurred., Conclusions: TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study., Competing Interests: Potential conflicts of interest. O. R. has received support from Gilead Sciences to attend the EACS conference. D. B. has received honoraria and/or study grants from Janssen Pharmaceutica, Merck Sharp & Dohme Corp, Gilead Sciences and ViiV Healthcare. D. K. has received payment/honoria from Janssen Pharmaceutica for a presentation on a HIV symposium; participates on an advisory board on HPV vaccines of Merck Sharp & Dohme Corp; received support from Gilead Sciences, Viiv Healthcare and Pfizer to attend the ID-week and the ECCMID. A. C. has received honoraria from Merck Sharp & Dohme Corp 2021, fee is paid to the institution; is an unpaid co-chair of the pediatric antiretroviral working group (PAWG). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Bariatric surgery is increasingly applied among people living with HIV to reduce obesity and the associated morbidity and mortality. In people living with HIV, sufficient antiretroviral exposure and activity should always be maintained to prevent development of resistance and disease progression. However, bariatric surgery procedures bring various gastrointestinal modifications including changes in gastric volume, and acidity, gastrointestinal emptying time, enterohepatic circulation and delayed entry of bile acids. These alterations may affect many aspects of antiretroviral pharmacokinetics. Some drug characteristics may result in subtherapeutic exposure and the potential related risk of treatment failure and resistance. Antiretrovirals that require low pH, administration of fatty meals, longer intestinal exposure, and an enterohepatic recirculation for their absorption may be most impacted by bariatric surgery procedures. Additionally, some antiretrovirals can interact with the polyvalent cations in supplements or drugs inhibiting gastric acid, thereby preventing their use as these comedications are commonly prescribed post-bariatric surgery. Predicting pharmacokinetics on the basis of drug characteristics solely proved to be challenging, therefore pharmacokinetic studies remain crucial in this population. Here, we discuss general implications of bariatric surgery on antiretroviral outcomes in people living with HIV as well as drug properties that are relevant for the choice of antiretroviral treatment in this special patient population. Additionally, we summarise studies that evaluated the pharmacokinetics of antiretrovirals post-bariatric surgery. Finally, we performed a comprehensive analysis of theoretical considerations and published pharmacokinetic and pharmacodynamic data to provide recommendations on antiretrovirals for people living with HIV undergoing bariatric surgery., (© 2022. The Author(s).)

Background: High-grade anal intraepithelial neoplasia (HGAIN; AIN2-3) is highly prevalent in HIV+ men, but only a minority of these lesions progress towards cancer. Currently, cancer progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN., Methods: A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+ men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series., Results: Methylation levels of all genes increased with increasing severity of disease (P < .05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC = 0.88) for AIN3+ detection, slightly improved by addition of ASCL1 and SST (AUC = 0.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers., Conclusions: We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Aim: Women with a history of human papillomavirus (HPV)-related cervical, vaginal or vulvar high-grade squamous intra-epithelial lesions (HSILs) or cancer are at increased risk of developing anal squamous intra-epithelial lesions (SILs) or a squamous cell carcinoma of the anus (SCCA). Screening for intra-anal SILs with high-resolution anoscopy (HRA) in high-risk populations is a subject of debate. In this study we aimed to answer the following question: what is the prevalence of intra-anal (H)SIL in women with HPV-related vulvar and/or perianal disease using HRA for screening?, Method: A retrospective study was performed to evaluate the prevalence of intra-anal (H)SIL in women with a history of vulvar and/or perianal HSIL or (superficially invasive) squamous cell carcinoma (SCC). This study was performed between 2015 and 2018 following implementation of a protocol for intra-anal screening using HRA., Results: Twenty-seven patients, 10 with a history of (superficially invasive) SCC (four vulvar, five perianal, one multizonal) and 17 with HSIL as the worst diagnosis (two perianal, 15 multizonal) were screened for intra-anal lesions using HRA. No anal cancer was found at screening, 6 (22%) patients were diagnosed with intra-anal HSIL and 12 (44%) patients with intra-anal low-grade SIL., Conclusions: We found a high prevalence of intra-anal HSIL in women previously diagnosed with vulvar and perianal HSIL. Given the clear link between HSIL and SCCA, screening for intra-anal lesions in women with HPV-related genital pathology seems warranted. Future studies should focus on the effect of HSIL treatment on the prevention of anal cancer., (© 2020 The Association of Coloproctology of Great Britain and Ireland.)

Background: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at risk of anal squamous cell carcinoma. Data are limited on the natural history of the precursor to this carcinoma, anal squamous intraepithelial lesions (SILs)., Methods: HIV-positive MSM were screened for histopathological SILs by means of high-resolution anoscopy (HRA). For participants without SILs at baseline, we estimated the cumulative incidence and risk factors for SILs. For those with low-grade SILs (LSILs) at baseline, the risk of progression to high-grade SILs (HSILs) and the clearance rate were estimated at the lesion level., Results: Of 807 men without SILs at baseline, 107 underwent follow-up HRA between 1 to 4.5 years later. At the second visit 18 men (16.8%) showed LSIL, and 25 (23.4%) HSIL. Age was associated with incident LSILs (adjusted odds ratio [aOR], 2.10 per 10-year increase in age; P = .01). Of 393 men with LSILs at baseline, 114 underwent follow-up HRA 0.5 to 2.5 years later. Of the 177 LSILs found at baseline, 87 (49.2%) had cleared at the second visit, and 29 (16.4%) had progressed to HSILs., Conclusion: Incident LSILs and HSILs were common during follow-up among HIV-positive MSM without dysplasia at baseline. Among men with LSILs at baseline, nearly half of these lesions cleared, and a small portion progressed., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: The aim of the study was to develop recommended techniques and quality assurance metrics for the practice of Digital Anal Rectal Examination (DARE)., Materials and Methods: The International Anal Neoplasia Society undertook a literature review and, using the AGREE II technique, developed guidelines for performing DARE., Results: A consensus was formed regarding the optimum conditions and characteristics of DARE. Several Quality Assurance metrics were developed., Conclusions: Digital Anal Rectal Examination is a cheap and potentially universally available technique, which has the potential to facilitate the early diagnosis of anal cancers, when they are most amenable to treatment. These guidelines provide a basis for teaching the technique and may be used as for evaluation research.

Background: High-grade anal intraepithelial neoplasia (AIN2/3; HGAIN) is highly prevalent in human immunodeficiency virus positive (HIV+) men who have sex with men (MSM), but only a minority will eventually progress to cancer. Currently, the cancer risk cannot be established, and therefore all HGAIN is treated, resulting in overtreatment. We assessed host cell deoxyribonucleic acid (DNA) methylation markers for detecting HGAIN and anal cancer., Methods: Tissue samples of HIV+ men with anal cancer (n = 26), AIN3 (n = 24), AIN2 (n = 42), AIN1 (n = 22) and HIV+ male controls (n = 34) were analyzed for methylation of 9 genes using quantitative methylation-specific polymerase chain reaction. Univariable and least absolute shrinkage and selection operator logistic regression, followed by leave-one-out cross-validation, were used to determine the performance for AIN3 and cancer detection., Results: Methylation of all genes increased significantly with increasing severity of disease (P < 2 × 10-6). HGAIN samples revealed heterogeneous methylation patterns, with a subset resembling cancer. Four genes (ASCL1, SST, ZIC1,ZNF582) showed remarkable performance for AIN3 and anal cancer detection (area under the curve [AUC] > 0.85). ZNF582 (AUC = 0.89), detected all cancers and 54% of AIN3 at 93% specificity. Slightly better performance (AUC = 0.90) was obtained using a 5-marker panel., Conclusions: DNA methylation is associated with anal carcinogenesis. A marker panel that includes ZNF582 identifies anal cancer and HGAIN with a cancer-like methylation pattern, warrantingvalidation studies to verify its potential for screening and management of HIV+ MSM at risk for anal cancer., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

The worldwide rapid increase in antibiotic resistance means that new therapeutic measures are urgently needed. Older antibiotics, such as colistin, fosfomycin, minocycline, mecillinam and temocillin, which had fallen from grace due to the development of more effective and less toxic drugs are now of renewed interest in the treatment of infections caused by multiresistant bacteria. Two new glycopeptides (oritavancin and dalbavancin) and a new oxazolidinone (tedizolid) are now registered for the treatment of acute skin and soft-tissue infections. In the treatment of infections caused by Gram-negative bacteria, cephalosporins are combined with beta-lactamase inhibitors which protect them from various beta-lactamases and also make them effective against extended spectrum beta-lactamase-producing bacteria. Examples of these are ceftolozane-tazobactam, ceftazidime-avibactam and meropenem-vaborbactam. Results of preclinical research on the effectiveness of new antibiotics are hopeful. There has been a great increase in investment in the development of new antimicrobials. Also, regulatory agencies have accelerated their assessment of these new - and urgently needed - drugs.

The number of infectious disease outbreaks and the number of unique pathogens responsible have significantly increased since the 1980s. HIV-positive men who have sex with men (MSM) are a vulnerable population with regards to the introduction, spread and clinical consequences of (newly introduced) STIs. After the introduction of combination antiretroviral treatment (cART), the incidence of sexually acquired hepatitis C virus (HCV) infection and human papillomavirus (HPV)-induced anal cancers have significantly increased among HIV-positive MSM. The introduction and expansion of HCV is the result of increased sexual risk behaviour and sexually acquired mucosal trauma within large interconnected networks of HIV-positive MSM in particular. With the availability of cART, postexposure and pre-exposure prophylaxis (PEP and PrEP) and direct-acting antivirals (DAAs) for HCV, less concern for HIV and HCV might require a new approach to develop effective behavioural intervention strategies among MSM. The marked rise in HPV-induced anal cancers can be ascribed to the long-term immunologic defects in an ageing population affected by HIV. More evidence with regards to effective treatment options for anal dysplastic lesions and the usefulness of anal malignancy screening programmes is urgently needed. Most anal cancers in the future generation of HIV-positive MSM could be prevented with the inclusion of boys in addition to girls in current HPV vaccination programmes., Competing Interests: Competing interests: None., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose of Review: Anal cancer is a serious health problem in HIV-positive men who have sex with men, and precursor lesions, anal intraepithelial neoplasia, are well defined. Given the similarities with cervical cancer, screening for and treatment of anal intraepithelial neoplasia might prevent anal cancer. Screening programmes should meet the Wilson and Jungner criteria. We used these criteria to evaluate the current body of evidence supporting a screening programme for anal dysplasia., Recent Findings: The natural history of anal intraepithelial neoplasia is gradually becoming more clear, and three prospective studies are now being performed to conclusively address this issue. High-resolution anoscopy stays the gold standard to diagnose anal intraepithelial neoplasia. The International Anal Neoplasia Society has recently published Practice Standards in the Detection of Anal Cancer Precursors. The main issue, however, is treatment. Although response rates are reasonable at early evaluation, the majority of patients has a recurrence., Summary: At present, an anal cancer screening programme for HIV-positive men who have sex with men meets most of the Wilson and Jungner criteria. Given that high-resolution anoscopy is the gold standard for screening, important issues that need addressing are the need for a less invasive screening procedure and the cost-effectiveness of screening. The main issue is treatment. Development and evaluation of new treatment strategies are essential for an effective and sustainable screening programme.

Background: Anogenital warts are often presumed to represent nondysplastic or low-grade anal intraepithelial neoplasia (LGAIN). We previously demonstrated that up to 20% of intra-anal warts in HIV-positive men who have sex with men (MSM) contain regions of high-grade AIN (HGAIN)., Objectives: To determine the causative human papillomavirus (HPV) types of low- and high- grade dysplastic areas in warts from HIV-positive MSM., Methods: A total of 42 intra-anal warts from 41 HIV-positive MSM were graded as nondysplastic, LGAIN or HGAIN. Whole-tissue sections (WTS) were analysed with the SPF10 polymerase chain reaction/LiPA25 HPV genotyping system. If the WTS contained multiple HPV types, dysplastic regions were isolated by laser capture microdissection (LCM) for HPV genotyping., Results: Overall, 38 of 42 (91%) WTS tested positive for HPV DNA. Of these, 23 (61%) contained a single HPV type and 15 (39%) contained multiple HPV types. All LCM-selected regions contained no more than one HPV type. Ten of 42 (24%) WTS contained HGAIN disease, of which six (60%) were associated with a high-risk HPV (hrHPV) genotype. Twenty-three of 42 WTS contained LGAIN disease, of which two (9%) were associated with hrHPV. AIN lesions containing hrHPV types were identified using p16 staining., Conclusions: LGAIN lesions can be caused by high-risk HPV genotypes and vice versa. We therefore recommend routine follow-up and treatment of all dysplastic intra-anal warts for HIV-positive MSM., (© 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: The impact of the treatment of precursor lesions of anal cancer (anal intraepithelial neoplasia) on health-related quality of life has not been investigated., Objective: This study aimed to evaluate the impact of 3 treatment options for anal intraepithelial neoplasia on health-related quality of life and sexual functioning in HIV-positive men who have sex with men., Design: The prospective cohort was embedded in a randomized clinical trial evaluating the optimal treatment of anal intraepithelial neoplasia., Setting: This study was performed at the HIV outpatient clinic of the Academic Medical Center, Amsterdam, the Netherlands., Patients: Included in the study were HIV-positive men who have sex with men with anal intraepithelial neoplasia., Intervention: Treatment with imiquimod (n = 54), topical fluorouracil (n = 48), or electrocautery (n = 46) was given for 16 weeks., Main Outcome Measures: Health-related quality of life and sexual functioning were assessed before, during, and 4 weeks after treatment. Health-related quality of life was assessed using the EQ5D, sexual functioning was assessed using items derived from the International Index of Erectile Function, and the female sexual function index adapted for anal intercourse., Results: One hundred forty-five patients (98%) completed at least 1 questionnaire. There was a significant different pattern of change over time in health-related quality of life among the 3 treatment groups. Patients in the imiquimod group were more likely to report pain/discomfort at week 8 than patients in the electrocautery group. Patients in the electrocautery group were more likely to report anxiety/depression and were less satisfied with their overall sex life at week 16 than patients in the imiquimod and fluorouracil groups, and patients in the electrocautery group were also more likely to report pain/discomfort and problems with usual activities at week 20 than patients in the fluorouracil group., Limitations: The follow-up method differed slightly among treatment groups. There is no standardized, validated sexual functioning questionnaire for HIV-positive men who have sex with men., Conclusions: All treatment options have a negative impact on aspects of health-related quality of life. Electrocautery has significantly more negative effects on health-related quality of life than imiquimod and fluorouracil and also has a negative effect on sexual functioning.

We surveyed trends in incidence (1995-2012) and risk factors for anal cancer in the Dutch HIV-positive population. After an initial increase with a peak incidence in 2005-2006 of 114 [95% confidence interval (CI): 74 to 169] in all HIV+ patients and 168 (95% CI: 103 to 259) in HIV+ men who have sex with men (MSM), a decline to 72 (95% CI: 43 to 113) and 100 (95% CI: 56 to 164), respectively, was seen in 2011-2012. Low nadir CD4, alcohol use, and smoking were significantly associated with anal cancer in MSM. In conclusion, anal cancer remains a serious problem in predominantly HIV+ MSM. However, it seems that incidence rates are leveling off.

HIV infection is one of the strongest risk factors for anal squamous cell cancer (ASCC). Most ASCC are caused by HPV, and most HPV-associated ASCC are caused by HPV-16. Anal HPV infections are very common in men who have sex with men (MSM), and nearly universal among HIV-infected MSM. High-grade anal intraepithelial neoplasia (HGAIN), the precursor for ASCC, is present in about 30 % of HIV+ MSM, but neither the progression rate to ASCC nor the regression rate are known. The incidence rate of ASCC among HIV-infected people has risen in the first decade after cART became available, but appears to be plateauing recently. Anal cytology has poor sensitivity and specificity. High resolution anoscopy (HRA) is advocated by some as a screening tool in high-risk groups, but is cumbersome and time-consuming and it is unknown whether HRA followed by treatment of HGAIN prevents ASCC. More research is needed on progression and regression rates of HGAIN, on effective therapy of HGAIN, and on biomarkers that predict HGAIN or anal cancer. HPV vaccination and earlier start of cART may prevent most anal cancers in the long run.

Background: High-grade anal intraepithelial neoplasia (AIN) is present in many human immunodeficiency virus (HIV)-positive men who have sex with men. The major etiologic factor is infection with an oncogenic human papillomavirus (HPV) genotype. We investigated whether individual components of high-grade AIN are caused by single HPV types., Methods: DNA was isolated from whole-tissue sections of 31 high-grade AIN that were recovered from 21 HIV-positive men who have sex with men. The SPF10 PCR/LiPA25 HPV genotyping system was used for DNA analysis. In whole-tissue sections with multiple HPV types, polymerase chain reaction was repeated in regions of AIN sampled by laser-capture microdissection. The results were compared with HPV types in anal swabs., Results: A single HPV type was observed in 15 (48%) of 31 whole-tissue sections. In an additional 14 whole-tissue sections, 1 HPV type was found in each lesion sample evaluated by laser-capture microdissection. Consequently, in 29 of 31 biopsy specimens (94%), a single HPV type was found in each lesional component studied. Two whole-tissue sections contained collision regions, each with 2 HPV types. HPV16 was presumed to be causative in 14 of 31 biopsy specimens (45%). More than half of the anal swabs did not contain all causative HPV types., Conclusions: Individual components of high-grade AIN are caused by single HPV types (the so-called one lesion, one virus concept). HPV16 is causative in <50% of cases. Anal swabs are not useful for detecting lesion-specific HPV types.

We studied 3 patients with focal intra-anal tissue high-grade squamous intraepithelial lesions (HSILs). All had increased human immunodeficiency virus type 1 (HIV-1) RNA and DNA in lesions compared with that in healthy mucosa. HIV-1 RNA and HIV-1 episomal DNA were indicative of ongoing viral replication, more so in anal HSILs.

Objective: Anal Intraepithelial Neoplasia (AIN) is present in the majority of HIV+ men who have sex with men (MSM) and routine AIN-screening is subject of discussion. In this study we analysed a wide range of potential risk factors for AIN in order to target screening programs., Methods: We screened 311 HIV+ MSM by high resolution anoscopy, with biopsies of suspect lesions. HIV-parameters, previous sexual transmitted infections (STI's), anal pathology, sexual practices and substance use were analysed in relation to AIN by uni- and multivariable logistic regression., Results: AIN (any grade) was found in 175/311 MSM (56%), high grade (HG)AIN in 30%. In the univariable analysis, years since HIV diagnosis, years of antiretroviral therapy (cART) and anal XTC use decreased AIN risk, while a history of anogenital warts and use of GHB (γ-hydroxybutyric acid) increased this risk. In the multivariable analysis three parameters remained significant: years of cART (OR=0.92 per year, p=0.003), anal XTC use (OR=0.10, p=0.002) and GHB use (OR=2.60, p=0.003). No parameters were significantly associated with HGAIN, but there was a trend towards increased risk with anal enema use prior to sex (>50 times ever; p=0.07) and with a history of AIN (p=0.06). CD4 count, STI's, anal pathology, smoking, number of sex partners and anal fisting were not associated with (HG)AIN., Conclusion: GHB use increases the risk for AIN, while duration of cART and anal XTC use are negatively correlated with AIN. Given the high prevalence of AIN in HIV+ MSM, these associations are not helpful to guide a screening program.

Background: High-resolution anoscopy is increasingly advocated to screen HIV+ men who have sex with men for anal cancer and its precursor lesions, anal intraepithelial neoplasia. A systematic comparison between clinical features and the histopathology of suspect lesions is lacking., Objective: This study aims to analyze interobserver agreement in classifying features of intra-anal lesions suspect for anal intraepithelial neoplasia and to compare these features with their histopathological outcome., Design: This study is a cross-sectional survey regarding high-resolution anoscopy with images and biopsies of suspect lesions. Two dermatologists experienced in high-resolution anoscopy, blinded for histopathological outcome, independently classified the lesions on clinical features., Setting: This investigation was conducted at the Dermatology outpatient clinic of the Academic Medical Center in Amsterdam, The Netherlands., Patients: Included in the study were 163 HIV+ men who have sex with men, older than 18 years, with no history of anal cancer., Main Outcome Measures: The primary outcomes measured were the κ-coefficient for interobserver agreement and the proportions of anal intraepithelial neoplasia per clinical feature., Results: Three hundred four biopsies were taken from 163 patients. One hundred sixty-eight biopsies (55%) showed anal intraepithelial neoplasia, and 67/304 (22%) showed high-grade anal intraepithelial neoplasia. The κ-coefficient was 0.65 for condylomatous lesions, 0.14 for surface configuration, 0.54 for punctation, 0.08 for mosaicism, and 0.43 for atypical vessels. Condylomatous lesions showed high-grade anal intraepithelial neoplasia in 18% (95% CI, 11%-27%). In lesions with flat leukoplakia, punctation, and atypical vessels, high-grade anal intraepithelial neoplasia was seen in 25%, 30%, and 23%. In lesions with the combination punctation/atypical vessels and punctation/flat leukoplakia/atypical vessels, high-grade anal intraepithelial neoplasia was found in 38% and 40%., Limitations: We did not take biopsies of healthy-looking mucosa. Furthermore, the real-time description of features during high-resolution anoscopy, instead of the use of images, would improve the recognition of subtle mucosal abnormalities., Conclusions: A moderate to substantial interobserver agreement was demonstrated in recognizing condylomas, punctation, and atypical vessels. Furthermore, high-grade anal intraepithelial neoplasia is present in a high proportion of intra-anal condylomata. A combination of punctation, flat leukoplakia, and atypical vessels is the best predictor for high-grade anal intraepithelial neoplasia.

Background: Anal cancer incidence is gradually increasing. The cause of this increase is not exactly known. This systematic literature review aimed to investigate the trend in time of anal cancer incidence and to find an explanation for the supposed increase., Methods: The TRIP database and PubMed were searched for trends in time in incidence of anal cancer in the general population, for risk factors and risk groups for anal cancer, and for incidence trends in time in these risk groups., Results: Age-adjusted incidence rates have increased in all Western countries during the last decades, up to 2.2% per year. Infection with the oncogenic human papilloma virus is the most important aetiological factor. Besides increasing age, other risk factors have been identified: smoking, sexual practices, in particular receptive anal intercourse, and being human immunodeficiency virus (HIV) positive. The standardised incidence ratio (SIR) is significantly increased in HIV-positive men who have sex with men (MSM) (SIR 77.8), organ transplant recipients (SIR approx. 6) and women with a history of cervical cancer (SIR 6) or cervical intraepithelial neoplasia (SIR 16). Absolute numbers of HIV-positive MSM and organ transplant recipients have increased significantly in the last decades., Conclusion: The increasing incidence of anal cancer can be partially explained by an increase in the incidence rate in and absolute number of the most important risk group: HIV-positive MSM. The increasing number of renal transplant recipients probably also contributes. Further studies should answer the question whether these risk groups would benefit from preventive screening for anal cancer.

Background: Anal cancer is an increasing issue in HIV-positive men who have sex with men (MSM). Screening for its precursor, anal intraepithelial neoplasia (AIN), is subject of discussion. Current treatment options are suboptimum and have not been compared in a prospective trial. We compared efficacy and side-effects of imiquimod, topical fluorouracil, and electrocautery for the treatment of AIN., Methods: In this open-label randomised trial, we included HIV-positive MSM older than 18 years visiting the HIV outpatient clinic of the Academic Medical Center, Amsterdam, Netherlands. Patients with histologically confirmed AIN were randomly assigned to receive either 16 weeks of imiquimod (three times a week), 16 weeks of topical fluorouracil (twice a week), or monthly electrocautery for 4 months. Randomisation was done with random block sizes of three and six, stratified for AIN grade (AIN grades 1, 2, or 3) and AIN location (peri-anal or intra-anal). Participants were assessed by high-resolution anoscopy 4 weeks after treatment. Responding patients returned for follow-up 24 weeks, 48 weeks, and 72 weeks after treatment. The primary endpoint was histological resolution of AIN measured 4 weeks after treatment and AIN recurrence at week 24, week 48, and week 72 after treatment. The primary analysis was done in a modified intention-to-treat population, including all patients who had received their assigned treatment at least once. The trial is registered at the Netherlands Trial Register, number NTR1236., Findings: Between Aug 12, 2008, and Dec 1, 2010, we screened 388 HIV-positive MSM for AIN by high resolution anoscopy. Of the 246 (63%) patients who had AIN, 156 (63%) were randomly assigned to either receive imiquimod (54 patients), topical fluorouracil (48 patients), or electrocautery (46 patients) following withdrawing of consent by eight patients. Modified intention-to-treat analysis showed a complete response in 13 (24%, 95% CI 15-37) patients in the imiquimod group, eight (17%, 8-30) of patients in the fluorouracil group, and 18 (39%, 26-54) of patients in the electrocautery group (p=0·027). At week 24, 11 (22%) of 50 responders had recurrence; at week 48, 22 (46%) of 48 had recurred; and at week 72, 30 (67%) of 45 had recurred. Recurrence was observed at 72 weeks in 10 (71%) of 14 patients treated with imiquimod, seven (58%) of 12 patients treated with fluorouracil, and 13 (68%) of 19 patients treated with electrocautery. Grade 3-4 side-effects were noted in 23 (43%) of 53 patients in the imiquimod group, 13 (27%) of 48 patients in the fluorouracil group, and eight (18%) patients in the electrocautery group (p=0·019). The most common side-effects were pain, bleeding, and itching. Seven serious adverse events occurred, all not related to the study., Interpretation: Electrocautery is better than imiquimod and fluorouracil in the treatment of AIN, but recurrence rates are substantial., Funding: Anna Maurits de Cock foundation provided funding for the video colposcope., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)-induced potential precursor lesion of anal cancer, is frequent among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). So far, only a few prospective studies have been performed on the topical treatment of AIN, especially at the intra-anal location., Objectives: To evaluate the efficacy and safety of self-administered topical 5-fluorouracil (5-FU) treatment of AIN in HIV-positive MSM., Methods: High-resolution anoscopy (HRA) was performed and patients with AIN (grade 1-3) were treated with 5-FU twice weekly for a total of 16 weeks. HRA-guided lesional biopsies were repeated after 5-FU treatment for histopathological evaluation. Lesional swabs were obtained before and after treatment for HPV typing and HPV-DNA load determination of the high-risk types HPV16, 18, 31 and 33. Responding patients returned 6 months after treatment for follow-up., Results: A total of 46 patients with AIN were included in this open prospective pilot study; 76% had multifocal disease and 74% had high-grade lesions (AIN 2 or 3). In an intention-to-treat analysis, 26 of 46 patients (57%) responded to 5-FU treatment. Eighteen patients (39%) had a complete clearance of AIN and eight patients (17%) had a partial response. Seventeen patients (37%) did not respond (unchanged grade of AIN in 16 patients and progression from low- to high-grade AIN in one patient). 5-FU treatment led to a significant decrease of HPV16-DNA load and cumulative high-risk HPV-DNA load in both responding and nonresponding patients. Thirty-nine patients (85%) experienced side-effects during therapy, but only two discontinued 5-FU treatment. One patient was lost to follow-up. Six months later, 50% of the complete responders had a recurrence., Conclusions: A substantial proportion of HIV-positive MSM with AIN completely cleared their lesions with topical 5-FU treatment. In those with partial response, pretreatment with topical 5-FU might facilitate subsequent ablative therapy., (© 2010 The Authors. BJD © 2010 British Association of Dermatologists.)

Objective: Hyperthermia enhances carboplatin cytotoxicity preclinically, and clinical studies have shown radiant heat Whole Body Hyperthermia (WBH) to be safe. In this study, the efficacy and toxicity of the combination of 41.8 degrees C WBH and carboplatin in recurrent and/or metastatic cervical cancer were explored., Methods: Recurrent and/or metastatic cervical cancer patients were treated with 41.8 degrees C WBH and concurrent carboplatin, cycled every 28 days (max. 6 cycles)., Results: Twenty-one of 25 participants were evaluable for response: one complete remission, six partial responses, stable disease in nine patients and progression in five, leading to a response rate of 33%. Three of four evaluable chemotherapy pre-treated patients progressed, while this was seen in only 2 of 17 chemotherapy-naive patients. The median survival is 7.8 months (range 1.3 to 43+) and no patients were lost to follow up. Grades 3/4 toxicities were common: leukopenia in 35%, thrombopenia in 61% and anemia in 22% of all treatments. Excessive, partly reversible renal toxicity was seen in two patients (grades 3 and 4)., Conclusion: The efficacy of WBH and carboplatin in recurrent and/or metastatic cervical cancer seems comparable to that of other palliative chemotherapy regimens in this disease. The considerable toxicity, though largely manageable, includes unexpected and severe unacceptable renal toxicity. This regimen seems less suitable for palliative care.