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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 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.

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 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.

Contains fulltext : 251179.pdf (Publisher’s version ) (Open Access) 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.

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BackgroundHuman 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).MethodsHIV-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.ResultsOf 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.ConclusionIncident 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.

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, Independent validation of host cell DNA methylation markers associated with anal carcinogenesis demonstrates their significant prognostic value for treatment decision making of high-grade anal intraepithelial neoplasia. This is further emphasised by a longitudinal analysis-based association with progression to anal cancer.

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., Deoxyribonucleic acid methylation is associated with anal carcinogenesis and has potential to detect high-grade anal intraepithelial neoplasia. This is a novel, more effective anal cancer screening procedure for human immunodeficicency virus positive men who have sex with men.

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.

Contains fulltext : 215651.pdf (Publisher’s version ) (Open Access) 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.

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.

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 -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 -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

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.

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.

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. HRAguided 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.

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.

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

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.

Summary 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.

Background Prevention and treatment of anal intraepithelial neoplasia (AIN) in HIV+ men who have sex with men (MSM) is subject of discussion. Knowledge on causative HPV types is crucial in understanding AIN and in vaccination studies. However, data on AIN-specific HPV are limited and whole tissue sections (WTS) often show multiple HPV infections. In this study, we analysed whether WTS and subsequent laser capture micro-dissection (LCM) with HPV PCR genotyping accurately detects type-specific HPV DNA in individual areas of high grade (HG)AIN. Methods 31 WTS with HGAIN of 21 HIV+ MSM were analysed by the SPF10 PCR/LiPA25 (version 1) HPV genotyping system. In case of multiple HPV types, PCR was repeated in selected areas of AIN, isolated by LCM. Results WTS PCR showed a single HPV type in 17 (55%). In the remaining 14 WTS sections with multiple HPV types, PCR was repeated in LCM-isolated dysplastic areas (median: 4 per WTS). In 12 of 14 these samples, the number of HPV types could be reduced to single HPV types within discrete areas of a lesion, resulting in a total of 29 (17+12), in which (components of) HGAIN show a singe HPV type. HPV 16 was found in 14/29 (48%), HPV 18 in 3 and HPV 58 in 3. The remaining HPV types that could be linked to a lesional area were HPV 26, 31, 35, 39, 52, 53, 54, 59, 67, 68/73, 74, 91 and one indeterminate HPV type. Conclusion WTS PCR and subsequent LCM PCR is accurate in detecting lesion specific HPV types in AIN and it seems that 94% of the AIN-lesions (on macroscopic or microscopic level) are caused by a single HPV type. Apart from HPV 16, the predominant type, a wide range of other HPV types are responsible for HGAIN, which has consequences for vaccination development.

Background Anal cancer incidence has been increasing in the combined antiretroviral therapy (cART) era in HIV+ patients. In this study we surveyed trends in anal cancer incidence between 1995 and 2012, and analysed a range of potential risk factors. Methods: We retrieved data for all patients diagnosed with anal cancer from the Dutch HIV observational cohort (ATHENA) database. Incidence rates were calculated per 100 000 person-years of follow-up (FU), for the whole period of 18 years, and per 2-year blocks. Potential risk factors were analysed in a uni- and multivariable Cox proportional hazard model. Results: For all HIV+ patients, men who have sex with men (MSM), and heterosexual men and women, respectively, the incidence of anal cancer was 83 (95% CI 70–99), 116 (95% CI 95–140), 44 (95% CI 21–83) and 12 (95% 3–30) per 100 000 person-years of FU. In 2005–2006, a peak in incidence rates was observed of 114 (95% CI 74–169) in the total HIV population and 168 (95% CI 103–259) among HIV+ MSM, followed by a decrease to 72 (95% CI 42–113) and 100 (95% CI 56–164), respectively, in 2011–2012. Low nadir CD4 (

Background Anal intraepithelial neoplasia (AIN) is present in the majority of HIV+ men who have sex with men (MSM). The main aetiological factor is human papilloma virus (HPV). We analysed whether HPV PCR genotyping of whole tissue sections (WTS) and subsequent laser capture microdissection (LCM) detects type-specific HPV DNA in individual areas of HGAIN, and compared these lesional HPV genotypes with HPV types in anal swabs. Methods: DNA was isolated from anal swabs and WTS of 31 HGAIN biopsies obtained from 21 HIV+ MSM and analysed by the SPF10 PCR/LiPA25 HPV genotyping system. In case of multiple HPV types per WTS, PCR was repeated in selected areas of AIN obtained by LCM. Results: A single HPV type was observed in 15 (48%) of 31 WTS. In the 16 WTS with multiple HPV types, LCM-isolated dysplastic areas were studied. In 14 of the 16 WTS, one single HPV type was demonstrated within each discrete area of the lesion, resulting in a total of 29 (15+14) biopsies in which a single HPV type was found in (all components of) the lesion. HPV 16 was found in 14 of 31 biopsies (45%). In almost half the biopsies, lesional HPV types were not detected in the anal swabs. Conclusions: WTS PCR and subsequent LCM PCR is accurate in detecting lesion-specific HPV types in HGAIN and in 94% of the biopsies a single HPV was found in (each component of) the HGAIN lesion. In the majority, HPV16 was not the causative type and HPV genotyping of anal swabs was not useful in detecting the lesion-specific type.