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Background Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV. Methods We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks. Results The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P =.008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers. Conclusions The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents. [ABSTRACT FROM AUTHOR]

Background Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis (CT) serovars L1, L2, and L3 and is endemic among men who have sex with men (MSM) in Europe. We evaluated weekly oral azithromycin 1 g for 3 weeks as a treatment for LGV proctitis. Methods This is an open clinical trial with convenience allocation according to treating physician preferences. Adults with clinical proctitis received a single dose of 1 g of intramuscular ceftriaxone and were subsequently allocated to receive (i) doxycycline 100 mg twice daily for 21 days (Doxycycline group) or (ii) azithromycin 1 g orally once weekly for 3 weeks (Azithromycin group). LGV cure (primary endpoint) was defined as resolution of symptoms at week 6 (clinical cure, LGV-CC), with an additional supporting negative rectal polymerase chain reaction (PCR) at week 4 (microbiological cure, LGV-MC), if available. Results One hundred and twenty-five individuals with LGV clinical proctitis were included. All were MSM, and 96% were living with human immunodeficiency virus (HIV). Eighty-two were in the Azithromycin group, and 43 were in the Doxycycline group. LGV cure on a modified intention-to-treat analysis (primary endpoint), occurred in 80 of 82 (98%) in the Azithromycin group versus 41 of 43 (95%) in the Doxycycline group (treatment difference [95% confidence interval {CI}] 2.2% [−3.2, 13.2]). LGV-MC occurred in 70 of 72 (97%) vs 15 of 15 (100%) in the Azithromycin group and Doxycycline group, respectively (treatment difference [95% CI] −2.8% [−9.6; 17.7]). Adverse events were similar in both treatment groups. Conclusions Our findings support extended azithromycin dosing as an alternative treatment option for symptomatic LGV proctitis and provides the rationale for future randomized trials. [ABSTRACT FROM AUTHOR]

Background Women living with human immunodeficiency virus (WLHIV) have disproportionately high rates of squamous cell carcinoma of the anus compared with the general population of women. Anal high-grade squamous intraepithelial lesions (HSILs) precede anal cancer, and accurate studies of HSIL prevalence among WLHIV in the United States are lacking. Methods The AIDS Malignancy Consortium 084 study was a multicenter national trial to evaluate the prevalence of and risk factors for anal HSIL in a US cohort. Eligible participants were WLHIV aged ≥18 years with no history of anal HSIL. Study participants had an examination including collection of cervical/vaginal and anal specimens, followed by high-resolution anoscopy with biopsy. Results We enrolled 256 women with evaluable anal pathology. The mean age was 49.4 years, 64% women were non-Hispanic black, 67% were former or current smokers, and 56% reported ever having anal sex with a man. The median CD4 T-cell count was 664 cells/μL. The prevalence of anal histologic HSIL (hHSIL) was 27% (95% confidence interval [CI], 22%–33%). There was a strong concordance (240/254) between local and consensus pathologists for hHSIL vs less than hHSIL (κ = 0.86 [95% CI,.79–.93]). Current CD4 count of ≤200 cells/μL was the strongest predictor of consensus anal hHSIL diagnosis (adjusted odds ratio [aOR], 10.34 [95% CI, 3.47–30.87]). History of anoreceptive intercourse was also associated with hHSIL (aOR, 2.44 [95% CI, 1.22–4.76]). Conclusions The prevalence of anal hHSIL in WLHIV in the United States was 27% in this study where all participants received high-resolution anoscopy and biopsy. [ABSTRACT FROM AUTHOR]

Topical imiquimod is a potential treatment for intra-anal condyloma and squamous intraepithelial lesions caused by human papillomavirus (HPV). We aimed to assess the effectiveness and tolerability of imiquimod suppositories for the treatment of anal high-grade intraepithelial lesions (HSIL) and condylomas in HIV-infected patients. We conducted a retrospective analysis in a prospectively followed cohort. High-resolution anoscopy was used for diagnosis and assessment following treatment. Patients' tolerability was assessed with a self-administered survey. Ninety-five patients (94.7% men) were analyzed. All were on combination antiretroviral therapy. Median CD4 T-cell count was 690 cells/µL, 89% had undetectable plasma viral load. Response to imiquimod was seen in 46.3% (complete: 12.5%, partial: 33.8%) in the intent-to-treat analysis, and in 55.2% (complete: 14.9%, partial: 40.3%) in the on-treatment analysis. Higher response rates were observed for anal condyloma compared with HSIL. A significantly poorer response rate was observed in smokers and in individuals with lower nadir CD4 T-cell counts. Imiquimod tolerability was "good" in 57.1% (n = 36), "acceptable" in 33.3% (n = 21), and "poor" in 9.5% (n = 6). Systemic side effects were reported in 20.7% (n = 13). There was no association between treatment effect and tolerability. In conclusion, imiquimod stands as a well-tolerated option for the treatment of HPV-associated intra-anal pathology in HIV-infected individuals. [ABSTRACT FROM AUTHOR]

Background Anal high-grade squamous intraepithelial lesions (HSILs) ablation may reduce the incidence of invasive cancer, but few data exist on treatment efficacy and natural regression without treatment. Methods An open-label, randomized, multisite clinical trial of human immunodeficiency virus (HIV)–infected adults aged ≥27 years with 1–3 biopsy-proven anal HSILs (index HSILs) without prior history of HSIL treatment with infrared coagulation (IRC). Participants were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]). Participants were followed every 3 months with high-resolution anoscopy. Treatment participants underwent anal biopsies of suspected new or recurrent HSILs. The AM participants underwent biopsies only at month 12. The primary end point was complete clearance of index HSIL at month 12. Results We randomized 120 participants. Complete index HSIL clearance occurred more frequently in the treatment group than in the AM (62% vs 30%; risk difference, 32%; 95% confidence interval [CI], 13%–48%; P <.001). Complete or partial clearance (clearance of ≥1 index HSIL) occurred more commonly in the treatment group (82% vs 47%; risk difference, 35%; 95% CI, 16%–50%; P <.001). Having a single index lesion, compared with having 2–3 lesions, was significantly associated with complete clearance (relative risk, 1.96; 95% CI, 1.22–3.10). The most common adverse events related to treatment were mild or moderate anal pain and bleeding. No serious adverse events were deemed related to treatment or study participation. Conclusion IRC ablation of anal HSILs results in more clearance of HSILs than observation alone. [ABSTRACT FROM AUTHOR]

We examined product adherence among 187 men who have sex with men and transgender women enrolled in a phase II, crossover trial comparing safety and acceptability of an oral tablet and a rectal gel used daily for HIV prevention. Participants reported adherence via daily text messages during 8-week periods. Trajectory analysis identified weekly patterns. Polytomous logistic regression identified characteristics associated with higher probability of trajectory group membership. We identified 3 groups per product: high-adherers (72% daily oral, 70% daily gel); decreasing-adherers (20% daily oral, 22% daily gel); and low-adherers (8% daily oral, 9% daily gel). Daily oral high-adherers (compared with low-adherers) were more likely to self-identify as male (OR = 4.76, 95% CI:1.35-16.67), to have more sexual partners (OR = 1.67, 95% CI:1.04-2.63), and to find the tablet easy to swallow (OR = 2.22, 95% CI:1.08-4.76). Daily gel high-adherers (compared with low-adherers) were more likely to be older (OR = 1.16, 95% CI:1.05-1.28), to find gel application easier at the last few applications (OR = 2.27, 95% CI:1.01-5.00), and to report a change in routine if gel was not used (OR = 5.26, 95% CI:1.23-100.00). Characteristics of participants likely to be high-adherers to product use vary according to product. Evaluation of acceptability prior to phase II/III trials could identify participants likely to maintain high adherence. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) prevalence varies by population. This study investigated anal HPV type detection risk by country in a population of men who have sex with men (MSM) and transgender women (TW) at risk of HIV. Sexually active HIV-1-uninfected MSM and TW were enrolled at eight sites: four in the United States (US), two in Thailand, one in Peru, and one in South Africa. Baseline anal HPV swabs were collected, and DNA typing was performed. One hundred and ninety-five participants, 76 (42%) from the US, had a mean age of 30.9 years (range 18-64). In 182 participants with results available, anal HPV infection was common with 169 (93%) with ≥1 type, 132 (73%) with ≥1 nine-valent vaccine types, and 66 (36%) with HPV 16. Participants in the US had a higher prevalence of HPV 16 (56%, p = 0.004) and HPV 6 (69%, p < 0.001) compared to the other regions. Stimulant drug use was significantly associated with HPV 6 detection. Anal HPV is highly prevalent in this population of MSM and TW sampled from four countries, with HPV 16 the most commonly detected type. The nine-valent HPV vaccine has the potential to provide significant protection if given prior to exposure. [ABSTRACT FROM AUTHOR]

Objective: During a Phase 2 rectal microbicide trial, men who have sex with men and transgender women (n = 187) in 4 countries (Peru, South Africa, Thailand, United States) reported product use daily via short message service (SMS). To prevent disclosure of study participation, the SMS system program included privacy and security features. We evaluated participants' perceptions of privacy while using the system and acceptability of privacy/security features.Materials and Methods: To protect privacy, the SMS system: (1) confirmed participant availability before sending the study questions, (2) required a password, and (3) did not reveal product name or study participation. To ensure security, the system reminded participants to lock phone/delete messages. A computer-assisted self-interview (CASI), administered at the final visit, measured burden of privacy and security features and SMS privacy concerns. A subsample of 33 participants underwent an in-depth interview (IDI).Results: Based on CASI, 85% had no privacy concerns; only 5% were very concerned. Most were not bothered by the need for a password (73%) or instructions to delete messages (82%). Based on IDI, reasons for low privacy concerns included sending SMS in private or feeling that texting would not draw attention. A few IDI participants found the password unnecessary and more than half did not delete messages.Discussion: Most participants were not concerned that the SMS system would compromise their confidentiality. SMS privacy and security features were effective and not burdensome.Conclusion: Short ID-related passwords, ambiguous language, and reminders to implement privacy and security-enhancing behaviors are recommended for SMS systems. [ABSTRACT FROM AUTHOR]

Adherence to product use in biomedical HIV prevention trials is essential to success. In MTN-017, a Phase 2 rectal microbicide gel trial, participants discussed applicator-inserted gel use in the context of receptive anal intercourse (RAI) with adherence counselors. We analyzed counseling session data to identify barriers to and facilitators of gel use for 26 participants in the United States who used gel with RAI as their first of three study regimens. The most common barriers were finding the gel application process cumbersome, physical discomfort after applying gel, difficulty with BAT-24 dosage regimen, and negative effects of gel on sex. The most common facilitators were incorporating gel use into routines, using gel in anticipation of sex, carrying gel when going out, reminders received via short message service, and ease of gel use. These findings can inform product development and future adherence counseling interventions for rectal gel trials to improve adherence outcomes. [ABSTRACT FROM AUTHOR]

Rectal microbicides, formulated as a gel to be applied before and/or after intercourse, are promising HIV prevention agents and are now in Phase II trials. However, both an optimal formulation and a practical delivery system are needed to ensure that the target population will use the product once efficacy is demonstrated. The precise dynamics of lubricant application by gay and bisexual men who practice anal sex and the qualities they seek in these products are underexplored. As part of a Phase I microbicide acceptability and adherence study conducted in one Puerto Rican and two continental U.S. cities, we recruited 124 young men who have sex with men (YMSM) with a history of unprotected receptive anal intercourse (RAI) and provided them with 40 rectal applicators containing a placebo gel to use prior to RAI during a 12-week period as a proxy for an eventual rectal microbicide. Ninety-five YMSM completed the trial. Their varied preferences as to product viscosity, durability, residue, and mode of application provide important lessons for the design of a product that will be satisfactory to users. Despite many reservations, the participants used the product frequently and found ways to overcome a range of obstacles. A successful rectal microbicide product may need to be presented in a range of viscosities to attract a broad client base. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. Methods. MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/ TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. Results. MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). There were no differences in ≥grade 2 adverse event rates between daily gel (incidence rate ratio [IRR], 1.09; P = .59) or RAI gel (IRR, 0.90; P = .51) compared to FTC/TDF. High adherence (≥80% of prescribed doses assessed by unused product return and Short Message System reports) was less likely in the daily gel regimen (odds ratio [OR], 0.35; P < .001), and participants reported less likelihood of future daily gel use for HIV protection compared to FTC/TDF (OR, 0.38; P < .001). Conclusions. Rectal application of RG TFV gel was safe in MSM and TGW. Adherence and product use likelihood were similar for the intermittent gel and daily oral FTC/TDF regimens, but lower for the daily gel regimen. [ABSTRACT FROM AUTHOR]

This study examined how acceptability of placebo gel with receptive anal intercourse (RAI) and likelihood of future rectal microbicide use varied across partner types. Because no rectal microbicide is available yet, use of placebo permitted the study of gel use behavior in real-life circumstances. A total of 87 men who have sex with men (MSM) aged 18 to 30 years inserted placebo gel rectally before RAI during 12 weeks. Using mixed-methods design, participants completed a behavioral questionnaire and in-depth interview. In all, 62 men (71.3%) reported gel use with a lover (i.e., spouse equivalent, boyfriend), 32 (36.8%) with a one-night stand (i.e., man with whom you had sex once), and 29 (33.3%) with an "other" male partner. While gel acceptability was high across partner types, use with lovers was facilitated by trust and familiarity; yet trust made participants believe protection was less necessary. Conversely, participants expressed high likelihood of using gel with one-night stands, whom they perceived as riskier; yet they felt less comfortable discussing gel with them, often resorting to covert use or forgoing gel. A successful microbicide will be positioned as a sexual pleasure enhancer so that men can present it to their lovers and other partners as a gel that improves sex and secondarily prevents human immunodeficiency virus (HIV). [ABSTRACT FROM AUTHOR]

Objectives: The purpose of Project Gel was to determine the safety and acceptability of rectal microbicides in young men who have sex with men (MSM) and transgender women (TGW) at risk of HIV infection. Methods: MSM and TGW aged 18–30 years were enrolled at three sites; Pittsburgh, PA; Boston, MA; and San Juan, PR. Stage 1A was a cross-sectional assessment of sexual health and behavior in MSM and TGW. A subset of participants from Stage 1A were then enrolled in Stage 1B, a 12-week evaluation of the safety and acceptability of a placebo rectal gel. This was followed by the final phase of the study (Stage 2) in which a subset of participants from Stage 1B were enrolled into a Phase 1 rectal safety and acceptability evaluation of tenofovir (TFV) 1% gel. Results: 248 participants were enrolled into Stage 1A. Participants’ average age was 23.3 years. The most common sexually transmitted infection (STIs) at baseline were Herpes simplex (HSV)-2 (16.1% by serology) and rectal Chlamydia trachomatis (CT) (10.1% by NAAT). 134 participants were enrolled into Stage 1B. During the 12 week period of follow-up 2 HIV, 5 rectal CT, and 5 rectal Neisseria gonorrhea infections were detected. The majority of adverse events (AEs) were infections (N = 56) or gastrointestinal (N = 46) and were mild (69.6%) or moderate (28.0%). Of the participants who completed Stage 1B, 24 were enrolled into Stage 2 and randomized (1:1) to receive TFV or placebo gel. All participants completed Stage 2. The majority of AEs were gastrointestinal (N = 10) and of mild (87.2%) or moderate (10.3%) severity. Conclusions: In this study we were able to enroll a sexually active population of young MSM and TGW who were willing to use rectal microbicides. TFV gel was safe and acceptable and should be further developed as an alternative HIV prevention intervention for this population. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The association between oral human papillomavirus 16 (HPV16) DNA load and infection clearance was evaluated among 88 individuals with oral HPV16 infection who were identified within a prospective cohort of 1470 HIV-infected and uninfected individuals. Oral rinse specimens were collected semiannually for up to 5 years. The oral HPV16 load at the time of the first positive test result was significantly associated with the time to clearance of infection (continuous P trends <.01). Notably, clearance rates by 24 months were 41% and 94% in the highest and lowest HPV16 load tertiles (P = .03), respectively. High oral HPV16 load warrants consideration as a biomarker for infection persistence, the presumed precursor of HPV16-associated oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

This study examines awareness of and experiences with post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP) among 228 men recruited in Boston, Pittsburgh, and San Juan between 12/2010 and 6/2012. All of them reported having condomless anal sex with a man in the prior year. Overall, 41% had heard of PEP, ranging from 16% in San Juan to 64% in Boston. Only 21% had heard of PrEP, ranging from 8% in San Juan to 36% in Boston. Three had used PEP, and none had used PrEP. After the methods were described to participants, interest in both was high, with intentions to use PEP and PrEP respectively at 9.1 and 7.7 (10-point scale). Increased public education is needed to raise awareness of these HIV prevention methods, especially among MSM who acknowledge potential risk behavior. It also seems likely that many such men would use these methods once they become aware of them. [ABSTRACT FROM AUTHOR]

Objectives: The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. Methods: Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. Results: All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. Conclusions: All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the development of a standardized approach to the collection of intestinal tissue from healthy volunteers, isolation of gut associated lymphoid tissue mucosal mononuclear cells (MMC), and characterization of mucosal T cell phenotypes by flow cytometry was sufficient to minimize differences in the normative ranges of flow parameters generated at two trial sites. Forty healthy male study participants were enrolled in Pittsburgh and Los Angeles. MMC were isolated from rectal biopsies using the same biopsy acquisition and enzymatic digestion protocols. As an additional comparator, peripheral blood mononuclear cells (PBMC) were collected from the study participants. For quality control, cryopreserved PBMC from a single donor were supplied to both sites from a central repository (qPBMC). Using a jointly optimized standard operating procedure, cells were isolated from tissue and blood and stained with monoclonal antibodies targeted to T cell phenotypic markers. Site-specific flow data were analyzed by an independent center which analyzed all data from both sites. Ranges for frequencies for overall CD4+ and CD8+ T cells, derived from the qPBMC samples, were equivalent at both UCLA and MWRI. However, there were significant differences across sites for the majority of T cell activation and memory subsets in qPBMC as well as PBMC and MMC. Standardized protocols to collect, stain, and analyze MMC and PBMC, including centralized analysis, can reduce but not exclude variability in reporting flow data within multi-site studies. Based on these data, centralized processing, flow cytometry, and analysis of samples may provide more robust data across multi-site studies. Centralized processing requires either shipping of fresh samples or cryopreservation and the decision to perform centralized versus site processing needs to take into account the drawbacks and restrictions associated with each method. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown. Methods: Free testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing. Results: Participants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty-four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence=17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/18 infection in unadjusted and adjusted analyses. Conclusions: Higher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study. [ABSTRACT FROM AUTHOR]

The article presents a study evaluating the effects of the Tenofovir gel, which is being assessed for vaginal and rectal pre-exposure prophylaxis against HIV transmission, on the mucosa. Topics discussed include confirmatory reverse transcription digital droplet polymerase chain reaction (RT-ddPCR) quantification and in situ immunostaining in additional study participants, gene expression patterns and functional pathways, and similarities between vaginal keratinocytes and rectal biopsies.

Human papillomavirus (HPV) causes the majority of oropharyngeal cancers in the United States, yet the risk factors for and natural history of oral HPV infection are largely unknown. In 2010–2011, a US-based longitudinal cohort study of 761 human immunodeficiency virus (HIV)-infected and 469 at-risk HIV-uninfected participants from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study was initiated. Semiannually collected oral rinses were evaluated for 37 HPV genotypes using the Roche LINEAR ARRAY HPV Genotyping Test (Roche Molecular Systems, Pleasanton, California), and factors associated with oral HPV incidence and clearance were explored using adjusted Wei-Lin-Weissfeld modeling. Through 2013, the 2-year cumulative incidence of any type of oral HPV infection was 34% in HIV-infected persons and 19% in HIV-uninfected persons. However, many of these infections cleared. Seven percent of incident infections and 35% of prevalent infections persisted for at least 2 years. After adjustment for other risk factors, HIV infection (adjusted hazard ratio = 2.3, 95% confidence interval: 1.7, 3.2), reduced current CD4 cell count, and increased numbers of oral sex and “rimming” partners increased the risk of incident oral HPV infection, whereas male sex, older age, and current smoking increased the risk of oral HPV persistence (each P < 0.05). This helps explain the consistent associations observed between these factors and prevalent oral HPV infection in previous cross-sectional studies. [ABSTRACT FROM PUBLISHER]

Objectives: This study was designed to assess the dose-response relationship between tissue, blood, vaginal and rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and ex vivo rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and rectal administration of TFV 1% vaginally-formulated gel. Design: Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females. Methods: Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 2∶1 to receive a single then seven-daily rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and ex vivo HIV-1 challenge. Results: There was a significant fit for the TFVdp dose-response model for rectal tissue (p = 0.0004), CD4+MMC (p<0.0001), CD4−MMC (p<0.0001), and TotalMMC (p<0.0001) compartments with r2 ranging 0.36–0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC50 of rectal tissue TFVdp predicted to be necessary to suppress HIV in rectal tissue. The EC50 for CD4+MMC was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided in-vivo doses predicted to provide for 50% efficacy in the ex vivo assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC90 biopsy efficacy for CD4−MMC, CD4+MMC and TotalMMC compartments. Conclusion: The TFVdp MMC compartment (CD4+, CD4− and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression. : ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including anogenital human papillomaviruses (HPV) in men who have sex with men, human immunodeficiency virus (HIV) in women and vaccination for communicable diseases.

The incidence of anal cancer is elevated in human immunodeficiency virus (HIV)-infected men-who-have-sex-with-men (MSM) compared to the general population. Anal high-grade squamous intraepithelial lesions (HSIL) are common in HIV-infected MSM and the presumed precursors to anal squamous cell cancer; however, direct progression of HSIL to anal cancer has not been previously demonstrated. The medical records were reviewed of 138 HIV-infected MSM followed up at the University of California, San Francisco, who developed anal canal or perianal squamous cancer between 1997 and 2011. Men were followed up regularly with digital anorectal examination (DARE), high-resolution anoscopy (HRA) and HRA-guided biopsy. Although treatment for HSIL and follow-up were recommended, not all were treated and some were lost to follow-up. Prevalent cancer was found in 66 men. Seventy-two HIV-infected MSM developed anal cancer while under observation. In 27 men, anal cancer developed at a previously biopsied site of HSIL. An additional 45 men were not analyzed in this analysis due to inadequate documentation of HSIL in relation to cancer location. Of the 27 men with documented progression to cancer at the site of biopsy-proven HSIL, 20 men progressed from prevalent HSIL identified when first examined and seven men from incident HSIL. Prevalent HSIL progressed to cancer over an average of 57 months compared to 64 months for incident HSIL. Most men were asymptomatic, and cancers were detected by DARE. Anal HSIL has clear potential to progress to anal cancer in HIV-infected MSM. Early diagnosis is facilitated by careful follow-up. Carefully controlled studies evaluating efficacy of screening for and treatment of HSIL to prevent anal cancer are needed. [ABSTRACT FROM AUTHOR]

Background. Adults aging with HIV infection are at risk for age-related comorbidities and syndromes, such as frailty. The objective of this study was to evaluate the expression and predictors of the frailty phenotype (FP) among HIV-infected (HIV+) and HIV-uninfected (HIV−) men who have sex with men. Methods. A prospective, observational cohort study was nested in the Multicenter AIDS Cohort Study from October 2007–September 2011. FP conversion was defined as the onset of FP over two consecutive study visits. Adjusted odds ratios and 95% confidence intervals ([,]) for FP conversion were estimated using logistic regression models with generalized estimating equations. Results. Of 10,571 completed study visits from 1,946 men who have sex with men, 12% and 9% were FP+ among HIV+ and HIV− men, respectively (p = .002). The proportion of FP+ visits increased with age regardless of HIV status, but was significantly greater in HIV+ compared to HIV− men aged 50–64 years. Of the 10,276 consecutive visit pairs contributed by participants, 5% (537) were classified as FP conversion, and 45% of the men with FP conversion had only one FP+ study visit. FP conversion was significantly associated with a history of AIDS (adjusted odds ratios = 2.26 [1.50, 3.39], but not with HIV+ alone (adjusted odds ratios = 1.26 [0.98, 1.64]). Among men who had one or more FP+ visits, 34% of HIV+ and 38% of HIV− men had less than two comorbidities. Conclusions. These findings suggest that expression of the FP can be measured in men who have sex with men with and without HIV infection and reflects multisystem dysfunction in this population; further investigations are needed to better understand clinical utility. [ABSTRACT FROM PUBLISHER]