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.
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.
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.
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.
ClinicalTrials.gov NCT01283360.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MSM are at higher risk for invasive anal cancer. Twelve human papillomaviruses (HPVs) cause cervical cancer in women (Group 1 high-risk HPVs (hrHPVs)) and 13 HPVs are probable/possible causes (Group ...2 hrHPVs) of cervical malignancy. HPVs rarely associated with malignancy are classified as lower-risk HPVs (lrHPVs).
Dacron-swab anal-cytology specimens were collected from and data complete for 97% (1262/1296) of Multicenter AIDS Cohort Study (MACS) men tested for HPVs using the Linear Array assay. Multivariate Poisson regression analyses estimated adjusted prevalence ratios for Group 1/2 hrHPVs and lrHPVs, controlling for the effects of age, race, ethnicity, sexual partnerships, smoking; HIV-infection characteristics, treatment, and immune status among HIV-infected men.
HIV-infected men showed 35-90% higher prevalence of Group 1/2 hrHPVs and lrHPVs than HIV-uninfected men, and higher prevalence of multi-Type, and multiple risk-group infections. CD4+ T-cell count was inversely associated with HPV Group 2 prevalence (p<0.0001). The number of receptive anal intercourse (RAI) partners reported in the 24 months preceding HPV testing predicted higher prevalence of Group 1/2 hrHPVs. Men reporting ≥30 lifetime male sex partners before their first MACS visit and men reporting ≥1 RAI partners during the 24 months before HPV testing showed 17-24% and 13-17% higher prevalence of lrHPVs (p-values ≤0.05). Men reporting smoking between MACS visit 1 and 24 months before HPV testing showed 1.2-fold higher prevalence of Group 2 hrHPVs (p = 0.03). Both complete adherence to CART (p = 0.02) and HIV load <50 copies/mL (p = 0.04) were protective for Group 1 hrHPVs among HIV-infected men.
HIV-infected men more often show multi-type and multi-group HPV infections HIV-uninfected men. Long-term mutual monogamy and smoking cessation, generally, and CART-adherence that promotes (HIV) viremia control and prevents immunosuppression, specifically among HIV-infected MSM, are important prevention strategies for HPV infections that are relevant to anal cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To evaluate the prevalence of anal cytology (ACyt) abnormalities among HIV-infected and HIV-uninfected men who have sex with men (MSM).
DESIGN:Multicenter cohort study of 723 HIV-infected ...and 788 HIV-uninfected MSM with ACyt, with a second ACyt collected 2 years later. A referral for high-resolution anoscopy was suggested for abnormal ACyt.
METHODS:ACyt samples were collected using a polyester swab and liquid cytology media and read in a central laboratory.
RESULTS:Prevalence of any abnormal ACyt was 25% in HIV-uninfected MSM and increased to 38%, 41%, and 47% among HIV-infected MSM with current CD4 T-cell counts ≥500, 350–499, and <350 cells/mm (P < 0.001), respectively. Anal HPV16 DNA was also more common in HIV-infected than HIV-uninfected MSM (25% versus 16%, P < 0.001). Abnormal baseline ACyt together with prevalent HPV16 DNA detection was present in only 7% of HIV-uninfected MSM compared to 18% of HIV-infected MSM with current CD4 < 350, P < 0.001. Among HIV-infected men, 56% of the men with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions ASCs-US/LSILs and 81% of men with atypical squamous cells cannot exclude high-grade (ASC-H/)/high-grade squamous intraepithelial lesions (HSIL) had lower grade ACyt findings 18–30 months later (“regressed”). However, 19% of untreated HIV-infected men with ASC-H/HSIL cytology maintained that same grade of cytology in their second test approximately 2 years later, and 15% with ASC-US/LSIL “progressed” to ASC-H/HSIL. Abnormal ACyt had high sensitivity (96%) but low specificity (17%) for biopsy-proven HSIL.
CONCLUSIONS:Prevalence of abnormal ACyt remains elevated in HIV-infected men during the current antiretroviral therapy era.
Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic ...profile of long-acting rilpivirine.
We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose. We obtained plasma specimens, genital and rectal fluids, and tissue samples (rectal, cervical, and vaginal) before and after exposure to long-acting rilpivirine for assessment of pharmacokinetics and ex-vivo biopsy challenge with HIV-1. Our primary objective was to characterise product safety, and the analysis included all enrolled participants. This trial is registered with ClinicalTrials.gov, number NCT01656018.
36 participants were enrolled into the study, of whom 24 were women and 12 men. 12 women and six men received each dose. 204 adverse events were reported among the 36 participants, of which 200 (98%) were grade 1-2. The most common adverse event was injection site reaction. All grade 3 and 4 adverse events were deemed not related to rilpivirine. Geometric mean (90% CI) concentrations in plasma of rilpivirine at day 28 post dose were 53 ng/mL (38-67) in women and 43 ng/mL (23-63) in men for the 1200 mg dose and 28 ng/mL (19-37) in women and 17 ng/mL (9-24) in men for the 600 mg dose. The tissue-to-plasma ratio for rilpivirine in rectal tissue was about two-fold higher than in vaginal and cervical tissue (1·10-1·53 vs 0·61-0·72 and 0·50-0·71, respectively). Exposure to long-acting rilpivirine suppressed viral replication significantly in rectal tissue (p<0·0001), and this suppression persisted for up to 4 months. By contrast, no viral suppression was seen in cervical or vaginal tissue.
Ongoing research will characterise longer term safety and acceptability of multiple injections and help ascertain whether long-acting rilpivirine should advance to assessment of efficacy in preventing HIV-1 infection.
Bill & Melinda Gates Foundation.
OBJECTIVE:HIV-infected women (WLHIV) have more than 10-fold higher risk for squamous cell cancer of the anus. Experts suggest cytology-based strategies developed for cervical cancer screening may ...prevent anal cancer by detecting anal cytologic or histological high-grade squamous intraepithelial lesion (hHSIL) for treatment. Currently, there is no consensus on anal-hHSIL screening strategies for WLHIV.
DESIGN:Between 2014 and 2016, 276 WLHIV were recruited at 12 US AIDS Malignancy Consortium clinical trials sites to evaluate hHSIL prevalence and (test) screening strategies.
METHODS:Participants completed detailed questionnaire, underwent anal assessments including high-risk human papillomavirus (hrHPV) testing using hrHPV-Hybrid Capture 2 (HC2) and hrHPV-APTIMA, anal cytology, and concurrent high-resolution anoscopy. Screening test characteristics for predicting hHSIL validated by central review of histologic diagnosis were estimated sensitivity, specificity, positive predictive value, and false-omission rate. Paired analyses compared sensitivity and specificity for hrHPV single tests to anal cytology alone.
RESULTS:83% (229/276) of enrolled WLHIV had complete anal assessment data and were included in this analysis. Mean age was 50, 62% black and 60 (26%) had hHSIL. Anal cyotology (>atypical squamous cells of undetermined significance), hrHPV-HC2, and hrHPV-APTIMA sensitivity estimates were similarly high (83, 77, and 75%, respectively, P values > 0.2). Specificity was higher for both hrHPV-APTIMA and hrHPV-HC2 compared with anal cytology (67 vs. 50%, P < 0.001) and (61 vs. 50%, P = 0.020), respectively.
CONCLUSION:Anal hrHPV testing demonstrated similar sensitivity for anal cytology (>atypical squamous cells of undetermined significance) to predict anal hHSIL. Among tests with similar sensitivity, the specificity was significantly higher for hrHPV-APTIMA and hrHPV-HC2. Thus, anal hrHPV testing may be an important alternative strategy to anal cytology for anal hHSIL screening among WLHIV.
The objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype.
A substudy of HPTN ...069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group.
Plasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy 'explants' challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype.
Thirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P < 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P < 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3-7% higher CD69+/CD8+ cells throughout Weeks 24-49 in CGW compared with MSM (P < 0.05).
Colorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.
Ablative treatment of intra-anal high-grade squamous intraepithelial lesions (HSIL) reduces the risk of progression to anal squamous cell carcinoma. Our objective was to assess the short-term ...effectiveness and tolerability of the carbon dioxide laser for treating intra-anal HSIL in patients at high risk of anal cancer.
This is an exploratory, pilot, single-arm, clinical trial of treatment response for anal HSIL in people living with HIV diagnosed with ≤3 not previously treated HSILs. Individuals were treated with one carbon dioxide laser treatment session. Clinical assessment by high resolution anoscopy and systematic recording of adverse events was performed.
Fifty-two patients with 72 HSILs were included. Response to treatment was assessed in 48 (92.3%) patients; in the per-protocol population analysis, complete, partial, and no response was seen in 50% (
= 24), 20.8% (
= 10) and 29.1% (
= 14), respectively. Being older than 40 years and having a CD4 T-cell count lower than 200 cells/μL at diagnosis of HSIL were significantly associated with a poor response to treatment. Data on adverse events was recorded for 49 patients and 69.4% (
=34) reported no symptoms after the procedure.
Carbon dioxide laser ablation is a promising and well tolerated treatment for intra-anal HSIL.
Human papillomavirus (HPV) is a common sexually transmitted agent that causes anogenital cancer and precancer lesions that have an inflammatory infiltrate, may be friable and bleed. Our aim was to ...determine the association between anal HPV infection and HIV acquisition.
A prospective cohort study.
We recruited 1409 HIV-negative men who have sex with men from a community-based setting in Boston, Denver, New York and San Francisco. We used Cox proportional hazards regression modeling and assessed the independent association of HPV infection with the rate of acquisition of HIV infection.
Of 1409 participants contributing 4375 person-years of follow-up, 51 HIV-seroconverted. The median number of HPV types in HPV-infected HIV-seroconverters was 2 (interquartile range 1-3) at the time of HIV seroconversion. After adjustment for sexual activity, substance use, occurrence of other sexually transmitted infections and demographic variables, there was evidence (P = 0.002) for the effect of infection with at least two HPV types (hazard ratio 3.5, 95% confidence interval 1.2-10.6) in HIV seroconversion.
Anal HPV infection is independently associated with HIV acquisition. Studies that incorporate high-resolution anoscopy to more accurately identify HPV-associated disease are needed to determine the relationship between HPV-associated disease and HIV seroconversion.
The Microbicide Trials Network-017 study was undertaken to characterize the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic profile of the reduced-glycerin (RG) 1% tenofovir (RG-TFV) ...gel compared to oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). The study was a Phase 2, three-period, randomized sequence, open-label, expanded safety and acceptability crossover study. In each 8-week study period, HIV-1-uninfected 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. A mucosal substudy was conducted at sites in the United States and Thailand. Samples were collected to evaluate PK and
biopsy challenge with HIV-1. A total of 195 men who have sex with men and transgender women were enrolled in the parent study and 37 in the mucosal substudy. As previously reported, both products were found to be safe and acceptable. Systemic TFV concentrations were significantly higher following oral exposure and daily rectal administration compared to RAI-associated product use (
< .001). All three routes of pre-exposure prophylaxis (PrEP) administration resulted in the inhibition of explant infection (
< .05), and there was a significant inverse correlation between explant HIV-1 p24 and tissue concentrations of TFV and FTC (
< .0001). Despite significant differences in systemic and mucosal drug concentrations, all three PrEP regimens were able to protect rectal explants from
HIV infection. These data suggest that there is a rationale for co-development of oral and topical antiretroviral PrEP for HIV prevention. Clinical Trial Registration number: NCT01687218.
HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 was a study of 48-week oral pre-exposure prophylaxis (PrEP) regimens in MSM and transgender women. A rectal substudy was included to ...evaluate drug concentrations in rectal compartment vs. blood, gut-associated lymphoid tissue (GALT) responses to four antiretroviral PrEP regimens maraviroc (MVC), MVC + emtricitabine (FTC), MVC + tenofovir (TFV) disoproxil fumarate, and TFV disoproxil fumarate + FTC, and to determine whether ARV exposure was associated with ex-vivo suppression of HIV infection in colorectal explants.
C-C chemokine receptor type 5 (CCR5) genotype was characterized using PCR. At baseline and at Weeks 24, 48, and 49, GALT phenotype was characterized by flow cytometry, rectal biopsies were challenged with HIV-1BaL, and tissue and plasma pharmacokinetics were measured via mass spectrometry.
Exposure to MVC was not associated with increased expression of CD4+/CCR5+ HIV target T cells. Significant ex-vivo viral suppression compared with baseline was seen at Weeks 24 and 48, ranging from 1.4 to 1.8 log10 for all study regimens except the MVC-alone arm which did not show statistically significant viral suppression at Week 48. Tissue concentrations of TFV, TFV-diphosphate, and FTC were correlated with viral suppression.
MVC-containing HIV PrEP regimens did not increase GALT CD4+ T-cell activation or the CD4+/CCR5+ phenotype. No virologic suppression was seen with MVC-alone at Week 48 compared with combination regimens, suggesting MVC monotherapy might be less effective than combination antiretroviral PrEP regimens.
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