Tenofovir Douche as HIV Preexposure Prophylaxis for Receptive Anal Intercourse: Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics (DREAM 01).

BACKGROUND: Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option. METHODS: Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics. RESULTS: The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect. CONCLUSIONS: All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.

Acceptability of a rectal microbicide douche for HIV prevention: a mixed-methods analysis of a first-in-human formulation pilot study.

OBJECTIVES: DREAM-01 was an open label, dose-escalation and variable osmolarity study to identify a tenofovir HIV-prevention douche/enema that could achieve protective colon tissue cell concentrations and high acceptability. To assess impact on sexual enjoyment, iso-osmolar and hypo-osmolar placebo douches were provided for at-home use before receptive anal sex (RAS). METHODS: Eighteen HIV-uninfected men who have RAS were administered three tenofovir douches at the research clinic: Product A, an iso-osmolar dose; Product B, an iso-osmolar escalation dose; and Product C, a hypo-osmolar escalation dose. Following Products A and C, participants were given a saline douche of matching osmolarity to use at home before RAS. Participants reported acceptability via a computer-assisted self-interview and in-depth interview in this mixed-methods study. RESULTS: All three products were rated acceptable by 17 (95%) of the participants. A majority (94%) would be likely or very likely to use any of the three products before RAS. Of those who used the saline douches before RAS and then rated their sexual enjoyment, most reported that their sexual enjoyment was not affected. Interview data revealed that participants found the product easy to incorporate into their regular routine, but would prefer to use more liquid for cleansing. CONCLUSIONS: These findings indicate that the hypo-osmolar Product C, which also provides the most rapid delivery of tenofovir for HIV prevention, is acceptable for future safety trials and that our sample reports high likelihood of using a rectal microbicide douche for HIV prevention. Our findings support continued pursuit of a tenofovir rectal microbicide douche. TRIAL REGISTRATION NUMBER: NCT02750540.

Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis.

INTRODUCTION: Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. METHODS: A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. RESULTS: Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. CONCLUSIONS: In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP.

BACKGROUND: Although CD4+ memory T cells are considered the primary latent reservoir for HIV-1, replication competent HIV has been detected in tissue macrophages in both animal and human studies. During in vitro HIV infection, the depleted nucleotide pool and high dUTP levels in monocyte derived macrophages (MDM) leads to proviruses with high levels of dUMP, which has been implicated in viral restriction or reduced transcription depending on the uracil base excision repair (UBER) competence of the macrophage. Incorporated dUMP has also been detected in viral DNA from circulating monocytes (MC) and alveolar macrophages (AM) of HIV infected patients on antiretroviral therapy (ART), establishing the biological relevance of this phenotype but not the replicative capacity of dUMP-containing proviruses. RESULTS: As compared to in vitro differentiated MDM, AM from normal donors had sixfold lower levels of dTTP and a sixfold increased dUTP/dTTP, indicating a highly restrictive dNTP pool for reverse transcription. Expression of uracil DNA glycosylase (UNG) was eightfold lower in AM compared to the already low levels in MDM. Accordingly, ~ 80% of HIV proviruses contained dUMP, which persisted for at least 14-days due to low UNG excision activity. Unlike MDM, AM expression levels of UNG and SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) increased over 14 days post-HIV infection, while dUTP nucleotidohydrolase (DUT) expression decreased. These AM-specific effects suggest a restriction response centered on excising uracil from viral DNA copies and increasing relative dUTP levels. Despite the restrictive nucleotide pools, we detected rare replication competent HIV in AM, peripheral MC, and CD4+ T cells from ART-treated donors. CONCLUSIONS: These findings indicate that the potential integration block of incorporated dUMP is not realized during in vivo infection of AM and MC due to the near absence of UBER activity. In addition, the increased expression of UNG and SAMHD1 in AM post-infection is too slow to prevent integration. Accordingly, dUMP persists in integrated viruses, which based on in vitro studies, can lead to transcriptional silencing. This possible silencing outcome of persistent dUMP could promote viral latency until the repressive effects of viral dUMP are reversed.

Population pharmacokinetics of tenofovir, emtricitabine and intracellular metabolites in transgender women.

AIMS: Transgender women (TGW) have been underrepresented in trials and use gender-affirming hormonal therapies (GAHT) that may alter renal function by significantly increasing creatinine clearance. Population pharmacokinetic (popPK) models and simulations would aid in understanding potential differences in emtricitabine/tenofovir disproxil fumarate (F/TDF) parent-metabolite concentrations in TGW on GAHT when compared to cisgender men (CGM) not exposed to GAHT. METHODS: Pharmacokinetic (PK) data from a Phase 1, open-label clinical trial with directly observed therapy of daily F/TDF consisting of 8 TGW and 8 CGM was utilized for model building. PopPK analysis was performed using nonlinear mixed effects modelling (NONMEM 7.5.0). Covariates of body weight, creatinine clearance, and gender were evaluated. Final models were subjected to Monte Carlo simulations to compare drug exposure following once daily and on-demand (IPERGAY 2 + 1 + 1) dosing of F/TDF. RESULTS: Tenofovir (TFV) and emtricitabine PK were best described by a 2-compartment model, first-order absorption/elimination with absorption lag time. Parent models were linked to their metabolites by first order formation and elimination. Creatinine clearance was a significant covariate influencing clearance in both models. Simulations demonstrated that at least 2, weekly 2 + 1 + 1 cycles of on-demand dosing in TGW on GAHT is necessary for TFV-diphosphate to reach similar exposure after the initial week of on-demand dosing in CGM not on GAHT. CONCLUSION: PopPK models of TFV, emtricitabine and intracellular metabolites in TGW were established. Dose simulations revealed that TGW should be treated for at least 2 weeks to have comparable exposures to CGM.

Multiparametric magnetic resonance imaging to characterize cabotegravir long-acting formulation depot kinetics in healthy adult volunteers.

AIM: Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection. METHODS: Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic-guided injection targeting the gluteal muscles. MRI was performed to determine injection-site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue and combined IM/SC compartments, and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3 and 8. Linear regression analysis examined correlations between MRI-derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (Cmax ) and partial area under the concentration-time curve (AUC) through Weeks 4 and 8. RESULTS: Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n = 2), combined IM/SC compartments (n = 4), SC compartment (n = 1) and retroperitoneal cavity (n = 1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, Cmax and partial AUC through Weeks 4 and 8. CONCLUSION: MRI clearly delineated cabotegravir LA injection-site location and depot kinetics in healthy adults. Although injection-site variability was observed, drug depot surface area correlated with both plasma Cmax and partial AUC independently of anatomical distribution.

Multicompartmental pharmacokinetic evaluation of long-acting cabotegravir in healthy adults for HIV preexposure prophylaxis.

AIMS: Cabotegravir is an integrase strand transfer inhibitor in clinical development as long-acting (LA) injectable HIV preexposure prophylaxis. METHODS: This phase I study assessed pharmacokinetics of cabotegravir in plasma and anatomical sites associated with sexual HIV-1 transmission after repeated oral and single intramuscular (IM) LA dosing in healthy adults. Following a 28-day oral lead-in period of cabotegravir 30 mg and a washout period of 14-42 days, participants were administered a single ultrasound-guided gluteal IM cabotegravir LA 600-mg injection. The study objective was to characterize cabotegravir concentrations in plasma, cervical, vaginal and rectal tissues, and cervicovaginal and rectal fluids and up to Week 12 after IM injection. RESULTS: Nineteen participants enrolled and 16 completed the study through Week 52. Cabotegravir was detected in plasma and all tissues and fluids. Median plasma cabotegravir concentrations exceeded the in vitro protein-adjusted 90% maximal inhibitory concentration through Week 12. Median tissue- and fluid-to-plasma cabotegravir concentration ratios across all visits were 0.32 for rectal fluid and 0.08-0.16 for other tissues and fluids. Adjusted R2 coefficients between cabotegravir concentrations in plasma and cervical, vaginal and rectal tissues were 0.78, 0.79 and 0.90, respectively. Injection-site reactions were common (88% of participants) and were mostly grade 1 in intensity (82%). Two participants reported 11 non-drug-related serious adverse events. CONCLUSION: Concentrations of cabotegravir in tissues and fluids were proportional to plasma over time, with strong correlations between tissue and plasma concentrations. Cabotegravir LA tissue-to-plasma ratios may be important for understanding its use as preexposure prophylaxis.

Rectal Douching Practices Associated with Anal Intercourse: Implications for the Development of a Behaviorally Congruent HIV-Prevention Rectal Microbicide Douche.

Tenofovir administration via rectal douching results in higher rectal-mucosa drug concentration than oral administration. Many who engage in receptive anal intercourse (RAI) use cleansing rectal douches. To inform development of a behaviorally-congruent tenofovir douche, 4751 individuals ≥ 18 years-old, born male, from all US states/territories, who engaged in anal intercourse responded to an online survey. Of those who reported RAI in the prior 3 months, 80% douched beforehand, 82% within 1 h, mean 2.9 consecutive applications; 27% douched afterwards, 83% within 1 h, mean 1.7 consecutive applications. Among multidose users, 78% applied doses within 2 min, and 76% retained liquid < 1 min. Most used tap water (89%) in an enema bottle (50%) or rubber bulb (43%), and douched for cleanliness (97%), to avoid smelling bad (65%), and to enhance pleasure (24%). 98% reported high likelihood of using an HIV-prevention douche. An ideal product will protect within a user's typical number of applications, within 1 h, and be dissolvable in tap water.

Fecal Coliform Bacterial Detection to Assess Enema Adherence in HIV Prevention Clinical Studies.

Evaluating the efficacy of any HIV prevention strategy is dependent on ensuring and objectively monitoring adherence to the intervention. Medicated rectal enemas are a potential method for providing topical, episodic HIV prophylaxis during receptive anal intercourse. Assessing adherence to recommended enema dosing regimens is essential in evaluating the utility of this strategy. We utilized fecal coliform bacteria on used enema tips as a marker for enema use. Enema tip coliforms were tested by repurposing a microtiter plate-based water quality test designed to detect fecal contamination of water. Coliform detection occurred with 100% sensitivity and specificity when tips were assayed on day of use. The assay performed well post-7 day sample storage at room temperature, yielding a sensitivity of 80% and specificity of 93%. All (n = 64) samples collected in a subset of the DREAM-01 rectal microbicide enema clinical trial tested positive, even when tips were evaluated > 7 days post-reported use. The coliform-based enema tip assay allows monitoring of adherence in interventions involving rectal enemas in a sensitive, specific and inexpensive manner. The test performs well in clinical trial settings.

Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection.

Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and ex vivo efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high-dose (5.28 mg/ml) and low-dose (1.76 mg/ml) formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsy specimens, and rectal CD4+ T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high-dose formulation than with all other formulations tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high-dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP amounts in tissues collected at 1 and 24 h were 7 times and 5 times higher, respectively (P < 0.01), than the ones collected in tissues with the IOsm formulation. The HOsm high-dose formulation prevented infection in ex vivo challenges of rectal tissues collected at 1, 24, and 72 h after the intrarectal dosing, whereas the same TFV dose formulated as an IOsm enema was less effective.

MALDI Mass Spectrometry Imaging Reveals Heterogeneous Distribution of Tenofovir and Tenofovir Diphosphate in Colorectal Tissue of Subjects Receiving a Tenofovir-Containing Enema.

Efforts to prevent human immunodeficiency virus (HIV) infection via pre-exposure prophylaxis (PrEP) include the development of anti-HIV drugs as microbicides for topical application to the mucosal sites of infection; however, although understanding the distribution profiles of these drugs in target mucosal tissues is of critical importance to guiding their optimization, data in this regard are largely lacking. With this in mind, we developed a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) approach to visualize tenofovir (TFV), an HIV nucleotide analog reverse-transcriptase inhibitor under investigation for use as a topical microbicide, and its active metabolite TFV-diphosphate (TFV-DP) in colorectal biopsies obtained from healthy volunteers who received TFV-containing enemas. Application of MALDI MSI resulted in sufficient spatial resolution to visualize both TFV and TFV-DP and revealed heterogeneity in the distribution profiles of both analytes, including the presence of regions in which TFV and TFV-DP were undetectable, in colorectal tissue at two different time points and concentrations. Cell-specific staining for CD4 T and CD11c dendritic cells, which are important to the establishment of HIV infection, demonstrated that the TFV and TFV-DP distributions were independent of these cell types. MALDI MSI of endogenous lipids demonstrated that the heterogeneity observed for TFV and TFV-DP was not a function of tissue composition or processing. These data provide unique insight into the spatial distribution of TFV and TFV-DP in human colorectal tissue. In addition, this work establishes an approach that can be leveraged to directly detect and visualize these clinically important analytes more broadly in tissue.

Rectal Douching Associated with Receptive Anal Intercourse: A Literature Review.

To inform the development of HIV-prevention rectal douches, we reviewed the scientific literature and online instructional videos on rectal douching associated with receptive anal intercourse (RAI). Up to 88% of men who practice RAI ever have douched, while 43-64% have douched recently. Of them, 87-97% douche before RAI and 13-48% afterwards. Water, occasionally mixed with soap or salt, is used most often, although up to 31% of men use commercial products. Douching is more common among individuals reporting substance use, sexually transmitted infections, or being HIV-infected. Scant literature is available on women's rectal douching practices, but it is apparently less frequent than among men (32 vs. 70%). Videos advise using 2-3 doses of liquid and retaining it for 10-30 s before expelling. These findings can inform the development of a safe and acceptable rectal douche for HIV prevention.

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients.

OBJECTIVES: The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. METHODS: Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N = 14; weight-based dosing) or weight-based ribavirin + abacavir (N = 14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. RESULTS: Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin + abacavir and 12 received ribavirin alone. Mean ±â€ŠSD plasma ribavirin trough concentrations (µg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54 ±â€Š0.60, 1.93 ±â€Š0.54, 2.14 ±â€Š0.73 and 2.54 ±â€Š1.05) compared with ribavirin alone (1.48 ±â€Š0.32, 2.08 ±â€Š0.41, 2.32 ±â€Š0.47 and 2.60 ±â€Š0.62) (P > 0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/10(6) cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98 ±â€Š9.86 and 15.87 ±â€Š12.52) and non-users (15.91 ±â€Š15.58 and 15.93 ±â€Š12.69) (P > 0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. CONCLUSIONS: Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations.

CYP3A5 genotype impacts maraviroc concentrations in healthy volunteers.

CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild-type allele *1 and dysfunctional alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in three groups (n = 8 each): homozygous dysfunctional (two dysfunctional alleles), heterozygous (one *1 allele and one dysfunctional allele), and homozygous wild-type (two *1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. The homozygous wild-type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curves from time 0 to infinity (AUC0-inf) were 2099 (1422-2568) ng⋅h/ml, 1761 (931-2640) ng⋅h/ml, and 1238 (1065-1407) ng⋅h/ml for the homozygous dysfunctional, heterozygous, and homozygous wild-type groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5*1 allele, including almost one-half of African Americans.

Quantitative assessment of altered rectal mucosal permeability due to rectally applied nonoxynol-9, biopsy, and simulated intercourse.

BACKGROUND: Microbicide toxicity may reduce the efficacy of topical preexposure prophylaxis for human immunodeficiency virus (HIV) transmission. Noninvasive quantitative measures of microbicide toxicity would usefully inform microbicide development. METHODS: Ten subjects received 3 one-time interventions: 5 mL of Normosol-R fluid alone (negative control), 5 mL of 2% nonoxynol-9 (N-9) gel, and 5 mL of Normosol-R with coital simulation and sigmoidoscopic biopsy (CS + BX). Each dose of N-9 and Normosol-R contained 500 µCi of (99m)technetium-diethylene triamine pentaacetic acid. Plasma and urine radioactivity was assessed over 24 hours. RESULTS: The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was 12.0 times (95% confidence interval [CI], 6.8-21.0) and 8.4 times (95% CI, 5.2-13.5) the mean concentration after Normosol-R control receipt and CS + BX receipt, respectively; paired differences persisted for 24 hours. After N-9 dosing, the urine isotope level was 3.6 times (95% CI, 1.1-11.4) the level observed 8 hours after Normosol-R control receipt and 4.0 times (95% CI, 1.4-11.4) the level observed 4 hours after CS + BX receipt. Permeability after CS + BX receipt was greater than that after Normosol-R control receipt in 0-2-hour urine specimens only (mean permeability, 2.4; 95% CI, 1.0-5.8) but was not greater in blood. CONCLUSIONS: Plasma sampling after rectal radioisotope administration provided quantitative estimates of altered mucosal permeability after chemical and mechanical stresses. Permeability testing may provide a useful noninvasive adjunct to assess the mucosal effects of candidate microbicides. Clinical Trials Registration. NCT00389311.

Mapping Colorectal Distribution of Cell-free and Cell-associated HIV Surrogates Following Simulated Anal Intercourse to Aid Rectal Microbicide Development.

BACKGROUND: Anal sex remains the greatest HIV transmission risk for men who have sex with men and carries substantial population attributable risk among women. Despite a growing array of HIV pre-exposure prophylaxis (PrEP) options, rectal microbicides remain desirable as on demand, non-systemic PrEP. Rectal microbicide product development for PrEP requires understanding the spatiotemporal distribution of HIV infectious elements in the rectosigmoid to optimize formulation development. SETTING: Outpatient setting with healthy research participants. METHODS: Six healthy men underwent simulated receptive anal sex with an artificial phallus fitted with a triple lumen catheter in the urethral position. To simulate ejaculation of HIV-infected semen, autologous seminal plasma laden with autologous blood lymphocytes from apheresis labeled with 111Indium-oxine (cell-associated) and 99mTechnetium-sulfur colloid (cell-free) as HIV surrogates were injected into the rectal lumen through the phallic urethra. Spatiotemporal distribution of each radioisotope was assessed using SPECT/CT over eight hours. Analysis of radiolabel distribution used a flexible principal curve algorithm to quantitatively estimate rectal lumen distribution. RESULTS: Cell-free and cell-associated HIV surrogates distributed to a maximal distance of 15 and 16 cm, respectively, from the anorectal junction (∼19 and ∼20 cm from the anal verge), with a maximal signal intensity located 6 and 7 cm, respectively. There were no significant differences in any distribution parameters between cell-free and cell-associated HIV surrogate. CONCLUSIONS: Cell-free and cell-associated HIV surrogate distribution in the rectosigmoid can be quantified with spatiotemporal pharmacokinetic methods. These results describe the ideal luminal target distribution to guide rectal microbicide development.

Distribution of cell-free and cell-associated HIV surrogates in the female genital tract after simulated vaginal intercourse.

BACKGROUND: Rational development of drugs to prevent human immunodeficiency virus (HIV) transmission benefits from an understanding HIV distribution in the female genital tract after intercourse. This study describes HIV distribution using surrogates of cell-free and cell-associated HIV and semen. METHODS: Apheresis-derived, autologous, lymphocyte-rich cells radiolabeled with 3.7-MBq (100-µCi) indium 111 ((111)In)-oxine (cell-associated HIV surrogate) and 18.5-MBq (500-µCi) technetium 99m ((99m)Tc)-sulfur colloid (HIV-sized 100-nm particle, cell-free HIV surrogate) were resuspended in 3 mL of hydroxyethylcellulose gel (semen simulant) with gadoteridol and dosed via artificial phallus after simulated intercourse. Postdosing dual-isotope single photon emission computed tomography with computed tomography (SPECT/CT) and magnetic resonance (MR) images were acquired to determine the surrogates' distribution. Seven hours after dosing, vaginal biopsy and luminal samples were collected at discrete locations in 8 subjects. RESULTS: SPECT/CT and MR analysis showed HIV and semen surrogate distribution with highest signal intensity in the vaginal pericervical area, without detectable signal in the uterus. One-third of the administered dose was retained in the female genital tract after 4 hours. Cell-free and cell-associated surrogate distribution coincided. CONCLUSIONS: We demonstrate the feasibility of dual-isotope SPECT/CT and MR imaging to determine the distribution of HIV and semen surrogates after simulated intercourse without disrupting vaginal contents. Surrogate distribution suggests topical microbicides do not need to reach the uterus for efficacy.

EVG/COBI/FTC/TAF Bioequivalence Comparing Whole Tablets with Tablets Dissolved in Tap Water.

Medication adherence can be challenging for persons with difficulty swallowing tablets. We investigated the bioequivalence of a dissolved tablet when compared with that of a whole tablet of the fixed-dose combination elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir (TFV) alafenamide fumarate (TAF). A within-subject fixed-order two-period open-label study was conducted in 12 HIV-negative research participants after obtaining informed consent. Participants took a single dose each of the whole tablet and dissolved tablet under direct observation, separated by a 14-day washout period. The dissolved tablet was prepared by adding one whole EVG/COBI/FTC/TAF tablet to 120 mL tap water and stirring. Both dosage types were taken with a standardized meal. Plasma samples were obtained for 72 h postdose. Plasma EVG, FTC, TAF, and TFV were analyzed with liquid chromatographic-tandem mass spectrometric methods. Peak plasma concentration (Cmax) and the area under the concentration-time curve extrapolated to infinity (AUC0-∞) were estimated using WinNonlin software (v.8.3). The primary outcome was bioequivalence consistent with FDA guidance using the 90% confidence interval or the geometric mean ratio. Of 12 participants, 7 were black (58%) and 5 were white (42%), 4 were women (33%), 8 were men (67%), and the mean age was 43.6 years (23-54). There were no complaints about taste with the dissolved tablet. Bioequivalence was established only for FTC. EVG Cmax and AUC0-∞ were higher by 18% and 12%, respectively, when taking the dissolved compared with the whole tablet. TAF AUC0-∞ and Cmax were both 8% lower, whereas TFV Cmax and AUC0-∞ were 8% and 5% lower, respectively, when taken after dissolution. EVG/COBI/FTC/TAF dissolved rapidly in water and had no unpleasant taste. Increases in EVG and decreases in TAF and TFV concentrations were observed when taking dissolved EVG/COBI/FTC/TAF. These changes were judged to be clinically insignificant. Dissolving EVG/COBI/FTC/TAF in water may be suitable for those with pill swallowing challenges. The trial was registered on (//clinicaltrials.gov NCT03717129).

Interaction of Depot Medroxyprogesterone Acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood Mononuclear Cells and Cervical Tissue Susceptibility to HIV Infection and Pharmacokinetics.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is highly effective in reducing HIV acquisition in women. We sought to determine the impact of DMPA on F/TDF pharmacokinetics and pharmacodynamics. METHODS: Twelve healthy premenopausal cisgender women were enrolled and each completed 4 sequential conditions: (1) baseline, (2) steady-state F/TDF alone, (3) steady-state F/TDF + DMPA, and (4) DMPA alone. Assessments included clinical, pharmacokinetic, viral infectivity (ex vivo challenge of peripheral blood mononuclear cells by X4- and R5-tropic green fluorescent protein pseudoviruses and cervical tissue by HIV BaL ), endocrine, immune cell phenotyping, and renal function. RESULTS: Compared with baseline, F/TDF (± DMPA) significantly decreased both %R5- and X4-infected CD4 T cells and F/TDF + DMPA decreased cervical explant p24 (all P < 0.05). The %R5- and X4-infected CD4 T cells were higher during DMPA alone than during F/TDF periods and lower than baseline (not statistically significant). Cervical explant p24 fell between baseline and F/TDF values (not statistically significant). There were neither statistically significant differences in F/TDF pharmacokinetics, including total or renal clearance of either antiviral drug, nor changes in glomerular filtration rate with the addition of DMPA. There were few immune cell phenotypic differences across conditions. CONCLUSIONS: F/TDF decreased HIV infection in both challenge assays, whereas DMPA alone did not enhance HIV infection in either challenge assay. DMPA did not alter F/TDF pharmacokinetics or renal function.

The slippery slope: lubricant use and rectal sexually transmitted infections: a newly identified risk.

BACKGROUND: Use of lubricant products is extremely common during receptive anal intercourse (RAI) yet has not been assessed as a risk for acquisition of sexually transmitted infections (STIs). METHODS: Between 2006 and 2008, a rectal health and behavior study was conducted in Baltimore and Los Angeles as part of the University of California, Los Angeles Microbicide Development Program (NIAID IPCP# #0606414). Participants completed questionnaires, and rectal swabs were tested for Neisseria gonorrhoeae and Chlamydia trachomatis with the Aptima Combo 2 assay, and blood was tested for syphilis (for RPR and TPHA with titer) and HIV. Of those reporting lubricant use and RAI, STI results were available for 380 participants. Univariate and multivariate regressions assessed associations of lubricant use in the past month during RAI with prevalent STIs. RESULTS: Consistent lubricant use during RAI in the past month was reported by 36% (137/380) of participants. Consistent past month lubricant users had a higher prevalence of STI than inconsistent users (9.5% vs. 2.9%; P = 0.006). In a multivariable logistic regression model, testing positive for STI was associated with consistent use of lubricant during RAI in the past month (adjusted odds ratio: 2.98 95% confidence interval: 1.09, 8.15) after controlling for age, gender, study location, HIV status, and numbers of RAI partners in the past month. CONCLUSIONS: Findings suggest some lubricant products may increase vulnerability to STIs. Because of wide use of lubricants and their potential as carrier vehicles for microbicides, further research is essential to clarify if lubricant use poses a public health risk.