Trends, patterns, and factors associated with HIV infection among males diagnosed with syphilis, 2014-2019, Hawaii.

OBJECTIVE: This study describes HIV infection and associated risk factors among males diagnosed with syphilis in Hawaii. METHODS: Hawaii sexually transmitted infection (STI) registry records of males diagnosed with syphilis, 2014-2019, were crossmatched with Hawaii HIV surveillance registry records through 2020 using CDC's Registry Plus Link Plus software. HIV status from the STI registry was validated by matching results. Logistic regression was used to examine demographic and behavioral factors associated with HIV infection. RESULTS: Among the 947 male syphilis cases, 257 (27.1%) had both syphilis and HIV infections. Dual infection rates were higher in earlier years (39.5% in 2015), among older patients (41.6% among persons ≥45 years old), males who have sex with males (MSM, 36.6%), and cases with repeated syphilis events (59.5%). The overall agreement on HIV status between the STI registry and matching results was 95.7%. CONCLUSIONS: Over a quarter (27.1%) of male syphilis cases were living with HIV. HIV infection rates were higher among older patients, MSM, and males with repeated syphilis events. Periodic matching between STI and HIV registries provides opportunities for quality control to both registries and opportunities to identify patients not linked to HIV care or who have fallen out of HIV care.

Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.

BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives.

This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (Ci) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (Ci-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked Ci-polyvinyl alcohol-boric acid (Ci-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to Ci gelling properties) on vaginal application (at acidic pH of ~3.5-4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7-8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the Ci-PBA gel was formed by ionic interactions whereas Ci-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the Ci-PBA and Ci-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the Ci-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40-60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.

Incident Cases of Sexually Transmitted Infections among Users of Pre-Exposure Prophylaxis for HIV Prevention in Honolulu, Hawai'i.

Emtricitabine/tenofovir disoproxil fumarate [FTC-TDF] is a daily oral medication taken by HIV-negative individuals for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus (HIV) infection. A higher incidence of sexually transmitted infections (STIs) among PrEP users has been reported compared to STI incidence before PrEP use. Asymptomatic incident STI rates were investigated among 78 patients presenting for PrEP in Honolulu, Hawai'i, from April 2018 to May 2019. Testing for oropharyngeal gonorrhea, urethral gonorrhea and chlamydia, rectal gonorrhea and chlamydia, and syphilis was performed. Incident STI percentages were calculated at each follow-up visit. Ninety-seven percent of patients were men who have sex with men (MSM). Forty-seven percent of patients had follow-up data 6 months after initiation and 28% after 1 year. Thirty-two percent of patients self-reported an STI before initiating PrEP. More than half reported anonymous partners. There were 35 positive STI tests during the study period, and 25% of patients had one or more positive tests during this time. At initiation, 17% of patients were found to have an STI, followed by 16% at 3 months, 14% at 6 months, 8% at 9 months, and 5% at 12 months. At all visits, chlamydia was the most common STI detected; at 6 months, 18% of all rectal tests were positive for chlamydia. There were inconsistent condom use and high STI rates from screening during PrEP initiation and follow-up, offering an opportunity to identify asymptomatic STIs in this population. This study is the first report in Hawai'i of STI rates among PrEP users.

Patient and provider characteristics associated with retention in HIV medical care and viral suppression among in care patients in Hawaii.

The percentages of retention in care and viral suppression among persons living with HIV (PLWH) in the United States from 2015 to 2018 were far below the 2020 national goals. This study aims to examine disparities in retention in care and viral suppression. The study population included PLWH diagnosed through 2016, residing in Hawaii at year-end 2016 and 2017, and who were in care in 2017 defined as having ≥1 CD4/viral load tests in 2017. Care providers were categorized as "very frequent" (≥50 patients), "frequent" (25-49 patients), "occasional" (10-24 patients), and "infrequent" (<10 patients). Among the 1752 patients included, 28.0% were not retained in care in 2017 (i.e., <2 CD4/VL tests performed at least 3 months apart), of whom 89.2% had only a single viral load test. Patients receiving care from the "infrequent" group of providers were less likely to be retained in care (adjusted odds ratio (aOR) = 0.48; 95% CI = 0.33, 0.69) or virally suppressed (aOR = 0.39; 95% CI = 0.24, 0.63), than patients receiving care from the "very frequent" group of providers. Percentages of three-year (2016-2018) in care and viral suppression were lowest among patients receiving care from "infrequent" care providers. Patients <45 years old were less likely to be retained in care (aOR = 0.53; 95% CI = 0.41, 0.68) or be virally suppressed (aOR = 0.59; 95% CI = 0.40, 0.86) than those 45 years or older. Patients of multiple races were less likely to be virally suppressed than whites (aOR = 0.38, 95% CI = 0.23, 0.64). Establishing a long-term relationship with an experienced HIV provider appears beneficial to achieve sustainable viral suppression and provision of uninterrupted HIV medical care.

Preclinical evaluation of UC781 microbicide vaginal drug delivery.

UC781 is a potent nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide to prevent transmission of HIV-1 both vaginally and rectally. This study was designed to investigate the in vitro drug release, in vitro permeability/safety, and in vivo pharmacokinetics in rabbits of a vaginal gel prepared with micronized or nonmicronized UC781 (UC781m and UC781nm, respectively). Gels prepared with UC781m had greater in vitro release rates (Franz cells) and permeability/tissue-associated UC781 concentrations than gels prepared with UC781nm (EpiVaginal tissues). Both gels were well tolerated under in vitro conditions compared with controls using EpiVaginal tissues. Following intravaginal administration of both gels to rabbits, tissue concentrations typically ranged from 1,000 to over 10,000 ng/g regardless of dosing regimen (single dose or 7 days once daily dosing) and sampling times (2 and 24 h post-dose). Tissue-associated concentrations were highly variable, and no statistically significant differences were found between test conditions. Plasma levels were generally low after vaginal administration: following a single dose, the concentrations were between 0.5 and 1.0 ng/mL. After 7 days repeated once daily dosing, UC781 concentrations were slightly higher ranging from below 1.0 to about 2 ng/mL, although none of the differences were statistically significant. Based on these results, gels prepared with either form of UC781 led to tissue concentrations well in excess of UC781's EC50 under in vitro conditions (~3 ng/mL).

In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials.

The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.

Determination of degradation products of squalamine lactate using LC/MS.

Heat, acid and base stress methods were applied to study the stability of squalamine lactate. Liquid chromatography coupled with mass spectrometry was used to analyze the degraded samples and tentative structural identifications were assigned based on their molecular weight measurements, reactivity and MS/MS fragmentation. Solid squalamine lactate generated a new amide, namely lactyl squalamide, when heated to 80 degrees C. Chemical structure for this new compound has been established by NMR and MS data interpretation and confirmed by direct comparison between the degradant and the synthesized compound. Squalamine lactate in pH 4 acetate buffer solution produced more degradants under stressed conditions. These degradants are formed due to the loss of the sulfate functionality. Squalamine lactate is stable in refrigerated conditions as well as in basic solution.

Chromatographic performance of large-pore versus small-pore columns in micellar liquid chromatography.

Micellar liquid chromatography (MLC) is useful in bioanalysis because proteinaceous biofluids can be directly injected onto the column. The technique has been limited in part because of the apparently weak eluting power of micellar mobile phases. It has recently been shown [Anal. Chem. 72 (2000) 294] that this may be overcome by the use of large pore size stationary phases. In this work, large-pore (1000 A) C(18) stationary phases were evaluated relative to conventional small-pore (100 A) C(18) stationary phases for the direct sample injection of drugs in plasma. Furthermore, the difference between the large and small pore phases in gradient elution separations of mixtures of widely varying hydrophobicities was investigated. Large-pore stationary phases were found to be very effective for eluting moderately to highly hydrophobic compounds such as ibuprofen, crotamiton, propranolol, and dodecanophenone, which were highly retained on the small-pore stationary phases typically used in MLC. The advantages of direct introduction of biological samples (drugs in plasma) and rapid column re-equilibration after gradient elution in MLC were maintained with large-pore phases. Finally, recoveries, precision, linearity, and detection limits for the determination of quinidine and DPC 961 in spiked bovine plasma were somewhat better using MLC with wide pore phases.