Understanding Retention in Pre-Exposure Prophylaxis Care in the South: Insights from an Academic HIV Prevention Clinic.

HIV pre-exposure prophylaxis (PrEP) is poorly utilized in the southern United States. We examined PrEP retention in care and sexually transmitted infections (STIs) through a retrospective review of the Duke University PrEP Clinic from January 1, 2015 to October 15, 2019. We evaluated short-term (3 months), long-term (additional 8-12 months), and longitudinal retention in care in our clinic. Adjusted odds ratios (aOR) were generated to explore demographics associated with retention. Kaplan-Meier curves were generated to view retention longitudinally. STIs were examined at baseline (1 year before initial PrEP visit) and while retained in care. Of a total of 255 patients; 88% were men, 37% were black, and 73% were men who have sex with men (MSM). Short- and long-term retention in care were met by 130/237 (55%) and 80/217 (37%) patients, respectively. MSM were more likely to be retained in the short term (aOR = 5.22, 95% confidence interval [CI] = 1.57-17.32). Self-referred patients were more likely to be retained in the long term (aOR = 2.18, 95% CI = 1.12-4.23). Uninsured patients were less likely to be retained in the long term (aOR = 0.32, 95% CI = 0.11-0.91). STI diagnoses include 42 infections at baseline and 69 infections during follow-up. STI diagnosed while in PrEP care was associated with longer retention in care over time. Patients discontinue PrEP care over time and STIs were frequently encountered. Additional studies are needed to determine the best way to retain patients in HIV preventative care.

Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma.

RATIONALE: Exhaled breath nitric oxide (Fe(NO)) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). OBJECTIVES: We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. METHODS: Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. Fe(NO) was assessed predose on Days 1, 7, 10, and 14. Adenosine 5'-monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. MEASUREMENTS AND MAIN RESULTS: GW274150 reduced predose Fe(NO) by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce Fe(NO). GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced Fe(NO) levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. CONCLUSIONS: Selective iNOS inhibition effectively reduces Fe(NO) but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00273013).

GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo.

1 GW274150 ([2-[(1-iminoethyl) amino]ethyl]-L-homocysteine) and GW273629 (3-[[2-[(1-iminoethyl)amino]ethyl]sulphonyl]-L-alanine) are potent, time-dependent, highly selective inhibitors of human inducible nitric oxide synthase (iNOS) vs endothelial NOS (eNOS) (>100-fold) or neuronal NOS (nNOS) (>80-fold). GW274150 and GW273629 are arginine competitive, NADPH-dependent inhibitors of human iNOS with steady state K(d) values of <40 and <90 nM, respectively. 2 GW274150 and GW273629 inhibited intracellular iNOS in J774 cells in a time-dependent manner, reaching IC(50) values of 0.2+/-0.04 and 1.3+/-0.16 microM, respectively. They were also acutely selective in intact rat tissues: GW274150 was >260-fold and 219-fold selective for iNOS against eNOS and nNOS, respectively, while GW273629 was >150-fold and 365-fold selective for iNOS against eNOS and nNOS, respectively. 3 The pharmacokinetic profile of GW274150 was biphasic in healthy rats and mice with a terminal half-life of approximately 6 h. That of GW273629 was also biphasic in rats, producing a terminal half-life of approximately 3 h. In mice however, elimination of GW273629 appeared monophasic and more rapid (approximately 10 min). Both compounds show a high oral bioavailability (>90%) in rats and mice. 4 GW274150 was effective in inhibiting LPS-induced plasma NO(x) levels in mice with an ED(50) of 3.2+/-0.7 mg kg(-1) after 14 h intraperitoneally (i.p.) and 3.8+/-1.5 mg kg(-1) after 14 h when administered orally. GW273629 showed shorter-lived effects on plasma NO(x) and an ED(50) of 9+/-2 mg kg(-1) after 2 h when administered i.p. 5 The effects of GW274150 and GW273629 in vivo were consistent with high selectivity for iNOS, as these inhibitors were of low potency against nNOS in the rat cerebellum and did not cause significant effects on blood pressure in instrumented mice.