Topical Microbicides and HIV Prevention in the Female Genital Tract

Worldwide, HIV disproportionately affects women who are often unable to negotiate traditional HIV preventive strategies such as condoms. In the absence of an effective vaccine or cure, chemoprophylaxis may be a valuable self-initiated alternative. Topical microbicides have been investigated as one such option. The first generation topical microbicides were non-specific, broad-spectrum antimicrobial agents, including surfactants, polyanions, and acid buffering gels, that generally exhibited contraceptive properties. After extensive clinical study, none prevented HIV infection, and their development was abandoned. Second generation topical microbicides include agents with selective mechanisms of antiviral activity. Most are currently being used for, or have previously been explored as, drugs for treatment of HIV. The most advanced of these is tenofovir 1% gel: the first topical agent shown to significantly reduce HIV infection by 39% compared to placebo. This review summarizes the evolution of topical microbicides for HIV chemoprophylaxis, highlights important concepts learned, and offers current and future considerations for this area of research

Clinical Pharmacokinetic, Pharmacodynamic and Drug-Interaction Profile of the Integrase Inhibitor Dolutegravir

Dolutegravir is a second generation integrase strand transfer inhibitor (INSTI) currently under review by the US FDA for marketing approval. Dolutegravir’s in vitro, protein adjusted 90% inhibitory concentration (IC90) for wild-type virus is 0.064 μg/ml, and it retains in vitro anti-HIV 1 activity across a broad range of viral phenotypes known to confer resistance to the currently marketed INSTIs, raltegravir and elvitegravir. Dolutegravir has a half-life (t½) of 13 to 14 hours and maintains concentrations over the in vitro, protein adjusted IC90 for more than 30 hours following a single dose. Additionally, dolutegravir has comparatively low intersubject variability compared to raltegravir and elvitegravir. A plasma exposure-response relationship has been well described, with antiviral activity strongly correlating to trough concentration (Ctrough) values. Phase III trials have assessed the antiviral activity of dolutegravir compared with efavirenz and raltegravir in antiretroviral (ARV)-naïve patients and found dolutegravir to achieve more rapid and sustained virologic suppression in both instances. Additionally, studies of dolutegravir activity in patients with known INSTI-resistant mutations have been favorable, indicating that dolutegravir retains activity in a variety of INSTI resistant phenotypes. Much like currently marketed INSTIs, dolutegravir is very well tolerated. Because dolutegravir inhibits the renal transporter, organic cation transporter (OCT) 2, reduced tubular secretion of creatinine leads to non-progressive increases in serum creatinine. These serum creatinine increases have not been associated with decreased glomerular filtration rate or progressive renal impairment. Dolutegravir’s major and minor metabolic pathways are UDP glucuronosyltransferase (UGT)1A1 and cytochrome (CYP)3A4, respectively, and it neither induces nor inhibits CYP isozymes. Thus dolutegravir has a modest drug interaction profile. However, antacids significantly decrease dolutegravir plasma exposure and should be separated by 2 hours before, or 6 hours after, a dolutegravir dose. In summary, dolutegravir is the first of the second generation INSTIs, which exhibits a predictable pharmacokinetic profile and a well-defined exposure-response relationship. Dolutegravir retains activity despite the presence of some class resistant mutations and achieves rapid and sustained virologic suppression in ARV-naïve and -experienced patients. Clinically dolutegravir is poised to become a commonly used component of antiretroviral regimens

No ‘silver bullet’:Multiple factors control population dynamics of european purple sea urchins in Lough Hyne marine reserve, Ireland

Two-decade-long monitoring studies at Europe\u27s first statutory marine reserve—Lough Hyne in SW Ireland—indicate that benthic communities are rapidly changing. Populations of the ecologically important purple urchin (Paracentrotus lividus) have fluctuated widely, most recently with a population boom in the late 1990s, followed by a mass mortality that persists to the present day. Eight general hypotheses have been proposed to account for the urchin decline including cold temperature limiting reproduction, ephemeral algal exudates disrupting urchin fertilization, low larval availability (due to over-harvesting and/or episodic recruitment), high mortality of settlers and juveniles due to hypoxia, hyperoxia, or predation (a trophic cascade hypothesis), and increased mortality due to pathogens (stress hypothesis). The cold-temperature and the trophic cascade hypotheses appear unlikely. The remaining hypotheses, however, all seem to play a role, to some degree, in driving the urchin decline. Ulvoid exudates, for example, significantly reduced urchin fertilization and few larvae were found in plankton tows (2012–2015), indicating low larval availability in summer. Whilst settling urchins regularly recruited under shallow-subtidal rocks until 2011, no settlers were found in these habitats from 2011 to 2014 or in field experiments (2012–2018) using various settlement substrata. Seawater quality was poor in shallow areas of the lough with extreme oxygen fluctuations (diel-cycling hypoxia), and 1-day experimental exposures to DO values < 1 mg L−1 were lethal to most juvenile urchins. Multiple increases of the predatory spiny starfish (Marthasterias glacialis) population in recent decades may also have contributed to the demise of the coexisting juvenile urchins. Finally, urchins of all sizes were seen suffering from dropped spines, tissue necrosis, or white-coloured infection, suggestive of stress-related pathogen mortality. There was a paucity of broken tests, indicating limited predation by large crustaceans; the large number of adult urchins ‘missing’ and few P. lividus tests on the north shore points to possible urchin removal by poachers and/or starfish predation. While these ecological, environmental, and anthropogenic processes occur on open coast rocky shores, many are exacerbated by the semi-enclosed nature of this fully marine sea lough due to its limited flushing. Multiple factors, including low larval availability and rapidly expanding starfish populations, coupled with degraded habitat quality (ephemeral algal mats and extreme oxygen fluctuations), indicate that the purple urchin populations will not recover without an improvement in the water quality of Lough Hyne Marine Reserve, the restocking of urchins, and protection from poaching