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Summary: Background: Long-acting subcutaneous lenacapavir (LEN), a first-in-class HIV capsid inhibitor approved by the US FDA for the treatment of multidrug-resistant HIV-1 with twice yearly dosing, is under investigation for HIV-1 pre-exposure prophylaxis (PrEP). We previously derived a simian-tropic HIV-1 clone (stHIV-A19) that encodes an HIV-1 capsid and replicates to high titres in pigtail macaques (PTM), resulting in a nonhuman primate model well-suited for evaluating LEN PrEP in vivo. Methods: Lenacapavir potency against stHIV-A19 in PTM peripheral blood mononuclear cells in vitro was determined and subcutaneous LEN pharmacokinetics were evaluated in naïve PTMs in vivo. To evaluate the protective efficacy of LEN PrEP, naïve PTMs received either a single subcutaneous injection of LEN (25 mg/kg, N = 3) or vehicle (N = 4) 30 days before a high-dose intravenous challenge with stHIV-A19, or 7 daily subcutaneous injections of a 3-drug control PrEP regimen starting 3 days before stHIV-A19 challenge (N = 3). Findings: In vitro, LEN showed potent antiviral activity against stHIV-A19, comparable to its potency against HIV-1. In vivo, subcutaneous LEN displayed sustained plasma drug exposures in PTMs. Following stHIV-A19 challenge, while all vehicle control animals became productively infected, all LEN and 3-drug control PrEP animals were protected from infection. Interpretation: These findings highlight the utility of the stHIV-A19/PTM model and support the clinical development of long-acting LEN for PrEP in humans. Funding: Gilead Sciences as part of a Cooperative Research and Development Agreement between Gilead Sciences and Frederick National Lab; federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024/HHSN261201500003I; NIH grant R01AI078788.

Pathogens and nutrients released from on-site sewage systems represent a risk to surface and ground water quality, particularly where there are sensitive receiving waters such as in drinking water catchments. Buffer zones between on-site systems and waterways are one barrier used to protect water quality. The increased time and distance they provide increases the opportunities for the effluent purification functions of the soil to occur. A risk management model is proposed to assess the efficacy of the buffer zones in Sydney's drinking water catchments. The model is the basis for the development of performance based setback distances for on-site systems from waterways, and incorporates stochastic analysis of pathogen and nutrient transport in the environment and consideration of the effluent quality variability from on-site systems. Catchment-scale integration of contaminant transport is employed to facilitate a risk assessment of on-site systems. The risk management model also allows for the impact of on-site system management and maintenance on catchment water quality to be assessed through scenario building and feedback mechanisms. [ABSTRACT FROM AUTHOR]