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Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.

In the past decade, the field of organic synthesis has witnessed tremendous advancements in the areas of photoredox catalysis, electrochemistry, C–H activation, reductive coupling and flow chemistry. While these methods and technologies offer many strategic advantages in streamlining syntheses, their application on the process scale is complicated by several factors. In this Review, we discuss the challenges that arise when these reaction classes and/or flow chemistry technology are taken from a research laboratory operating at the milligram scale to a reactor capable of producing kilograms of product. We discuss how these challenges have been overcome through chemical and engineering solutions. Specifically, this Review will highlight key examples that have led to the production of multi-hundred-gram to kilogram quantities of active pharmaceutical ingredients or their intermediates and will provide insight on the scaling-up process to those developing new technologies and reactions. State-of-the-art synthetic methods regularly encounter challenges associated with cost, safety and/or efficiency when proposed for large-scale applications. This Review highlights recent applications of novel reactions/technologies (e.g. photoredox, electrochemistry, C–H activation, reductive coupling and flow chemistry) on the process scale.

Introduction Electronic and other new media technologies (eHealth) can facilitate large‐scale dissemination of information and effective delivery of interventions for HIV care and prevention. There is a need to both monitor a rapidly changing pipeline of technology‐based care and prevention methods and to assess whether the interventions are appropriately diversified. We systematically review and critically appraise the research pipeline of eHealth interventions for HIV care and prevention, including published studies and other funded projects. Methods Two peer‐reviewed literature databases were searched for studies describing the development, trial testing or implementation of new technology interventions, published from September 2014 to September 2018. The National Institutes of Health database of grants was searched for interventions still in development. Interventions were included if eHealth was utilized and an outcome directly related to HIV treatment or prevention was targeted. We summarized each intervention including the stage of development, eHealth mode of delivery, target population and stage of the HIV care and prevention continua targeted. Results and discussion Of 2178 articles in the published literature, 113 were included with 84 unique interventions described. The interventions utilize a variety of eHealth technologies and target various points on the prevention and care continua, with greater emphasis on education, behaviour change and testing than linkage to medical care. There were a variety of interventions for HIV care support but none for PrEP care. Most interventions were developed for populations in high income countries. An additional 62 interventions with funding were found in the development pipeline, with greater emphasis on managing HIV and PrEP care. Conclusions Our systematic review found a robust collection of eHealth interventions in the published literature as well as unpublished interventions still in development. In the published literature, there is an imbalance of interventions favouring education and behaviour change over linkage to care, retention in care, and adherence, especially for PrEP. The next generation of interventions already in the pipeline might address these neglected areas of care and prevention, but the development process is slow. Researchers need new methods for more efficient and expedited intervention development so that current and future needs are addressed.

Antiretroviral treatment for HIV-infection before immunologic decline (early ART) and pre-exposure chemoprophylaxis (PrEP) can prevent HIV transmission, but routine adoption of these practices by clinicians has been limited. Between September and December 2013, healthcare practitioners affiliated with a regional AIDS Education and Training Center in New England were invited to complete online surveys assessing knowledge, beliefs and practices regarding early ART and PrEP. Multivariable models were utilized to determine characteristics associated with prescribing intentions and practices. Surveys were completed by 184 practitioners. Respondent median age was 44 years, 58% were female, and 82% were white. Among ART-prescribing clinicians (61% of the entire sample), 64% were aware that HIV treatment guidelines from the Department of Health and Human Services recommended early ART, and 69% indicated they would prescribe ART to all HIV-infected patients irrespective of immunologic status. However, 77% of ART-prescribing clinicians would defer ART for patients not ready to initiate treatment. Three-fourths of all respondents were aware of guidance from the U.S. Centers for Disease Control and Prevention recommending PrEP provision, 19% had prescribed PrEP, and 58% of clinicians who had not prescribed PrEP anticipated future prescribing. Practitioners expressed theoretical concerns and perceived practical barriers to prescribing early ART and PrEP. Clinicians with higher percentages of HIV-infected patients (aOR 1.16 per 10% increase in proportion of patients with HIV-infection, 95% CI 1.01-1.34) and infectious diseases specialists (versus primary care physicians; aOR 3.32, 95% CI 0.98-11.2) were more likely to report intentions to prescribe early ART. Higher percentage of HIV-infected patients was also associated with having prescribed PrEP (aOR 1.19, 95% CI 1.06-1.34), whereas female gender (aOR 0.26, 95% CI 0.10-0.71) was associated with having not prescribed PrEP. These findings suggest many clinicians have shifted towards routinely recommending early ART, but not PrEP, so interventions to facilitate PrEP provision are needed.

Background Beginning May 7, 2022, multiple nations reported an unprecedented surge in monkeypox cases. Unlike past outbreaks, differences in affected populations, transmission mode, and clinical characteristics have been noted. With the existing uncertainties of the outbreak, real-time short-term forecasting can guide and evaluate the effectiveness of public health measures. Methods We obtained publicly available data on confirmed weekly cases of monkeypox at the global level and for seven countries (with the highest burden of disease at the time this study was initiated) from the Our World in Data (OWID) GitHub repository and CDC website. We generated short-term forecasts of new cases of monkeypox across the study areas using an ensemble n-sub-epidemic modeling framework based on weekly cases using 10-week calibration periods. We report and assess the weekly forecasts with quantified uncertainty from the top-ranked, second-ranked, and ensemble sub-epidemic models. Overall, we conducted 324 weekly sequential 4-week ahead forecasts across the models from the week of July 28th, 2022, to the week of October 13th, 2022. Results The last 10 of 12 forecasting periods (starting the week of August 11th, 2022) show either a plateauing or declining trend of monkeypox cases for all models and areas of study. According to our latest 4-week ahead forecast from the top-ranked model, a total of 6232 (95% PI 487.8, 12,468.0) cases could be added globally from the week of 10/20/2022 to the week of 11/10/2022. At the country level, the top-ranked model predicts that the USA will report the highest cumulative number of new cases for the 4-week forecasts (median based on OWID data: 1806 (95% PI 0.0, 5544.5)). The top-ranked and weighted ensemble models outperformed all other models in short-term forecasts. Conclusions Our top-ranked model consistently predicted a decreasing trend in monkeypox cases on the global and country-specific scale during the last ten sequential forecasting periods. Our findings reflect the potential impact of increased immunity, and behavioral modification among high-risk populations.

Introduction Discontinuations of HIV preexposure prophylaxis (PrEP) by at‐risk individuals could decrease the effectiveness of PrEP. Our objective was to characterize patterns of, reasons for, and clinical outcomes associated with PrEP discontinuations in primary care. Methods We conducted medical chart reviews for patients prescribed PrEP during 2011 to 2014 at a Boston community health centre specializing in healthcare for sexual and gender minorities. Patients were followed through 2015. We characterized patients’ sociodemographics, relationship status, behavioural health conditions, patterns of and reasons for PrEP discontinuations, and HIV seroconversions. Cox proportional hazards models were used to assess patient factors associated with PrEP discontinuations. Results Of the 663 patients prescribed PrEP, the median age was 33 years, 96% were men who have sex with men (MSM) and 73% were non‐Hispanic white; 40% were in committed relationships and 15% had HIV‐infected partners. Patients either used PrEP continuously (60%), had 1 or more discontinuations (36%), or did not initiate PrEP (4%). Discontinuations were most often due to a decrease in HIV risk perception (33%), non‐adherence to care plans (16%), or insurance barriers (12%). Of the 7 (1.1%) PrEP patients diagnosed with HIV, 1 was HIV‐infected at baseline, 2 seroconverted while using PrEP, and 4 seroconverted after discontinuations. In a multivariable model adjusted for race/ethnicity, relationship status, substance use disorders, and insurance status, those who were less than 30 years old (aHR 2.0, 95% CI 1.4 to 2.9 for ages 18 to 24, aHR 2.2, 95% CI 1.6 to 3.1 for ages 25 to 29, vs. ages 30 to 39 years), who identified as transgender women (aHR 2.0, 95% CI 1.2 to 3.4, vs. cisgender men), and who had mental health disorders (aHR 1.2, 95% CI 1.1 to 1.4 for each additional disorder) were more likely to have discontinuations. Conclusions Discontinuations of PrEP use among this American sample of predominately MSM were common, particularly among patients who were younger, identified as transgender women, or had behavioural health issues. As HIV seroconversions occurred after discontinuations of PrEP, strategies to prevent inappropriate discontinuations are needed.

Purpose To study the effect of three nonionic surfactants on the protein-silicone oil interactions. Methods The adsorption of Tween® 80, Pluronic® F68 and Tween® 20 at the silicone oil/water interface (using shifts in frequency (ΔF) and resistance (ΔR) with quartz crystal microbalance) was compared to the adsorption at air/water interface (using surface tension). Effect of surfactants on protein adsorption to the silicone oil/water interface was studied in sequential- and co-adsorption modes. Protein-surfactant binding in the bulk was measured using dynamic surface tension method. Results Saturation of air/water and silicone oil/water interfaces by surfactants was observed at similar bulk concentrations. ΔF due to protein adsorption to the interface decreased only when surfactant was present as a pre-adsorbed species. Insignificant differences in the dynamic surface tension values of surfactant solutions were observed in the presence of protein. Conclusions Similar hydrophobic forces were responsible for driving the surfactant adsorption at both air/water and silicone oil/water interfaces. Surfactants were effective in reducing the protein adsorption to the silicone oil only when introduced before or along with the protein. No significant binding between the protein and surfactants was observed in the bulk.

PurposePolysorbates are commonly added to protein formulations and serve an important function as stabilizers. This paper reviews recent literature detailing some of the issues seen with the use of polysorbate 80 and polysorbate 20 in protein formulations. Based on this knowledge, a development strategy is proposed that leads to a control strategy for polysorbates in protein formulations.MethodsA consortium of Biopharmaceutical scientists working in the area of protein formulations, shared experiences with polysorbates as stabilizers in their formulations.ResultsBased on the authors experiences and recent published literature, a recommendation is put forth for a development strategy which will lead into the appropriate control strategy for these excipients.ConclusionsAn appropriate control strategy may comprise one or more elements of raw material, in-process and manufacturing controls. Additionally, understanding the role, if any, polysorbates play during stability will require knowledge of the criticality of the excipient, based upon its impact on CQAs due to variations in concentration and degradation level.

Amphetamine use is higher among men who have sex with men (MSM) compared with other men, and is associated with sexual behavior linked to HIV transmission. No national estimates of amphetamine use among MSM with HIV have been published. We used data from the Medical Monitoring Project, a nationally representative sample of persons with diagnosed HIV, to describe patterns in amphetamine use in the past 12 months among MSM during 2015–2016 (N = 3796). Prevalence of amphetamine use in this population was 9.6% (95% CI 7.6, 11.6%) in the past 12 months. MSM who used amphetamines were more likely to have condomless sex with partners without HIV or of unknown serostatus (PR 1.87; 95% CI 1.62, 2.16) and less likely to be durably virally suppressed (PR 0.81; 95% CI 0.71, 0.91). Interventions to address amphetamine use and associated transmission risk behaviors among MSM living with HIV may decrease transmission.

Seroadaptive behaviors help reduce HIV risk for some men who have sex with men (MSM), and have been well documented across MSM populations. Advancements in biomedical prevention have changed the contexts in which seroadaptive behaviors occur. We thus sought to estimate and compare the prevalence of four stages of the “seroadaptive cascade” by PrEP use in the recent era: knowledge of own serostatus, knowledge of partner serostatus; serosorting (matching by status), and condomless anal intercourse. Serosorting overall appeared to remain common, especially with casual and one-time partners. Although PrEP use did not impact status discussion, it did impact serosorting and the likelihood of having condomless anal intercourse. For respondents not diagnosed with HIV and not on PrEP, condomless anal intercourse occurred in just over half of relationships with HIV-positive partners who were not on treatment. Biomedical prevention has intertwined with rather than supplanted seroadaptive behaviors, while contexts involving neither persist.