Southern African HIV Clinicians Society Guideline for the clinical management of syphilis.

Syphilis, 'the great imitator', caused by Treponema pallidum infection, remains a complex and multifaceted disease with a rich history of clinical diversity. This guideline aims to be a comprehensive guide for healthcare workers in Southern Africa, offering practical insights into the epidemiology, pathogenesis, clinical manifestations, diagnostic testing, therapeutic principles, and public health responses to syphilis. Although the syphilis burden has declined over the years, recent data indicate a troubling resurgence, particularly among pregnant women and neonates. This guideline highlights the diagnostic challenges posed by syphilis, stemming from the absence of a single high-sensitivity and -specificity test. While treatment with penicillin remains the cornerstone of treatment, alternative regimens may be used for specific scenarios. We highlight the importance of thorough patient follow-up and management of sex partners to ensure optimal care of syphilis cases. In the context of public health, we emphasise the need for concerted efforts to combat the increasing burden of syphilis, especially within high-risk populations, including people living with HIV.

Novel point-of-care cytokine biomarker lateral flow test for the screening for sexually transmitted infections and bacterial vaginosis: study protocol of a multicentre multidisciplinary prospective observational clinical study to evaluate the performance and feasibility of the Genital InFlammation Test (GIFT).

INTRODUCTION: A prototype lateral flow device detecting cytokine biomarkers interleukin (IL)-1α and IL-1ß has been developed as a point-of-care test-called the Genital InFlammation Test (GIFT)-for detecting genital inflammation associated with sexually transmitted infections (STIs) and/or bacterial vaginosis (BV) in women. In this paper, we describe the rationale and design for studies that will be conducted in South Africa, Zimbabwe and Madagascar to evaluate the performance of GIFT and how it could be integrated into routine care. METHODS AND ANALYSIS: We will conduct a prospective, multidisciplinary, multicentre, cross-sectional and observational clinical study comprising two distinct components: a biomedical ('diagnostic study') and a qualitative, modelling and economic ('an integration into care study') part. The diagnostic study aims to evaluate GIFT's performance in identifying asymptomatic women with discharge-causing STIs (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG)) and BV. Study participants will be recruited from women attending research sites and family planning services. Several vaginal swabs will be collected for the evaluation of cytokine concentrations (ELISA), STIs (nucleic acid amplification tests), BV (Nugent score) and vaginal microbiome characteristics (16S rRNA gene sequencing). The first collected vaginal swab will be used for the GIFT assay which will be performed in parallel by a healthcare worker in the clinic near the participant, and by a technician in the laboratory. The integration into care study aims to explore how GIFT could be integrated into routine care. Four activities will be conducted: user experiences and/or perceptions of the GIFT device involving qualitative focus group discussions and in-depth interviews with key stakeholders; discrete choice experiments; development of a decision tree classification algorithm; and economic evaluation of defined management algorithms. ETHICS AND DISSEMINATION: Findings will be reported to participants, collaborators and local government for the three sites, presented at national and international conferences, and disseminated in peer-reviewed publications.The protocol and all study documents such as informed consent forms were reviewed and approved by the University of Cape Town Human Research Ethics Committee (HREC reference 366/2022), Medical Research Council of Zimbabwe (MRCZ/A/2966), Comité d'Ethique pour la Recherche Biomédicale de Madagascar (N° 143 MNSAP/SG/AMM/CERBM) and the London School of Hygiene and Tropical Medicine ethics committee (LSHTM reference 28046).Before the start, this study was submitted to the Clinicaltrials.gov public registry (NCT05723484). TRIAL REGISTRATION NUMBER: NCT05723484.

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.

Outcomes of the Internal Medicine Supplemental Application: Preliminary Data on the 2022-2023 Match.

INTRODUCTION: Preference signaling (program signals and geographic preference divisions) was introduced as a component of the supplemental application for internal medicine applicants applying to programs within the United States (USA) during the 2021-22 cycle. These signals were intended to address application inflation by allowing applicants to express interest in and increase their likelihood of receiving interviews from their top programs. There is little published data, however, to describe the impact of preference signaling on the likelihood of receiving interviews from a program. This study thus sought to analyze, in a small subset of US applicants, whether preference signals were associated with a higher likelihood of obtaining a residency interview. METHODS: A survey was distributed in March 2023 to US MD seniors from the four allopathic medical schools in North Carolina who applied to categorical internal medicine residency programs during the 2022-23 application cycle. The survey was developed by the research team to provide respondents with the opportunity to report data from the electronic residency application service (ERAS) application and provide data on interviews received, actions taken throughout the application season, and outcomes of the National Residency Match Program (NRMP) using a combination of free response and multiple choice questions. RESULTS: Forty-seven out of a total of 85 contacted (55%) applicants completed some or all of the survey. Of those who completed the entirety of the survey, 39 (82.98%) completed the supplemental portion of the application and the available preference signaling. Applicants in this study were 2.95 (Odds ratio, 95% confidence interval [CI] 2.20 - 3.97, p<0.01) times as likely to receive an interview invitation from a program if they used a program signal. Applicants were 1.75 (odds ratio, 95% CI 1.38 - 2.21, p<0.01) times as likely to receive an interview invitation from a program in an indicated geographic preference division. Forty-seven percent (95% CI 31 - 64%) matched to a program they had sent a program signal to, and 97% (95% CI 78 - 100%) matched to a program in an indicated geographic preference division. CONCLUSIONS: The program signals and geographic preference division components of the supplemental application increased the likelihood of receiving an interview invitation but did not have a clear impact on match outcomes. Further research with larger sample sizes will be necessary to determine how these signals actually modify the outcomes of the NRMP.

Clinicians' power in the inpatient care of anorexia nervosa: A qualitative investigation of consumer perspectives.

Medically compromised people with anorexia nervosa are cared for in inpatient settings where clinicians closely monitor health and safety. Clinicians are in a position of power, with the capacity to impose mandated weight gain to achieve medical stabilisation. Consumers are in a vulnerable position, compelled to temporarily relinquish autonomy and to accept coercive practices that often diminish the quality of the therapeutic relationship. Clinicians' position of power in mental healthcare has a dual potential for both healing and harm, and limited attention has been given to consumers' views of clinicians' power. The aim of this qualitative descriptive study was to investigate the consumer perspective of clinicians' power in the inpatient care of anorexia nervosa, establishing insight into the beneficence and maleficence of the power asymmetry. Ten women with anorexia nervosa in the community participated in semi-structured interviews online. The COREQ checklist was used to ensure accuracy and completeness of reporting. Thematic analysis revealed that abuses of power were common in the course of inpatient AN care, however life-saving measures were regarded as defensible. The perception of clinicians' power was determined by the strength of interpersonal relationships and clinicians' clinical competence. To mitigate the potential for harmful experiences, clinicians' use of power must be exercised with close consideration for consumer perspectives, with the integration of person-centred care and trauma-informed care principles.

The focus on weight in the inpatient care of anorexia nervosa: A qualitative investigation of consumer perspectives.

Anorexia nervosa has a high mortality rate and is often treated in the inpatient setting, where close monitoring and medical support are available. Consistent with objective biomedical benchmarks, conventional inpatient treatment is often focussed on weight gain. Consumers report that clinicians provide care focussed on weight and physical restoration without adequate consideration of their full spectrum of needs. The aim of this study was to explore consumers' perspectives of the biomedical focus on weight gain in the inpatient care of anorexia nervosa. This study employed a qualitative approach, involving semistructured interviews, and participants were recruited from relevant social media communities. This study was ethically approved by a university ethics committee and the COREQ checklist ensured ethical reporting. Ten women participated in interviews. Participants reported that the biomedical imperative of weight gain is focussed on at the exclusion of other relevant determinants of well-being, and the narrow focus on weight gain does not suitably prepare consumers for discharge. The conflict between clinicians' biomedical focus and consumers' broader unmet needs leads to harmful interpersonal dynamics and feelings of invalidation. The inpatient care of anorexia nervosa needs to develop beyond biomedically driven objectives and incorporate the merits of an approach that substantively integrates person-centred care, therapeutic relationships and trauma-informed principles.

Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants.

Background: We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. Methods: A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results: No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion: In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841. Funding: South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH).

"It's already in your body and it's preventing": a qualitative study of African female adolescent's acceptability and preferences for proxy HIV prevention methods in Cape Town, South Africa.

BACKGROUND: Advances in biomedical HIV prevention will soon offer young women a choice of HIV prevention methods, including various pre-exposure prophylaxis (PrEP) modalities such as daily oral pills, dapivirine vaginal ring, and long-acting injectable agents. By understanding preferences for contraceptive methods, we may draw analogies for the HIV prevention needs of young women. The UChoose Study was an open-label randomised cross-over study designed to evaluate the acceptability and preference for several contraceptive options as a proxy for HIV prevention methods that use similar types of administration. The study enrolled healthy HIV uninfected young women aged 15 to 19 years. At enrolment, participants were randomly assigned to a contraceptive method for a period of 16 weeks in the form of monthly Nuvaring® (vaginal ring), daily combined oral contraceptive (daily pills), or bi-monthly injectable contraceptive (injectable). After 16 weeks, participants crossed over to another contraceptive method, and those who had received the injectable and the daily pills received the vaginal ring for another 16 weeks, whereas those who had received the vaginal ring were able to choose between the injectable and daily pills, to ensure that all participants tried the vaginal ring-the least familiar option to the study population. RESULTS: Thirty-three participants were purposively recruited to participate in seven focus group discussions (FGD) and completed a pre-survey for their assigned group. Our sample comprised 14 participants randomised to use of the vaginal ring and daily pills and 19 participants randomised to use of the vaginal ring and injectable. For most participants, their preferences for a prevention method were based primarily on their desire to avoid negative aspects of one method rather than their positive user experience with another method. Most participants expressed initial hesitancy for trying new contraception method products; however, a lack of familiarity was moderated by a strong interest in diverse user-controlled prevention methods. Participants valued methods that had infrequent dosing and simplified use requirements. The injection and vaginal ring were preferred over daily pills as a potential HIV prevention method. CONCLUSION: Expanding the availability of diverse products could provide adolescents with multiple choices in HIV prevention for the uninitiated. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02404038 ). Registered March 31, 2015-Registered.

"Words are too small": exploring artmaking as a tool to facilitate dialogues with young South African women about their sexual and reproductive health experiences.

Background: Adolescents and young women are at high risk for sexually transmitted infections (STIs) and unintended pregnancies. However, conversations about sexual and reproductive health (S&RH) are difficult and stigmatised. Visual art-based approaches have been a useful adjunct to language-dependent interviews, encouraging embodied memory recall. Here, we explored a novel visual art-based methodology-"Stories from the Edge"-with a cohort of young women to understand how artmaking might facilitate dialogue of how S&RH experiences influenced behaviour, to enrich dialogues captured in the individual in-depth interviews (IDIs). Methods: Seven isiXhosa-speaking young women (aged 21-25 years) were recruited into a six-session art-based engagement, painting the stories of their S&RH experiences. Large format artmaking and IDIs contributed to the data set. IDIs were audio recorded, transcribed, and translated and then analysed thematically. Results: Young women felt that the visual art-based methodology eased barriers to communicating experiences of S&RH-seeking behaviours, with one woman commenting that "words are too small" to capture lived experiences. Artmaking provided the opportunity to express emotional complexities of the pleasures of intimate relationships and the heartbreak of betrayal for which they had no language. Significant social relationships (family, partners, peers) influenced sexual and reproduction attitudes and practices more than healthcare facilities and staff and more distal socio-cultural attitudes/practices. These influences shifted from adolescence to adulthood-from family to peer and partners. Conclusion: Young women valued using the art-based methodology, which facilitated recall and verbalising their S&RH experiences more fully than language-only research. The process outlined here could provide a creative method that builds communication skills to negotiate the needs and desires of young women with partners and staff at S&RH services.

Post-COVID symptom profiles and duration in a global convalescent COVID-19 observational cohort: Correlations with demographics, medical history, acute COVID-19 severity and global region.

Background: Post-COVID conditions are characterised by persistent symptoms that negatively impact quality of life after SARS-CoV-2 diagnosis. While post-COVID risk factors and symptoms have been extensively described in localised regions, especially in the global north, post-COVID conditions remain poorly understood globally. The global, observational cohort study HVTN 405/HPTN 1901 characterises the convalescent course of SARS-CoV-2 infection among adults in North and South America and Africa. Methods: We categorised the cohort by infection severity (asymptomatic, symptomatic, no oxygen requirement (NOR), non-invasive oxygen requirement (NIOR), invasive oxygen requirement (IOR)). We applied a regression model to assess correlations of demographics, co-morbidities, disease severity, and concomitant medications with COVID-19 symptom persistence and duration across global regions. Results: We enrolled 759 participants from Botswana, Malawi, South Africa, Zambia, Zimbabwe, Peru, and the USA a median of 51 (interquartile range (IQR) = 35-66) days post-diagnosis, from May 2020 to March 2021. 53.8% were female, 69.8% were 18-55 years old (median (md) = 44 years old, IQR = 33-58). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), human immunodeficiency virus (HIV) infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR = 47.4%; NIOR = 22.9%; IOR = 5.8%). Median COVID-19 duration among symptomatic participants was 20 days (IQR = 11-35); 43.4% reported symptoms after COVID-19 resolution, 33.6% reported symptoms ≥30 days, 9.9% reported symptoms ≥60 days. Symptom duration correlated with disease severity (P < 0.001, NIOR vs NOR; P = 0.003, IOR vs NOR), lung disease (P = 0.001), race (P < 0.05, non-Hispanic Black vs White), and global region (P < 0.001). Prolonged viral shedding correlated with persistent abdominal pain (odds ratio (OR) = 5.51, P < 0.05) and persistent diarrhoea (OR = 6.64, P < 0.01). Conclusions: Post-COVID duration varied with infection severity, race, lung disease, and region. Better understanding post-COVID conditions, including regionally-diverse symptom profiles, may improve clinical assessment and management globally. Registration: Clinicaltrials.gov (#NCT04403880).

Cervicovaginal Human Papillomavirus Genomes, Microbiota Composition and Cytokine Concentrations in South African Adolescents.

The interaction between cervicovaginal virome, bacteriome and genital inflammation has not been extensively investigated. We assessed the vaginal DNA virome from 33 South African adolescents (15-19 years old) using shotgun DNA sequencing of purified virions. We present analyses of eukaryote-infecting DNA viruses, with a focus on human papillomavirus (HPV) genomes and relate these to the vaginal bacterial microbiota (assessed by 16S rRNA gene sequencing) and cytokines (assessed by Luminex). The DNA virome included single-stranded (Anelloviridae, Genomoviridae) and double-stranded DNA viruses (Adenoviridae, Alloherpesviridae, Herpesviridae, Marseilleviridae, Mimiviridae, Polyomaviridae, Poxviridae). We identified 110 unique, complete HPV genomes within two genera (Alphapapillomavirus and Gammapapillomavirus) representing 40 HPV types and 12 species. Of the 40 HPV types identified, 35 showed positive co-infection patterns with at least one other type, mainly HPV-16. HPV-35, a high-risk genotype currently not targeted by available vaccines, was the most prevalent HPV type identified in this cohort. Bacterial taxa commonly associated with bacterial vaginosis also correlated with the presence of HPV. Bacterial vaginosis, rather than HPV, was associated with increased genital inflammation. This study lays the foundation for future work characterizing the vaginal virome and its role in women's health.

Co-design and evaluation of a multidisciplinary teaching resource on mental health recovery involving people with lived experience.

BACKGROUND: Students from a range of health disciplines need to learn from people with lived experience of mental distress and recovery to develop recovery capabilities for mental health practice. AIMS: The aims of this study are to describe the co-design of a teaching resource, to explore the experience of people with lived experience during the resource development, and to evaluate the outcome of the resource on student recovery capabilities. METHOD: Using a sequential mixed method, a project group consisting of six people with lived experience and 10 academics from five health disciplines was convened to co-develop teaching resources. People with lived experience met independently without researchers on several occasions to decide on the key topics and met with the research team monthly. The teaching resource was used in mental health subjects for two health professional programmes, and the Capabilities for Recovery-Oriented Practice Questionnaire (CROP-Q) was used before and after to measure any change in student recovery capabilities. Scores were compared using the Wilcoxon signed rank test. The people with lived experience were also interviewed about their experience of being involved in constructing the teaching resources. Interviews were audiotaped, transcribed, and analysed thematically. RESULTS: The finished resource consisted of 28 short videos and suggested teaching plans. Occupational therapy and nursing student scores on the CROP-Q prior to using the educational resource (n = 33) were 68 (median) and post scores (n = 28) were 74 (median), indicating a statistically significant improvement in recovery capability (P = 0.04). Lived experience interview themes were (i) the importance of lived experience in education; (ii) personal benefits of participating; (iii) co-design experience; and (iv) creating the resource. CONCLUSION: Co-design of teaching resources with people with lived experience was pivotal to the success and quality of the final product, and people with lived experience described personal benefits of participating in resource development. More evidence to demonstrate the use of the CROP-Q in teaching and practice is needed.

Genome Sequences of Anelloviruses, a Genomovirus, Microviruses, Polyomaviruses, and an Unclassified Caudovirus Identified in Vaginal Secretions from South African Adolescents.

Other than for papillomaviruses, there is a paucity of whole-genome sequences for bacteriophages and eukaryote-infecting viruses isolated from the female genital tract. Here, we report the genome sequences of 16 microviruses, 3 anelloviruses, 2 polyomaviruses, 1 genomovirus, and 1 caudovirus that were identified in vaginal secretion samples from adolescents in South Africa.

Understanding Oral Prep Interest Among South African Adolescents: The Role of Perceived Parental Support and PrEP Stigma.

We examined oral PrEP interest among adolescents and its association with perceived parental support and PrEP stigma. Cross-sectional data were collected during baseline procedures of the "Our Family Our Future" intervention trial in South Africa. Adolescents (14-16 years) at elevated risk for acquiring HIV and their parents or caregivers were dyadically enrolled from 2018 to 2021. There were 879 complete adolescent-parent dyads. Among adolescents, 27% had heard about PrEP, 67% reported they would want to use PrEP, and 58% thought their parent would want them to use PrEP. Among parents, 33% had heard about PrEP and 85% reported they would want their adolescent to use PrEP. Adolescents who thought their parent would want them to use PrEP were more likely to be interested in PrEP than adolescents who thought their parent would not want them to use PrEP (adjusted prevalence ratio (aPR) = 2.11, 95% CI 1.82, 2.44). Further, adolescents with higher average PrEP stigma scores above the adolescent sample median were less likely to be interested in PrEP than adolescents with lower average PrEP stigma scores (aPR = 0.81, 95% CI 0.72, 0.91). In conclusion, parents were more supportive of their adolescent taking PrEP than adolescents perceived they would be, and perceptions of low parental support and greater PrEP stigma were associated with reduced PrEP interest among adolescents. Interventions should aim to improve adolescent-parent communication around sexual health and effective HIV prevention tools.

What about value for money? A cost benefit analysis of the South Eastern Sydney Recovery and Wellbeing College.

BACKGROUND: Recovery Colleges assist people in their personal recovery journeys by offering an approach that transforms conventional mental health care by using an educational framework. While evaluations of these colleges have demonstrated effectiveness in promoting personal recovery, scant research has been published regarding their economic evaluation. AIMS: To conduct a cost-benefit analysis of the South Eastern Sydney Recovery and Wellbeing College in Australia by exploring health utilisation and direct costs. METHOD: The overall costs of the Recovery College sample (reported from 2014 to 2017) were used to derive a per person, per year cost, adjusted for inflation to 2020 Australian dollars. Benefits were determined by analysing pre/post health service utilisation by service users, and subsequently calculating a net cost saving. RESULTS: There was a statistically significant reduction in Emergency Department and inpatient mental health utilisation following participation in the Recovery College. The net cost savings was A$269 per student per year. CONCLUSIONS: This study indicates that the Recovery College can play an important role in decreasing mental health service and ED utilisation. This reflects reduced reliance on traditional mental health services, thus suggesting that students develop improved self-agency and ability to manage their own mental health.

Erratum: Southern African HIV Clinicians Society 2022 guideline for the management of sexually transmitted infections: Moving towards best practice.

[This corrects the article DOI: 10.4102/sajhivmed.v23i1.1450.].

Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors.

Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients. Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations. Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old. Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults. Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.

Application of physiologically based pharmacokinetic models for therapeutic proteins and other novel modalities.

The past two decades have seen diversification of drug development pipelines and approvals from traditional small molecule therapies to alternative modalities including monoclonal antibodies, engineered proteins, antibody drug conjugates (ADCs), oligonucleotides and gene therapies. At the same time, physiologically based pharmacokinetic (PBPK) models for small molecules have seen increased industry and regulatory acceptance.This review focusses on the current status of the application of PBPK models to these newer modalities and give a perspective on the successes, challenges and future directions of this field.There is greatest experience in the development of PBPK models for therapeutic proteins, and PBPK models for ADCs benefit from prior experience for both therapeutic proteins and small molecules. For other modalities, the application of PBPK models is in its infancy.Challenges are discussed and a common theme is lack of availability of physiological and experimental data to characterise systems and drug parameters to enable a priori prediction of pharmacokinetics. Furthermore, sufficient clinical data are required to build confidence in developed models.The PBPK modelling approach provides a quantitative framework for integrating knowledge and data from multiple sources and can be built on as more data becomes available.