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The enhanced package of AHD care includes CD4 and tuberculosis lipoarabinomannan (TB-LAM) tests and the initiation of patients on TB prophylaxis \[TPT and CPT\], offered through a hub-and-spoke facility system, with continuous quality improvement (QI)

Enhanced package for AHD care

Thulani Maphosa, PhD

Appolinaire Tiam, MBChB, MMed, PhD

Rose Nyirenda, MPH, PhD

This study will evaluate the implementation of an enhanced package of care, CD4 and tuberculosis lipoarabinomannan (TB-LAM) tests and the initiation of patients on TB prophylaxis \[TPT and CPT\], on retention in care and viral suppression ((\<50 copies/ml) at 6 and 12 months after AHD care and treatment enrollment. The study will also assess the change in AHD screening, management and service uptake indicators among PLHIV clients before and after implementation of the QI collaborative implementation (QICI) project, evaluate the acceptability and feasibility of the AHD package of care among patients and HCWs providing related health services, and conduct a cost analysis of implementing the enhanced AHD package of care in a hub-and-spoke implementation of care model.

Background Despite significant advances in the diagnosis of human immunodeficiency virus (HIV) and expanded access to anti-retroviral therapy (ART), recent data suggest that a third of people living with HIV/AIDS (PLHIV) starting ART do so with advanced HIV disease (AHD), and an increasing number of patients require advanced HIV disease care following a period of disengagement. Despite considerable effort to implement the AHD model in Malawi and bring it to scale, several challenges regarding AHD implementation and outcomes still exist.

Description of Study Intervention:

To optimize the package of care offered to HIV-infected clients with advanced HIV disease in Malawi, a hub-and-spoke model will be designed and implemented to bring AHD services geographically closer to patients. An enhanced package of AHD interventions such as decentralized cluster of differentiation 4 (CD4) tests, Tuberculosis lipoarabinomannan (TB-LAM) and initiation of patients on prophylaxis \[TPT and CPT\] will be implemented \[system strengthening through quality improvement (QI)\]. A client and systems focus will identify challenges experienced by providers and clients while at the same time describing the contextual factors that affect the delivery of AHD services. These lessons learnt will be used to optimize client flow, enhance sample transportation regulation and increase client engagement.

Evaluation Description The evaluation will be a mixed method design study: (1) the quantitative component which will be a non-randomized cluster design based on control of intervention vs control sites for outcomes evaluation (2) the qualitative component that will aim at evaluating acceptability and feasibility of the strengthened AHD service provision (3) cost evaluation that will use quantitative methods.

Specific Objectives

1. To determine the effect of implementation of enhanced AHD package of care in intervention sites versus control sites on the proportion of PLHIV with AHD who are alive and retained in care at 6 and 12 months after diagnosis of AHD and enrolment into AHD care.
2. To determine the effect of implementation of enhanced AHD package of care in intervention sites versus control sites on the proportion of PLHIV with AHD, who achieve viral suppression (\<50 copies/ml) at 6 and 12 months after AHD care and treatment enrollment
3. To estimate the change in AHD screening, management and service uptake indicators among PLHIV clients before and after implementation of the QI collaborative implementation (QICI) project
4. To evaluate the acceptability and feasibility of the AHD package of care among patients utilizing AHD services and HCWs providing related health services
5. To conduct a cost analysis of implementing the hub and spoke enhanced AHD package of care to improve AHD differentiated care in selected sites in Malawi.

Endpoints

1. Proportion of PLHIV with advanced disease who will be alive and retained in care at 6 and 12 months after antiretroviral therapy (ART) initiation and after diagnosis of AHD.
2. Proportion of PLHIV with AHD enrolled in care and treatment who are virally suppressed at 6 and 12 months.

Study Population:

The study population for quantitative study component will include children, adolescents and adults of all ages in all the intervention and control sites identified for the project evaluation who are diagnosed with AHD. The study population for the qualitative component will include PLHIV, HCWs and lay cadre supporting the health facility 18 years of age and above available and willing to participate.

Description of Sites/Facilities Enrolling Participants:

The project will be implemented in twenty-two intervention sites in Malawi three selected districts and thirteen control sites in other districts where the intervention is not implemented.

Study duration: The study will take a period of 18 months, including 4 to 6 months enrolment and up to 12 months follow-up.

Non-randomized controlled clustered study

Evaluation of Advanced HIV Disease Differentiated Care Model in Malawi

Evaluation of Advanced HIV Disease Differentiated Care Model in Malawi: A Mixed Methods Non-randomized Cluster Study

Number of AHD patients alive and retained in care divided by the number of AHD patients initiated on antiretroviral therapy (ART) after diagnosis of AHD

Number of AHD patients in care and treatment virally suppressed (\<50 cells/ml) divided by the number of AHD patients in care and treatment

Estimation of total costs, costs per patients with the intervention, and cost drivers

Bill and Melinda Gates Foundation

Elizabeth Glaser Pediatric AIDS Foundation

Skin and Connective Tissue Diseases

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Nervous System Diseases

Behaviors and Mental Disorders

Digestive System Diseases

Blood and Lymph Conditions

Heart and Blood Diseases

Musculoskeletal Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Diseases and Abnormalities at or Before Birth

Substance Related Disorders

Eczema

Kidney Diseases

Diabetes Mellitus

Hypercholesterolemia

Alzheimer Disease

Depression

Depressive Disorder

Liver Diseases

Leukemia

Obesity

Heart Diseases

Arthritis

Liver Cirrhosis

Osteoporosis

Bulimia

Bulimia Nervosa

Influenza, Human

Hypersensitivity

Intestinal Diseases

Dyspepsia

Gout

Bronchitis

Appendicitis

Cellulitis

Liver Diseases, Alcoholic

Infectious Mononucleosis

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Renal Insufficiency

Dementia

Brain Diseases

Central Nervous System Diseases

Tauopathies

Neurodegenerative Diseases

Neurocognitive Disorders

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Female Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

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Metabolic Diseases

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Hyperphagia

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Skin Diseases

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Suppuration

Connective Tissue Diseases

Inflammation

Hyperlipidemias

Hyperlipoproteinemias

Dyslipidemias

Lipid Metabolism Disorders

Alcohol-Induced Disorders

Alcohol-Related Disorders

Substance-Related Disorders

Chemically-Induced Disorders

Chronic Graft Versus Host Disease

Familial Alzheimer Disease

Philippe B Wilson

Daniel JS Wolski

Imran Kapasi

Rishabh Prasad

This research programme seeks to combine the resources of NHS primary care, with the leading spectroscopic work in low-magnetic fields of the Wilson Group (Nottingham Trent University) to demonstrate the potential for benchtop Nuclear Magnetic Resonance (NMR) spectroscopy in human clinical pathology. This is an instrument assessment study for point of care viability which will also result in enhanced patient care (pending their consent) in blood screenings and metabolic health data.

The research project aims to gauge the efficacy of benchtop Nuclear Magnetic Resonance devices in a primary health care setting. The study design and methodology is as follows:

Typically, before a patient attends their routine standard of care blood test, they will speak with their local General Practitioner (GP) or a Registered Nurse (RN). At these visits, the medical professional will gauge the interest of the patient and test if they are eligible. If the patient is interested in becoming involved with research, and they are eligible for the study, they will be given a 'Study Information and Informed Consent Form' to read before their next visit. This allows for ample time to become fully informed on what the study entails, as well as to ask any questions they may have.

The 'Study Information and Informed Consent Form' document contains all information detailing: the purpose of the study, the significance of the research, and the patient's right to withdraw at any time (as in accordance with General Data Protection Regulations \[GDPR\] 2018), potential risks and benefits of taking part in the study and who to contact if the patient had any further questions to be asked.

At the patient's routine standard of care visit, they will present their signed and dated consent form to the medical professional taking the biological samples. If the patient loses their consent form before this visit, they will be given another to complete in full before any residual biological samples are taken. This will be counter-signed by the medical professional present at their visit. The patient will then be anonymised by being given a unique identifier in the form of a barcode. This barcode will be applied to the consent form, and the form will act as a linking document. The patient will only be referred by their unique identifier for the remainder of the study. This anonymisation of identifiable patient information (such as name, Date of Birth \[DoB\], etc.) extends to any data produced by analysing the patient's samples. The patient will keep a copy of the consent form for their own records, whilst the original document will be held by the research team to be stored on-site behind several layers of security. A copy of the consent form will also be uploaded onto the patients SystmOne profile. SystmOne is a clinical computer system used by medical professionals to log patient visits, review tests results and upload any new relevant data.

After sample collection, no further actions are required of the patient for the remainder of the study. The patient will be given a debriefing document thanking them for their contribution. Within this document there are contact details of the researchers involved and other contact telephone numbers to a variety of organisations and helplines specialising in emotional support, if the patient feels in any way affected by the study. The patient will also be offered the opportunity to be given a copy of their bio fluid spectral data should they be interested in this. This will be accompanied by explanatory notes.

The biological samples collected from the patient will go to two different locations: samples taken as part of the patient's routine standard of care will go to a local diagnostics lab where they will be tested on a variety of metrics. Residual biological samples will be processed and tested at the local Willows Health Near Patient Testing laboratory, before being frozen at -80oC.

The test results provided by the diagnostics lab will be uploaded to the patient's SystmOne account, where they will be scribed and used for the study, as outlined in the 'Study Information and Informed Consent Form' document. Results gathered from the Willows Health Near Patient Testing laboratory will also be uploaded to the patients SystmOne account and stored for later use within the study. The combination of these two sets of data will form the Near Patient Testing data set.

The residual biological samples frozen at Willows Health will then be transferred in batch format to Nottingham Trent University's (NTU's) benchtop Nuclear Magnetic Resonance device. They will then be thawed, prepared further and analysed using the benchtop Nuclear Magnetic Resonance device. The resultant spectra will be stored on the password protected device to form the benchtop Nuclear Magnetic Resonance data set. With both sets of data gathered (Near Patient Testing suite and benchtop Nuclear Magnetic Resonance spectra), a machine learning algorithm will cross-compare the data sets to 'teach' a program to 'read' the benchtop Nuclear Magnetic Resonance spectra and output data in the form of Near Patient Testing machines.

On average, \~42 patients attend the Willows Health Medical Centre for routine standard of care visits per week in which biological samples are collected for pathology lab testing. This equates to \~168 samples per month. With the sample collection window planned to take a year, this calculates to \~2016 potential participants being involved within the study. This is an estimated maximum, as not all patients who come for their annual review may not consent to the research study. Additionally, some religious events and holidays may limit the uptake of potential participants, for example: during Ramadan, although it is not strictly prohibited, blood tests may be avoided due to the weakening effect it may have. This, in conjunction with fasting, may dissuade potential participants from joining the study.

Given the substantial volumes of data required to 'train' software when utilising machine learning algorithms, the sample size needs to be large. This is imperative to produce accurate and reliable results from training and test sets for machine learning algorithms.

This research will result in several advantages for both clinical care and patients. For instance, efficient and rapid analysis of biological fluids will help to overcome the limitations associated with diagnosis of a variety of diseases such diabetes, chronic kidney disease, cancer and any other conditions that might go asymptomatic in the early stages. This work has the potential to pave the way for new clinical pathological techniques to support the early diagnosis of diseases.

Residual samples will be collected from patients visiting the Willows Health Medical Centre for their routine standard of care checkups.

Residual biological samples will be comprised of whole blood which will be processed into serum, analysed on local Near Patient Testing machines and frozen at -80'C. They will then be transported to Nottingham Trent University, thawed and analysed on the benchtop Nuclear Magnetic Resonance device.

Benchtop NMR Spectroscopy for Assessment of Clinical Human Pathologies (BRANCH-P STUDY)

Preclinical Drug Discovery Informed by Public Health: Initiating a Step-Change in the Development of New Human Models

An \>0.97 (or 97%) area under the receiver operating characteristic (AUROC) of benchtop Nuclear Magnetic Resonance versus current Point of Care (POC) testing sensitivity/specificity in conditional classification of samples.

Nottingham Trent University

Willows Health

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Evaluation of Advanced HIV Disease Differentiated Care Model in Malawi	NCT05510973	Opportunistic I... Cryptococcal In... AIDS With Tuber... AIDS-related Ka... AIDS and Infect...	Enhanced packag...	-	Elizabeth Glaser Pediatric AIDS Foundation
Benchtop NMR Spectroscopy for Assessment of Clinical Human Pathologies (BRANCH-P STUDY)	NCT05473325	Diabetes Chronic Kidney ... Cancer Bowel Disease Cardiovascular ... Mononucleosis Flu Heart Diseases HIV Infections AIDS and Infect... Bulimia Chest Infection... Arthritis Leukaemia Alcoholic Liver... Allergies Alzheimer Disea... Appendicitis Eczema Bronchitis Cellulitis Cirrhosis Depression Gout High Cholestero... Indigestion Obesity Osteoporosis		18 Years -	Willows Health

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