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Trial registered on ANZCTR


Registration number
ACTRN12616000734460
Ethics application status
Approved
Date submitted
6/05/2016
Date registered
3/06/2016
Date last updated
30/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the impact of the Xpert (Registered Trademark) HIV-1 QUAL test in infants born to Human Immunodeficiency Virus (HIV)-positive mothers in Myanmar and Papua New Guinea
Scientific title
Evaluating the impact of the Xpert (Registered Trademark) HIV-1 QUAL test in HIV-exposed infants in Myanmar and Papua New Guinea: A multinational multi-centre cluster-randomised controlled stepped-wedge intervention trial.
Secondary ID [1] 289149 0
Nil known
Universal Trial Number (UTN)
Trial acronym
AAMI Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HIV 298677 0
Condition category
Condition code
Infection 298731 298731 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
During the intervention phase, HIV-infected women and their infants aged less than 28 days presenting at the health facility will be invited to participate. At approximately six weeks post-delivery, enrolled infants will have either a heel prick or venous blood sample taken – depending on the local hospital guidelines - and tested for HIV infection using the Xpert (Registered Trademark) HIV-1 QUAL test. In addition, up to six dried blood spot circles (from the same blood draw as for the Xpert (Registered Trademark) HIV-1 QUAL test) will be collected, up to five for the HIV PCR laboratory-based assay to assess Xpert (Registered Trademark) HIV-1 QUAL test performance and confirm diagnosis, and one to be stored for quality assurance purposes. In total, 300 microlitres will be collected from each infant for standard of care and storage, and 100 microlitres for the Xpert (Registered Trademark) HIV-1 QUAL test (total 400 microlitres). It is anticipated that the Xpert (Registered Trademark) HIV-1 QUAL test will be performed the same day by a trained health worker or assigned clinic staff member. Test results will be communicated to the parent / caregiver as soon as the test result is available or soon thereafter. The Xpert (Registered Trademark) HIV-1 QUAL test takes 90 minutes to complete, therefore it is anticipated that results will be conveyed to the parent/caregiver after 90 minutes. Infants testing positive on the Xpert (Registered Trademark) HIV-1 QUAL test (or once confirmed by the HIV PCR laboratory-based assay if indicated by the in-country regulations) will receive antiretroviral (ARV) treatment as soon as possible according to WHO guidelines. HIV-exposed infants testing HIV negative will receive standard care as per national guidelines. In both arms, ARV treatment and prophylaxis will be provided as per national and WHO guidelines ensuring intervention sustainability.

Across the 6 sites, 45 cumulative enrolment months are allocated to the intervention phase.
Intervention code [1] 294670 0
Diagnosis / Prognosis
Comparator / control treatment
During the standard care (control) phase, infants born to HIV-infected women and presenting at the health facility will be screened for eligibility. Enrolled infants will have their blood drawn for HIV testing (at approximately six weeks post-delivery) using a dried blood spot specimen evaluated at the centralised laboratory using a PCR test for HIV (standard of care). Up to six dried blood spot circles will be collected for each infant, five to be sent to the laboratory for testing and one to be stored for confirmatory diagnosis if required. Laboratories processing the specimens will either have an External Quality Assurance program in place or one will be established as part of the study. Test result communication and ARV commencement will occur as per the standard of care.

Across the 6 sites, 33 cumulative enrolment months are allocated to the control phase.
Control group
Active

Outcomes
Primary outcome [1] 298208 0
Proportion of HIV-exposed infants and their caregivers who received an infant HIV test result by 3 months of age. This will be assessed using study-specific forms that record whether or not caregivers receive the HIV test results of the infants, and how old the infant is when the results are received.
Timepoint [1] 298208 0
This outcome will be assessed at 3 months of age for all infants in both the intervention and the control group.
Secondary outcome [1] 323513 0
Median duration between blood sample drawn for HIV test and communication of results to parents/caregivers. This will be assessed using study-specific forms that record when the infant's blood sample is taken and how old the infant is when the HIV test results are received.
Timepoint [1] 323513 0
This outcome will be assessed when each infant's caregiver in both the control and the intervention phase receives an HIV test result.
Secondary outcome [2] 324130 0
Median infant age at which HIV-exposed infants and their caregivers received HIV test result. This will be assessed using study-specific forms that record how old the infant is when the results are received.
Timepoint [2] 324130 0
This outcome will be assessed when each infant's caregiver in both the control and the intervention phase receives an HIV test result.
Secondary outcome [3] 324131 0
Proportion of HIV-exposed infants and their caregivers who received an infant HIV test result by 6 months of age. This will be assessed using study-specific forms that record whether or not caregivers receive the HIV test results of the infants, and how old the infant is when the results are received.
Timepoint [3] 324131 0
This outcome will be assessed at 6 months of age for all infants in both the intervention and the control group.
Secondary outcome [4] 324132 0
To assess field performance of the Xpert (Registered Trademark) HIV-1 QUAL assay compared to laboratory-based polymerase chain reaction for HIV (standard of care). This will be assessed using study-specific forms that record the results of the Xpert (Registered Trademark) HIV-1 QUAL assay and the PCR testing.
Timepoint [4] 324132 0
This outcome will be assessed after each infant in the intervention phase has both an Xpert (Registered Trademark) HIV-1 QUAL test and a laboratory-based polymerase chain reaction test for HIV completed.
Secondary outcome [5] 324133 0
This composite outcome is to assess the operational feasibility and acceptability of the Xpert (Registered Trademark) HIV-1 QUAL during provision of infant care services. This outcome will be assessed through structured quantitative questionnaires and qualitative interviews with caregivers of HIV-exposed infants, health care workers involved in the study using the Xpert test, and key informants such as policy makers, facility managers and community leaders. These questionnaires were designed specifically for this study.
Timepoint [5] 324133 0
This outcome will be assessed after 45 cumulative months of intervention phase across the 6 sites.
Secondary outcome [6] 324134 0
To assess the cost-effectiveness of the Xpert (Registered Trademark) HIV-1 QUAL compared with standard of care and to make recommendations on the optimal combination of each type of test at different sites for implementation beyond this study. This outcome will be assessed with a facility audit in each study site conducted once during the control phase and once during the intervention phase. The audit will consist of a semi-structured interview with the person responsible for the child health services as well as direct observation of the clinic’s equipment, supplies, and infrastructure. The audit will address service delivery components, including total and marginal costs of service delivery, client flow analysis, procurement and logistic systems. Costs collated will include commodities, human resources (clinician, nursing, administrative), on-costs attributable to the programs (e.g. rent or electricity), courier costs, laboratory costs, and other costs aligned with the auditing process to be associated with the standard of care or Xpert (Registered Trademark) HIV-1 QUAL test.
Timepoint [6] 324134 0
This outcome will be assessed following 33 cumulative control months, and after 45 cumulative months of intervention phase across the 6 sites.

Eligibility
Key inclusion criteria
i) Infants born to confirmed HIV-infected mothers (i.e. with documentation of prior counselling and HIV testing, with a confirmed positive HIV test result) and requiring HIV testing;
ii) Newborn infants within the first 28 days of life;
iii) Parent/caregiver residing, and planning to continue to reside, within the site-specific catchment area for the next six months;
iv) Parent/caregiver able and willing to give informed consent for enrolment of their infant in the study.
v) Parent/caregiver providing consent is aged 18 years or older
vi) Parent/caregiver is willing to provide reliable contact information (e.g. mobile phone number, home address, description of how to find their house if they live in a rural area), and consent to be contacted by a member of the research team in the community to remind them to re-attend for follow-up.
Minimum age
0 Days
Maximum age
28 Days
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) Participant is enrolled in another research study which interferes with this study, or previously enrolled in this study;
ii) Parent/caregiver and/or participant has a medical or non-medical issue incapacitating participation in the research as decided by the local Principal Investigator.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software, stratified by country
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Using a cluster-randomised controlled (at health facility level) stepped-wedge design, we will assess the impact of the Xpert (Registered Trademark) HIV-1 QUAL early infant diagnosis of HIV to increase uptake of results communication and enable earlier initiation of infant ARV treatment. This study will implement the Xpert (Registered Trademark) HIV-1 QUAL (intervention) in a total of 6 facilities in Myanmar (n=4) and PNG (n=2).

The intervention will be introduced in a step-wise approach with facilities enrolling HIV-exposed infants before and after the introduction of the intervention. This will enable prospective comparisons of intervention and standard care within (before and after intervention introduction) and between sites (with and without intervention) in an ethical research framework. Computer random allocation will decide the order and timing of intervention introduction. Individual randomisation is not feasible for ethical reasons as some infants visiting the same site would receive an immediate result and care and some would have a deferred result and care.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The study has been powered to detect a significant difference in the proportion of infants receiving an EID test result by 3 months of age. We have acceptable power (80%) to detect a clinically meaningful change in the proportion of HIV-exposed infants receiving a test result by 3 months of age using a random effect semi-parametric survival analysis. Based on an estimated 50% of infants receiving an EID test result by 3 months of age we are powered approximately (80% power, 95% confidence level and intraclass correlation coefficient = 0.05) to detect an increase in 3-month EID test result receipt to 84% (risk ratio = 3.6). Given the mixed modelling approach proposed, and with all other factors being equal, statistical power will be higher if a greater level of between-clinic heterogeneity in receipt of EID testing is observed in the sample.

A generalised mixed model approach will be used to analyse the effect of the intervention with respect to the likelihood of infants receiving an EID test result at three months of age. Appropriate survival analyses will assess time to event outcomes. In analyses, intervention and study period will be modelled as fixed factors with clinic (study cluster or psu) treated as a random term. The effect of study site (i.e. country) will also be explored. In all analyses statistical significance will be assessed at p <0.05.

To assess test performance of the Xpert (Registered Trademark) HIV-1 QUAL, correlation of values compared to gold standard reference tests will be assessed through determination of misclassification, sensitivity, specificity, and negative and positive predictive value, and reported following STARD guidelines. The failure rate of the Xpert (Registered Trademark) HIV-1 QUAL will be determined as the proportion of performed tests during which no test result could be established either through an indeterminate result or test failure (invalid test).

To assess the operational feasibility and acceptability of the Xpert (Registered Trademark) HIV-1 QUAL during provision of infant care services, we will describe perspectives from both clients as well as health workers. Operational feasibility of the Xpert (Registered Trademark) HIV-1 QUAL will be assessed in comparison with standard of care. A comprehensive approach will also be used to assess operational characteristics of the Xpert (Registered Trademark) HIV-1 QUAL tests for suitability for use in Myanmar and PNG using the WHO ASSURED criteria for HIV assays operation in resource-constrained settings.

Assessment of the cost-effectiveness of the Xpert (Registered Trademark) HIV-1 QUAL compared with standard of care the following will be calculated:
i) estimated incremental cost per additional day of known HIV status;
ii) estimated incremental cost per DALY averted when cohorts are model projected out to age 5 years;
Moreover, the optimal combination of current standard of care and Xpert (Registered Trademark) HIV-1 QUAL will be estimated across different clinical sites to maximize the return on investment and epidemiological impact of testing strategies.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 7860 0
Papua New Guinea
State/province [1] 7860 0
Eastern Highlands, Western Highlands
Country [2] 7861 0
Myanmar
State/province [2] 7861 0

Funding & Sponsors
Funding source category [1] 293533 0
Government body
Name [1] 293533 0
National Health and Medical Research Council
Address [1] 293533 0
GPO Box 1421
Canberra ACT 2601
Country [1] 293533 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Burnet Institute
Address
85 Commercial Rd, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 292351 0
None
Name [1] 292351 0
Address [1] 292351 0
Country [1] 292351 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294966 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 294966 0
The Alfred Hospital
55 Commercial Road
Melbourne, Victoria 3004
Ethics committee country [1] 294966 0
Australia
Date submitted for ethics approval [1] 294966 0
25/01/2016
Approval date [1] 294966 0
14/04/2016
Ethics approval number [1] 294966 0
500/14
Ethics committee name [2] 294970 0
Institutional Review Board - Institute of Medical Research
Ethics committee address [2] 294970 0
PO BOX 60
GOROKA, Eastern Highlands Province 441
Ethics committee country [2] 294970 0
Papua New Guinea
Date submitted for ethics approval [2] 294970 0
15/01/2016
Approval date [2] 294970 0
11/02/2016
Ethics approval number [2] 294970 0
1602
Ethics committee name [3] 294971 0
Medical Research Advisory Committee
Ethics committee address [3] 294971 0
PO Box 807
Waigani 131, NCD
Ethics committee country [3] 294971 0
Papua New Guinea
Date submitted for ethics approval [3] 294971 0
15/01/2016
Approval date [3] 294971 0
04/07/2016
Ethics approval number [3] 294971 0
16.19
Ethics committee name [4] 294972 0
Department of Medical Services
Ethics committee address [4] 294972 0
Office No. 4,
Department of Medical Services,
Ministry of Health,
Naypyitaw,
Myanmar.
Ethics committee country [4] 294972 0
Myanmar
Date submitted for ethics approval [4] 294972 0
06/05/2016
Approval date [4] 294972 0
09/09/2016
Ethics approval number [4] 294972 0
008816

Summary
Brief summary
The overall aim of the study is to improve child health in resource-constrained and rural settings in the Asia and Pacific region by increasing uptake and timely initiation of lifesaving antiretroviral interventions for HIV-exposed infants through the use of a novel point-of-care (POC) early infant diagnostic test. The use of this novel POC test will enable caregivers of HIV-exposed infants to receive HIV test results sooner, and consequently result in HIV-infected infants starting on lifesaving treatment faster.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65658 0
A/Prof Stanley Luchters
Address 65658 0
Burnet Institute
85 Commercial Rd,
Melbourne VIC 3004
Country 65658 0
Australia
Phone 65658 0
+61 3 8506 2378
Fax 65658 0
Email 65658 0
stanley.luchters@burnet.edu.au
Contact person for public queries
Name 65659 0
Ms Yasmin Mohamed
Address 65659 0
Burnet Institute
85 Commercial Rd,
Melbourne VIC 3004
Country 65659 0
Australia
Phone 65659 0
+61 3 8506 2349
Fax 65659 0
Email 65659 0
yasmin.mohamed@burnet.edu.au
Contact person for scientific queries
Name 65660 0
A/Prof Stanley Luchters
Address 65660 0
Burnet Institute
85 Commercial Rd,
Melbourne VIC 3004
Country 65660 0
Australia
Phone 65660 0
+61 3 8506 2378
Fax 65660 0
Email 65660 0
stanley.luchters@burnet.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary