Xpert Ultra and Xpert HIV-VL in People Living With HIV

Study Overview
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Brief Summary
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TB is increasingly diagnosed using the GeneXpert platform, which can be used for a variety of tests (not just TB). HIV viral load monitoring is required at least annually in patients on ART to detect failure of virologic suppression, however, most HIV VL testing is done centrally. A patient with virologic failure is more likely to get TB. The investigators wish to see if Xpert done at the clinic results in faster patient TB diagnosis and treatment initiation compared to sending specimens away for central testing. In a different patient group (PLHIV returning for HIV treatment monitoring), the investigators wish to see if POC Xpert HIV-1 viral load (Xpert VL) testing results in faster patient viral load quantification compared to centralised testing. Both POC tests will use the same testing hardware. This polyvalent utility of the GeneXpert system is hitherto uninvestigated in this local setting. Newly diagnosed pre-ART HIV positive patients will be approached and asked to be a part of this study. Patients will be randomly assigned to Ultra done at the clinic or the normal off-site laboratory TB testing. The time taken for patients to get diagnosed and time-to-treatment will be recorded. We will also do exploratory diagnostic accuracy evaluations including but not limited to, Ultra when done on mouth samples, the new SILVAMP FujiLAM on urine, and host RNA blood signatures for active TB. Additionally, a different group of HIV positive patients (on ART) returning to the clinic for annual follow-up visits will also be asked to join the study. These patients will be randomly selected for either Xpert VL testing done at the clinic or the normal off-site testing. The time taken for patients to receive viral load results will be recorded. Should the patient's viral loads be found to be higher than anticipated and considered by the clinical to indicate a lack of viral suppression, the time taken for patients to have ART regimen adjusted, receive adherence counselling or received HIV drug susceptibility testing will be recorded. This project will confirm if Ultra TB testing performs well in PLHIV irrespective of symptoms and may produce evidence that supports universal TB testing in this important and vulnerable patient group, including using novel diagnostics on non-traditional specimen types. The investigators will also assess whether POC placement of Ultra and Xpert VL has benefits (e.g., more patients diagnosed for TB or VL monitored during the same day visit).

Detailed Description
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Sensitive and rapid point-of-care diagnostics should improve TB treatment outcomes, however, tests meeting these criteria have, until recently, been unavailable, especially in PLHIV. PLHIV often have early stage TB disease at the time of ART initiation and paucibacillary sputum. The current frontline test for TB is the Xpert MTB/RIF, which uses the GeneXpert platform, and is deployed primarily at centralised reference laboratories (Clouse et al., 2012; Hanrahan et al., 2015). This approach has two major limitations: 1) the instruments' far-patient placement likely undermines its potential clinical impact; 2) Xpert MTB/RIF has suboptimal sensitivity in PLHIV 3) the GeneXpert platform is primarily used only for TB testing and no other assays such as Xpert HIV-1 Viral Load (VL). Xpert MTB/RIF has been succeeded by Xpert MTB/RIF Ultra (Xpert Ultra), which promises to increase the speed and sensitivity of TB diagnosis. Although Xpert Ultra will doubtlessly improve the detection of symptomatic patients, its greatest incremental benefit will likely arise in patients with low bacillary load (e.g., unselected HIV-positive patients initiating ART). Thus, Xpert Ultra has the potential to alter how TB is diagnosed in PLHIV by detecting TB before the disease has a chance to progress and before substantial transmission has occurred. The investigators will, in addition to Xpert Ultra on sputum, also perform TB testing using the urinary lateral flow (LF) LAM test, which may detect mycobacteria in asymptomatic PLHIV patients (Lawn et al., 2011). Moreover, investigators will also perform Xpert Ultra and Fujifilm SILVAMP (FujiLAM) on urine in ART initiators. Oral sampling will be done which includes the use of Ultra on tongue swabs and oral washes, inhouse PCR testing MGIT960 liquid culture from PLHIV (ART initiators) as part of preliminary investigation will also be explored, as well the use of blood RNA signatures for TB diagnosis. These novel test investigations are exploratory, and the results will not yet be used for patient management. This study will address the following research questions: (1) What is the sensitivity and specificity for each approach, overall, and after stratification by viral load/CD4, and (2) What is the proportion of patients that could not expectorate sputum were detected by non-sputum based tests? The polyvalent utility of the GeneXpert hardware platform is, however, hitherto largely unexplored despite the widespread deployment of machines. HIV VL testing is currently done in South Africa according to the National HIV Treatment guidelines, which advise measuring HIV VL every six months for the first year of treatment and annually thereafter. HIV VL testing involves collection of a blood sample, transporting it to a centralised laboratory for VL quantification, reporting the result back to the clinic, and calling the patient back. If HIV VL is found to be over 1000 genomes per ml, the patient may not be adherent to the prescribed ART or may have drug-resistant HIV and, now that a failure of virologic suppression has been confirmed, the patient may be asked to give a second blood sample for drug susceptibility testing and may have a counselling visit scheduled, in order to improve the patient's adherence. There is, however, a large amount of discretion at local clinics as to what constitutes virologic failure and patients with increased VL may still receive these interventions, even if below the 1000 genomes per ml threshold. The investigators also intend to perform Xpert HIV-1 VL testing and, compared to patients who receive the standard-of-care of centralised VL testing, evaluate the proportion of patients without virologic suppression who are referred to a follow-up intervention (DST and/or adherence counselling). The investigators propose a study which implements Xpert Ultra (in unselected PLHIV) and Xpert HIV-1 VL (in PLHIV on ART) in Cape Town, South Africa. Furthermore, the GeneXpert platform's polyvalent feasibility, time-to-result and -treatment (Xpert Ultra and LF LAM), and effect on interventions to improve VL (Xpert HIV-1 VL) will be examined.

Official Title
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Feasibility, Accuracy, and Effect of Polyvalent Point-of-care Xpert MTB/RIF Ultra and Xpert HIV-1 Viral Load Testing in HIV-positive Patients Initiating ART: a Randomised Controlled Trial

Conditions
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HIV/AIDS, TB - Tuberculosis, Antiretroviral Therapy, Highly Active

Intervention / Treatment
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* Diagnostic Test: PLHIV Point of Care Xpert Ultra
* Diagnostic Test: PLHIV Point of Care Xpert VL


Participation Criteria
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Eligibility Criteria
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HIV-positive viral load monitoring patients Inclusion Criteria: Informed consent obtained from patient Patient is more than 18 years old Patient is HIV positive Patient is receiving follow-up ART Patient is willing to provide blood specimens for study Exclusion Criteria: Informed consent not obtained from patient Patient is less than 18 years old Patient is HIV negative or has unknown HIV status Patient is coming into clinic for first time ART Patient is not willing to provide blood specimens for study TB patients Inclusion Criteria: Informed consent obtained from patient Patient is more than 18 years old Patient is HIV positive Patient is coming into clinic for first ART visit Patient is willing to provide sputum and urine (blood is desirable, but not mandatory) specimens for study Exclusion Criteria: Informed consent not obtained from patient Patient is less than 18 years old Patient is HIV negative or has unknown HIV status Patient is not coming into clinic for first time ART Patient has been on TB treatment within the last 60 days Patient is not willing to provide sputum and urine specimens for study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: PLHIV Centralised Xpert Ultra<br>Patient sputum specimen collected at Kraaifontein Community Health Centre (KCHC) and sent for centralised Xpert Ultra TB testing at the National Health Laboratory Services (NHLS) facility in Greenpoint, Cape Town, South Africa. Centralised testing uses the established NHLS transportation, testing and report-back to clinic infrastructure according to the national algorithm. | |
| Active Comparator: PLHIV Point of Care Xpert Ultra<br>Patient sputum specimen collected at KCHC and Xpert Ultra TB testing done on site at point of care (POC). | Diagnostic Test: PLHIV Point of Care Xpert Ultra<br>* Sputum-based TB diagnostic test that takes 80 min to run. Test performed on the same day as the patient visit.<br>* Other names: GeneXpert;|
| No Intervention: PLHIV Centralised Xpert VL<br>Patient blood specimen collected at Kraaifontein Community Health Centre (KCHC) and sent for centralised viral load testing at the NHLS facility in Tygerberg Hospital, Cape Town, South Africa. Centralised testing uses the established NHLS transportation, testing and report-back to clinic infrastructure according to the national algorithm. | |
| Active Comparator: PLHIV Point of Care Xpert VL<br>Patient blood specimen collected at KCHC and Xpert HIV-1 viral load testing done on site at point of care (POC). | Diagnostic Test: PLHIV Point of Care Xpert VL<br>* Blood-based HIV-1 VL diagnostic and monitoring test that takes 60 min to run. Test performed on the same day as the patient visit.<br>* Other names: GeneXpert;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment time | Time-specific proportion of patients starting TB treatment (all patients and confirmed cases) in centralised diagnosis and treatment arm compared to POC arm (Xpert Ultra). | Up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TB diagnosis time | Time-specific proportion of patients diagnosed in centralised diagnosis and treatment arm compared to POC arm (Xpert Ultra for TB and XpertVL for VL) | Up to 8 weeks | 
| Urine LF-LAM, urine FujiLAM and urine Xpert Ultra in people investigated for TB | Diagnostic accuracy and concordance compared to a sputum culture reference standard | Up to one week | 
| Tongue swab and oral wash Xpert Ultra, tongue swab in-house PCR, and tongue swab culture in people investigated for TB | Diagnostic accuracy and concordance compared to a sputum culture reference standard and vs. the tongue swab culture | Up to one week | 
| Candidate host RNA blood signatures for active TB specified in Turner LRM et al., 2020 in people investigated for TB | Diagnostic accuracy and concordance compared to a sputum culture reference standardUU | Up to one week | 
| HIV DST or adherence counselling | Time-specific proportion of patients without virologic suppression identified to require adherence counselling and/or HIV drug susceptibility testing | Up to one week | 
| Time to referral for HIV regimen adjustment or adherence counselling in patients without virologic suppression | Time-specific proportion of patients without virologic suppression referred for adherence counselling and/or switching to a second-line ART regimen | Up to 8 weeks | 
| Initial lost to follow-up | Time-specific proportion of patients with a known TB diagnosis or increase in HIV VL that do not successfully start treatment (TB) or HIV adherence counselling, DST or regimen change (VL) | Up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Xpert Ultra, People Living with HIV (PLHIV), Xpert HIV-1 Viral Load (Xpert VL), Antiretroviral treatment (ART)