Evaluating the Accuracy of New Tests for TB Infection Diagnosis

Latent TB infection, hereafter referred to as TB infection, continues to be a significant driver of the global TB burden. A recent re-estimation using mathematical modeling demonstrated that to end TB by 2050, at least one-quarter of the global population living with TB infection would require TB preventive therapy (TPT).

The Tuberculin Skin Test (TST) and Interferon-Gamma Release Assays (IGRA) are the two preferred diagnostic methods for detecting TB infection. TST utilizes Tuberculin PPD RT 23 intradermally, which is low-cost and can easily be performed in the field. TST is currently the most frequently used TB infection test in Vietnam. However, TST has a low sensitivity and specificity, particularly in people who have had the BCG vaccine or are immunocompromised. IGRAs are more costly and more technically complex, requiring blood to be processed within a limited time-frame in a laboratory. Neither method is ideal for the detection of TB infection during community TB screening and contact investigations. Therefore, there is a need for a simple, affordable, and accurate diagnostic test for TB infection, to scale up TPT in Vietnam and globally.

Cy-TB (Serum Institute of India Pvt. Ltd, Pune, India) is a Mycobacterium Tuberculosis (MTB) antigen-based skin test, representing a new class of skin tests that were recommended by the World Health Organization in 2022. Cy-TB's MTB-specific antigens (ESAT6 and CFP10) are injected intradermally and provide results after 48-72 hours, similar to TST. The literature indicates that Cy-TB has a similar sensitivity and specificity to QuantiFERON TB Gold Plus.

Simplified versions of IGRAs are emerging, including TB-Feron (SD BIOSENSOR, INC, Gyeonggi-do, Republic of Korea). TB-Feron testing requires less manual handling than other IGRAs and testing takes only 15 minutes to complete after the specimen has been incubated for 16-24 hours. A recent clinical trial comparing the sensitivity and specificity of the TB-Feron against QIAreach QuantiFERON-TB (QIAGEN, Venlo, The Netherlands) showed that the TB-Feron has high accuracy in TB infection diagnosis (the sensitivity was 88.89% and specificity was 92.5%). There are currently no published evaluations comparing the performance of Cy-TB and TB-Feron to QFT-Plus in the literature.

Therefore, this study aims to evaluate the sensitivity and specificity of the Cy-TB and TB-Feron testing for the diagnosis of TB infection.

Aims

• Main objective To evaluate the accuracy of the Cy-TB and TB-Feron tests versus the QFT-Plus assay as TB infection diagnostic methods in Vietnam, a high TB burden setting.
• Specific objectives Objective 1: To verify the sensitivity of the Cy-TB and TB-Feron tests for TB infection diagnosis among adults with microbiologically confirmed pulmonary TB using QFT-Plus as the reference standard.

Objective 2: To evaluate the specificity and sensitivity of the Cy-TB test and TB-Feron tests compared to the QFT-Plus assay for the diagnosis of TB infections.

Inclusion criteria

• All participants:

• Agree to remain in contact and provide updated information as necessary, and have no current plans to relocate outside the designated area for the duration of the study
• Capable of providing signed informed consent and informed assent (as appropriate)
• Group 1:

+ Microbiologically-confirmed pulmonary TB (either drug-susceptible TB or drug-resistant TB) via Xpert MTB/RIF or Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, California) and abnormal chest X-ray (CXR) result*

*To reduce the false positive rate of molecular diagnostic assays for M. tuberculosis

• Group 2:

+ Household contacts without symptoms of active TB disease of people with microbiologically-confirmed, pulmonary TB who initiated treatment with residents in Ha Noi, Vietnam.

• Group 3:

• Known past negative IGRA test results among those at low risk for TB infection
• No known and/or reported history of contact or exposure to either TB disease or M. tuberculosis bacteria.

Exclusion criteria

• All participants:

+ Declines to provide informed consent to participate in the study

• Groups 2 &3:

• Presumed TB disease with symptoms (cough, fever, night sweats, unintentional weight loss) and/or an abnormal CXR result suggestive of TB disease
• Microbiologically - or clinically-confirmed TB disease in all forms or report having taken treatment for TB disease.
• History of TB infection (self-record or documented).