Background
HIV is the greatest risk factor for progression of recent or latent tuberculosis infection (LTBI) to active tuberculosis (TB) disease. The risk of developing active TB is more than 20 times greater in HIV patients as compared to immunocompetent persons [
1,
2]. Given this extremely high risk, the accurate diagnosis and subsequent treatment of LTBI among persons living with HIV (PLHIV) is regarded as an essential component of TB control strategy [
3,
4]. Yet, the best available diagnostic tools for LTBI are not fully defined.
T-cell based interferon-gamma release assays (IGRA) offer several advantages over the tuberculin skin test (TST), including better specificity (especially among those with Bacille Calmette-Guérin [BCG] vaccination), elimination of the subjectivity of TST reading, and logistic convenience [
5,
6]. However, the data comparing IGRAs and the TST in immunocompromised persons is limited and shows no clear superiority of one test over another [
7].
Following the collapse of Soviet Union, the country of Georgia experienced significant socio-economic upheavals resulting in a deterioration of public health infrastructure and resurgence of TB in the 1990s. TB incidence rates increased from 28/100,000 to 186/100,000 between 1990 and 1997 and continue to remain high at 125 TB cases per 100,000 population in 2011 [
8]. While Georgia has been able to avoid a large-scale HIV epidemic, 3,642 HIV cases have been reported since 1989. The estimated adult HIV prevalence in Georgia is 0.2%, [
9] but the number of reported HIV cases has been steadily increasing. Similar to other Eastern European countries the HIV epidemic in Georgia has been driven by injection drug use (IDU) accounting for 54% of total reported cases. HIV, substance abuse, incarceration and low socioeconomic status are well-known risk factors for TB, [
10‐
12] which may contribute to the significant impact of TB among PLHIV in Georgia. Data from the national HIV/AIDS clinical program found that 20% of registered HIV patients had received a diagnosis of TB, and that TB was responsible for 25% of all deaths among PLHIV in the country [
13].
Addressing the TB/HIV co infection has become a country health priority and a national TB/HIV strategic plan was developed in 2007. While there is well established collaborative network ensuring free access to both TB and HIV medical care in Georgia the diagnosis and treatment of LTBI among PLHIV needs to be scaled-up. The objectives of the present study were to assess the performance of two commercially available IGRAs (QuantiFERON-TB Gold in Tube [QFT-GIT] and T-SPOT.TB [TSPOT]) compared to the TST for the diagnosis of LTBI in HIV-infected patients, and to identify risk factors for LTBI in effort to improve the TB prevention and care among PLHIV in Georgia.
Discussion
We found that a high proportion of HIV-infected patients in the country of Georgia had at least one positive LTBI test result (45%) with either the TST, QFT-GIT, or TSPOT assay. The higher proportion of positive IGRA test results as compared to the TST was most pronounced among patients with CD4 counts ≤ 100 μl, suggesting the IGRAs may perform better in highly immunocompromised patients. However, the lack of a gold standard for the diagnosis of LTBI, scarcity of data regarding the long term predictive value of IGRAs, and the very poor agreement among the three tests makes it unclear which test is optimal. While it is unclear which LTBI test performed best, our study does demonstrate that LTBI is common among HIV infected patients in Georgia and is an urgent problem that needs addressing.
The diagnosis and treatment of LTBI is a key component of the WHO three I’s program for decreasing the impact of TB among HIV-infected persons [
3,
4]. Accurate identification of patients with LTBI remains challenging. In the absence of gold standard, agreement between tests serves as surrogate marker for performance. Our study showed poor agreement both between IGRAs and TST, and between the two IGRAs. Agreement was especially low between QFT-GIT and TSPOT (k = 0.18), which is similar to other reports [
21‐
23]. Some studies have reported better agreement, but never surpassing moderate levels [
24,
25]. The reason for discordance between the two IGRAs in our patient population is unclear. Additionally, we found no difference in quantitative QFT-GIT values based on TSPOT results further confirming the discordance between the two tests. Indeterminate results were more common with T.SPOT (8%) compared to QFT (1%). In our study, indeterminate results did not seem to be associated with degree of immunodeficiency as seen elsewhere [
22,
26,
27]. Given the poor concordance between diagnostic tests, our study suggests the urgent need for new and better diagnostic tests for LTBI, especially among HIV-infected persons who are at greatest risk for progression to active TB disease following infection.
The proportion of patients with positive test results among those with severe immunodeficiency (CD4 count <100 cells/μl) was higher with IGRAs as compared to the TST (26% vs. 13%, p = 0.12) but the differences were not statistically significant. The TSPOT and QFT-GIT also yielded higher proportions of positive test results that the TST among patients with CD4 count <200 cells/μl (TSPOT 29% vs. TST 16%, p = 0.01 and QFT-GIT 25% vs. TST 16%, p = 0.10). Additionally, in contrast to prior studies, reporting significantly lower proportion of positive IGRA test results in patients with CD4 count <200cell/μl, in our study both the QFT-GIT and TSPOT had similar proportions of positive test results for patients above and below a CD4 count of 200 cells/μl [
7]. Some authors have suggested, [
25,
28] that the IGRAs are more sensitive for detection infection with
M. tuberculosis in immunosuppressed patients than TST. However, absence of gold standard makes it difficult to conclude whether IGRAs outperformed TST, or if there is a higher rate of false positive results. One recent study found a high rate of positive QFT-GIT tests that reverted to negative upon repeat testing in low risk HIV-infected patients [
29]. The reversion rate was much higher in American born HIV-infected patients (80%) as compared to patients originally from high incidence TB countries (25%), such as Georgia.
Multivariate analysis of risk factors for LTBI showed heterogeneity across diagnostic tests. Positive TST was associated with co-infection with hepatitis C and being on ART (protective effect), male gender was associated with positive QFT-GIT test, and increasing age together with chronic hepatitis B infection were significantly associated with positive TSPOT result. Well known risk factors for tuberculosis, such as imprisonment and drug abuse, [
30] were associated with the outcome only in univariate analysis, but not in multivariate. Association of viral hepatitis co-infection with TST and TSPOT positivity merits further exploration.
This study has several limitations. Although our study sample size is comparable to previous reports, we had a relatively small number of HIV-infected patients with low CD4 counts. Our study was cross sectional so there was no patient follow up for the development of active tuberculosis. This prohibited us from evaluating the predictive value of IGRAs for the development of active tuberculosis among HIV-infected patients. Further studies are needed to assess the predictive value of IGRAs for active TB, especially among immunocompromised patients such as those with HIV infection [
31‐
33].
There remains uncertainty about which is the best diagnostic test for LTBI among HIV-infected persons. Despite the uncertainty, a growing number of guidelines support the use of IGRA for the diagnosis of LTBI (either in combination with TST or alone) [
34]. In addition, recent ART guidelines from the WHO Regional Office for Europe identifies IGRAs as preferred diagnostic method for LTBI screening in HIV patients WHO does not support the use of IGRAs in low and middle income countries, [
35] Given the poor concordance among the three diagnostic tests (and between the two commercially available IGRAs), our data supports the WHO recommendations regarding the use of these diagnostic tests in low and middle income countries. Recent U.S. CDC guidelines recommend use IGRAs in persons with BCG vaccination and those with low rates of returning to have TST read [
17]. The CDC and Canadian Tuberculosis Committee (CTC) guidelines also discuss the possible utility of dual testing with IGRAs and TST for LTBI among high-risk individuals [
17,
36]. The CTC specifically recommends performing an IGRA in immunocompromised individuals with a strong suspicion for LTBI if the initial TST is negative. If this strategy was used for our patient cohort an additional 44 patients and 36 patients would have been diagnosed with LTBI by the QFT-GIT and TSPOT tests respectively. Given the varying performance and agreements of LTBI tests across different settings it is likely that different strategies will be needed depending on the population. Additional factors that need to be taken into consideration included patients preferences, logistics, and test cost. The cost of a single IGRA may be up to three times as a high as the cost of a TST [
37,
38].
Conclusion
In summary, we report the first study to evaluate performance of three diagnostic tests for LTBI in HIV patients in the Eastern European region. While our study showed a high prevalence of LTBI we also found a poor concordance between all LTBI diagnostic tests (QFT-GIT, TSPOT, and TST) including between the two different commercially available IGRAs. Multivariate analysis did not identify one specific population sub-group at higher risk of LTBI. Variation in risk factors for LTBI across the tests reflects poor agreement between available diagnostic modalities. This lack of agreement makes it difficult to identify most appropriate test for LTBI diagnosis among HIV-infected patients. Without clear evidence of superiority of IGRAs, choosing test for LTBI, particularly in resource-limited settings, should account for costs and logistics. While long-term follow-up studies will help to better understand the role of IGRAs among HIV infected patients, improved modalities are needed to accurately identify HIV-infected patient at highest risk of developing active TB, who will benefit the most from LTBI treatment.
Author’s contributions
NC contributed to study design, data management, also drafted and revised the manuscript. RRK was responsible for data management and analysis, and revised the manuscript. ND and LA performed all interferon-gamma release assays and contributed to the methods section of the manuscript. LS and PG were responsible for enrollment, data collection and oversaw performance of TST. HMB contributed to concept and study design, also critically reviewed and edited the manuscript. CDR and TT contributed to the concept and study design, provided oversight of the study and edited the manuscript. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.