Screening of HIV-Infected Patients with IGRAs for LTBI Kentaro Sakashita, Akira Fujita, Shuji Hatakeyma Stay strong, Japan! Tokyo Metropolitan Tama Medical Center Department of Pulmonary Medicine Background Tuberculosis is the most prevalent opportunistic infection in HIV-infected patients in the world. It is believed that IGRAs has low sensitivity among HIV-infected patients due to their immune-suppressed status. This study aims to assess whether IGRAs can be used as a screening tool to detect LTBI in asymptomatic, HIV-infected patients in Japan.
TB Statistics in Japan in 2010 Newly notified TB patients 23,361361 cases in the whole country Rate 18.2* 3,045 cases in Tokyo Rate 23.1* Sputum smear positive pulmonary TB 9,019 cases in the whole country Rate 7.1* 1,099 cases in Tokyo Rate 8.3* *per 100,000 Moderate incidence country cases 1800 1600 1400 1200 1000 800 600 400 200 0 Newly Notified HIV Infection in Japan 1,544 new cases in 2010 400 Cumulative HIV cases 18,447 AIDS prevention Information Network in Japan, http://api-net.jfap.or.jp/status/index.html
Comparison of TB Notification Rates and HIV Prevalence in 2009 Japan Tokyo South east Asia U.S. 1 (2008) Newly notified TB* 19 25 118 4.1 HIV prevalence* 15 36 300 469 *per 100,000 Reference -AIDS prevention Information Network in Japan -WHO Global TB Control Report 2010 -UNAIDS REPORT ON THE GLOBAL AIDS EPIDEMIC 2010 1 CDC. HIV Surveillance --- United States, 1981--2008. MMWR 2011 60(21); 689-693. HIV/TB Co-infection in Japan, 2009 (Only cases reported about HIV status to public health center) Active tuberculosis Pulmonary TB 27 Sputum smear positive 15 Other bacillary positive 11 Bacillary negative 1 Extra-pulmonary TB 25 Total 52 Cumulative HIV cases in 2009 16,903 cases Estimated active TB among HIV-infected patients roughly 0.3% (307 per 100,000) Tuberculosis Annual Report 2009, Series 7. Condition of TB (2), Tuberculosis Surveillance Center, RIT, JATA
Objective To evaluate the utility of QuantiFERON -TB Gold In-Tube (QFT-GIT) as a screening tool to detect LTBI in HIVinfected patients in Japan. Subjects 44 HIV-infected patients Setting: Two HIV hub hospitals in Tokyo -Tokyo Metropolitan Tama Medical Center -Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital. 34 cases in outpatient clinic 10 cases on admission From January 2011 to November 2011 All patients are Japanese living in Tokyo. Exclusions -Active TB -Recent TB exposure -Past TB history -Past LTBI treatment
Methods We conformed to the product guideline of QFT- GIT approved by the Ministry of Health, Labor and Welfare, Japan. Whole blood (1ml) into each of three blood collection tubes: -A negative (Nil) control tube -A tube containing TB-specific test antigens (ESAT-6, CFP-10 and TB7.7) -A positive (Mitogen) control tube Incubated at 37 for 16 to 24 hours. Interferon-gamma concentration in the plasma is determined using a sensitive ELISA. Methods - Interpretation Criteria for QFT-GIT Interpretation Positive Doubtful positive* Negative TB Specific Antigen Response (IU/mL) 0.35 (and 25% of Nil) Nil Control (IU/mL) Mitogen Control (IU/mL) 0.35 8.0 any 0.1 and <0.35 0.5 < 0.35 (or < 25% of Nil) 8.0 0.5 < 0.35 8.0 < 0.5 Indeterminate (or < 25% of Nil) any > 8.0 any *Definition of doubtful positive in Japan
Basic Characteristics Total n=44 Age 47 ± 13 yrs [28-80] Age 70 yrs 4 (9.0%) Sex Male 37 (84.0%) Female 7 (16.0%) CD4 cell count 398 ± 275 /mm 3 [6-1180] CD4 cell count <200 /mm 3 7 (16.0%) Diabetes mellitus 2 (4.5%) Chronic kidney disease 0 Immune-suppressive therapy 0 Number of Patients by CD4 Cell Count (n) (n=44) 12 10 8 6 4 2 0 (/mm 3 )
Dot Plot of Individual Response to Mitogen for HIV-infected Patients (n=44) IU/ml > 10 8 6 4 2 0 0 200 400 600 800 1000 1200 CD4 cell count (/mm 3 ) Dot Plot of TB-Ag-Nil for HIV-infected Patients (n=42, excluding two indeterminate cases) IU/ml 0.6 0.56 0.5 0.4 0.35 0.3 0.2 01 0.1 0.24 0.11 0.34 04 0.4 Doubtful positive 0-0.1-0.2 CD4 cell count (/mm 3 )
Result of QFT Interpretation QFT n Positive 2 (4.5%) Negative 37 (84%) Doubtful positive* 3 (6.8%) Indeterminate 2 (4.5%) Total 44 *Definition of doubtful positive in Japan 0.1 TB-Ag-Nil<0.35 IU/mL and Mitogen-Nil>0.5 IU/mL Result of QFT Interpretation in Patients with CD4 Cell Count below 200 or over 200/mm 3 CD4 <200/mm 3 200/mm 3 Total Interpretation Positive 0 2 2 Negative 5 32 37 Doubtful positive 0 3 3 Indeterminate 2 0 2 Total 7 37 44
Profiles of QFT Positive Cases Case 1 44 yrs M Case 2 56 yrs M TB-Ag-Nil (IU/ml) 0.56 0.4 Mitogen-Nil (IU/ml) >10 >10 CD4 (/mm 3 ) 1,102 359 ART TDF/FTC +EFV AZT/3TC +LPV/RTV None Symptom Sputum smear Negative AFB culture Negative Chest X-ray No abnormality Treatment INH 300mg 9 months TDF=Tenofovir, FTC=Emtircitabine, EFV=Efavirenz, RAL=Raltegravir Profiles of QFT Doubtful Positive Cases Case 3 59 yrs M Case 4 49 yrs M Case 5 36 yrs M TB-Ag-Nil (IU/ml) 0.34 0.1 0.24 Mitogen-Nil (IU/ml) >10 >10 >10 CD4 (/mm 3 ) 624 580 216 ART Symptom Sputum smear AFB culture Chest X-ray Treatment TDF/FTC +EFV TDF/FTC +EFV None Negative Negative No abnormality Watchful observation TDF+EFV +RAL
1 Harada N. et al. J Infect 2008;56:348-353 This study is the only one published study which are inspected about the specificity of QFT-GIT in healthy population in Japan. Result of QFT-GIT Interpretation in Low Risk Adults QFT n Positive 2 (1.1%) 1%) Negative 152 (90%) Doubtful positive 8 (4.7%) Indeterminate 6 (3.5%) Total 168 We made this figure according to data of the original paper. 1 Harada N. et al. J Infect 2008;56:348-353
Summary Our study showed that the positive rate for QFT (QFT-GIT) among HIV-infected patients was 4.6%. It seems to be higher than that of the healthy population, which was shown to be 1.1% in the prior study in Japan. 1 1 Harada N. et al. J Infect 2008;56:348-353 QFT positive cases have been treated with INH. Doubtful positive cases are kept under watchful observation. Discussion
Our Situation TB incidence in Japan is still high, compared with that in other developed countries. In Japan, positive predictive value for IGRAs is expected to be reliable, especially in high risk groups including HIV-infected persons. No official recommendation for the treatment of LTBI in HIV-infected persons has been issued in Japan. QFT in HIV-infected Patients Our limited data found that QFT(QFT-GIT) might be useful to detect LTBI among asymptomatic, HIV infected patients in Tokyo. However, the usefulness was shown to be limited in low CD4 cell counts cases. 1 Fujita et al. showed that the frequency of an indeterminate QFT-G test was significantly higher in those with a CD4 cell count less than 50/mm 3. 2 1 Horsburght CR et al. N Engl J Med 2011;364:1441-8. 2 Fujita A, et al. Clin Dev Immunol.vol. 2011, pii:325295, 1-6,2010
Limitations of this Study The number of subjects was small. We only did single test in each patient We had no control group (just compared with other studies) A gold standard for determining TB infection is lacking QFT-positive result might be false-positive depending on the TB prevalence or the degree of TB risks. Further Investigation The adjustment of the cut off value in HIV- infected patients with a low CD4 cell count might be needed. Indication of LTBI treatment for doubtful positive cases with HIV-infection could be considered. We are likely to consider the timing of retest of IGRAs in indeterminate cases after immune-status recovery.
Conclusion In countries with moderate tuberculosis incidence, screening of HIV-infected patients with IGRAs(QFT-GIT) for LTBI may be beneficial. i Acknowledgment Atsushi Ajisawa, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital