Stages of pregnancy and HIV affect diagnosis of tuberculosis infection and Mycobacterium tuberculosis (MTB)-induced immune response: Findings from PRACHITi, a cohort study in Pune, India

Abstract

Background: Accurate tuberculosis infection (TBI) tests are critical for pregnant women, especially those with HIV, who have a high risk of TB disease.

Methods: We enrolled interferon gamma release assay (IGRA)+ pregnant women with and without HIV in a longitudinal study, followed up at delivery and 6 months postpartum. Tuberculin skin test (TST) and IGRA were compared by HIV status at each timepoint.

Results: Of 165 enrolled IGRA+ pregnant women: 35 (21%) had HIV and were on antiretroviral therapy with median CD4 of 476 (IQR 399-586). Compared to antepartum, significantly fewer women remained IGRA+ at delivery [HIV+ n=21/35 (62%, p=0.009); HIV- n=100/130 (77%, p=0.002)] and postpartum [HIV+ n=30/35 (87%, p=0.03); HIV- n=116/130 (89%, p=0.01)]. IGRA/TST discordance was high in pregnant women (HIV+: 51%; HIV-: 25%). Median IFN-γ was lowest for all women at delivery; significantly lower in women with HIV at all timepoints compared to women without HIV. TB incidence was 50/ 1000 person-years and 18/1000 person-years among women with and without HIV respectively.

Conclusions: Pregnancy affects TBI test results and reduces IFN-γ response to M. tuberculosis stimulation. Despite adequate CD4 counts, women with HIV express less IFN-γ than women without HIV, which may explain the high TB incidence in postpartum women with HIV.

Keywords: Interferon Gamma (IFN-γ); Interferon Gamma Release Assay (IGRA); Tubercular Infection (TBI); Tuberculin Skin Test (TST); pregnancy, Human Immune Deficiency Virus (HIV).

Figure 1.. PRegnancy Associated CHanges in Tuberculosis Immunology (PRACHITI) subanalysis of IGRA+ subjects study design.

Individuals who were symptom screen and TBI negative [IGRA negative, n=69 (HIV+ n=44; HIV− n=25)] were not included in the present analysis to understand the impact of HIV and pregnancy stage on quantitative and qualitative changes in IGRA results. a 121 subjects expected for third trimester follow-up. b Assessments made at six months postpartum.

Figure 2.. Performance of IGRA and TST is inconsistent during peripartum.

Qualitative performance of an interferon gamma release assay (IGRA) and tuberculin skin test (TST) at each pregnancy stage in a longitudinal cohort of initially IGRA+ pregnant women with and without HIV in Pune, India (n=165)., IGRA performance declined at delivery, characterized by lowest IGRA positivity (proportion ≥0.35IU/mL) and highest rate of indeterminant results (nil >8.0IU/mL or mitogen <0.50IU/mL); IGRA positivity did not differ significantly according to HIV status, although women without HIV tended to remain IGRA+ at delivery (p=0.07. IGRA+/TST+ concordance was particularly low among women living with HIV compared to those without HIV (p=0.003); TST positivity improved at delivery and 6 months postpartum with no significant differences by HIV status.

Figure 3.. IFN-γ response decreased from pregnancy to delivery and increased from delivery to 6 months postpartum regardless of HIV status.

Quantitative IFN-γ response (median IFN-γ concentration measured in TB antigen 1 tube using the QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold plus assay) to Mycobacterium tuberculosis antigen stimulation at each pregnancy stage in a longitudinal cohort of initially IGRA+ pregnant women with and without HIV in Pune, India. Response decreased from pregnancy to delivery (p<0.01) and increased from delivery to 6 months postpartum (p<0.01), regardless of HIV status. Women living with HIV had a lower IFN-γ response than women without HIV at all timepoints; the difference was significant during pregnancy and delivery, as indicated by the asterisk (p<0.01). Error bar represents 95% confidence interval.