The Dynamics of HIV RNA, CD4+ Count and Mycobacterium tuberculosis (Mtb) Antigen Specific Cytokines in TB/HIV Patients Following Successful Tuberculosis.

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The Dynamics of HIV RNA, CD4+ Count and Mycobacterium tuberculosis (Mtb) Antigen Specific Cytokines in TB/HIV Patients Following Successful Tuberculosis (TB) Treatment Desta Kassa (MSc, PhD student) Ethiopian Health and Nutrition Research Institute (EHNRI) ICASA December 4-8, 2011 Addis Ababa

Infection with M tuberculosis (Mtb): Th1/Th2 dichotomy determines clinical outcome (Schkuger NW and Rom WN, 1998) Th1 (IL-2, IFN-g) : activate macrophage for mycobacterium killing Th2 (IL-10 ): enhance bacilli survival and replication Th17 (IL-17): plays protective role (Khader SA, Cooper AM, 2008) Findings are not always consistent (Lin, Y et al, 1996; Cozemic , et al, 2007) Immunity against TB is not fully understood Areas of investigation: Mtb specific Th1/Th2/Th17 cytokines during TB disease and infection Effect of HIV co-infection on the modulation of these cytokines Effect of anti-TB treatment on the modulation of these cytokines

Effect of TB during HIV infection (Wallis R S. and ElIner JJ, 1994) Questions: Does early initiation of TB treatment (deferring HAART) able to: Suppress viral replication Restore CD4+ count Restore immune function specific to TB: Th1 (IFN-γ, IL-2), Th2 (IL-10), Th-17 (IL-17) Previous studies: Viremia suppressed (Goletti et al , 1996), Viremia not suppressed (Lawn SD et al, 1999); Persistent immune activation (Wolday et al, (2003) . Increase immune activation/cytokines (TNF….) . Increase HIV RNA level . Increase depletion of CD4+ . Increase immune dysfunction specific to TB . ……. results in TB infectivity, morbidity, mortality

Objectives To assess the pattern of Th1 (IL-2, IFNg) Th2 (IL-10) and inflammatory ( IL-17) cytokines during TB disease and infection To assess the effect of HIV co-infection and TB treatment on the modulation of these cytokines To assess the effect TB treatment on the polarization of Th1/Th2/Th17 cytokines To investigate whether TB treatment (with no HAART) in TB/HIV patients : Suppress viral replication Restore CD4+ cell counts Restores immune responses specific to Mtb (FN, IL-2, IL-10, IL-17)

Methods Study design: Prospective cohort study Study sites: St petrer Specialized TB Hospital Akaki and kality Health centers Study groups Adults (15-60 years) ,of both sexes Naive for anti-TB and ART HIV positive TB cases (HIV+TB+) HIV negative TB cases (HIV-TB+) Latent TB groups (HIV-TST+) Controls (HIV-TST-) Follow-up visit . TB patients followed at 6th and 18th months Sample collection: 10 ml whole blood

Methods … cont Laboratory tests: Plasma HIV RNA level (PVL) (copies/ml): NucliSens EasyQ CD4+ count (cells/l): FACSCalibur (Becton Dickinson) Immune responses specific to Mtb (FN, IL-2, IL-10, IL-17) Whole blood (baseline, 6 and 18 months) Stimulated with Mtb specific antigen (ESAT-6/CFP-10) Supernatant collected at 7th day (store -80) Cytokines measured using Luminex assay

Results

Baseline characteristics Mean Age (Yrs) Female (%) CD4+ (cells/ul) BMI (kg/m2) Hgb (g/dl) PVL (log 10 copies/ml) HIV+TB+ (n=30) 34.4 43.3 232.3 18.8 12.4 5.2 HIV-TB+ (n=61) 28.5 31.9 472.7 18.9 13.5 HIV-TST+ (22) 26.6 62.5 787.3 21.4 16.3 Controls (n=23) 24.6 64.0 754.8 17.9 . Does the depletion in CD4+ count at periphery associated with immune dysfunction specific to TB ? .

The Th1/Th2/Th17 cytokine profile during TB disease and infection Modulation with HIV co-infection?

The effect of TB treatment in: HIV-TB+ HIV+TB+ Immunologic (CD4+ count) recovery viral suppression (PVL) Mtb specific immune reconstitution

1) Immunologic (CD4+ count) recovery 2) Plasma viral suppression HIV+TB+ (n=12) M0 M6 M0-M6 P value PVL (copies/ml) 166366.8 398750.1 + 232383.3 0.37 (lo10copies/ml) 5.2 5.6 +0.4

3) Reconstitution of Mtb specific immune response after six month of TB treatment

Correlation of CD4+ count recovery and immune reconstitution specific to TB (HIV-TB+)

Conclusions At baseline We found an Increase in IFNg and IL-17 in Latent TB but decrease in TB patients Decrease in IL-10 during TB disease HIV coinfection alters the cytokine profile After six month of TB treatment: In TB/HIV patients , there was no significant: Reduction in HIV viral replication, increase in CD4+ count recovery, and improve in immune responses (Th1, Th17) In HIV negative TB patients CD4+ count were normalized immune function was restored Polarizes to Th1 arm IFNg restoration was correlated with CD4+ count recovery

Conclusion/recommendation …cont Our results showed : Combination of IFNg and IL-17 might strengthen immunodiagnosis of LTBI relative to TST and IGRAs Support the notion of early initiation of HAART in TB/HIV patients which might preserve the number and function of immune cells.

List of collaborators Yodit Alemayehu Gebremedhin Gebremichael Amelewerk Alemu Leonie Ran Wudneh Gebremeskel Mekashaw Tebeje Dr Belete Tegbaru Dr Dawit Wolday Dr Tsehaynesh Messele Dr Debbie van Baarle

Acknowledgements Study participants EHNR

Thank you