Gene Expression in HIV and Tuberculosis Co-infection

Tuberculosis (TB) remains one of the deadliest infections throughout the world, particularly
in the setting of HIV infection. In China, TB is a frequently diagnosed complication of HIV
infection. The immunopathogenesis of TB remains unclear, and although it is known that HIV
infection increases the risk of developing active TB, either through infection or
reactivation of latent disease, how it does so has yet to be determined. It is also known
that patients co-infected with HIV and TB and na(SqrRoot) ve to antiretroviral therapy (ART)
have a particularly high risk of developing Immune Reconstitution Inflammatory Syndrome
(IRIS) after ART therapy is initiated, but the immunopathogenesis of this reaction is also
unclear.

The use of genomics has significantly improved the understanding of disease pathogenesis and
is increasingly being used to predict responses to therapy as well. Recently, blood
transcriptional signatures capable of distinguishing active and latent TB infection have been
identified using highly parallelized analytical platforms capable of simultaneous survey of
transcription of known genes. These signatures have hinted at a complex role for type I
interferons in the development of active TB infection, but this has not yet been studied in
people with HIV and TB co-infection. Further in depth studies are needed to characterize the
spectrum of responses to TB/HIV co-infection, and how these responses correlate with clinical
data.

We propose a cross-sectional cohort study, to be conducted in both the US and in China, to
identify blood mRNA expression profiles distinguishing TB mono-infected and TB/HIV
co-infected ART-na(SqrRoot) ve patients from treated patients with and without TB-IRIS.
Secondary objectives will include correlating gene expression levels with clinical outcomes
and soluble biomarkers. The study will comprise a test set (in China) of up to 140 patients
divided among the different cohorts and a validation set (in the US) of up to 125 patients
divided among the three groups Participation will involve a single study visit to consist of
small volume phlebotomy (approximately 25 mL for safety labs, transcriptome analysis,
lymphocyte counts, and serum and plasma storage) a urine sample and information gleaned from
the clinical record entered into a coded Case Report Form (CRF). The U.S. cohort will have an
additional 40 mLs of blood collected for mononuclear cells (total of approximately 65mLs).The
study will exclude women who are pregnant or breast-feeding (which can be associated with
immune compromise and changes in markers associated with inflammation), and persons with
anemia (who may be unable to tolerate phlebotomy solely for research purposes).

- INCLUSION CRITERIA:

For all patients:

- Adults, age 18 or older

- TB diagnosis, ascertained as follows:

1. specimen or biopsy smear, culture, or PCR positivity or

2. compatible clinical presentation and imaging with strong suspicion for TB that
necessitates initiation of empiric TB therapy (in which case the confirmation by
culture or other laboratory means may follow enrollment, or alternatively
clinical improvement in response to TB therapy may confirm the diagnosis).

If the TB diagnosis cannot be confirmed as above (i.e. culture positive for NTM), the
patient will be excluded from final analysis.

- Ability and willingness of subject or legal guardian/representative to understand
study requirements and give informed consent. In the event an adult subject is unable,
due to illness or mental incapacity, to give informed consent, a person authorized
with durable power of attorney (DPA) or legal guardian may give consent for the
subject s blood to be obtained, shipped, and tested under this protocol.

- Agree to storage of study data and biologic specimens for use in future studies of
immune function, tuberculosis, genetics, and/or HIV pathogenesis.

Patients in TB mono-infected arm (Group A) would additionally be eligible if:

- HIV negative (documented seronegative within 1 month of study visit)

- Not receiving TB therapy for more than 7 days prior to study visit (Group A1) or

- Currently on TB therapy for >7 days and < 5 months (Group A2)

Patients in TB/HIV co-infected arm (Group B) would additionally be eligible if:

- HIV positive (outside HIV testing will be accepted)

- Not receiving TB therapy for more than 7 days prior to study visit

- Untreated or ART na(SqrRoot) ve (will be accepted if they had been on ART in the past
but none within the last 6 months).

Patients in TB/HIV co-infected, treated arm (Group C) would additionally be eligible if:

- HIV positive

- Currently receiving TB therapy

- Currently receiving ART (The subset of patients without TB-IRIS will have been on
antiretroviral therapy for at least 8 and not more than 12 weeks. The subset of
patients with TB-IRIS will be enrolled at the time of their TB-IRIS event) with some
evidence of adherence (often measured by clinical improvement, medication refills or
laboratory values)

- The TB-IRIS subset of patients (15 patients at NIAID and 20 patients at SHAPHC) would
also need to meet criteria for paradoxical TB-IRIS

EXCLUSION CRITERIA:

Pregnancy or post-partum period (6 months post-partum or while breast-feeding, whichever is
longer).

Documented history of hemoglobin from most recent blood draw less than 7g/dL.