PROJECT SUMMARY
Tuberculous meningitis (TBM) causes death or neurological disability in up to 50% of those affected and is
particularly devastating in people living with HIV (PLHIV). There is an urgent need to improve therapy as current
first-line TBM treatment, including standard dose rifampin (10 mg/kg daily), results in low concentrations in the
Central Nervous System (CNS). In HARVEST, a phase III trial in Uganda, South Africa, and Indonesia, we
currently test whether high dose (35 mg/kg) rifampin will reduce mortality and disability compared to standard
dose (10 mg/kg) rifampin in people with TBM. HARVEST will answer key clinical research questions, but
important knowledge gaps are not directly addressed. There is scanty data on exposure to first-line TB drugs in
the CNS and the extent to which this is influenced by brain injury and inflammation and drug transport
mechanisms. Optimal targets for drug exposure are lacking and it is unknown whether patient subgroups, such
as PLHIV, critically ill patients or pediatric patients, require tailored doses of TB drugs. It is also unknown whether
higher doses of rifampin require a change in dose of co-administered antiretroviral drugs in PLHIV.
We propose HARVEST-PK to test our central hypothesis that plasma and CNS concentrations of TB drugs
are the key intermediary link between administered doses and disease outcome. We will measure concentrations
of TB/HIV drugs as well as inflammatory and brain injury markers in carefully timed and collected samples from
HARVEST and apply state-of-the-art modelling and simulation techniques to build a comprehensive exposure-
response model that will fill aforementioned knowledge gaps. More specifically, we will define the relationship
between administered doses and concentrations achieved (pharmacokinetics, PK), identify predictors of TB drug
exposure and CNS drug entry, and elucidate the relationship between TB drug concentrations achieved and
response (pharmacodynamics, PD). HARVEST-PK will determine critical exposure thresholds associated with
improved TBM survival and identify corresponding optimal drug doses in adult TBM patients and patient
subgroups. Finally, HARVEST-PK aims to demonstrate that high dose rifampin compared to standard dose
rifampin does not significantly compromise exposure to anti-retroviral drugs, and does not impact virological
outcomes in TBM patients living with HIV.
HARVEST-PK uniquely leverages our existing phase III TBM trial to gain key pharmacological insight in the
PK-PD of TB drugs in TBM treatment. This will result in the identification of optimal exposure targets for high
dose rifampin and other drugs in adults and children with TBM. Members of our consortium have studied TBM
in Asia and Africa for more than 15 years and we have a longstanding interest in optimization of TBM treatment
based on PK and PD principles. HARVEST-PK will enable optimal dosing recommendations based on PK and
PK-PD evaluations, which seeks to impact U.S. and international treatment guidelines.
