TB and HIV are immuno-pathologically interacting ep
idemic infectious diseases affecting the lives of millions
globally & sub-Saharan African region accounts the
highest burden of both diseases. Although effectiv
e therapies
are available for the management of each, TB-HIV co
-treatment has faced challenges mainly due to drug-
drug
interactions & overlapping drug toxicities. To over
come these, efavirenz (EFV) based highly active ant
iretroviral
therapy (HAART) is the preferred regimen while rifa
mpicin (RIF) based anti-TB treatment regimen is a c
hoice to
treat TB-HIV co-infection in resource-limited setti
ngs. RIF is a known enzyme & drug transporter induc
er and/or
inhibitor. The dose of EFV to be used in the presen
ce of RIF is, however, controversial. This thesis i
s primarily
carried out to investigate the pharmacogenetic and
pharmacokinetic aspect of drug-drug interaction bet
ween RIF &
EFV aiming to optimize the dose of EFV to be used i
n TB-HIV co-infected Ethiopian patients.
This study was designed to be carried out in two su
b-Saharan African countries (Ethiopia and Tanzania)
, owning to
the heterogeneity of the region genetically and cul
turally. This thesis focuses on the Ethiopian popul
ation. The thesis
was conducted by prospectively recruiting cohort of
HIV infected individuals without TB (Arm 1; N = 28
5) in
parallel to another cohort of HIV co-infected with
active TB (Arm 2; N = 196). All study participants
were adults
with baseline CD
4
count less than 200 cells per mm
3
and were followed for a year. At baseline and foll
ow up periods,
clinical chemistry (liver and kidney function tests
), hematological parameters (complete and different
ial blood cell
counts) and HAART outcome monitoring (CD
4
counts and HIV RNA viral load) were done. In addit
ion, genotyping
for
CYP2B6*6, CYP3A5 (*3, *6, *7), UGT2B7*2, NAT2, ABCB
1 (3435 C > T & 3842 A > G) & SLCO1B1 (*1b &
*5)
were also done. Pharmacokinetic variables such as
plasma/intracellular concentrations of EFV, 8-hydro
xy-
efavirenz (major metabolite) & metabolic ratio were
determined at weeks 4 and/or 16, 16±1h post-dose.
Besides,
cholesterol, 4
ß
-hydroxy-cholesterol (biomarker for
CYP3A
activity) & metabolic ratio at weeks 0, 4, 16 & 48
were
also determined to investigate time-dependent effec
t of EFV on
CYP3A
enzyme. Socio-demographic factors (Age,
sex, baseline body weight and BMI) were also record
ed.
This thesis reports paradoxical increase in plasma/
intracellular EFV concentrations by RIF co-therapy;
coherent to
this is improved immunological outcomes among indiv
iduals co-treated for TB and HIV with comparable vi
rologic
success to HAART than those without RIF co-treatmen
t. The thesis also shows wide between-subject varia
bility in
the long-term auto-induction by EFV based on
CYP2B6
genotype. Between & within-subject variability in
plasma
EFV concentration and immunological outcome are sho
wn to be influenced by RIF co-therapy,
CYP2B6
genotype
and baseline body weight. Besides, the thesis demon
strates the influence of
CYP2B6
genotype on CYP3A auto-
induction by EFV in a gene-dose dependent manner,
CYP2B6 (*6/*6 > *1/*6 > *1/*1)
. Furthermore, the thesis
reveals the importance of differences in ethnicity
& environmental factors contributing to wide betwee
n-population
variability in EFV auto-induction comparing Ethiopi
an & Tanzanian patients. In addition, associations
of
CYP2B6,
ABCB1 (3842A >G),
slow
NAT2
metabolizing genotypes & plasma concentration of E
FV with increased incidences
of drug-induced liver injury (DILI) and correlation
of plasma and intracellular concentrations of EFV
are reported in
the thesis. The thesis also shows the long-term but
not short-term effects of sex and
UGT2B7
genotype in predicting
auto-induction as well as plasma concentration of E
FV.
In conclusion, EFV dose-escalation from 600mg to 80
0mg is not required during TB-HIV co-treatment in E
thiopian
patients.
CYP2B6*6
genotype is not only a strong predictor for EFV ph
armacokinetics but also could predict EFV-
based HAART outcomes, DILI &
CYP3A
auto-induction by EFV. In addition to pharmacogene
tic variability, the
importance of differences in ethnicity & environmen
tal factors are highlighted to optimize HIV treatme
nt across sub-
Saharan Africa.