Antiretroviral Treatment in the
Context of TB/HIV Co-infection
Major Aspects of Background Document 2
Marco Vitoria
HIV/AIDS Department
WHO Geneva
Feb 2005
ART for HIV+ with TB
• Possible Strategies currently recommended:
– Delay ART (and treat TB with RMP based
regimens)
– Use any ART regimen + anti-TB regimens
without RMP
– Use a RMP-compatible ART regimen
• 2 NRTI + NNRTI (EFV or NVP) -1st line
• 2 NRTI + PI/r (SQV/r or LPV/r + RTV) -2nd line
• 3 NRTI ( with ABC) – Alternative 1st line
Important Concepts to be consider
in TB/HIV treatemnt
• Rifampin and CYP 450 (3A4, 2B6, 3A5)
• CYP and Host Genetics("Farmacogenomics")
• ART pK and Safety (hepatic) in patients with
TB/HIV co-infection under dual treatment
(ART & RMP)
Objectives
• Review of the Literature (Pub Med)
• Overview of concomitant use of NNRTI and PI with
antituberculous drugs (emphasis in safety and efficacy of
NNRTI and PI when used concomitantly with RMP)
• What we need to know ?
• List of major ongoing & planned studies on ART in
TB/HIV patients
• What to do in the meantime?
Major Questions
• Nevirapine versus Efavirenz
– Efficacy in TB/HIV
• Nevirapine and Rifampin
– Resistance & Efficacy (pK interactions)
– Toxicity Risk
• Efavirenz and Rifampin
– Safest Dose (efficacy vs adverse effects)
• PI and Rifampin
– Efficacy and safety (hepatic)
NVP vs EFV: What is the better
drug in HIV Treatment ?
Current WHO Guidelines
• NVP: 1st line regimens in RPS, available as FDC
(adherence, cost, operational aspects). Good
tolerance, favourable lipid profile (reducing
coronary risk). Led in dose. Hepatotoxicity and
Rash.
• EFV: 1st line regimen - Preferential drug in
TB/HIV, contraindicated in pregnancy and
psychiatric disorders. Once daily drug . CNS
symptoms, hypercolesterolemia and
ginecomastia.
NVP vs EFV: What is the better
drug in HIV Treatment ?
• Metanalysis: Equivalent virologic
suppression and short term efficacy at 24
and 48 weeks
• One non controlled study showed limited
virologic and immunologic advantage of
EFV in the first 12 months, but no relevant
efficacy difference throughout 18 months
comparison
NVP vs EFV: What is the better
drug in HIV Treatment ?
• Pharmacokinetics: NVP and EFV partially
metabolized by CYP 3A4 and CYP 2B6
and mild inducers of this enzyme system
• RMP pK don't change significantly.
• Small pK studies show large interpatient
variability
NVP vs EFV: What is the better
drug in HIV Treatment ?
• Different side effect profile:
– Hypersensitivity syndrome & skin rash
• NVP (7%) versus EFV (4%)
– Hepatitis
• NVP (2%) versus EFV (0,3%)
– CNS Symptoms
• EFV (40-50% in the first weeks of treatment. Suicidal attempting
1-3%)
• Clinical Practice: Drugs are equivalent options:
choice should be based on safety profile and
specific contraindications
NVP and RMP: Concerns about
Resistance, Efficacy and Toxicity
• Drug Interaction and NVP Resistance/Faliure:
– NVP: High Therapeutic Index
– Reduction of NVP serum levels (31-58%) but generally
above the viral inhibitory concentration
– Good immunological and virological response in small
studies (non controlled)
– No dose adjustment recommended by majority of
experts
– Large intervariability independently of RMP
concomitant use (further investigation required)
Rifampin – NVP case serie from
HIVNAT pK Lab (n=60)
Nevirapine + Rifampicin
16
NVP conc.
14
12
10
8
6
4
2
0
0
3
6
9
12
15
Time (h)
85% of NVP levels in therapeutic range
David Burger; 2005 BKK Symp HIV Med, data provided by Saskia Autar
NVP and RMP: Concerns about Resistance,
Efficacy and Toxicity
General NVP Toxicity Profile
• Concern about RMP-NVP use (lack of solid data about concomitant use)
• Mechanisms: Direct and immune mediated hepatic & skin involvement
– Stratified & comparative risk of any hepatic reaction with NVP use in HIV+
patients (studies without TB):
• NVP versus other ARV (10x)
• NVP in with CD4 > 400/mm3 (3x)
• NVP in  with CD4 > 250/mm3 (12x)
– Presence of liver disease
•
•
•
•
•
HBV and HCV co-infection
Histological stage and fibrosis
pK of NNRTI not significantly modified
NVP accelerating hepatic fibrosis ?
No data on additive risk of hepatotoxicity of TB drugs in HIV-HBV or HIV-HCV coinfection
– Elevated plasma levels (hepatic disease or slower clearance- CYP2B6)
– NVP plasma levels > 6 mg/l (92% of liver toxicity)
– NVP levels > 5.3 mg/l in 1st 90 days (2.5 x for rash)
– However other studies (observational cohorts) didn't find any correlation
NVP and RMP: Concerns about Resistance,
Efficacy and Toxicity
NVP Toxicity Profile (cont'd)
• Increase in liver enzymes are common but generally
asymptomatic and in low/moderate grade (small and non
controlled studies).
• Analysis of Clinical Trials with NVP (17 studies)
– 10% of NVP treated patients with elevated ALT (> 5x), but more
than 2/3 asymptomatic (almost half of symptomatic with
concomitant rash).
• Analysis of Observational Studies: NVP use not associated
with significant increase in the risk of severe clinical
hepatic events when compared with other ARV drugs.
• Small non controlled studies shown increase in ALT and
clinical hepatitis when NVP used with RMP
• WHO recommendation: NVP and RMP should be use with
caution only no alternative available and with close
monitoring
EFV dose in TB/HIV co-infection
treated with RMP (600 versus 800 mg)
•
•
Similar pK phenomena observed with NVP and RMP interaction (reduction in
EFV levels:13-33%).
Safety profile:
– Apparently is dose related
– CNS adverse effects are frequent in the beginning of treatment (50%) but
transitory (5-10% after 3 months).
– Neuropsychiatry symptoms after 3 months in 25% of patients.
– Sleep abnormalities associated with higher plasma levels (>4 mg/l).
•
•
Small non controlled studies shown effective, pharmacological, clinical,
immunological and virologic response with conventional 600 mg EFV dose
pK studies accordingly body weight: EFV plasma concentration patients
using RMP:
–
Patients with less than 50-60 Kg: similar to patients without TB (600 mg is
adequate)
– More than 50-60 kg : need better evaluation (small study shown EFV
concentrations 50% lower)
•
•
Large interpatient variability in small pK studies
Clearance of EFV was higher in Caucasians than in Afro-Americans and
Hispanics (impact on safety profile)
EFV and Rifampin: TDM and Efficacy Study
Plasma EFV (C12) levels of EFV 600 vs. 800 mg group
mg/L
25
TDM at Week 2 after treatment
EFV 800
20
n = 40
15
10
EFV 600
92% of patients with
therapeutic levels
n = 38
8% < 1mg/L
5
Appropriate EFV level 1-4
3.02
0% < 1mg/L
3.39
0
Weerawat Manosuthi et al. Bangkok AIDS Conf .2004
(TDM done at HIVNAT; study Supported by HSRI, Thailand); D. Burger, 2005 BKK Symp HIV Med
Protease Inhibitors and Rifampin:
Safety and Clinical Efficacy
• Impact of RMP on PI levels: 80-90% reduction
• "Pharmacoenhancement" with low dose RTV can overcome RMP
induction effect of some PIs:
– SQV/r (1000/100 BID, 400/400 BID, 1600/200 MID)
– LPV/r + RTV (400/100 + 300 BID)
•
•
Pharmacological booster increase the side effect risk and can compromise
adherence
- Major side effect associated with boosted PIs: Hepatotoxicity
– HBV & HCV co-infection associated with higher risk of elevation of liver
enzymes (higher rates of grade 3 / 4 ALT elevations)
– Comparative studies: No difference in ARV discontinuation, other hepatic events
or death when compared without HBV & HCV co-infection
– pK of PIs can be altered by hepatic disease but no change in doses are
recommended for SQV/r and LPV/RTV (limited data)
– Large majority of patients treated without side effects (low dose RTV didn't affect
hepatic safety profile of PI based therapy)
Protease Inhibitors and Rifampin:
Safety and Clinical Efficacy
• Retrospective and comparative study in patients using
RMP - 3 NRTI, 2NRTI/NNRTI and 2NRTI/SQVr: well
tolerated and safe but data is limited
• TB/HIV using RMP and SQV/r:
– SQV/r 1600/200 (SQV AUC reduced by50% but still
under therapeutic concentrations and clincial efficacy
mantained)
– SQV/r 1000/100 in HIV+: clinical efficacy and safety ,
but small Phase I study in HIV negative patients
shown high rate of clinical hepatitis (AE less
pronounced in HIV+?)
– SQV/r 400/400, and LPV/RTV 400/400 – Apparently
effective and safe but even more limited data
Conclusion: More studies are
needed…
•
•
•
•
Few published data (safety profile)
Limited number of patients
No controlled studies
Mixed and conflicting results
What We Need to Know?
• ART & RMP: Studies on safety, efficacy,
pK evaluation and pharmacovigilance
(better define ART strategy in TB/HIV)
• Review the role of Triple Nukes in TB/HIV
co-infection (DART Trial)
• Ongoing and planned studies on ART for
HIV-infected TB patients (see database)
What to Do in the Mean Time?
• Need more clear recommendations and best
informed practice in ART management of TB/HIV
• Better inform HCW about potential risks and
benefits of ART & RMP and mixed/conflicting
results in scientific literature
• EFV - Preferential drug (no dose adjustment for
patients with less 50-60 kg)
• PI/r & NVP in patients using RMP– Use with
caution
• Establish the potential role of some triple nukes
regimens in TB/HIV treatment