Transcript OIs/TB - UK-CAB

TB and HIV
Dr A.L. Pozniak
Chelsea and Westminster Hospital
London, UK
Chemopreventative therapy
Treatment and side effects
What with… when…
IRIS
MDRTB
TB and HIV
• Chemopreventative therapy
• Is it useful in HIV ?
INH for TB/HIV
Tuberculin skin test positive patients
Tuberculin skin Favours isoniazid
test positive
patients
Favours control
All Studies
0.05
.1
.2 .3 .4 .5
1
2
Risk ratio & 95% CI
3 4 5
10
20
Isoniazid (INH) for TB/HIV
Tuberculin skin test negative patients
Tuberculin skin
test negative
Favours isoniazid
Risk ratio & 95% CI Favours control
patients
All Studies
0.05
.1
.2
.3 .4 .5
1
2
3 4 5
10
Effect of INH on TB incidence in HIV+
% reduction in TB incidence, INH vs. placebo
all
90
70
50
*
*
TST+ TST- / anergic
*
*
*
*
*
60%
42%
*
30
10
-10 Uganda Zambia Kenya Zambia
-30
US
Mexico
Haiti
pooled
*P<0.05
Bucher, AIDS
1999;13:501
Efficacy of other TBPT regimes in HIV+
Country,
reference
Regime,
population
Incidence of
TB
RR
(95% CI)
US, Mexico,
Haiti, Brazil
2RZ vs. 12H
N=1583, TST+
0.8 vs. 1.1
per 100 pyrs
0.72
(0.4-1.31)
2RZ2 vs. 6H2
N=750, TST+
5.4% vs. 5.1%
at 3yrs
1.1
3HR vs. 6H
3RHZ vs. 6H
N=1554, TST+
na
0.72 (0.42-1.25)
0.60 (0.32-1.12)
JAMA 2000;283:1445
Haiti
Lancet 1998;351:786
Uganda
AIDS 2001;15:2137
NB RX deaths in HIV neg with2RZ3
Proportion of Individuals Dropping
Out of Preventative Therapy (PT) in
Feasibility Studies
HIV+
Those
HIV
persons
entering the
seroprevalence entering the process who
in study
PT process
started PT Adherence
Year Country population (%)
(%)
(%)
(%)
1995
1995
1995
1997
1998
1999
Uganda
Rwanda
Zambia
Thailand
Uganda
Brazil
23
53
47
100
100
100
15
95
34
100
51
100
30
12
38
89
38
75
62
69
70
61
Who should receive TB preventive therapy?
• effect of TBPT only demonstrated in TST+
• Proportion HIV patients TST+ small
• TST difficult to perform
–
–
–
–
requires return after 48hrs
requires skilled staff
lack of tuberculin
risk of transmission of blood-borne pathogens
• ? not required if high prevalence of latent TB
(prisoners, miners, household contacts etc)
Secondary preventive therapy
Post treatment prophylaxis
• In industrialised countries, risk of relapse
and reinfection after TB treatment low,
hence “secondary PT” not required
• in regions with high TB prevalence, risk of
reinfection may be significant
Contribution of reinfection to recurrent TB in
gold miners in South Africa
Incidence of recurrent TB
20
all
HIV-pos HIV-neg
15
10
5
0
all recurrence
relapse
reinfection
Sonnenburg et al, Lancet 2001;358:1687 & Lancet
2002;359:1619-1620
Efficacy of secondary TB preventive
therapy
Country,
reference
Population
Incidence of
recurrent TB
(PT vs. placebo)
DR Congo
NEJM 1995;332:779
Côte d’Ivoire
Chemotherapy
1999;45:452
Haiti
Lancet 2000;356:1470
South Africa
Barcelona 2002
ThPeB7275
% reduction
(95% CI)
HIV+ pts completing
TB Rx, randomised to
6RH2 vs. placebo
1.9% vs. 9%
at 18m
na
HIV+ pts completing
TB Rx, randomised to
INH & SP vs. placebo
for <2y
2.1 vs. 7.0
per 100 pyrs
70%
(6-91)
HIV+ pts completing
TB Rx, randomised to
12H vs. placebo
1.4 vs. 7.8
per 100 pyrs
82%
(17-96)
Observational cohort:
HIV+ pts on INH/CTX
vs. no INH/CTX
8.6 vs. 19.1
per 100 pyrs
55%
(22-74)
Advantages of secondary TBPT
• in settings of high TB transmission:
– eligible patients easier to identify
– HIV test done at TB diagnosis
– sputum smear done routinely at
treatment completion - no need to rescreen for active TB
– if giving primary TBPT, why exclude
people with previous TB?
– But ? lifelong
Effect of CD4 count on risk of TB
among HIV-infected people
Incidence of TB (per 100 pyrs)
20
>350 200-350 <200
15
10
5
0
Italy
US
South Africa
Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123; Badri Lancet
2002;359:2059
Effect of HAART on TB incidence
Country,
reference
Population
TB incidence w/o adj. % red.
HAART
(95% CI)
(per 100pyrs)
USA
16032 pyrs
0.19
80%
(50-90%)
2272 pyrs
62% asymptomatic,
7% TST+
0.79 overall
92%
(12-99%)
N=255,
CD4<15%
8.4
80%
(-13 –96%)
375 pyrs HAART, 770
pyrs no HAART
9.7
81%
(62-91%)
IJTLD 2000;4:1026
Italy
AIDS 2000;14:1985
Brazil
Clin Infect Dis
2002:34:543
South Africa
Lancet 2002;359:2059
Operational use of TB secondary
prophylaxis
• In countries with significant rates of
reinfection
• For patients enrolling into HIV treatment
programmes whose CD4 is < 200
• Once CD4 has risen prophylaxis stopped
Issues in initiating
antiretroviral therapy in
HIV patients with TB
Absorption
Drug-drug interactions
TB/HIV
CYP3A4
Metabolism
PIs
Metabolism
NNRTIs
Elimination
Absorption
Drug-drug interactions
TB/HIV
Rifampicin
↑CYP3A4
Metabolism
PIs
Metabolism
NNRTIs
Elimination
Rifampin Effects on HIV Drugs
• Protease inhibitors
– Saquinavir
80 % decrease
– Ritonavir
35 % decrease
– Indinavir
92 % decrease
– Nelfinavir
82 % decrease
– Amprenavir
81 % decrease
• Nonnucleoside reverse transcriptase
inhibitors (NNRTI)
– Nevirapine
37 % decrease
– Efavirenz
26 % decrease
• Reverse transcriptase inhibitors
– No effect
TB Treatment Regimens
RIFAMPICIN / HAART
HAART
Dose
TB
Dose
therapy
3/4NRTI
rit/saq
rit/saq
No change
1000mg/100 mg
1600mg/100 mg
RIF
RIF
RIF
No change
600 mg 3/7
600 mg od
nevirapine
nevirapine
efavirenz
200 mg bd
300 mg bd
800 mg od
RIF
RIF
RIF
600 mg 3/7
600 mg od
600 mg od
RBT(Rifabutin)/Rifapentine for Treatment
of Pulmonary Tuberculosis
Regimen
Patients Bacteriological
relapse %
n
South Africa
Argentina/Thailand/
Brazil
2RHZE/4HE(2)
**2RbHZE/4RbHE(2)
106
98
3.8
5.1
2HRZE/4HR
**2RbHZE/4RbH
*2RbHZE/4RbH
175
171
174
0.6
1.2
1.2
2HRSZ(3)
+4HR(3)
4HRp(1)
4HRp(1)*2-3
190
199
203
3.2
7.5
9.4
Hong Kong
Every 2nd or 3rd dose omitted
Rifabutin dosage 300mg/day
R = rifampicin, Rp = rifapentine, Rb = rifabutin
Rifabutin dosage 150mg/day
E = ethambutol, Z = pyrazinamide, H = isoniazid
TB Treatment Regimens
Rifabutin
HAART
Dose
TB
Dose
therapy
3/4NRTI
nelfinavir
indinavir
amprenavir
Boosted PI
nevirapine
efavirenz
No change
1750 mg bd
1000 mg tds
1200 mg bd
No change
200 mg bd
600 mg od
RBT
RBT
RBT
RBT
RBT
RBT
RBT
No change
150 mg od
150 mg od
150 mg od
150 mg 2-3/7
300 mg od
450 mg od
Antiretroviral Therapy Options
•
•
•
•
•
•
•
•
Triple or Quad NRTI with Rifampicin
EFV* with Rifampicin
NVP plus intermittent Rifampicin
Ritonavir + saquinavir with Rifampicin
EFV* with Rifabutin
Protease inhibitor (IDV, NFV, APV)* with Rifabutin
Boosted PI plus Rifabutin* Intermittent 2-3/7
? In complex regimens eg Boosted PI plus NNRTI
*Dose adjusted
TB
• 109 HIV +ve patients with TB
• Only risk factor for TB relapse was low CD4 count
• 98 HIV +ve patients on 2 NRTIs + EFV + rifampicin
• Co-administration of EFV + rifampicin was welltolerated and immunologically effective
• 98 HIV +ve patients on 2 NRTIs + EFV 600mg +
rifampicin
• 80% had TB resolution
• EFV 600mg was sufficient to treat HIV/TB patients on
rifampicin
Nettles R et al. 10th CROI, Boston MA, February 2003. Abs 137;
Patel A et al. 10th CROI, Boston MA, February 2003. Abs 138;
Pedral-Samapio D et al. 10th CROI, Boston MA, February 2003.
Abs 784
TB and HIV Adverse Events
Peripheral
Neuro
31 (22%)
n
3.6
Onset months
52%
<2 months
d4T
AVR association
Rash
Hepatitis
19 (13.6%) 11 (7.8%)
74%
91%
nevirapine isoniazid
efavirenz rifampicin
Dean et al AIDS 2001
AIDS + Drug absorption
Median AUC
HIV +
HIV AIDS
P
N
13
14
-
INH
1248
1062
0.5
PZA
22392
23117
0.5
RIF
3604
1665
0.001
Taylor IUTBLD NB No diff in, TMAX,CMAX 2 hr value NOT reflect
CMAX 1998
How Long to Treat?
TB / HIV
Duration of Treatment HIV/ TB Patients:
Data
• 4/6 studies show acceptable (< 5 %) relapse rate
with 6-month course
• 2 studies showed > 9 % relapse with
6-month course
• Relapse vs. re-infection
HIV and TB
Duration Rx and Relapse
Duration
months
F/U
months
Relapse/
failure
6
51
2*
9
50
1
* = new infection by RFLP
Duration of Treatment
HIV/ TB Patients:
• 6-month course for drug-sensitive,
uncomplicated cases
• Longer course for cases with CNS disease
• Longer course for MDRTB and with
non-Rifampicin regimens
Examples of TB regimens used in
new TB cases
INITIAL PHASE
CONTINUATION PHASE
2 ERHZ
4 RH
2 SRHZ
4 R3 H3
2 S3 R3 H3 Z3
6 EH
6 R3 H3 Z3 plus S3or E3
Don’t use twice weekly regimens in patients with CD4
counts <100
Antiretroviral Therapy and TB
When to start HAART?
TB and HIV:
Immediate vs. Delayed HAART
Arguments for delaying potent HIV therapy until TB is
treated:
1. HIV is a chronic disease.
2. Adherence may be compromised.
3. Toxicity management is more complex.
4. Immune restoration may produce “paradoxical
reactions.”
TB and HIV:
Immediate vs. Delayed HAART
Arguments for initiating potent HIV therapy at the onset
of TB:
1. TB is associated with immune activation, increased
HIV replication, and HIV disease progression.
2. Potent antiretroviral therapy can reduce HIV RNA
levels, improve immune function and slow HIV
disease progression.
3. HIV therapy reduces risk of developing other
opportunistic infections
Don’t Wait till it’s too late
Further AIDS
27/188 TB/HIV patients developed further AIDS
On HAART =3
Not on HAART= 24
median CD4 in this group was 70 cells
90% had median CD4 <100 4 months post TB
16 died only 4 on HAART (3 short term)
Dean et al AIDS
2001
TB and HIV:
Immediate vs. Delayed HAART
• TB treatment must be given urgently.
• The urgency of HIV treatment depends on
predictors of HIV disease progression especially
the CD4 cell count.
• <100 cells/mm3 HAART ASAP
• 100-200 cells/mm3 - HAART after 2 months
• >200 cells/mm3 - HAART after TB RX finished
Immune Reconstitution Inflammatory
Syndrome (IRIS)
IRIS
• Worsening of original disease
• No evidence of bacteriological relapse or
recurrence*
• May have high fevers – must exclude
concomitant disease
• Related to start of ARV not to TB Rx
• May respond to steroids /IL-2 and GM-CSF
• Often prolonged
• Recurrent aspiration –not biopsy
* NB not always the case
IRIS
• Thought to be due to increased proliferation
of peripheral blood mononuclear cells and
interferon- response to tuberculous antigens
• ?genetic predisposition
• Lack polymorphism in the cytokine gene
TNFA-308*2.
• Increased levels of IL-6 have also been
found.
IRIS
• TB and severe immunosuppresion
• Rx HAART
• Some patients expand abnormal/anergic
T cell clone
• leads to abnormal response decrease IL-2
and cell signalling
• Rx with IL-2 and GM-CSF can lead to
resolution of IRIS
Pires et al submitted
MDR - TB outbreaks
• Factors responsible
– Inadequate control programmes
– Inadequate compliance
– Infection control procedure breakdown
– Immunosuppressed convergence
– Index of suspicion low
– Inadequate lab. communication
– Infectiousness prolonged
MDR – TB outbreak
• Argentina
16
2
HIV Unit
8
102
Resistant to 6 drugs
8
Resistant to 10 drugs
MDR -TB
• Mortality
– 87 died prior to Rx starting
– 49 died on standard Rx
– 10 died on tailored Rx
– 16 alive on tailored Rx
• Epidemiology
– 77/92 indistinguishable RFLP TYPE
– all 77 contact with index case
• Control
– cohort nursing
– contact tracing
cost of 1case =£60000 in UK
HIV and TB
Thanks to
SE TB research group
LSTMH
Dr Alison Grant
ICSM
Dr Imami
Chelsea and Westminster Hospital
Prof Gazzard