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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 ?
0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10 20
Favours isoniazid Favours controlTuberculin skintest positive patients
INH for TB/HIVTuberculin skin test positive patients
All Studies
Risk ratio & 95% CI
0.05 .1 .2 .3 .4 .5 1 2 3 4 5 10
Favours isoniazid Risk ratio & 95% CI Favours controlTuberculin skintest negative patients
Isoniazid (INH) for TB/HIVTuberculin skin test negative patients
All Studies
Effect of INH on TB incidence in HIV+
-30
-10
10
30
50
70
90
Uganda Zambia Kenya Zambia US Mexico Haiti pooled
all TST+ TST- / anergic
% reduction in TB incidence, INH vs. placebo
*P<0.05
Bucher, AIDS 1999;13:501
*
*
***
*42%
*60%
*
Efficacy of other TBPT regimes in HIV+
Country, reference
Regime, population
Incidence of TB
RR
(95% CI)
US, Mexico, Haiti, BrazilJAMA 2000;283:1445
2RZ vs. 12H
N=1583, TST+0.8 vs. 1.1per 100 pyrs
0.72(0.4-1.31)
HaitiLancet 1998;351:786
2RZ2 vs. 6H2
N=750, TST+
5.4% vs. 5.1% at 3yrs
1.1
UgandaAIDS 2001;15:2137
3HR vs. 6H 3RHZ vs. 6H
N=1554, TST+
na 0.72 (0.42-1.25)
0.60 (0.32-1.12)
NB RX deaths in HIV neg with2RZ3
1995Uganda
1995Rwanda
1995 Zambia
1997Thailand
1998Uganda
1999 Brazil
HIV seroprevalence
in study population (%)
HIV+ persons
entering the PT process
(%)
Those entering the process who started PT
(%)
235347
100100100
Adherence(%)Year Country
159534
10051
100
301238893875
62--
697061
Proportion of Individuals Dropping Out of Preventative Therapy (PT) in
Feasibility Studies
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 therapyPost 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
0
5
10
15
20
all recurrence relapse reinfection
all HIV-pos HIV-neg
Incidence of recurrent TB
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)
% reduction
(95% CI)
DR CongoNEJM 1995;332:779
HIV+ pts completing TB Rx, randomised to 6RH2 vs. placebo
1.9% vs. 9%at 18m
na
Côte d’IvoireChemotherapy 1999;45:452
HIV+ pts completing TB Rx, randomised to INH & SP vs. placebo for <2y
2.1 vs. 7.0per 100 pyrs
70%(6-91)
HaitiLancet 2000;356:1470
HIV+ pts completing TB Rx, randomised to 12H vs. placebo
1.4 vs. 7.8per 100 pyrs
82%(17-96)
South AfricaBarcelona 2002 ThPeB7275
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 re-screen for active TB
– if giving primary TBPT, why exclude people with previous TB?
– But ? lifelong
Effect of CD4 count on risk of TBamong HIV-infected people
0
5
10
15
20
Italy US South Africa
>350 200-350 <200
Incidence of TB (per 100 pyrs)
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 HAART (per 100pyrs)
adj. % red.
(95% CI)
USAIJTLD 2000;4:1026
16032 pyrs 0.19 80% (50-90%)
ItalyAIDS 2000;14:1985
2272 pyrs
62% asymptomatic, 7% TST+
0.79 overall 92%(12-99%)
BrazilClin Infect Dis 2002:34:543
N=255,
CD4<15%8.4 80%
(-13 –96%)
South AfricaLancet 2002;359:2059
375 pyrs HAART, 770 pyrs no HAART
9.7 81%(62-91%)
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
Drug-drug interactions TB/HIV
Metabolism
Absorption
Elimination
Metabolism
CYP3A4
PIs
NNRTIs
Drug-drug interactions TB/HIV
Metabolism
Absorption
Elimination
Metabolism
Rifampicin
↑↑CYP3A4
PIs
NNRTIs
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
HAART Dose TB Dose therapy
3/4NRTI No change RIF No changerit/saq 1000mg/100 mg RIF 600 mg 3/7rit/saq 1600mg/100 mg RIF 600 mg od
nevirapine 200 mg bd RIF 600 mg 3/7nevirapine 300 mg bd RIF 600 mg odefavirenz 800 mg od RIF 600 mg od
TB Treatment RegimensRIFAMPICIN / HAART
Rifabutin dosage 300mg/day
Rifabutin dosage 150mg/day
RBT(Rifabutin)/Rifapentine for Treatmentof Pulmonary Tuberculosis
Patientsn
Regimen
South Africa
Argentina/Thailand/Brazil
Hong Kong
2HRZE/4HR**2RbHZE/4RbH *2RbHZE/4RbH
2RHZE/4HE(2)**2RbHZE/4RbHE(2)
10698
175171174
2HRSZ(3)+4HR(3)4HRp(1)4HRp(1)*2-3
190199203
3.85.1
0.61.21.2
3.27.59.4
Every 2nd or 3rd dose omitted
Bacteriologicalrelapse %
R = rifampicin, Rp = rifapentine, Rb = rifabutin
E = ethambutol, Z = pyrazinamide, H = isoniazid
TB Treatment RegimensRifabutin
HAART Dose TB Dose therapy
3/4NRTI No change RBT No changenelfinavir 1750 mg bd RBT 150 mg odindinavir 1000 mg tds RBT 150 mg odamprenavir 1200 mg bd RBT 150 mg odBoosted PI No change RBT 150 mg 2-3/7nevirapine 200 mg bd RBT 300 mg odefavirenz 600 mg od RBT 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 well-tolerated
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
HepatitisPeripheralNeuro
31 (22%)
3.6
52%
d4T
Rash
19 (13.6%)
-
74%
nevirapine
efavirenz
11 (7.8%)
-
91%
isoniazid
rifampicin
n
Onset months
<2 months
AVR association
TB and HIV Adverse Events
Dean et al AIDS 2001
AIDS + Drug absorptionMedian AUC
HIV + HIV - P
AIDSN 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
Durationmonths
F/Umonths
Relapse/failure
6
9
51
50
2*
1
* = new infection by RFLP
HIV and TB Duration Rx and Relapse
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 lateFurther 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 outbreaksMDR - TB outbreaks
• Factors responsible– Inadequate control programmes– Inadequate compliance– Infection control procedure breakdown– Immunosuppressed convergence– Index of suspicion low– Inadequate lab. communication– Infectiousness prolonged
• 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
2162
102102 88
Resistant to 6 drugsResistant to 6 drugs Resistant to 10 drugsResistant to 10 drugs
HIV Unit
88
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 TBThanks to
SE TB research group
LSTMH
Dr Alison Grant
ICSM
Dr Imami
Chelsea and Westminster Hospital
Prof Gazzard
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