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TB and HIVand OIs
Dr A.L. Pozniak
Chelsea and Westminster HospitalLondon, UK
2
OI: A syndromic approach
• Short of breath• Diarrhoea• Difficulty swallowing• “Stroke”• Meningitis• Dementia• Eye problems• Constitutional
4
Dyspnoea
•Commonest cause bacterial pneumonia
Infectious Causes of Respiratory Disease
• 1.Bacteria - S. pneumoniae- H. influenzae- Pseudomonas
• 2.Mycobacteria - Tuberculosis• - MAI• - Other • mycobacterium
• 3.Viral CMV• EBV
• 4. FungalCandida
• -Aspergillus• -Histoplasmosis• -PCP
• 5. Protozoa• -Cryptosporidia• -Toxoplasmosis
PCP
•20-50% normal CXR•10% consolidation•Typically appears like pulmonary oedema
•SOB on exertion•No physical signs
7
Radiology of PCP
Diagnosis of PCP
•Blood gases (not diagnostic but prognostic)
•Induced sputum/bronchoscopy
•Mainly presumptive
PCP treatment - first line
•Cotrimoxazole 3860mg bd• Hypersensitivity• Stevens-Johnson syndrome• Nausea• Hepatitis• Bone marrow suppression•PaO2 <7.5 kPa add steroids (Methylprednisolone iv 40mg qds or Prednisolone po 40mg od 5 days)
PCP treatment – second line
• 3 Options:• 1. Pentamidine 4mg/kg i.v.daily
• 2.Trimethoprim 15mg/kg iv/po daily & dapsone 100mg po bd
• 3.Clindamycin 600mg iv/po qds & primaquine 15-30mg po od
• 4.Casperfungin?
11
Pulmonary nodules
•KS•Miliary TB•Lymphoid interstitial pneumonitis
Acute diarrhoea
Acute
Bacterial
Viral
Ciprofloxacin(ampicillin resistance)
Salmonella
Campylobacter
Shigella
Rotavirus etc
Long term maintenance
13
Chronic diarrhoea
Chronic
Cryptosporidium
Microsporidium
Auramine
Biopsy & stain
Treatment: HAART
Difficulty swallowing
Mouth
Candida
Fluconazole(Itraconazole if resistant)
No candida
Apthous
CMV (CD4 <50/mm3)
Herpes (rare)
15
Gastroscopy rarely necessary
CMV oesophagitis
CNS Disease in HIVMass Lesions 1° cerebral lymphomaToxoplasmosisPMLCMVTuberculosisCryptococcusAspergilloma
Diffuse EncephalitisCMVHSVHZV
“Stroke” syndrome
• Big 3• Toxoplasmosis• Cerebral lymphoma• Progressive multifocal leukoencephalopathy
• Rarities• Cryptococcoma• Tuberculoma• Aspergilloma• Arteritis• Tumour/metastases• Abscess
CT scan appearances
DIAGNOSIS CT SCAN
Toxoplasmosis Multiple, ring-enhancing
Cerebral lymphoma
Little enhancement
PML White matter changes
Toxo Lymphoma PML
Toxoplasmosis -treatment
Sulphadiazine 2g qdsPyrimethamine 75mg od Folinic acid 15my od
Clindamycin 600mg qdsPyrimethamine 75mg od Folinic acid 15my od
Steroids to reduce mass effect
Sulphonamide allergyLong-term maintenance
Meningitis
• Viral• Bacterial (including TB)• Fungal (Cryptococcus)• Neoplastic
Meningitis algorithm
Lumbar puncture
Normal glucoseLymphocytes
Viral
Low glucose
No papilloedema or focal neurology
TB (lymphocytes)
Cryptococcus (antigen)
Neoplastic (cells)
Bacteria (polymorphs)
OrganismsNB Measure opening pressure and repeat if high
24
Cryptococcal meningitis treatment
Obtunded Well
Amphotericin(renal & marrow toxicity)
Fluconazole 400mgMaintenance & HAART
5-Fluorocytosine may increase rateOf clearance of cryptococcus
Fluconazole 400mg bd
Maintenance untilCD4>100 / 6months
25
Eye problems
CMV (CD4 <50/mm3)
Toxoplasma
Rarities
Vitreous haemorrhage
Retinal detachment
Infections (TB, PCP)
Tumours
26
CMV retinitis treatment
•HAAART•and•Ganciclovir•Valganciclovir•Cidofovir
Constitutional symptoms
FeverWeight Loss Look everywhere Lymph nodes
Mouth
Skin
EyesDifferential diagnosis
SepsisTB MAI (CD4 <50/mm3)Lymphoma (LDH, CT if available)
28
MAI
•Anaemia•Weight loss•Fever•Abdominal pain / hepatomegally•CD4 <50/mm3
•Raised Alk Phos
MAI treatment
• HAART• and• Rifabutin• Clarithromycin• (Steroids)
Resistance develops rapidly
HIV wasting
•“Slim disease”•Usually OI •(oesophageal candida, cryptosporidiosis)
When to start HAART-ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs
Zolopa A, et al. CROI 2008. Abstract 142.
Immediate Antiretroviral TherapyInitiation within 48 hours of randomization and
within 14 days of starting OI treatment(n = 141)
Deferred Antiretroviral TherapyInitiation between Weeks 4 and 32
(n = 141)
HIV-infected patients receiving
treatment for presumed or
confirmed acute OI/BI*
(N = 282)
Stratified by CD4+ cell count < or 50 cells/mm3, PCP, BI, or other OI
48 weeks
48 weeks
*Patients with TB excluded.
ACTG A5164: Improved Outcomes With Immediate ART During Acute OI 92% treatment naive
– Median baseline CD4+ cell count 29 cells/mm3; HIV-1 RNA 5.07 log10 copies/mL
OIs with effective antimicrobial therapy only: PCP, bacterial infections, cryptococcal disease, MAC, toxoplasmosis
Median duration from start of OI treatment to initiation of HAART
– Immediate group: 12 days
– Deferred group: 45 days Week 48 virologic outcomes
similar between groups Safety and incidence of IRIS
similar between groupsZolopa A, et al. CROI 2008. Abstract 142.
Patie
nts
Prog
ress
ing
to A
IDS
or D
eath
at W
eek
48 (%
)
100
80
60
40
20
0
14.224.1
Immediate Deferred
P = .035
TB and HIV
Estimated CasesEstimated Deaths
All Forms TB 8.8 million 1.6 Million
MDRTB 424,000 116,000
XDR-TB 27,000 16,000
Global TB Estimates (2006)
35
TB
•More dissemination•Less cavitation•More blood culture positive
•Not every abnormal CXR is TB, treat for bacterial pneumonia first
TB/HIVMany Challenges
• Diagnosis of active or Latent TB• Chemopreventative therapy
• When to start Antiretroviral Therapy (ART)• What ART to start • Second Line ART during TB treatment • Drug interactions• Immune Reconstitution• XDR TB
Inability of the PPD in distinguishing active TB from inactive infection
Active TB
TB contacts
Latent TBinfection
Distribution of induration sizes of the tuberculin (10 IU) skin test healthy young students in
France
0
10
20
30
40
50
60
Num
ber o
f sub
ject
s
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Induration size of the tuberculin skin test (mm)
n = 435n = 435
Distribution of induration sizes of tuberculin (10IU) skin test in HIV+ & TB+ subjects in France
0
5
10
15
20
25
Num
ber o
f sub
ject
s
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Induration size (mm)
n = 49n = 49
Abandon PPD?In HIV patients.. In developing world • Screen for active tb with history and chest Xray give all rest Isoniazid chemoprophylaxis
• Don’t screen but give all asymptomatic patients Isoniazid chemoprophylaxis
• In developed world Give INH until CD4 is over 200
What else can we use?Gamma Interferon assays
Blood test looking for T cell response to Specific MTB antigen Recommended by CDC and NICE UK
Not yet approved for HIV-infected persons
Need technical expertise and costly but cost effective
T-SPOT.TB performance in HIV-1 patients is comparable to that reported in immune competent patients
Patient Group Sensitivity Specificity
Immune Competent * 83-97% 97% -100%
All HIV patients with active TB 89% 100%
HIV patients CD4 < 300 cells/ul
HIV patients CD4 < 200 cells/ul
HIV patients CD4 < 100 cells/ul
90%
88%
78%
100%
100%
100%
*Am J Resp Crit Care Med 2006 174;736-742
No correlation between CD4 T cell count and magnitude of TB antigen responses
8006004002000
CD4 T cell count (cells/ul)
2500
2000
1500
1000
500
0
No.
TB
ant
igen
spe
cific
T c
ells
/ 10
^6 P
BM
C’s
>300<300
HIV patients with positive ELISPOT stratified according to CD4 T cell count (cells/ul)
2500
2000
1500
1000
500
0
No
TB a
ntig
en s
peci
fic T
cel
ls /
10^6
PB
MC
's
n = 29 n = 15
TB/HIV interferon gamma
? Effect of CD4? Extrapulmonary TB? More indeterminates? Do they go negative with treatment?any quantitative differences comparing active with latent tb
TB prevention-use HAART!
• Many still like the INH prophylaxis plan –• How useful is it?• How practical is it?
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
1
2
4
5
3
study
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
1
2
3
5
4
study
1995Uganda
1995Rwanda
1995 Zambia
1997Thailand
1998Uganda
1999Brazil
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
clinicaloptions.com/hiv
-0.5
0.5
1.5
2.5
3.5
4.5
5.5
1 2 3 4 5
TB Incidence During HAART
P trend = .02
Years of HAART
TB In
cide
nce
Rat
e (C
ases
/100
PYs
)
Impact of HAART on Incidence of TB in HIV-Infected Adults
Lawn S, et al. CROI 2006. Abstract 68.
Adults
Initial reduction in TB incidence 11% to 3%
Incidence remained low over 5 years but still 1% per annum on HAART
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
Issues in initiating antiretroviral therapy in
HIV patients with TB
Treatment of drug sensitive TB
• 90% of MTB dead in 2 days when regimen includes INH
• 99% of MTB dead in 14 days when regimen also includes RIfampicin
• If INH and RIF and PZA given in first 2 months then total course of TB treatment is 6 months
• Debate whether HIV + should be treated for longer
• ? Quinolones will shorten to 4 months
If we are treating both HIV and TB..
• Have we enough evidence to give clear treatment recommendations for HIV and TB coinfection?
• What are the major drug issues for clinicians
• 1. NNRTIs and rifampicin• 2. Pis and rifampicin and rifabutin
Rifampicin
• The major problem is the use of rifampicin with HAART
• But at present it is an essential part of the solution for TB
Wilson. PXR, CAR, and drug metabolism. Nat Rev Drug Disc 2002
CYP3A4 Regulation
• PXR: pregnane X receptor; RXR: retinoid X receptor
• In vitro models now exist for identifying drugs that bind PXR
Drug-drug interactions TB/HIV
Metabolism
Absorption
Elimination
Metabolism
Rifampicin
↑↑CYP3A4
PIs
NNRTIs
Rifampin Effects on HIV Drugs• Protease inhibitors
– Boosted PIs should not be used with concomitant rifampicin-PK or safety or can they?
• Nonnucleoside reverse transcriptase inhibitors (NNRTI)– Nevirapine 37 % decrease what dose?– Efavirenz 26 % decrease what dose?
• Reverse transcriptase inhibitors– No significant effectEnfurvitide- No effect
Rifampin – NVP standard dose case series from HIVNAT pK Lab (n=60)
David Burger; 2005 BKK Symp HIV Med, data provided by Saskia Autar
Nevirapine + Rifampicin
02468
10121416
0 3 6 9 12 15Time (h)
NVP
con
c.
85% of NVP levels in therapeutic range
N=32, ARV naïve, TB/HIV, smear pos, CD4<200, RIF 2-6 weeks
2 weeks 4 weeks 12 weeks
Prospective, randomized, multicenter, open-label, 2-arm study
TDM of NVP
12 hr of NVP
+Assessments:
++
+
48 weeks14 days2-6 weeks of
TB treatment
24weeks interim analysis
Arm 1: NVP 400 mg/day ( GPOvir Z 1 tab po BID)( GPOvir Z 1 tab po BID)Lead in 14 days with NVP 200 QD
Arm 2: NVP 600 mg/day ( GPOvir Z 1 tab po BID+ NVP 1tab QD)( GPOvir Z 1 tab po BID+ NVP 1tab QD)Lead in 14 days with NVP 200 BID
All patients received AZT+3TC as a
backbone
24-Week Efficacy and safety of Nevirapine: 400 mg versus 600 mg based HAART in HIV-infected Patients with Active Tuberculosis Receiving Rifampicin W. Manosuthi1et al IAS2007
23
78.6
33.3
10918.8
0
20
40
60
80
100
Arm 1: NVP400 mg/dayArm 2: NVP 600 mg/day
% p
atie
nts
%
Week 2 Week 4 Week 12N = 14 16 13 11 12 10P-value 0.002 0.596 0.323
Proportion of c-min NVP < 3.1 mg/L
*p=<0.05
Summary of adverse events
* disseminated MAC, bloody pleural effusion and liver mass ** cardiomyopathy and heart failure
***
Efavirenz
• PK data• Standard dose?• Increased dose?
Population PK modeling in HIV-pts with TB treated with EFV and rifampicin
Soy et al. 2005
• • EFV dose 30% increase (from 600 to 800) adequate
• Body weight important determinant on CL
PK of EFV 800 mg plus rifampicin similar to those of EFV 600 mg without rifampicin
Lopez-Cortes et al. 2002
EFV levels in HIV-infected Thai patients with TB
% o
f pat
ient
s
0102030405060
< 1 1-4 > 4
Manisuthi et al. 2005600mg 800mg
Nevirapine and Efavirenz
• What is also important is
• Clinical outcome• Toxicity
18 month outcomes
• 1,283 started ART while on rifampicin: • 209 people on nevirapine and 1,074 on
efavirenz. • Those starting NVP with TB rx had a OR(CI)
of 2.9(1.8-4.7) of virological failure <400 copies compared with those on EFV or not on TB RX
Bollue 38th World Lung Health Conference 2007
Boosted PIs and Rifampin Interaction
Lopinavir/rit
•Ritonavir 400 bid required•GI toxicity and lipid perturbation•High rates of elevated transaminase1 (5/7 dropouts) 1/10 low trough concentrations
plus recent Pk study2
-LFT problems
Saquinavir/rit
1La Porte, AAC, 2004Berger pkw2007
•Early studies from SA suggested could be used •SQV 1000/rit100 BID•39% hepatitis•Transaminase elevations 20x upper normal2
2Roche Dear Doctor, 2005
HAART Dose TB Dose therapy
4NRTI No change RIF No changenevirapine 200 mg bd RIF 600 mg odnevirapine 300 mg bd? RIF 600 mg odefavirenz* 6-800 mg od RIF 600 mg od
TB Treatment RegimensRIFAMPICIN / HAART
*Dose adjusted?
Rifabutin• As “potent” as rifampicin but no long-term data for comparison
CYP3A4 CYP3A4Rifabutin
Active metabolites (i.e. 25-O-desacetyl,
31-hydroxy)
• CYP3A4 inhibitors increase rifabutin levels
Can be administered With PIs
Given at a dose of 150mg 3xWK
Expensive! Cost of 4 days of rifabutin = cost of an entire rifampin regimen
Toxicity: marrow suppression, arthralgias, uveitis
Dosing: Dose adjustments of ART regimens ? Dose with boosted PIs
Benefits Limitations
What about Rifabutin?
TB Treatment RegimensRifabutin
HAART Dose TB Dose therapy
4NRTI No change RBT No changeBoosted PI No change RBT 150? mg 2-3/7nevirapine 200 mg bd RBT 300 mg odefavirenz 600 mg od RBT 450 mg od
PI Rifampicin Rifabutin Comment
TMC 125
Little change use normal doses
TMC 278
APV AUC by 82%AUC, Cmax and Cmin decr by 80/69/89%;
Cmin by 49% Avoid co-adm. with rifampicin\?double dose 278 with rbt
Ral reduced the Cmin AUC and C max of MK-0518 by 61%, 40% and 38% respectively
?Avoid co-adm. with rifampicin
GS 9137
Not done Not done
MRV 6.6-fold increase in CYP3A4 induction with rifampin
Double dose of maraviroc will compensate
DRV Not done
T20 No change No change Can use
r = ritonavir; AUC = area under the curve; Cmax and Cmin= maximum and minimum concentrations; TDM = therapeutic drug monitoring
Newer HIV drugs
When to Start ART: in TB Immediately?
TB, HIV+CD4<350Or ?<200
TB TREATMENT
ANTIRETROVIRAL THERAPY-WHEN?
Months
1 2 6
Don't wait until its too late
• In Patients presenting with Ois including tuberculosis it is important to start ARVs as soon as is practicable
• Toxicity, adherence and IRIS are important but outweighed by the morbidity and mortality in those that dont start HIV treatment
Don’t Wait till it’s too lateFurther AIDS
27/188 TB/HIV patients developed further AIDS
On HAART =3Not on HAART= 24 median CD4 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
a)
Mortality among patients with prevalent Mortality among patients with prevalent active TB (n=73) initiating ARTactive TB (n=73) initiating ART
Awaiting ARTAwaiting ARTARTART
0.50
0.60
0.70
0.80
0.90
1.00
0 30 60 90 120 150 180Days from TB diagnosis
Surv
ival
pro
babi
lity
No difference in CD4 count or Stage 4 disease between those starting and not starting
HIV/TB
What is IRIS?
How is it diagnosed?
How is it managed?
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• Often prolonged
* NB not always the case
HIV/TB
Presenting features of IRIS n
Lymphadenopathy 12Fever 8Sternal skin lesion 2Spleen micro abscesses 1Gluteal abscess 1
Michaelidis AVT 2005
HIV/TBFactor IRIS Non-IRIS pN 14 41Baseline CD4 (cells/mm3) 80 (33 – 117) 139 (77 – 284 )0.050
Baseline CD4 < 100 11 (78.6) 16 (39.0) 0.011Baseline CD4 100 3 (21.4) 25 (61.0)
%Disseminated TB 8 (57) 7(17) 0.006
Fold change in CD4 count 1.5 0.7 0.046from baseline to 3 months (0.6 to 5.6) (-0.2 to 1.0)
Michaelidis AVT 2005
Cytokine gene SNP alleles are associated with immune restoration diseases
Non-HIV(N = >100)
HIV, Non-IRD(N = 33)
Herpesvirus(N = 25)
Mycobacterial(N = 11)
HCV(N = 13)
= IL-6 -174*C = TNFA-308*2 = IL-12-3’UTR*2 = IL-12-promoter*2
Price P et al, AIDS 2002,16:2043
*
*
*
* p<0.05(Compared with non-HIV controls)
Management of immune restoration disease
• Suppression of inflammatory response by corticosteroid therapy– Treatment (DTH > CD8+ T-cell response?)– Pre-emptive? (randomised controlled trials)
• Recurrent aspiration
• Immunomodulatory therapy - May respond to steroids /IL-2 and GM-CSF,OH
Chloroquine,NFkb receptor antaganist
• Cease/modify antiretroviral therapy
Other IRIS-types Unmasking of TB by HAART
• Problem for developing world HAART programs
• Potential for TB drug resistance if patients given INH prophylaxis when start HAART
• ? Screen patients for active TB-CXR may be normal and TST or Elispot won’t differentiate from latent TB
• MDR-TB = Resistance to at least Rifampicin and Isoniazid
• XDR-TB = MDR-TB plus resistance to:– a fluoroquinolone and – >1 of 3 injectable second-line drugs capreomycin, kanamycin,
amikacin(New definition agreed October 2006)
CausesPoor treatmentLack of resistance surveillanceInfection control
Definition of XDR-TB
Countries with confirmed XDR-TB
The bulk of the problem of XDR-TB resides in those countries with high numbers of MDR-TB and two thirds of MDR is in just 3 countries - China, India and the Russian Federation.