TB and HIV

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TB and HIV

• Dr A.L. Pozniak
• Chelsea and Westminster Hospital
• London, UK

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Chemopreventative therapyTreatment and side
effects What with when IRISMDRTB
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TB and HIV

• Chemopreventative therapy
• Is it useful in HIV ?

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INH for TB/HIVTuberculin skin test positive
patients
Tuberculin skin test positive patients
Favours isoniazid
Favours control
All Studies
0.05 .1 .2 .3 .4 .5 1
2 3 4 5 10 20
Risk ratio 95 CI
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Isoniazid (INH) for TB/HIVTuberculin skin test
negative patients
All Studies
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Effect of INH on TB incidence in HIV
reduction in TB incidence, INH vs. placebo

all
TST
TST- / anergic
90
60


70

42

50

30
10
-10
Uganda
Zambia
Kenya
Zambia
US
Mexico
Haiti
pooled
Plt0.05
-30
Bucher, AIDS 199913501
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Efficacy of other TBPT regimes in HIV
NB RX deaths in HIV neg with2RZ3
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Proportion of Individuals Dropping Out of
Preventative Therapy (PT) in Feasibility Studies
HIV persons entering the PT process ()
Those entering the process who started PT ()
HIV seroprevalence in study population ()
1995 Uganda 1995 Rwanda 1995 Zambia 1997 Thai
land 1998 Uganda 1999 Brazil
23 53 47 100 100 100
15 95 34 100 51 100
30 12 38 89 38 75
62 - - 69 70 61
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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)

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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

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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 20013581687 Lancet
20023591619-1620
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Efficacy of secondary TB preventive therapy
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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

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Effect of CD4 count on risk of TBamong
HIV-infected people
Incidence of TB (per 100 pyrs)
20
gt350
200-350
lt200
15
10
5
0
Italy
US
South Africa
Antonucci JAMA 1995274143 Markowitz Ann Int
Med 1997126123 Badri Lancet 20023592059
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Effect of HAART on TB incidence
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Operational use of TB secondary prophylaxis

• In countries with significant rates of
  reinfection
• For patients enrolling into HIV treatment
  programmes whose CD4 is lt 200
• Once CD4 has risen prophylaxis stopped

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Issues in initiating antiretroviral therapy in
HIV patients with TB
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Drug-drug interactions TB/HIV
Absorption
CYP3A4
Metabolism
PIs NNRTIs
Metabolism
Elimination
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Drug-drug interactions TB/HIV
Absorption
Rifampicin ?CYP3A4
Metabolism
PIs NNRTIs
Metabolism
Elimination
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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

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TB Treatment RegimensRIFAMPICIN / HAART
HAART Dose TB
Dose therapy 3/4NRTI No change
RIF No change rit/saq 1000mg/100 mg RIF
600 mg 3/7 rit/saq 1600mg/100 mg RIF 600 mg
od nevirapine 200 mg bd RIF 600 mg
3/7 nevirapine 300 mg bd RIF 600 mg
od efavirenz 800 mg od RIF 600 mg od
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RBT(Rifabutin)/Rifapentine for Treatmentof
Pulmonary Tuberculosis
Bacteriological relapse
Rifabutin dosage 300mg/day Rifabutin dosage
150mg/day
R rifampicin, Rp rifapentine, Rb
rifabutin E ethambutol, Z pyrazinamide, H
isoniazid
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TB Treatment RegimensRifabutin
HAART Dose TB
Dose therapy 3/4NRTI No change
RBT No change nelfinavir 1750 mg bd RBT
150 mg od indinavir 1000 mg tds RBT 150 mg
od amprenavir 1200 mg bd RBT 150 mg od Boosted
PI No change RBT 150 mg 2-3/7 nevirapine 200
mg bd RBT 300 mg od efavirenz 600 mg od RBT 450
mg od
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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
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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
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TB and HIV Adverse Events
Dean et al AIDS 2001
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AIDS Drug absorption

• Median AUC
• HIV HIV - P
• AIDS
• 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

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How Long to Treat?

• TB / HIV

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Duration of Treatment HIV/ TB Patients Data

• 4/6 studies show acceptable (lt 5 ) relapse rate
  with 6-month course
• 2 studies showed gt 9 relapse with 6-month
  course
• Relapse vs. re-infection

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HIV and TB Duration Rx and Relapse
Duration months
F/U months
Relapse/ failure
51 50
2 1
6 9
new infection by RFLP
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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

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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
  
• Dont use twice weekly regimens in patients with
  CD4 counts lt100

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Antiretroviral Therapy and TB

• When to start HAART?

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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.

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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

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Dont Wait till its 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 lt100 4 months post TB
• 16 died only 4 on HAART (3 short term)

Dean et al AIDS 2001
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TB and HIVImmediate 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.
• lt100 cells/mm3 - HAART ASAP
• 100-200 cells/mm3 - HAART after 2 months
• gt200 cells/mm3 - HAART after TB RX finished

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Immune Reconstitution Inflammatory Syndrome (IRIS)
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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

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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-3082.
• Increased levels of IL-6 have also been found.

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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

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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

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MDR TB outbreak

• Argentina

162
HIV Unit
8
8
102
Resistant to 10 drugs
Resistant to 6 drugs
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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
• 
  

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HIV and TB

• Thanks to
• SE TB research group
• LSTMH
• Dr Alison Grant
• ICSM
• Dr Imami
• Chelsea and Westminster Hospital
• Prof Gazzard