1. Dr A.L. Pozniak Chelsea and Westminster Hospital London, UK
TB and HIV
Dr A.L. Pozniak
Chelsea and Westminster Hospital
London, UK

2. Chemopreventative therapy Treatment and side effects
Chemopreventative therapy Treatment and side effects What with… when… IRIS MDRTB

4. Chemopreventative therapy Is it useful in HIV ?
TB and HIV
Chemopreventative therapy
Is it useful in HIV ?

5. INH for TB/HIV Tuberculin skin test positive patients
Favours isoniazid
Favours control
All Studies
Risk ratio & 95% CI

6. Isoniazid (INH) for TB/HIV Tuberculin skin test negative patients
Favours isoniazid
Risk ratio & 95% CI
Favours control
Tuberculin skin
test negative
patients
All Studies

7. 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
listed in order of study size. 6H except Haiti which was 12H
-10
Uganda
Zambia
Kenya
Zambia US
Mexico
Haiti
pooled
*P<0.05
-30
Bucher, AIDS 1999;13:501

9. Efficacy of other TBPT regimes in HIV+
Country, reference
Regime, population
Incidence of TB RR
(95% CI)
US, Mexico, Haiti, Brazil
JAMA 2000;283:1445
2RZ vs. 12H
N=1583, TST+
0.8 vs. 1.1 per 100 pyrs
0.72 ( )
Haiti
Lancet 1998;351:786
2RZ2 vs. 6H2
N=750, TST+
5.4% vs. 5.1% at 3yrs
1.1
Uganda
AIDS 2001;15:2137
3HR vs. 6H 3RHZ vs. 6H
N=1554, TST+ na
0.72 ( )
0.60 ( )
but more side effects with pyrazinamide. ?longer duration of action – see later
NB RX deaths in HIV neg with2RZ3

10. 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 (%)
Adherence
(%)
Year
Country
1995 Uganda
1995 Rwanda
Zambia
1997 Thailand
1998 Uganda
1999 Brazil 23 53 47
100 15 95 34
100 51 30 12 38 89 75 62 - 69 70 61

11. 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)

12. 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

13. 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
Incidence rates of relapse vs. reinfection are estimates, cited in letter to Lancet in second ref, not in original paper
all recurrence
relapse
reinfection
Sonnenburg et al, Lancet 2001;358:1687 & Lancet 2002;359:

14. Efficacy of secondary TB preventive therapy
Country, reference
Population
Incidence of recurrent TB (PT vs. placebo)
% reduction
(95% CI)
DR Congo
NEJM 1995;332:779
HIV+ pts completing TB Rx, randomised to 6RH2 vs. placebo
1.9% vs. 9% at 18m na
Côte d’Ivoire
Chemotherapy 1999;45:452
HIV+ pts completing TB Rx, randomised to INH & SP vs. placebo for <2y
2.1 vs. 7.0 per 100 pyrs
70% (6-91)
Haiti
Lancet 2000;356:1470
HIV+ pts completing TB Rx, randomised to 12H vs. placebo
1.4 vs. 7.8 per 100 pyrs
82% (17-96)
South Africa
Barcelona 2002 ThPeB7275
Observational cohort: HIV+ pts on INH/CTX vs. no INH/CTX
8.6 vs per 100 pyrs
55% (22-74)

15. 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

16. Effect of CD4 count on risk of TB among HIV-infected people
Incidence of TB (per 100 pyrs) 20
>350
<200 15 10 5
Antonucci includes people on ART but most likely not triple therapy since pre South Africa is people not receiving ART
Italy US
South Africa
Antonucci JAMA 1995;274:143; Markowitz Ann Int Med 1997;126:123; Badri Lancet 2002;359:2059

17. Effect of HAART on TB incidence
Country, reference
Population
TB incidence w/o HAART (per 100pyrs)
adj. % red.
(95% CI)
USA
IJTLD 2000;4:1026
16032 pyrs
0.19
80% (50-90%)
Italy
AIDS 2000;14:1985
2272 pyrs
62% asymptomatic, 7% TST+
0.79 overall
92% (12-99%)
Brazil
Clin Infect Dis 2002:34:543
N=255,
CD4<15%
8.4
80% (-13 –96%)
South Africa
Lancet 2002;359:2059
375 pyrs HAART, 770 pyrs no HAART
9.7
81% (62-91%)
TB incidence from Italy is total for all subjects, irrespective of whether on HAART or not

18. 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

19. Issues in initiating antiretroviral therapy in HIV patients with TB

20. Drug-drug interactions TB/HIV
Absorption
CYP3A4
Metabolism
PIs
NNRTIs
Metabolism
Elimination

21. Drug-drug interactions TB/HIV
Absorption
Rifampicin
↑CYP3A4
Metabolism
PIs
NNRTIs
Metabolism
Elimination

23. 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

24. TB Treatment Regimens RIFAMPICIN / 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

25. RBT(Rifabutin)/Rifapentine for Treatment of Pulmonary Tuberculosis
Patients n
Regimen
South Africa
Argentina/Thailand/
Brazil
Hong Kong
2HRZE/4HR
**2RbHZE/4RbH
*2RbHZE/4RbH
2RHZE/4HE(2)
**2RbHZE/4RbHE(2)
106 98
175
171
174
2HRSZ(3)
+4HR(3)
4HRp(1)
4HRp(1)*2-3
190
199
203
3.8
5.1
0.6
1.2
3.2
7.5
9.4
Every 2nd or 3rd dose omitted
Bacteriological
relapse %
R =rifampicin
Rp =rifappentine
Rb = rifabutin
E= ethambutol
Z=pyrazinamide
H = isoniazid
Rifabutin dosage 300mg/day
Rifabutin dosage 150mg/day
R = rifampicin, Rp = rifapentine, Rb = rifabutin
E = ethambutol, Z = pyrazinamide, H = isoniazid

26. TB Treatment Regimens Rifabutin
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 mg 2-3/7
nevirapine mg bd RBT 300 mg od
efavirenz 600 mg od RBT 450 mg od

27. 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

28. 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 Abs 137; Patel A et al. 10th CROI, Boston MA, February Abs 138; Pedral-Samapio D et al. 10th CROI, Boston MA, February Abs 784

29. TB and HIV Adverse Events
Hepatitis
Peripheral
Neuro
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
Dean et al AIDS 2001

30. AIDS + Drug absorption Median AUC AIDS INH 1248 1062 0.5
HIV + HIV - P
AIDS N
INH
PZA
RIF
Taylor IUTBLD NB No diff in, TMAX,CMAX 2 hr value NOT reflect CMAX 1998

31. How Long to Treat?
TB / HIV

32. 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

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

34. 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

35. Examples of TB regimens used in new TB cases
INITIAL PHASE CONTINUATION PHASE
2 ERHZ RH
2 SRHZ R3 H3
2 S3 R3 H3 Z EH
6 R3 H3 Z3 plus S3or E3
Don’t use twice weekly regimens in patients with CD4 counts <100

36. Antiretroviral Therapy and TB
When to start HAART?

37. 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.”

38. 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

39. 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 < months post TB
16 died only 4 on HAART (3 short term)
Dean et al AIDS 2001

40. 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/mm HAART ASAP
cells/mm HAART after 2 months
>200 cells/mm HAART after TB RX finished

41. Immune Reconstitution Inflammatory Syndrome (IRIS)

43. 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

44. 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.

45. 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

46. 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

47. MDR – TB outbreak 162 8 8 102 Argentina Resistant to 6 drugs
HIV Unit 8 8
102
Resistant to 6 drugs
Resistant to 10 drugs

48. MDR -TB Mortality Epidemiology Control 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

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