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 2012 by the author
ERS School Course on
TB and M/XDR-TB: from clinical management to control and elimination
Session III: Treatment and clinical management
TB/HIV management: what is new?
Giovanni Sotgiu and GB Migliori
Bucharest , Friday, 25 May 2012
TB/HIV co-infection
Special thanks to:
- Prof GB Migliori and Dr Alberto Matteelli
(TBPANET-funded courses of Sondalo, Italy)
- Dr Matteo Zignol (WHO office, Geneva, Switzerland)
for having shared their ppt materials.
TB/HIV co-infection: outline
 Epidemiology.
 TB/HIV collaborative activities:
-
ICF;
IPT;
ARV therapy;
HIV testing;
CPT.
 News from the scientific literature:
-
TB/HIV co-infection and IGRA testing;
TB/HIV co-infection and LAM urine assay.
Epidemiology
Global burden of TB/HIV in 2010
Cases
HIV-associated TB
Deaths
1.1 million (13%)
0.4 million
(range, 1.0–1.2 million)
(range, 0.32–0.39 million)
WHO. Global TB report 2011
Epidemiology
M. tuberculosis
Relative risk for TB:
HIV neg. = < 10% per lifetime
First
Infection
HIV positive
Re-infection
(exogenous)
HIV pos. ~ 3-7 % per year
Primary
TB
Latent
TB
Reactivation
(endogenous)
Progressive
Primary TB
Post-primary TB
Epidemiology
Incidence of TB, 2010
Prevalence of HIV among new TB patients, 2010
Epidemiology
Treatment outcomes for HIV-positive and HIV-negative TB patients, 2009.
HIV-pos 72% VS. HIV-neg 88%
Only 21% of the estimated global HIV-related TB cases (81 countries)
WHO. Global TB report 2011
Epidemiology
Treatment outcomes for HIV-positive and HIV-negative TB patients, 2009.
HIV-pos 20% VS. HIV-neg 3%
WHO. Global TB report 2011
Epidemiology
41 high TB/HIV burden countries,
2010
WHO. Global TB report 2011
Epidemiology
Epidemiology
Survey on TB/HIV co-infection in EU/EEA member states
Kruijshaar ME et al.Eur Respir J 2011; 38.
Epidemiology
Collection of HIV status in TB surveillance systems in EU/EEA member states
Kruijshaar ME et al.Eur Respir J 2011; 38.
Epidemiology
Policies of HIV testing in EU/EEA member states
Kruijshaar ME et al.Eur Respir J 2011; 38.
Epidemiology
TB/HIV co-infected patients in EU/EEA member states
Kruijshaar ME et al.Eur Respir J 2011; 38.
Epidemiology
 Proportion of TB/HIV patients reported to the national surveillance
systems is actually suboptimal (high variability in the EU/EEA).
 Main obstacles:
a) patient confidentiality;
b) anonymous testing of HIV pts.
 The majority of the member states recommend testing all TB pts for
HIV.
Kruijshaar ME et al.Eur Respir J 2011; 38.
Epidemiology
Epidemiology
 Systematic review of peer reviewed MS and‘‘grey literature’’ focused
on TB–HIV co-infection prevalence and risk factors in EU/EEA.
Kruijshaar ME et al.Eur Respir J 2011; 38.
Epidemiology
TB/HIV co-infection in EU/EEA member states
Pimpin L et al.Eur Respir J 2011; 38.
Epidemiology
Trends of TB/HIV co-infection in EU/EEA member states
Pimpin L et al.Eur Respir J 2011; 38.
Epidemiology
Socio-demographic characteristics of TB/HIV co-infected vs TB pts in EU/EEA
Pimpin L et al.Eur Respir J 2011; 38.
Epidemiology
 Males, young adults, migrants, those living in urban areas, IVDUs,
homeless and prisoners identified as high-risk groups for TB–HIV
coinfection.
Kruijshaar ME et al.Eur Respir J 2011; 38.
TB/HIV collaborative activities
WHO TB/HIV policy: from Interim to Definite
2004
2012
The Stop TB Strategy at a glance
Raviglione MC et al.Lancet 2006; 367.
TB/HIV collaborative activities
WHO. Interim Policy on Collaborative TB/HIV Activities. 2004.
TB/HIV collaborative activities
A. Establish the mechanisms for integrated TB and HIV services
1. Set up or strengthen a TB/HIV coordinating body effective at all levels
2. Conduct HIV and TB surveillance among TB and HIV patients respectively
3. Carry out joint TB/HIV planning
4. Conduct monitoring and evaluation
B. Decrease the burden of TB in PLHIV through earlier ART and Three Is for
HIV/TB
5. Intensify TB case finding and ensure quality TB treatment
6. Introduce TB prevention with IPT and ART
7. Infection control for TB in health care and congregate settings ensured
C. Decrease the burden of HIV in patients with presumptive and diagnosed TB
8. Provide HIV testing & counselling to patients with presumptive and diagnosed TB
9. Introduce HIV preventive methods patients with presumptive and diagnosed TB
10. Provide CPT for TB patients living with HIV
11. Ensure HIV prevention, treatment & care for TB patients living with HIV
12. Provide Antiretroviral therapy to TB patients living with HIV
WHO. Policy on Collaborative TB/HIV Activities. 2012.
TB/HIV collaborative activities
WHO. Policy on Collaborative TB/HIV Activities. 2012.
TB/HIV collaborative activities
TB
DOTS
+VCT
+Condoms
+HIV
surveillance
TB/HIV
Intensified casefinding
Isoniazid
preventive
therapy
Co-trimoxazole preventive therapy
Home- and community-based care
General health services
HIV
VCT + TB
screening
IEC
STIs
ARVs
TB/HIV collaborative activities
2,500,000
2003
2004
2,000,000
2005
2006
1,500,000
2007
2008
1,000,000
2009
2010
500,000
Tested for HIV-positive
HIV
CPT
ART
Screened for TB on ART
TB
register
IPT
TB/HIV collaborative activities
 Some progress in HIV care for people with TB, with
more TB patients being HIV tested, although too few
receive ARTs and co-trimoxazole prophylaxis
 Less progress on the "3Is": intensified case finding in
community and facilities; infection control; and
isoniazid preventive therapy
TB/HIV collaborative activities
 Some progress in HIV care for people with TB, with
more TB patients being HIV tested, although too few
receive ARTs and co-trimoxazole prophylaxis
 Less progress on the "3Is": intensified case finding in
community and facilities; infection control; and
isoniazid preventive therapy
TB/HIV collaborative activities
1.
Intensified case finding in the community (door-to-door, mobile
vans) and in health facilities using modern technology.
2.
Infection control in health facilities: facility-level and administrative
measures, environmental and personal protection.
3.
Isoniazid preventive therapy, irrespective of degree of immune
suppression and TST, but after careful screening to rule out active
TB.
TB/HIV collaborative activities
Intensified case finding (ICF)
 Screening and diagnosing TB in people living with HIV can be
challenging.
 ICF is a gatekeeper for the other 2 I’s: it rapidly identifyies TB
suspects (allowing triage and other measures to reduce
transmission) and allows provision of IPT to PLWHA who
don’t have active TB.
TB/HIV collaborative activities
Intensified case finding (ICF)
Adults and adolescents living with HIV should be screened with a
clinical algorithm and those who reported one of the following:
– current cough,
– fever,
– weight loss or
– night sweats
may have active TB and should be evaluated for TB and other diseases.
WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities
Intensified case finding (ICF)
 Presence of symptoms – work up for TB
– Sensitivity 79%
– Specificity 56%
 Absence of symptoms – proceed with INH preventive therapy
– Negative predictive value 97% (*)
– (*) at a prevalence of TB of 5%
Getahun H et al. Plos Med 2011; 8.
TB/HIV collaborative activities
Intensified case finding (ICF)
Getahun H et al. Plos Med 2011; 8.
TB/HIV collaborative activities
Intensified case finding (ICF)
The addition of abnormal findings on chest X-ray increases the
sensitivity from 79% to 91%, but the negative predictive value only
increases from 97.8% to 98.7%.
The benefits of radiology increase with the increase of TB prevalence
(significant for prevalence > 20%).
WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
Isoniazid 300 mg /daily for 6-9 months
WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
Incidence of TB
Akolo C et al. Cochrane Review 2010.
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
 In areas of high prevalence of TB (>30% infected):
All HIV infected individuals who are not affected by active TB
 In areas of lower prevalence of TB (<30% infected):
HIV infected individuals with a positive PPD test who are not
affected by active TB
Independently from CD4 cell count
Akolo C et al. Cochrane Review 2010.
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
Balcells M et al. EID 2006.
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
Samandari et al., CROI Conference, San Francisco, 2010
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks,
rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks,
isoniazid (300 mg) daily for up to 6 years (continuous isoniazid),
isoniazid (300 mg) daily for 6 months (control group)
Martinson NA, N Engl J Med 2011, 365
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
TB Cases
Incidence Rate
(per 100 PYs)
Percent
Reduction
(95% CI)
3,865
155
4.01 (3.40-4.69)
-
ART only
11,627
221
1.90 (1.66-2.17)
52%
(41-61%)
IPT only
395
5
1.27 (0.41-2.95)
68%
(24-90%)
Both
1,253
10
0.80 (0.38-1.47)
80%
(9-91%)
Total
17,140
391
2.28 (2.06-2.52)
Exposure
category
PersonYears
No Rx
Golub et al., AIDS 2007;21
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
South African Adults with HIV Infection
Person
-years
TB
cases
Incidence rate (per
100 PYs) (95%
CI)
Incidence rate
ratio (95% CI)
Adjusted hazard
ratio* (95% CI)
Naïve
2815
200
7.1 (6.2-8.2)
REF
REF
HAART
only
952
44
4.6 (3.4-6.2)
0.65 (0.46-0.91)
0.36 (0.25-0.51)
INH only
427
22
5.2 (3.4-7.8)
0.73 (0.44-1.13)
0.87 (0.55-1.36)
Both
93
1
1.1 (0.2-7.6)
0.15 (0.01-0.85)
0.11 (0.02-0.78)
4287
267
6.2 (5.5-7.0)
Exposure
category
TOTAL
* Adjusted for age, sex, CD4, prior history of TB, urban/rural
Golub et al, AIDS 2009;23
TB/HIV collaborative activities
Isoniazid Preventive Therapy (IPT)
TB/HIV Working Group of the Partnership
Focus on European Region, Almaty, May 2010
 There is no study on the threshold of resistance which
make IPT non more cost effective.
 Even with 50% resistance there will be 50% of the
subjects who will benefit from IPT.
 IPT recommended in Eastern Europe and Central Asia,
where INH resistance is highest.
TB/HIV collaborative activities
Anti-HIV therapy
 HAART reduces the incidence of TB by approximately 80% in high and
low burden countries.
 HAART reduces by >50% the rate of recurrent TB after completion of
TB treatment.
 HAART may be key to control MDR epidemics among HIV infected
persons.
 HAART may unmask TB in persons with low CD4 cell count.
 TB incidence in HIV infected persons receiving effective HAART is ~
10 times higher than that in the background population.
TB/HIV collaborative activities
Incidence of TB after initiation of HAART
During the initial months of HAART
incident TB cases may arise as a
consequence of “unmasking” of
previously subclinical disease or the
deterioration of a pre-existing disease
due to the reconstitution of the immune
system (Lawn, 2005)
Dembele M, Int J Tub
TB/HIV collaborative activities
Anti-TB treatment
a
b
c
d
Daily TB treatment is recommended in HIV-positive persons.
Direct observation of drug intake is recommended during the entire course of therapy, but particularly during the initial phase of treatment.
Streptomycin may be used instead of ethambutol. In meningeal TB, ethambutol should be replaced by streptomycin, which diffuses more in the meninges.
Whenever possible, drug sensitivity testing should be done to design standardized or individualized treatment regimen.
TB/HIV collaborative activities
Anti-HIV therapy
Decrease morbidity and mortality related to HIV/AIDS
WHO recommendation
• Start ART in all HIV infected individuals with active
tuberculosis irrespective of CD4 cell count
(strong recommendation – Low quality of evidence)
WHO, 2010: ART guidelines
TB/HIV collaborative activities
Anti-HIV therapy
Early (2 weeks) vs. late (8 weeks) initiation of HAART:
the CAMELIA study.
Mortality significantly reduced in early ART group (18% - 59/332), as
compared with the later-ART group (27%, 90/329) (HR, 0.62; 95% CI;
0.44 to 0.86; P = 0.006).
Blanc FX, NEJM 2011; 365
TB/HIV collaborative activities
Anti-HIV therapy
Timing of HIV therapy in 429 TB patients with CD4<500 in South Africa.
Earlier=< 4 wks, Later=8-12 wks (not statistically significant for TB and death)
Abdool Karim SS, NEJM 2011; 365
TB/HIV collaborative activities
Anti-HIV therapy
 The STRIDE and SAPIT trials found similar results of reduced deaths
and AIDS-related events with combined and earlier ART and anti-TB
treatment, by 42% and 68% respectively, especially among people
with a CD4 count less than 50 cells/mm3
Havlir D et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365(16):1482-91.
Abdool Karim SN et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365(16):1492-501
WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities
Anti-HIV therapy
 ART should be started within 2 weeks from TB therapy in TB/HIV
patients with CD4 < 50
 ART can be delayed up to the end of the intensive phase of TB
treatment in TB/HIV patients with CD4>50 (halved the risk of IRIS)
What if CD4 cannot be measured – or timely measured? Unclear at this
time
TB/HIV collaborative activities
Anti-HIV therapy
Constraints
Increased rate of paradoxical reactions (IRIS)
Additive toxicity
Reduced adherence
Operational delays
TB/HIV collaborative activities
Anti-HIV therapy_IRIS
(A) Antecedent requirements
• Diagnosis of tuberculosis before starting ART
• Initial response (stabilised or improved) to tuberculosis treatment
(B) Clinical criteria
• Onset of manifestations within 3 months of ART
Plus at least one major or two minor criteria
Major criteria
1) New or enlarging lymph nodes, or similar cold abscesses, 2) New or worsening radiological
features of TB; 3) New or worsening CNS TB; 4) New or worsening serositis
Minor criteria
1) New or worsening constitutional symptoms; 2) New or worsening respiratory symptoms; 3)
New or worsening abdominal pain
(C) Alternative explanations for clinical deterioration must be excluded if
possible
• Failure of tuberculosis treatment because of tuberculosis drug resistance
• Poor adherence to tuberculosis treatment
• Another opportunistic infection or neoplasm
• Drug toxicity or reaction
Meintjes G et al. Lancet ID 2008
TB/HIV collaborative activities
Anti-HIV therapy_IRIS
 Make certain of diagnosis
Rule out MDR TB or new opportunistic infection
 TB treatment should be continued
 ARV treatment should be continued
 Surgical drainage
 Non-steroidal anti-inflammatory drugs
 Steroids – 1.5 mg/kg prednisone
TB/HIV collaborative activities
Anti-HIV therapy_AEs
AE
TB Drugs
HIV Drugs
Rash
PZA, RIF, INH
NNRTIs, ABC, T/S
Hepatotoxicity
INH, RIF, PZA
PIs, NVP
Nausea
RIF, PZA, INH
RTV, AZT, APV
RBT, RIF
AZT, T/S
INH
EFV
Cytopenias
CNS
TB/HIV collaborative activities
Anti-HIV therapy
• First choice: standard TB regimen
• +
• 2NRTI + Efavirenz
• Is a first line option for HIV treatment
• Is the most widely used first line regimen in resource limited settings
• Allows for standard TB therapy
• Allows for once a day therapy with minimal pill burden (Atripla)
TB/HIV collaborative activities
Anti-HIV therapy_alternatives to EFV
TB/HIV collaborative activities
Anti-HIV therapy_alternatives to EFV
 Enfuvirtide: no interactions, but parenteral
 NNRTIs
Rifampicin decreases Etravirin exposure “significantly”. Combination not
recommended
 CCR5 Inhibitors
Rifampicin reduces maraviroc exposure by 63%. Maraviroc doses could
theoretically be doubled but no clinical experience
 Integrase inhibitors
Rifampicin reduces raltegravir exposure by 40-60%. Raltegravir 800 mg BID
suggested, but optimal concentration range of this drug is unknown
TB/HIV collaborative activities
Anti-HIV therapy_alternatives to EFV
Rifabutin can be used with LOPINAVIR, ATAZANAVIR, FOSAMPRENAVIR,
DARUNAVIR, TIPRANAVIR always with RITONAVIR boosting
RIFABUTIN acceptable substitute for rifampicin, in standard TB regimens
but:
- not widely available
- requires loose drugs
TB/HIV collaborative activities
Anti-HIV therapy_alternatives to EFV
Triple nuke regimens (zidovudine, lamivuine and abacavir)
should be used only if no alternative regimen is available
The potency (in virological terms) of this option is
significantly reduced
TB/HIV collaborative activities
Infection control
WHO. IPT/ ICF recommendations. 2011
TB/HIV collaborative activities
HIV testing in TB pts (2003-2010)
The number of notified new and retreatment cases is shown in blue and the number of cases for which the HIV status was recorded in
the TB register is shown in green. The percentage of notified TB cases with known HIV status is indicated above the green bars *
* The numbers under each year show the number of countries reporting data on HIV testing followed by the percentage of total estimated
HIV positive TB cases accounted for by reporting countries
WHO Global Report, 2011
TB/HIV collaborative activities
HIV testing in TB pts
WHO Global Report, 2011
TB/HIV collaborative activities
HIV testing in TB pts
Client initiated
Provider-initiated
 Voluntary counselling
and testing
(VCT)
 Routine offer of HIV
testing by health care
providers
 Diagnostic HIV testing
 Mandatory testing
TB/HIV collaborative activities
HIV testing in TB pts (3 C’s Principles)
I.
confidential.
II.
accompanied by counselling.
III. only be conducted with informed
consent, i.e. both informed and voluntary.
TB/HIV collaborative activities
CPT
Co-trimoxazole prophylaxis is a simple, well-tolerated and costeffective intervention for people living with HIV.
It should be implemented as an integral component of the HIV
chronic care package and as a key element of pre–antiretroviral
therapy care.
Co-trimoxazole prophylaxis needs to continue after
antiretroviral therapy is initiated until there is evidence of
immune recovery.
One double-strength tablet or two single-strength tablets once
daily: the total daily dose is 960 mg (800 mg sulfamethoxazole
+ 160 mg trimethoprim).
TB/HIV collaborative activities
CPT
Target Population
Recommendations
Do not discontinue CTX prophylaxis, particularly
in settings where bacterial infections and malaria
are common HIV-related events [A-IV].
CD4 testing
not available
(clinical assessment
only)
Consider discontinuation of CTX prophylaxis in those with evidence of
good clinical response to ART (absence of clinical symptoms after at
least one year of therapy), good adherence and secure access to ART. [CIV]
In countries where CTX prophylaxis is recommended only for
prevention of PCP and toxoplasmosis, it can be discontinued in those
with evidence of immune recovery on ART (CD4 ≥ 200/mm3at least 6
months on ART). [B-I]
HIV-infected adults
and adolescents
CD4 testing
available (clinical
and immunologic
assessment)
In countries with high incidence of bacterial infections and malaria,
discontinue CTX prophylaxis in those with evidence of immune
recovery related to ART
(CD4 ≥ 350/mm3at least 6 months on ART). [C-IV]
TB/HIV collaborative activities
CPT
Globally, the number of TB patients living with
HIV who were enrolled on CPT levelled off
between 2009 and 2010, at just over 0.3 million.
This was equivalent to 77% of TB patients known
to be HIV-positive
WHO Global Report, 2011
Diagnosis
Diagnosis_IGRA
To evaluate the sensitivity of T-SPOT.TB vs. TST to identify HIV+ pts
with LTBI (Swiss HIV Cohort Study).
242 HIV+ pts developed culture-confirmed TB between 1993 and
2005.
64 pts had viable lymphocytes collected prior to TB diagnosis (within
6 months).
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
T-SPOT.TB assay resulted positive in 25 (39%), negative in 18 (28%)
and indeterminate in 21 (33%).
T-SPOT.TB sensitivity: 39% (95% CI: 27-51%) including all results,
58% (95% CI: 43-74%) if indeterminate results are excluded.
TST resulted positive in 22/44; TST sensitivity: 50% (95% CI: 3565%).
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
Factors associated with a positive T-SPOT.TB
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
Factors associated with a negative T-SPOT.TB
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
Results of T-SPOT.TB assay according to (A) CD4 and (B) CD8 cell count
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
Proportion of positive test results of TST and T-SPOT.TB and indeterminate
TSPOT. TB results according to CD4 cell count
Elzi L et al.BMC ID 2011; 11.
Diagnosis_IGRA
T-SPOT.TB and TST have similar sensitivity to detect LTBI in HIV+
pts.
Combination of TST and T-SPOT.TB with at least one test positive
significantly increased sensitivity.
Elzi L et al.BMC ID 2011; 11.
Diagnosis
Diagnosis_LAM
Lipoarabinomannan (LAM) is a glycolipid located in the cell wall of
Mtb.
Urinary samples are simple to collect (particularly in children), process
and store.
Fewer infection control concerns.
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Enrolled studies
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Forest plot of studies contributing to sensitivity
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Forest plot of studies contributing to specificity
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Pooled meta-analysis estimates
#: analysis excludes pts microbiologically negative, but with strong clinical/radiological suspicion for TB;
+: analysis groups the previous category with all other patients microbiologically negative to be reference
negative;
ƒ: analysis groups the first category with patients microbiologically positive as reference positive.
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Linear regression of sensitivity on the proportion of HIV-positive pts
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Proportion of specimens LAM+, by clinical status
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
Diagnostic accuracy, by CD4 cell counts
Minion J et al.Eur Respir J 2011; 38.
Diagnosis_LAM
LAM urine assay is a potentially useful rule-in TB diagnostic.
Inadequate sensitivity in unselected cohorts.
The assay performs better in HIV+ (mainly in those with low CD4 cell
counts).
Even in HIV+ pts the sensitivity is suboptimal.
Minion J et al.Eur Respir J 2011; 38.
Alerts
 All TB patients, regardless of their perceived risk of HIV infection,
should be offered an HIV test (increased no. of co-infected pts).
 In HIV infected patients clinical features of TB can be unusual.
 Multidisciplinary team: respiratory medicine and infectious diseases
specialists.