Challenges of TB-HIV coinfection

2016 6 3 08:00-08:50

Outline • Epidemiology of TB/HIV: a syndemic • Active TB infection in HIV – Prompt detection (Diagnosis) – Treatment regimens and duration – Optimal timing to start antiretroviral therapy – Immune reconstitution inflammatory syndrome

(IRIS)

• Latent TB infection in HIV – Risk of TB with and without antiretroviral therapy – Diagnosis & Treatment

Syndemic of TB/HIV

Kwan. Clin Microb Rev 2011;24(2):351-376.

A syndemic is defined as the convergence of two or more diseases that act synergistically to magnify the burden of disease.

TB/HIV co-infection Impact of HIV on TB • Risk of acquiring TB

– Increased susceptibility to TB disease (defective macrophage response) (Patel. J Leukoc Biol 2009)

– Similar risk as HIV-negative (Meltzer Annu Rev Immunol 1990; Whalen PLoS One 2011)

• Risk of progression: 26 times more likely to reactivate, even at high CD4 counts (Sonnenberg. JID 2005; Moore AIDS 2007; Van Rie. J AIDS 2011; Gupta PLoS One 2012)

• Atypical presentation with low CD4 counts

• Increased risk of death

Impact of TB on HIV • Increases risk of HIV progression

(Badri. IJTLD 2001)

• Increases risk of death (Lopez-Gatell. Am J Epidemiol 2007)

• Increased immune activation and expression of coreceptors on CD4 cells (Vanham. Clin Exp Immunol 1996, Wolday. J AIDS 2005)

• Elevated HIV RNA levels (Goletti. J Immunol 1996)

– Activation of latent HIV in macrophages

– Dysregulated cytokines • Lowered HIV RNA levels (Srikantiah. J

AIDS 2008)

Estimated numbers of TB cases and TB deaths (1990-2015)

Source of data: WHO Global TB Report 2015

Global HIV prevalence in TB cases (2014)

Source of data: WHO Global TB Report 2015

TB is a leading killer of HIV-positive people: in 2014, 1 in 3 HIV deaths was due to TB.

Source of data: WHO Global TB Report 2015

Global epidemiology of HIV-associated TB disease and mortality (2014)

0%

20%

40%

60%

80%

100%

TB incident cases TB mortality

HIV+HIV-

9,600,000 1,500,000

33%

13%

Source of data: WHO Global TB Report 2015

TB case fatality rate

Global Epidemiology of TB/HIV Active TB • TB is the most common presenting illness among people living

with HIV, including those who are taking antiretroviral treatment.

• 1.2 million HIV+ new TB cases in 2014 • 390,000 HIV+ died of TB in 2014 (32% reduction since 2004) Latent TB • 1/3 of 37 million HIV-infected persons have latent TB infection • HIV-infected persons are 26 times more likely to reactivate.

WHO TB factsheet 2015.

2715 3358 4100

5482

8635

11293 12951

14345 15643

17093 18627

20468 22304

24111

36 61 68 85 107 106 76 92 80 105 101 0 0 0

14486

16758

15042

16784 15378

14480 14265

13400 13336 13237

12634 12338

11528

11238

0.2% 0.4% 0.5% 0.5% 0.7% 0.7% 0.5% 0.7% 0.6% 0.8% 0.8%

0 0 0

0.5% 0.8% 1.0%

1.4% 2.0%

2.2%

1.6% 2.0%

1.9%

2.50% 2.5%

0 0 0 0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

0

5000

10000

15000

20000

25000

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

No. of cases

Year

People living with HIVHIVcasesTB cases%HIV(+)%HIV(+) in 15-49y/o

Epidemiology of TB/HIV co-infection in Taiwan

Intermediate TB burden & Low HIV prevalence country

25954

2015

World TB Day 2016 “Unite to end Tuberculosis (TB)”

Ending TB by 2030 is a target of the Sustainable Development Goals (SDGs) and the goal of the WHO End TB Strategy.

*TB and HIV are leading causes of infectious diseases deaths. *TB causes 1/3 of AIDS-related deaths per yer

The WHO End TB Strategy

The WHO End TB Strategy Aims (2015-2030) • To reduce TB deaths by 90% • To cut new cases by 80% • To ensure that no TB-affected family faces

catastrophic costs due to TB.

Challenges in TB/HIV • Active TB – Prompt detection (Diagnosis) – Drug-drug interactions (Treatment regimen) – Treatment duration – Initiation of antiretroviral therapy – Paradoxical reaction: TB-IRIS

• Latent TB – Risk of reactivation – Detection of latent TB infection (Diagnosis) – Treatment

Clinical manifestations of TB/HIV

• Influenced by degree of immunosuppression: CD4 > 350: similar to non-HIV

• Minimal or nonspecific symptoms • Atypical CXR findings:

– Less cavitation, more lower, middle lobe, interstital and miliary infiltrates

– Normal CXR (2-22%)

• Smear-negative pulmonary TB • Subclinical disease: Unmasking with ART • Extrapulmonary TB: 40-80% in HIV+ (vs 10-20% in

HIV-) Sterling TR. CID 2010; 50(S3):S223–S230

De Cock. JAMA. 1992;268(12):1581-1587

Clinical manifestations of TB/HIV varies with immune status

High proportion of smear-negative and non-cavitary pulmonary TB with lower CD4 levels

Proportion with negative AFB smears Increases with reducing CD4 counts

Proportion with cavitation on CXR Increases with increasing CD4 counts

Chamie. IJTLD 2010;14(10):1295-1302.

WHO Policy Update on TB Diagnostics

• Urinary lipoarabinomannan (LAM) Antigen for diagnosis of active TB

• Use of Xpert MTB/RIF to diagnose – Pulmonary TB – Rifampin resistance – Extrapulmonary TB

Urinary lipoarabinomannan (LAM) Antigen for diagnosis of active TB

• detection of mycobacterial lipoarabinomannan (LAM) antigen in urine have emerged as potential point-of-care tests for tuberculosis (TB).

• LAM antigen is a lipopolysaccharide present in mycobacterial cell walls, which is released from metabolically active or degenerating bacterial cells and appears to be present only in people with active TB disease.

• Urine-based testing would have advantages over sputum-based testing because urine is easy to collect and store, and lacks the infection control risks associated with sputum collection.

WHO policy update 2013: Xpert MTB/RIF for Diagnosis of TB and RIF resistance

Use Sensitivity (95%CI)

Specificity (95% CI)

Initial diagnostic test (replace smear microscopy)

88% (84-92%) 99% (98-99%) 22 studies, N=9008

Add-on test for AFB negative results

68% (61-74%) 99% (98-99%) 23 studies, N=7151

Smear+ Culture+ TB 98% (98-99%) 23 studies, N=1952

Smear- Culture+ TB 68% (61-74%) 23 studies, N=7151

HIV+ 79% (70-86%) 7 studies, N=1470

HIV- 86% (76-92%) 7 studies, N=1470

Rifampin resistance 95% (90-97%) 98% (97-99%) 17 studies, 555/2624 specimens 24 studies, N=2414

WHO’s policy recommendations: Use of Xpert MTB/RIF to diagnose pulmonary TB and RIF resistance

• Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults and children

• MDR-TB (strong recommendation, high quality evidence)

• HIV-associated TB (strong recommendation, high quality evidence)

• Suspected TB in adults and children (conditional recommendation acknowledging resources, high quality evidence)

• Suspected TB not at risk for MDR-TB or HIV (conditional recommendation acknowledging resources, high quality evidence)

W.H.O.2013. Xpert MTB/assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy update.

WHO policy update 2013: XpertMTB/RIF for diagnosis of Extrapulmonary TB

WHO’s policy recommendations: Use of Xpert MTB/RIF to diagnose extrapulmonary TB

• Xpert MTB/RIF should be used in preference to conventional microscopy and culture as initial diagnostic test for CSF specimens in suspected TB meningitis (strong recommendation, very low-quality evidence)

• Xpert MTB/RIF may be used as a replacement test for usual practice for non-respiratory specimens (LN, tissues) suspected extrapulmonary TB (conditional recommendation, very low-quality evidence)

W.H.O.2013. Xpert MTB/assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy update.

Treatment outcome in TB/HIV

Murray J, Sonnenberg P, Shearer SC, Godfrey-Faussett P. HIV and the outcome of treatment for new and recurrent pulmonary TB in African patients.AM J RESPIR CRIT CARE MED 1999;159:733–740.

P<0.001

P = 0.765

*Cure rate excluding deaths. ** Mortality in HIV(+): 22.1% if CD4<14% vs 7.7% with CD4 14-28%. Causes of death: Autopsy in 12, 5 due to TB, 4 cryptococcus, 3 bronchopneumonia (1 hepatic failure/necrosis, 1 CVA, 1 TB)

**

• Lower sterilization rate of sputum at 2M of STH vs RHZ 37% vs 74%, p<0·001.

• Higher relative risk of death for STH: 1·57 (95% Cl 1·0-2·48)

TB treatment regimens without Rifamycins in HIV-infected

Okwera.Lancet 1994;344:1323-8

Active pulmonaryTB HIV + persons Uganda N=191

12M: STH2/TH10 2 months STH 10 months TH

9M: RHZ2/RH7 2 months RHZ 7 months RH

Intensive phase Continuation phase

S: streptomycin, T: thiacetazone, H: isoniazid, R: rifampin, Z: pyrazinamide

Jindani A. Lancet 2004;364:1244-51.

Regimen No HIV+ Poor outcome

Relapse Mortality AE 2M culture -

2ERHZ3/6HE 466 45 (10%) 48 (14%) 26 (5.6%) 4 (0.9%) 1.1% 333/433 (77%)

2ERHZ/6HE 456 45 (10%) 36 (10%) 17 (3.7%) 14 (3.3%) 2.6% 365/424(86%)

2EHRZ/4HR 433 37 (9%) 17 (5%) 5 (1.2%) 8 (1.8%) 2.5% 335/404 (83%)

Higher rates of Relapse in TB treatment regimens without Rifamycins throughout

8 months (N=466) Intensive: thrice weekly Continuation: NO RIF

6 months (N=433) Intensive: daily Continuation: RIF used

8 months (N=456) Intensive: daily Continuation: NO RIF

Unfavorable outcome at 12M in 6 vs 8 months: (African pts) HIV+ (N=68) 5% vs 27% (p=0.09) HIV- (N=311) 2% vs 9% (p=0.008)

Role of Rifamycin in HIV-related TB • HIV-related tuberculosis should be treated

with a regimen including a rifamycin for the full course of TB – In randomized trials, regimens without rifampin or in which rifampin

was only used for the first 2 months of therapy resulted in higher rates of TB treatment failure and relapse (Jindani.Lancet 2004;364:1244-51)

– In randomized controlled trials of 191 HIV+ adults, lower sterilization rate of sputum at 2M of STH (STH2/TH10) vs RHZ (RHZ2/RH7) 37% vs 74%, p<0·001. Higher relative risk of death for STH 1·57 (95% Cl 1·0-2·48).(Okwera.Lancet 1994;344:1323-8 )

Randomized trial of Daily vs Intermittent Rifabutin in TB/HIV

Culture-positive TB HIV + persons N=169

Advanced HIV disease • Median CD4: 90 (35-

175) • Log HIV viral load: 5.3

copies/mL Extrapulmonary TB: 22(13%) EPTB 54 (32%) Both Antiretroviral therapy (ART): 38 (22%) on ART at TB diagnosis 137/169 ( 81%) on ART

2 months DOT HEZ+Rifabutin

Daily for 2wks Thrice-weekly

4 months DOT H + Rifabutin Twice weekly

Burman. AJRCCM 2006;173;350-6.

9 (5.3%) Treatment failure (N=3) or Relapse (N=6) 8/9 (89%) Rifamycin resistance CD4 < 100 vs >100: 12.3% vs 0% (p<0.01) Mortality: 25 (14.8%): 0 TB, 17 due to AIDS

Daily for 2 wks Twice-weekly

Dosing interval of anti-TB drugs in TB/HIV

• Intensive phase (first 2 months): administered daily (5 to 7 days per week) (Burman.AJRCCM 2006, Nettles. CID 2004, Swaminathan. AJRCCM 2010, Menzies. PLoS Med 2009) – Intermittent dosing (once-, twice, or thrice weekly regimen) associated with

an increased risk of treatment failure or relapse with acquired rifamycin resistance especially during the intensive phase (first 2 months) of therapy, when bacillary load is still quite high.

– Esp in patients with advanced HIV disease (CD4 cell count < 100 cells/mm3)

• Continuation phase (4 months): administered daily (5 to 7 days per week) or thrice weekly – Intermittent dosing (once or twice weekly regimen) associated with an

increased risk of treatment failure or relapse with acquired rifamycin resistance (Vernon. Lancet 1999, Burman. AJRCCM 2006)

– Thrice weekly regimen not associated with treatment failure, relapse or rifamycin resistance. (Khan. CID 2010. Meta-analysis)

Treatment duration

• Optimal duration of treatment for drug-susceptible TB is unknown

• Low-burden country: Good outcomes with 6 months regimen (El-Sadr. CID 1998)

– Relapse rate 3.9% vs 2.0% in 6M vs 9M (p=1.00)

• High-burden country: Higher risk of relapse with 6 months regimen vs 9 or 12 months (Swaminthan. AJRCCM 2010; Perriens. NEJM 1995)

– Relapse rate: 15% vs 7% in 6 vs 9 months (p< 0.05) – Relapse rate: 9.0% vs 1.9% in 6 vs 12months (p<0.01)

Current guidelines for Treatment Duration of anti-TB drugs in HIV

• 6 months (BII) • 9 months (BII) with a positive 2-month

sputum culture • 9-12 months for TB meningitis (BII) • 6-9 months for bone and joint TB (BII) Taiwan guidelines (5th edition) • 9 months • 12 months for TB meningitis

Adjunctive Steroid therapy in TB/HIV

• Increases survival for patients with HIV-related TB (AI) – involving the CNS (Thwaites. NEJM 2004) – Involving the pericardium (Hakim. Heart 2000)

• Different doses and treatment duration unknown – CNS: dexamethasone 0.3-0.4mg/kg/day for 2-4 weeks, 0.1mg/kg per

week, 4mg per day, taper by 1mg/day, total 12wks – Pericardium Prednisolone 60mg/day, taper 10mg/week, total duration

6 weeks.

Thwaites. NEJM 2004 Oct 21;351(17): 1741-51. Hakim. Heart 2000;84(2):183-88.

Immune Reconstitution Inflammatory Response (IRIS) in TB/HIV

Pulmonary TB Extrapulmonary TB •Fever, malaise, BW loss •Worsening respiratory symptoms •Transient worsening radiologic abnormalities: - New parenchymal opacities - Enlarged intrathoracic lymph nodes •ARDS

•Enlarging lymphadenitis •New pleural effusions •Reappearance of fever with new infiltrates •Enlarging intracranial tuberculomas •Worsening meningitis or radiculomyelopathy

Manabe. J Infect Dis. 2009;199(3):437

Paradoxical Reaction in TB Non-HIV HIV

Meintjes. Lancet Inf Dis 2008;8(8):516-23 Manabe. J Infect Dis. 2009;199(3):437 Gopalan 2014 Expert Rev Clin Immunol 10(5):631-45.Muller. Lancet Infect Dis 2010;10:251-61.

Breen. Thorax 2004;59;704-707.

Immune reconstitution inflammatory syndrome (IRIS) �Paradoxical TB-IRIS -Deterioration of a treated TB infection after initiating ART (8-56%) �Unmasking TB-IRIS: - New presentation of active TB diagnosed within 3 months of ART use

�Paradoxical reaction to treatment of TB

Paradoxical reactions in TB in HIV versus non-HIV patients

Breen. Thorax 2004;59;704-707.

Risk Factors for HIV-related TB-IRIS

• Low CD4 cell count at baseline (< 100 cells/mm3)

• Disseminated TB or extrapulmonary TB • A short interval between starting anti-TB

treatment and ART (< 2 months) • Substantial increase in CD4 cell counts • Rapid drop in HIV viral load

Gopalan 2014 Expert Rev Clin Immunol 10(5):631-45.

Management of IRIS

• Most are self-limiting. Provide symptomatic therapy (analgesia, anti-emetics, anti-inflammatory, needle aspiration of effusions, abscesses)

• In severe cases, consider prescribing prednisone 1-2 mg/kg or equivalent for 1-2 weeks, followed by a taper 0.75mg/kg/day for 2 weeks.

• Except in severe cases, ARV therapy should not be interrupted in patients with IRIS.

What is the optimal timing to start antiretroviral therapy in TB/HIV co-infected patients?

When to start ART in HIV-infected TB patients?

SAPiT: Optimal Time to Initiate ART in HIV/TB-Coinfected Patients

HIV-infected patients diagnosed with TB and

CD4+ cell count < 500 cells/mm3

(N = 642)

Early ART ART initiated during intensive or continuation phase of TB therapy

(n = 429)

Sequential ART ART initiated after TB therapy

completed (n = 213)

Primary endpoint: all-cause mortality

From Larry William Chang, MD, MPH, Johns Hopkins School of Medicine, Cochrane Collaborative Group on HIV/AIDS at UCSF

Ann Intern Med. 2012;157:313-324.

SAPiT Trial: When to start ART in TB/HIV coinfected patients

Abdool Karim. NEJM 2010;362:697-706.

Mortality rate: 5.4 per 100 py

Mortality rate: 12.1 per 100 py

HR for mortality in the integrate dgroup: 0.44 (95% CI: 0.25-0.79, p=0.003)

Ann Intern Med. 2012;157:313-324.

SAPiT trial: IRIS incidence and types

Optimal Timing to Start ART [SAPIT trial, South Africa]

Outcome CD4 count (cells/ mm3)

Early ART (within 4 wks) (n=214)

Late ART (4-8weeks) (n=215)

Incidence Rate Ratio (IRR)

Incidence of AIDS or death

Any 6.9 per 100PY 7.8 per 100PY 0.89, p=0.73

< 50 8.5 per 100PY 26.3 per 100PY 0.32, p=0.06

> 50 6.6 per 100PY 4.4 per 100PY 1.51, p=0.34

Risk of IRIS

< 50 46.8 per 100PY 9.9 per 100PY 4.7, p=0.01

> 50 15.8 per 100 PY 7.2 per 100 PY 2.0, p=0.02

Kabdol Karim. NEJM 2010;362(8):697-706

CAMELIA study: Earlier Start of ART in HIV/TB coinfected patients (n=661)

Blanc FX. NEJM 2011 Oct 20; 365: 1471-1481. CAMELIA study.

Optimal Timing to Start Antiretroviral Treatment (ART)

Trial No CD4 Early start Late start Result

SAPiT (NEJM 2010) South Africa

642 CD4 < 500 AFS+

Integrated 4 weeks 8 weeks

Sequential (after tx complete)

Stopped early, mortality 56% lower in integrated groups

CAMELIA (NEJM 2011) Cambodia

661 Median CD4: 25

2 weeks 8 weeks Mortality 18% vs 27% (2 wks versus 8 wks)

ACTG A5221 (NEJM 2011) America Africa, Asia

809 Median CD4: 77 *CD4: <50

Immediate2 weeks

Early: 8-12 weeks

A new OI or death in immediate vs early ART: 12.9% vs 16.1% (p=0.45) 15.5% vs 26.6% (p=0.02)* IRIS incidence: 11% vs 5% (p=0.002)

PART study (JID 2011)

CD4 >350

TB diagnosis

CD4 < 250 Lower rates of AIDS or death

XDR-TB (Lancet 2010)

62% reduction in death

Abdool Karim. NEJM 2010;362(8):697-706.Blanc.NEJM 2011;365(16):1471-81. Havlir. NEJM 2011;365(16);1482-91. Nanteza. JID 2011;204(6):884-92. Dheda. Lancet 2010;375(9728):1798-1807.

Current guidelines for Treatment of TB/HIV

• ART recommended for all HIV-infected persons with TB (AI)

• ART-naïve patients, ART should be started (AI) – within 2 weeks when CD4 < 50 cells/mm3

– Within 4-8 weeks for all others

• When TB occurs in patients already on ART, treatment for TB must be started immediately (AIII), and ART should be modified to reduce the risk of drug interactions and maintain virologic suppression.

• Adherence support

Drug-drug interactions in TB/HIV should be managed, not avoided

Rifampin • 2 NRTIs + Efavirenz (AII) Efavirenz 600mg dose recommended

(BII) • Nevirapine: omit lead-in dose (Boulle. JAMA 2008; Manosuthi. AIDS 2006)

• Rifampin is not recommended in patients receiving HIV PIs, ETR, RPV, or EVG/COBI/TDF/FTC

Rifabutin • Ritonavir-boosted protease inhibitors (PI)(BIII) if NNRTI

intolerant or resistant • 150 mg of rifabutin daily (at least during the first 2months of

TB treatment) for patients who are on a PI-containing ARV regimen (BIII).

Rifabutin Dose adjustment in TB/HIV

Antiretroviral agent used

Rifabutin Dose Daily

Rifabutin dose 3x/week

Without protease inhibitors, EFV, RPV, or EVG/COBI/TDF/FTC

5mg/kg (300mg) 5mg/kg (300mg)

protease inhibitors (PI)

150mg 300mg

Efavirenz (EFV) 450-600mg 450-600mg EVG/COBI/TDF/FTC 150mg 150mg

a Acquired rifamycin resistance has been reported while on 150 mg twice weekly dosing together with ritonavir-boosted PIs. b Avoid co-administration of EVG/COBI/TDF/FTC with rifabutin, if possible. If used together, consider therapeutic drug monitoring andadjust dose accordingly. Key to Acronyms: COBI = cobicistat; EFV = efavirenz; EVG = elvitegravir;; FTC = emtricitabine; RPV= rilpivirine; TDF= tenofovir

Challenges in TB/HIV • Active TB – Prompt detection (Diagnosis) – Drug-drug interactions (Treatment regimen) – Treatment duration – Initiation of antiretroviral therapy – Paradoxical reaction: TB-IRIS

• Latent TB – Risk of reactivation – Detection of latent TB infection (Diagnosis) – Treatment

(70%) (30%)

Active TB (10%)

Active TB in HIV+:

5-8%

: 2 3.6 : 4.9

: 7 25 : 1.7 9

: 16 : 20 74

:26

Latent TB (90%)

TST+ IGRA+

TST: tuberculin skin test; IGRA: interferon-gamma release assay

10%

1.7 170

Lobue P & Menzies D. Respirology 2010;15:603–622. Am J Respir Crit Care Med 2000 Apr;161(4 Pt 2):S221-47.

Lawn SD. AIDS 2005;19:2109-2116.

Protective effect of HAART for TB in HIV-infected N=11,026 in HIV+ (Brazil, 2003-2005) Overall TB incidence: 2.28/100 PYs

TB incidence in Brazil (2005) * General population 41.8 per 100,000 * HIV+ under ART: 1010 per 100,000 = 24.3-fold

Lawn SD. AIDS 2009;23:1717-25.

Risk of TB related to CD4 cell count in HIV-infected persons

TB incidence CD4 > 500: 1.5 per 100 py Baseline: 0.7 per 100 py TB incidence in HIV+ is 2.1 times higher than in the general population 6.0-24.0 times if CD4< 500

ART reduced TB incidence in HIV-infected persons, but remains higher than the general population

Country Period TB incidence in HIV(+) persons (per 100 person-years)

Residual risk compared to the general population Without ART With ART

South Africa1 2002 9.7 2.4 5-fold South Africa2 2003-2007 7.1 4.6 10-fold Brazil3 2006 4.0 1.9 38-fold United States4 1992-1998 7.2 1.9 279-fold Switzerland5 1995 0.78 0.22 16-fold Taiwan6 1995-1999 54.5 10.5 (157-184-fold*) Taiwan7 2006-2010 0.41 0.47 7 to 8-fold* Taiwan8 2011-2013 0.599 (IGRA+ & 84% on ART) 11 to 12-fold**

*Calculated using 2006 and 2010 TB incidence: 67 and 57 per 100,000 population ** Calculated using 2011 and 20103TB incidence: 54.5 and 49.4 per 100,000 population

1. Badri et al. Lancet 2002;359:2059-64. 2. Golub.JE . AIDS 2009; 23:631-636. 3. Golub JE. AIDS 2007;21:1441-1448. 4. Jones 2000 Int J Tuberc Lung Dis;4:1026-31. 5. Ledergerber et al. JAMA 1999;282:2220-6. 6. Hung CC. J AIDS 2000;24(4):378-385. 7. Lee SS. PLoS One 2015 Aug 17; 10(8): e0135801. 8. Sun HY. PLoS One 2014;10(5): e0125260.

ART & Isoniazid Prevention Treatment (IPT) can Reduce TB Incidence in HIV-infected persons

Exposure Category

IR (per 100 PY) 95% CI

Incidence rate ratio (95% CI)

Adjusted HR (95% CI)

Brazil1 Naive 4.01 (3.40-4.69) 1.0 1.0 (N=11026) ART only 1.90 (1.66-2.17) 0.48 (0.39-0.59) 0.41 (0.31-0.54)

IPT only 1.27 (0.41-2.95) 0.32 (0.10-0.76) 0.57 (0.18-1.82) ART + IPT 0.80 (0.38-1.47) 0.20 (0.09-0.91) 0.24 (0.11-0.53) Total 2.28 (2.06-2.52)

South Naive 7.1 (6.2-8.2) 1.0 1.0 Africa2 ART only 4.6 (3.4-6.2) 0.65 (0.46-0.91) 0.36 (0.25-0.51) (N=2778) IPT only 5.2 (3.4-7.8) 0.73 (0.44-1.13) 0.87 (0.55-1.36)

ART + IPT 1.1 (0.02-7.6) 0.14 (0.02-1.03) 0.11 (0.02-0.78) Total 6.2 (5.5-7.0)

1. Golub JE. AIDS 2007;21:1441-1448. 2. Golub.JE . AIDS 2009; 23:631-636.

ART: antiretroviral therapy; IPT: isoniazid preventive treatment IR: incidence rate; TB: tuberculosis: ref: reference

Guidelines for LTBI in HIV

• LTBI treatment and ART act independently to decrease the risk of TB disease. Therefore, use of both interventions is recommended for those who have LTBI and an indication for ART (AII).

Diagnosis of Latent TB infection Mechanism of immunodiagnostic tests for

Mycobacterium tuberculosis infection

Andersen P et al. Lancet 2000;356:1099-104.

TST: Tuberculin Skin Test

IGRA: QuantiFERON TB-Gold test

in-vivo

Tuberculin Skin Test (TST)

Interferon-gamma Release Assay (IGRA)

Specificity Poor (false positives) • BCG vaccination • Non-tuberculous mycobacteria

High • M.kansasi, M.marinum, M.szulgai

Protein used Tuberculin ESAT-6, CFP-10, TB 7.7 (specific antigens to M.tuberculosis)

Sensitivity Poor (false negatives) • Active TB • Immunosuppression (HIV-infected, ESRD, newborns)

Higher ?

Booster effect YES No

Operational Inter-individual variation in application and interpretation

Simple, blood test with objective criteria

No of Visits Requires 2 patient visit Only 1 patient visit

Pai M et al. Lancet Infect Dis 2004;4:761-76.

Diagnostic Tests for Latent Tuberculosis Infection

Sensitivity of IGRA in HIV-infected persons with confirmed Active TB

Low/Middle Income Sensitivity % (95% CI)

• TSPOT: 72 (62-81) • QFT: 61 (47-85)

High Income Sensitivity % (95% CI)

• TSPOT: 94 (73-100) • QFT: 67 (47-83)

Cattamanchi A. Acquir Immune Defic Syndr. 2011 March ; 56(3): 230–238.

Diagnosis of Latent TB infection in HIV

• IGRAs have higher specificity (92%–97%) than TST (56%–95%), better correlation with surrogate measures of exposure to M. tuberculosis, and less cross reactivity because of BCG vaccination or other non-tuberculous mycobacteria exposure.

• Progressive immunodeficiency is associated with decreased sensitivity of IGRAs, although immunodeficiency may have less impact on the sensitivity of IGRAs than on the sensitivity of TST.

Menzies. Ann Intern Med 2007; Ewer. Lancet 2003; Raby. PLoS One 2008; Luetkemeyer. AJRCCM 2007; Talati. BMC Infect Dis 2009; Hill. CID 2009; Aichelburg. CID 2009.

Lowered IGRA & TST positivity in HIV-infected persons

Lin WC et al. JMII 2014 Nov 1. pii: S1684-1182(14)00179-0. doi: 10.1016/j.jmii.2014.08.010. [Epub ahead of print]

Predictive value of IGRA for Active TB in HIV-infected persons

Author Country PPV NPV Unadjusted Median (Year) (TB burden) (%) (%) RR (95% CI) F/U Aichelburg Austria 8.3 100.0 136.14 (7.16-2588.46) 1.58 PY (2009) (Low) (19 months)

Jonnalagadda Kenya 5.1 98.0 2.69 (0.69-10.52) 1.28 PY (2010) (High) Kim Korea 20.0 93.9 4.17 (1.51-11.48) 2.59 PY (2012) (Intermediate) (947 days)

Yang Taiwan 4.7 100.0 73.9 (3.9–1397.7) 2.97 PY (2013) (Intermediate) Sun Taiwan 1.6 100.0 2.58 PY (2015) (Intermediate) Lee Taiwan 6.7 98.5 4.18 (1.52-11.52) 5.21 PY (2015) (Intermediate)

PY: person-years, PPV: Positive predictive value, NPV: Negative predictive value, RR: rate ratio, F/U: follow-up Rangaka MX. Lancet 2012;12:45-55. Aichelburg MC. CID 2009;48(7):954-62. Jonnalagadda S. JID 2010;202(12):1826-35. Kim YS. AIDS Res Hum Retrovir 2012; 28(9):1038-43. Yang CH et al. (2013) PLoS One 8: e73069. Sun HY, et al. (2015) PLoS One 10: e0125260. Lee SS. (2015) PLoS ONE 10(8): e0135801

Guidelines for LTBI in HIV

• HIV-infected individuals who test positive for LTBI but have no evidence of TB disease should receive LTBI treatment (AI).

• HIV-infected close contacts of anyone who has infectious TB also should receive prophylaxis, regardless of results of screening tests for LTBI (AII).

• HIV-infected individuals who are anergic and have not had recent contact with anyone with infectious TB, treatment of LTBI is not associated with clinical benefit and is not recommended (AI)

Concerns with Isoniazid preventive treatment (IPT) in HIV-infected persons

in low-to-moderate TB burden settings

• Reasons for low uptake of IPT: – Lack of programs to implement the policy – Perceived low risk of active TB – Concerns with isoniazid hepatotoxicity – Lack of reliable test to accurately predict risk of TB in HIV-

infected persons

• Untargeted IPT will place large numbers of persons, who may never benefit from IPT, at risk for adverse drug reactions

• Justifiable only if IPT was targeted to those with significantly increased risk of TB.

Lee SS. (2015) PLoS ONE 10(8): e0135801

Cumulative incidence of active tuberculosis disease over 5 years in a cohort of HIV-infected adults (N = 772)

Rate of incident TB: 0.44 per 100 PY (95% CI:0.28-0.71) Develop TB within 2 years of follow-up: 8/17 (47.1%)

Lee SS. (2015) PLoS ONE 10(8): e0135801

Active TB: 17/772 (2.2%) IGRA+ in 6/17 (35%)

Kaplan-Meier curve to development of active tuberculosis disease by composite risk factor combining high HIV viral load of greater than 100,000 copies per mL, CD4 cell count and interferon-gamma release assay (IGRA)(N = 772)

Lee SS. (2015) PLoS ONE 10(8): e0135801

Lee SS. (2015) PLoS ONE 10(8): e0135801

A multivariable algorithm to predict risk of active tuberculosis in people with HIV infection using a composite risk factor of HIV viral load, CD4 cell count and interferon-gamma release assay (IGRA) result

the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5%to 99.2%. spared 468 (60.6%) from unnecessary TB preventive treatment.

Treatment of LTBI in HIV

Summary • HIV-TB is a syndemic, HIV and TB both are leading causes of

mortality • Diagnosis of TB/HIV is influenced by CD4 cell count • WHO endorsed new diagnostic test: Urine LAM Ag & Xpert Mtb • Treatment of TB in HIV requires rifamycins throughout the

treatment course • Daily regimens recommended in intensive phase, daily or

thrice-weekly in continuation phase • TB-IRIS is more frequent in HIV+, EPTB, and onset earlier • Risk of TB reactivation is higher in HIV+ patients even if on

antiretroviral therapy, and/or with high CD4 count recovery • Treatment of LTBI in HIV