IRZE Ant-HIV: NR - cqihiv.com• Data on DR-TB in children are sparse due to –Low C/S yield –...

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• Ant-HIV: NR

• Sputum AFB+

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• Epidemiology of tuberculosis (TB) in children

• Diagnosis and management of TB in children

Drug-resistant TB (DR-TB)

TB-HIV coinfection

• Management of children exposed to active TB cases

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http://apps.who.int/iris/bitstream/10665/137094/1/9789241564809_eng.pdf?ua=1

• 1.5 million TB death (1.1 million among HIV- and 0.4 among

HIV+ people)

– 80,000 (64, 000–97,000) among HIV-negative children (~7% of the

total TB deaths among HIV-negative people)

• 210,000 deaths from MDR-TB (130,000-290,000)

• In 2013, there were 9.0

million new TB cases

– 550,000 (470,000–

640,000) cases in

children(~6% of the new

cases)

• The predicted

proportion of TB

burden in children

for each country

correlated with

incidence, varying

between 4-21%

• India accounted for

27% (22-33) of the

total burden of

pediatric TB in the

22 countries

Dodd PJ, et al. Lancet Glob Health 2014;2(8):e453-9.

Lolekha R, et al. BMC Infectious Diseases 2008;8:94.

71%0%

1%

17%1%

8% 0% 2%

Pulmonary

Disseminated

Pleura

LN

Bone/joint

Meningeal

Pritoneal

Other/missing

• 279/14,487 (2%) occurred in children, median age 8 years (4 m-14 y)

•PTB 197 (70%), + smear 56 (28%)

•EPTB 82 (30%), LN is the most common EPTB

•32% were bacteriologically confirmed, 28% were smear-positive, 4% were

smear-, C/S +

• 75 (27%) had HIV co-infection, with mortality of 17% vs 2% among those

without HIV (p < 0.01)

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• Extensively drug-resistant TB (XDR-TB) has been reported by

100 countries. On average, an estimated 9.0% (95% CI: 6.5–

11.5%) of people with MDR-TB have XDR-TB

• Globally, ~3.5% (95% CI: 2.2–

4.7%) of new cases and 20.5%

(95%CI: 13.6–27.5%) of

previously treated cases have

MDR-TB

• In 2013, estimated 480,000

(range: 350,000‒610 ,000) new

cases of MDR-TB worldwide,

and ~ 210 000 (range: 130

000–290 000) deaths from

MDR-TB.

• HIV infection among TB cases 15%

http://www.who.int/tb/publications/global_report/gtbr14_annex2_country_profiles.pdf?ua=1

• Data on DR-TB in children are sparse due to

– Low C/S yield

– Low drug susceptibility done

• Children serve as a ―sentinel‖ of TB transmission in the

community, and drug resistance in this group mirrors the

situation in the adult population in the region

• Key reasons of DR-TB in children

– ―Primary resistance‖—transmitted from adults with MDR-TB

– Past treatment with anti-TB therapy

– Rather than secondary resistance from suboptimal therapy or non-

adherence*

12Shah I. Pediatr Infect Dis 2012;;31(9):970-2. Curr Infect Dis Rep 2013;15:356-63.

*Schaaf HS, et al. Am J Public Health 2009;99(8):1486–90.

• Of 230 children diagnosed with TB

in 2008-2011; 63% had identified

adult source cases

– Pulmonary only 155 (67%)

– Extrapulmonary with pulmonary 32 (14%)

– Extrapulmonary without pulmonary 43

(19%)

• Of the 195 (85%) specimens

submitted, 57 (25%) were positive

using culture or PCR

• The overall prevalence of drug-

resistant TB 14.3%; 34% (18/53) in

those with microbiologic confirmed

TB

Lapphra K, et al. Int J Tuberc Lung Dis 2013;17(10):1279-84.

• Resistance to INH is mediated by at least two genes1

– KatG

• Loss /reduced catalase-peroxidase activity (required for activation

INH to active form)

• Major mechanism, present in ~ 50–90 % of all INH-resistant

isolates

• Associated with relatively high-level resistance to INH

– InhA

• Also resistance to ethionamide (ETH)

• 86% of INH-resistant isolates with InhA were also ETH-resistant2

• Up to 25% of INH resistant isolates do not carry any of known

mutations C/S and standard DST are necessary 3

1. Guo H, et al. J Med Microbiol 2006;55:1527-31.

2. Schaaf HS, et al. Int J Tuberc Lung Dis 2009;13(11):1355-9.

3. Laurenzo D, et al. Acta Trop 2011 ;119(1):5-10.

• Rif resistance: assumed to be a surrogate marker for MDR TB,

> 90% of Rif resistant isolates are INH resistant1

• rpoB gene: accounts for > 90% of rifampicin resistance

• GeneXpert MTB/RIF (1,500 Bht, turn-around time 2 hr)

– Children: sensitivity 68.8% for GLA vs 90.0% for sputum; specificity 99.3% for

GLA and 98.5% for sputum for pulmonary TB diagnosis2

– Rif resistance : sensitivity 94–98% and specificity 98%, relative to phenotypic

DST3

– Some false-positive results confirmatory drug sensitivity testing is needed

1. Drobniewski FA. Microbiol 1998;47:189-196. 2. Bates M. Lancet Infect Dis 2013; 13: 36–42.

3. Niemz A, et al. Expert Rev Mol Diagn 2012;12(7):687-701. 4. WHO. Rapid implementation of the Xpert MTB/RIF diagnostic

test: technical and operational ‗how to‘ practical considerations, 2011.

WHO has recommended MDR treatment regimen in patients with

Rif-resistant pending for culture-based investigation and DST4

• Father: MDR-TB, Mother: Fully susceptible TB

Resistance

to

Suggested regimen Duration Comments

INH Rif, PZA, ETB (a FQN may

strengthen regimen in extensive

disease)

6-9 m > 95% success rate if Rif+ETB

or SM was used throughout,

best result if use 6 m of PZA

Rif INH, ETM, FQN, + PZA in 1st

two months (injectable agent may

be included for 2-3 m in

extensive disease)

12-18 m INH, PZA, and SM for 9 m

were effective

? ETB is effective as SM

CDC. MMWR 2003;52(RR11):1-77. WHO/HTM/ TB/2006.371; WHO/FCH/CAH/2006.

• The basic principles of MDR-TB treatment for children are

the same as adults; and is often based on susceptibility of

the source case

• Lack of pediatric formulations, paucity of PK data make

dosage challenging, however, when treated

appropriately, children with DR TB have good outcomes

19Curr Infect Dis Rep 2013;15:356-63.

*Schaaf HS, et al. Am J Public Health 2009;99(8):1486–90.

• Use any 1st line medication to which susceptibility is

documented or likely

– High-dose INH, unless high-level INH resistance or Kat-G mutation

is documented

– Consider PZA

• Use of at least 4 second-line drugs to which the strain is

likely to be sensitive, should include

– 1 injectable agent

– 1 fluoroquinolone

• DOT (directly observed therapy) to ensure that patients

adhere to treatment

20Curr Infect Dis Rep 2013;15:356-63.

• Regimen should include at least 4 susceptible anti-TB drugs:

AMK (Kanamycin), FQN (Ofloxacin, levofloxacin,

moxifloxacin), EMB, PZA,+ 2nd line agent (Etionamide, PAS,

Cycloserine, etc) Or

6PZA, Km, Oflox, Eto, Cycloserine (WHO)

• Treatment duration: 18–24 months

– Minimum duration of injectable agent: total 6 m or 4 m after culture

conversion

– At least 12 months after the last positive culture/smear with minimal

disease or 18 months with extensive (lung cavities or widespread

parenchymal involvement) disease

AAP. Red Book 2012; CDC. MMWR 2003;52(RR11):1-77.

WHO/HTM/TB/2011.6. Guidelines for the programmatic management of drug-resistant tuberculosis 2011 update.

• 16,533 strains of M. tuberculosis from smear-positive sputum samples sent

to laboratory, Siriraj Hospital, Bangkok, during 2003–2011, were isolated

and identified as Of

• 1447 (8.8%) strains were MDR-TB and 58 (4%) as XDR-TB

• Among those with known treatment history, MDR-TB were detected in

3.8% and 26.3% of new cases and previously treated cases

22Chaiprasert A, et al. Int J Tuberc Lung Dis 18(8):961–963

Berti et al. BMC Infectious Diseases 2014, 14(Suppl 1):S3

Ethionamide + PAS: increase incidence of hypothyroidism

Ethionamide: TSH should be measured at baseline and at monthly

B6 supplement

• Started anti-TB regimen 24/2/56

– Amikacin Kanamycin

– Ofloxacin Levofloxacin

– Ethionamide

– PAS

– Cycloserine

• 26/4/56 Hypothyroidim

consult endocrine on thyroid

supplement

• 7/5/56 Hallucination

• 21/8/56 Abnormal hearing

off injectable agent

ENT started NAC long

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• 8 studies reported treatment outcomes of 315 patients

• Time to appropriate treatment: 2 days - 46 months

• The pooled estimate for treatment outcomes

– Success 81·67% (95% CI 72·54–90·80)

– 5·9% (95% CI 1·3–10·5) died, 6·2% (2·3–10·2) defaulted

• 39·1% (28·7–49·4) had an adverse events(AEs)

– The most common AEs were nausea and vomiting

– Other serious AEs: hearing loss, psychiatric effects, and hypothyroidism

• Outcomes can be achieved at least as good as those reported for adults

25Ettehad D, et al. Lancet Infect Dis 2012;12: 449–56.

http://apps.who.int/iris/bitstream/10665/137095/1/WHO_HQ_TB_2014.12_eng.pdf

The safety and dosing of bedaquiline has not been

established in children and its use in this group should

The safety and dosing of bedaquiline has not been

established in children and its use in this group should

be avoided if possible (Phase II)

27

• A multicenter, study in Asian HIV-infected children in the TREAT Asia

Pediatric HIV Observational Database (TApHOD)

• PTB episodes between 12 months before ART initiation and Dec 2009

• 457/2678 (17.1%) (5.7-33.0% per country, 14.1% for Thailand) developed

PTB over a 13-year period

• The median (IQR) CD4+ were 9.0% (3.0-16.0%) and 183.5 (37.8-525.0)

cells/mm(3) at PTB diagnosis

• 34.4% had bacteriologic evidence of PTB

• 32.2% also had EPTB

• 34.4% contacted with TB cases within 12 m before PTB diagnosis

• 94% were family member

• 3.2% received chemoprophylaxis

• Outcome

• 81.9% have positive outcomes (cure, Rx completed, and improvement)

• There were 21 deaths (4.3%)28Sudjaritruk T, et al. AIDS Patient Care STDS 2013;27(12):649-56.

• Children most commonly are infected with TB from household

• HIV-infected infants and children should be treated

for LTBI if

• Exposure to a person with contagious TB

(after exclusion of active TB disease)

regardless of the TST results (AII)

• PPD > 5 mm (CDC recommended

annual TST but not in Thailand)

• Preferred regimen:

• Isoniazid (10-15 mg/kg/day) for 9 m

• Rifampicin (10-20 mg/kg/day) for 4-6 m for INH-resistance

CDC. MMWR 2009;58(RR-11):1-166.

• Clinical features are similar to those among

children without HIV infection, however

• Usually more severe

• Can be atypical

• Difficult to differentiate from other OIs

• More extra-pulmonary disease

CDC. MMWR 2009;58(RR-11):1-166.

• Anti-TB treatment must be started immediately in HIV-infected children diagnosed with TB (AIII)

• Issues to consider

• Drug interaction: rifampin-potent bactericidal properties and potent induction of CYP3A enzyme that precludes PIs treatment but may allow NNRTIs

• Overlapping toxicities

• Pill burden

(3 ARVs + 4 anti-TB + B6 + co-trimoxazole)

• Possible development of IRIS

CDC. MMWR 2009;58(RR-11):1-166.

Antiretroviral therapy of HIV infection in infants and children: towards universal access- 2010 revision. WHO 2010.

• When to start antiretroviral therapy?

• What to start ?

• How to treat TB in HIV-infected children

who need PIs ?

• When to start antiretroviral therapy?

• What to start ?

• How to treat TB in HIV-infected children

who need PIs ?

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

Integrated groups had Integrated groups had

more IRIS but 56%

less mortality

ART within 4 wks of TB RX ART within 4 wks after intensive TB Rx

ART within 4 wks after completing TB Rx

• When to start antiretroviral therapy?

• What to start ?

• How to treat TB in HIV-infected children

who need PIs ?

Boulle A. JAMA 2008;300:530-9.

• Patients starting NVP-based with concurrent TB were at a higher risk of

elevated viral load (OR, 2.1; 95% CI, 1.2-3.4) and developed virological failure

sooner (HR 2.2; 95% CI, 1.3-3.7), but not EFV-based

• If HAART was established before TB diagnosis, neither NVP nor EFV

regimens gave comparable virological outcome

Timing of ART

following TB Rx

Recommended ART regimen

Start ART 2-8

weeks following TB

treatment

In children <3 years

• Preferred 1st line regimen: 2 NRTIs + NVP*

(Except if <2 y and previously exposed to NVP) or

• Triple NRTI 1st line regimen (d4T or AZT) + 3TC + ABC

In children ≥3 years

Preferred 1st line regimen: 2 NRTIs + EFV

or

Triple NRTI 1st line regimen (d4T or AZT + 3TC + ABC)**

**preferable to switch to a standard 1st line regimen on

completion of TB treatment

* Lead-in dosing should not be used when initiating NVP-containing ART with TB

treatment , NVP dose should be the maximum dose of 200 mg/m2

Antiretroviral therapy of HIV infection in infants and children: towards universal access- 2010 revision. WHO 2010.

• When to start antiretroviral therapy?

• What to start ?

• How to treat TB in HIV-infected children

who need PIs ?

• PI

• Saquinavir80% decrease

• Ritonavir 35% decrease

• Indinavir 92% decrease

• Nelfinavir 82% decrease

• Amprenavir 81% decrease

• NNRTI

• Nevirapine 37% decrease

• Efavirenz 26% decrease

• NRTI

• No effect

RifampinRifampin strongly induce strongly induce

CYPCYP33AA4 4 and and

transmembranetransmembrane efflux efflux

pump Ppump P--glycoprotein. glycoprotein. ((NiemiNiemi

M. M. ClinClin PharmacokinetPharmacokinet 20032003;;4242::819819--850850))

ARV are substrates of ARV are substrates of

CYPCYP33AA4 4 and Pand P--

glycoprotein.glycoprotein.

• Few published data

• WHO recommend

• Increase LPV/r to a ratio of 1:1 to achieve adequate LPV exposure

• Where available, monitoring of therapeutic drug levels

Liquid RTV is not widely availableLiquid RTV is not widely availableLiquid RTV is not widely availableLiquid RTV is not widely available

Needs cold chainNeeds cold chainNeeds cold chainNeeds cold chain

Bad taste Bad taste Bad taste Bad taste

Impractical!!!Impractical!!!

Antiretroviral therapy of HIV infection in infants and children: towards universal access- 2010 revision. WHO 2010.

PI-based HAART was associated with significantly lower viral suppression at 6

and 12 mo if treated concurrently for TB, but not with NNRTI

Children < Children < 3 3 y received y received

dd44T+T+33TC+LPV/r TC+LPV/r

(double dose or (double dose or

superboostedsuperboosted 11::11))

Children > Children > 3 3 y received y received

dd44T+T+33TC+EFV TC+EFV

Zanoni BC, et al. AIDS 2011;25:49–55.

N = 1029

36% were cotreated for

HIV-TB

P < 0.0001

• For those to use NNRTI regimens, can take with rifampin

without dose adjustment

Prefer EFV than NVP in children > 3 year-old

• Consider 3NRTIs (AZT/d4T + 3TC + ABC) with rifampin

without dose adjustment. But may be less efficacious

• For those who need PI regimens

• If CD4 is very low, use rifampicin-free regimen using quinolones

or aminoglycosides

• If CD4 is not very low, defer/stop HAART for 2 months to finish

intensive phase with IRZE then use rifampicin-free maintenance

phase with resumption of PI-based HAART 2 weeks later (to

wash out rifampicin)

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• Infants and young children (< 5 yr of age)

• At high risk for progression to TB disease

• More likely to develop life-threatening TB, esp. meningeal and disseminated disease

• Risk of TB among children– Index case with + smear: 49-58%

– Index case with – smear: 16-17%

• Without chemoprophylaxis, chance of development of TB disease in 1–2 years

• 40–50% of infants

• 15% of older children

• 5-10% per life time in adults (5-10%/year in HIV-infected patients)Khan E, Starke J. Emerg Infect Dis 1995; 1: 115–23.

• Have more years at risk to develop TBMMWR 2000;49 (RR-6)

• สามารถใช IGRAs เปนการตรวจเพมเตม ในกรณไมแนใจผล TST เพอชวยสนบสนน LTBI หรอ active TB disease ในเดกโตได

• ไมแนะน าในเดกอายนอยกวา 4 ป และผทมภมคมกนผดปรกต เนองจาก T-cell response ยงไมด อาจใหผล indeterminate หรอผลลบปลอมได

สมาคมโรคตดเชอในเดกแหงประเทศไทย 2553

QuantiFERON®-TB Gold In-Tube T-SPOT TB®

• IFN-ɣ production from T-lymphocyte when stimulated With

M. tuberculosis complex specific antigens (ESAT-6,CFP-10 and

TB7.7)

• Absent from • All BCG strains

• Most NTM (except M. marinum, M. fortuitum and M. kansasii)

AAP. Red Book 2012.

CDC. MMWR 2005 / 54(RR15);49-55.

A: Null B: Antigen A C:Antigen B D:Positive

• Risk for TB infection was assessed by using TST (> 10 mm) vs IGRA

QuantiFERON Gold in Tube (n = 207 children in Nigeria, 90 % received

BCG)

– Contact with adults with smear-positive TB: 49% vs 74%

– Contact with adults with smear-negative TB: 16% vs 10%

– Controls: 13% vs 10.3%

Nakaoka H, et al. EID 2006;12(9):1383-8.

• Neither TST nor IGRA can distinguish between LTBI and TB disease

• Negative results cannot exclude LTBI or TB

• Ability of IGRAs to predict risk of subsequent active TB is limited

• Person with +TST: life time risk is 5-10%

• Very few longitudinal data exist on the ability of IGRA to predict risk of subsequent TB

• Expensive (~3,000 Bht)

• Need blood collection

• Not yet approved in children < 17 y, but demonstrated good results in

children > 5 y

• Studies in children are scant esp. in children < 5 years

• High indeterminate results (0-17%), mostly from low mitogen response (esp. in children < 4 years)

AAP. Red Book 2012

CDC. MMWR 2005 / 54(RR15);49-55. CDC. MMWR 2010;59(RR5):1-25.

TST preferred, IGRA acceptable

• Children <5 y of agea

IGRA preferred, TST acceptable

• Children ≥5 y of age who have received BCG vaccine

• Children ≥5 y of age who are unlikely to return for TST reading

TST and IGRA should be considered when: (routine testing with TST + IGRA is

geneally not recommended)

• The initial and repeat IGRA are indeterminate

• The initial test (TST or IGRA) is negative and:

Clinical suspicion for TB disease is moderate to highb

Risk of progression and poor outcome is highb

• The initial TST is positive and:

>5 y of age and history of BCG vaccination

Additional evidence needed to increase compliance

Non-tuberculous mycobacterial disease is suspected

a Positive result of either test is considered significant in these groupsb IGRAs should not be used in children <2 years of age unless TB disease is suspected. In children 2 -4 years, there are

limited data about the usefulness of IGRAs in determining TB infection, but IGRA testing can be performed if TB

disease is suspected.American Academy of Pediatrics. Red Book 2012

*Thailand: No chemoprophylaxis if contact with MDR-T B

cases*

AAP. Red Book 2012.; CDC. MMWR 2000;49(No.RR-6):1-51.

*แนวทางปฏบตส าหรบการวนจฉยและรกษาวณโรคระยะแฝงในเดก พศ.2553 สมาคมโรคตดเชอในเดกแหงประเทศไทย

LTBI Regimen

INH INH 6-9 m

Alternatives: INH + Rif or INH+ rifapentine

12 weeks

INH-

monoresistance

Rif 4-6 m

• Rifapentine + INH

– As effective and safe as INH-only for prevention of TB in children 2 - 17 y

– Had a higher treatment completion rate (88.1% vs 80.9%, p 0.003)

51Villarino ME, et al. JAMA Pediatr. 2015;169(3):247-255.

Safety and effectiveness

tuberculosis infection in

Safety and effectiveness

of 12 once weekly of

rifapentine + INH vs

9 months of INH

treatment for latent

tuberculosis infection in

children 2-17 y

• TB and HIV are major threats to public health worldwide

• Diagnosis and treatment of TB and TB/HIV in children remain challenging

• Drug resistance problems in adults effects children in the community, however, treatment outcome can achieved as good as in adults

• Effective household contact tracing and preventive therapy for children could substantial prevent future cases

• More studies are needed in children regarding burden, diagnosis, preventive therapy (esp. among HIV-infected children), treatment of DR-TB, and new effective TB vaccines

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