Status of Drug Resistant TB and efforts for its control in the … · STATUS OF DRUG RESISTANT TB IN THE AFRICAN REGION: BURDEN, CONTROL EFFORTS, CHALLENGES AND FUTURE PERSPECTIVES

STATUS OF DRUG RESISTANT TB IN THE AFRICAN REGION: BURDEN,

CONTROL EFFORTS, CHALLENGES AND FUTURE PERSPECTIVES

Henriette, Andre & Wilfred

Presentation for African Region NTP Managers’

meeting 14-16 October 2013, Nairobi, Kenya

11/5/2013 African Region TB Managers' meeting 2013 1

Outline of presentation

1) Basics on Drug Resistant TB

2) Pertinent aspects of Global burden of DR-TB

3) Regional Epidemiological and spatial distribution of DR-TB

4) Progress in control efforts, key issues and challenges, and future perspectives


Working definition: Bacilli continue to

multiply in the presence of adequate doses of

an otherwise efficacious anti-TB medicine…

1. Mono resistance: resistance to any single anti-TB medicine

2. Poly-resistance: resistance to more than one anti-TB medicine other that Rifampicin and Isoniazid together

3. Multi-Drug Resistance (MDR): resistance to at least Isoniazid and Rifampicin together

4. Extensive drug resistance (XDR-TB): MDR plus Resistance to: 1. A fluoroquinolone : e.g. Ofloxacin, Levofloxacin,

Moxifloxacin 2. At least one second line injectable agents, e.g.

Kanamycin, Amikacin, Capreomycin


Pathophysiological mechanisms of DR-TB 1) Arising from spontaneous chromosomal mutations at

low frequency. Amplification of the genetic mutation e.g. through human error results in clinically significant drug resistant TB.

2) As a result of man-made selection during treatment: e.g. through erratic drug supply, sub-optimal physician prescription and poor patient adherence…..Molecular mechanisms of drug resistance have been elucidated for the major first- and second-line drugs rifampicin, isoniazid, pyrazinamide, Ethambutol, the aminoglycosides and the fluoroquinolones.

3) Mathematical models predict that the future of an MDR or XDR TB will depend largely on the transmission efficiency or relative fitness of DR-TB compared to drug-susceptible strains (Borrell S, Gagneux S. Int J Tuberculosis and Lung Disease. 2009 Dec;13(12):1456-66.)…to date, this remains unsettled .. studies comparing the spread of DR to drug-susceptible strains suggest that MDR strains can be either 10 times more or 10 times less transmissible



Development DR-TB strains (1)


Development of DR-TB (2)



Causes related to Health care providers: leading to inadequate drug regimens

Causes related to anti-TB drugs: e.g. Inadequate supply or poor quality drugs

Causes related to patients: e.g. irregular or inadequate drug intake

Absence of guidelines Poor quality Poor adherence (or poor DOT)

Inappropriate guidelines Unavailability of certain drugs (stock outs or delivery disruptions)

Lack of information

Noncompliance with guidelines

Poor storage conditions Lack of money (no treatment available free of charge, no transport, etc)

Poor training Wrong dose or combination

Adverse drug effects

No monitoring of treatment Social barriers

Poorly organized or funded TB Control Programmes

Malabsorption (e.g. due to concurrent chronic illnesses

Drug Resistant TB is mostly a man-made problem: Common causes of drug resistant Tuberculosis


Aspects of Global DR-TB burden – M/XDR-TB


Estimated proportion of TB cases that have MDR-TB by WHO region, 2011. Source: Global TB Report 2012


Notified cases of MDR-TB as a percentage of MDR-TB cases estimated to occur among notified pulmonary TB cases, 2011


Countries that had reported at least one case of XDR-TB by end of 2011


Treatment outcomes for MDR-TB cases by WHO Region, 2009 cohort.


Regional epidemiological and spatial distribution of DR-TB (M/XDR-TB)


11/5/2013 African Region TB Managers' meeting 2013

Notified MDR & XDR-TB cases in the African

Region. 2004-2012

18

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

200

4

200

5

200

6

200

7

200

8

200

9

201

0

201

1

201

2

Tot

al

toda

te

MDR-TB 3501 4577 6120 9031 9751 10741 9340 123841812983574

XDR-TB 627 622 486 526 872 1603 3487

3501 4577 6120 9031 9751 10741 9340 12384 18129

83574

Axis

Tit

le

Notified MDR-TB cases East & Southern Africa sub-region


2004 2005 2006 2007 2008 2009 2010 2011 2012

ESA 3405 4391 6059 8791 9348 10383 8845 11760 17237

AFRO 3501 4577 6120 9031 9751 10741 9340 12384 18129

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000C

ase

s

Notified MDR-TB cases Central Africa sub-region


0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

2004 2005 2006 2007 2008 2009 2010 2011 2012CENTRAL 12 0 1 66 186 124 161 248 315

AFRO 3501 4577 6120 9031 9751 10741 9340 12384 18129

Cas

es

Notified MDR-TB cases West Africa sub-region


0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

2004 2005 2006 2007 2008 2009 2010 2011 2012WEST 84 186 60 174 217 234 334 376 577

AFRO 3501 4577 6120 9031 9751 10741 9340 12384 18129

Cas

es

44 countries have ever reported a case of MDR-TB in the African Region 2004-2012


Reported MDR cases by year. African Region 2004-2012

Country 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total to date % of notifications

Algeria 0 74 0 0 0 0 56 0 0 130 0.2

Angola 0 0 0 2 0 0 3 40 45 90 0.1

Benin 15 28 21 11 4 14 15 20 25 153 0.2

Botswana 0 12 0 139 126 101 106 46 52 582 0.7

Burkina Faso 0 3 6 31 16 19 31 42 38 186 0.2

Burundi 10 0 0 28 17 0 24 6 24 109 0.1

Cameroon 0 0 0 0 24 26 35 63 153 301 0.4

Cape Verde 0 0 0 5 0 n/r n/r n/r n/r 5 0.0

Central African Republic 0 0 0 0 12 7 9 15 28 71 0.1

Chad 0 0 0 0 0 0 3 0 0 3 0.0

Comoros 0 0 0 0 2 n/r n/r n/r n/r 2 0.0

Congo 0 0 0 21 0 n/r n/r n/r n/r 21 0.0

Côte d'Ivoire 36 47 0 0 24 43 50 30 221 451 0.5

Democratic Republic of the Congo 0 0 1 15 128 91 87 121 65 508 0.6

Equatorial Guinea 2 0 0 0 5 0 0 3 0 10 0.0

Eritrea 0 0 0 0 0 0 0 11 0 11 0.0

Ethiopia 0 0 0 145 130 233 140 212 284 1144 1.4

Gabon nr nr nr nr nr n/r n/r n/r n/r 0 nr Gambia 0 0 1 0 0 n/r n/r n/r n/r 1 0.0

Ghana 2 1 0 7 2 0 4 7 20 43 0.1

Guinea Conakry 1 20 25 36 72 69 31 78 69 401 0.5

Guinea-Bissau 0 0 0 0 0 0 0 2 6 8 0.0

Kenya 36 44 89 82 102 150 112 166 225 1006 1.2

Lesotho 4 0 0 46 0 0 117 64 46 277 0.3

Liberia 0 0 0 0 2 0 0 0 6 8 0.0

Madagascar 10 0 2 5 6 3 3 9 10 48 0.1

Malawi 0 9 0 12 25 6 40 26 27 145 0.2

Mali 8 2 0 11 7 22 12 10 12 84 0.1

Mauritania 0 11 7 14 6 0 35 8 1 82 0.1

Mauritius 0 0 2 0 1 1 2 1 0 7 0.0

Mozambique 75 115 129 163 181 140 165 283 266 1517 1.8

Namibia 0 0 0 291 221 301 214 192 210 1429 1.7

Niger 0 0 0 2 52 24 39 18 35 170 0.2

Nigeria 0 0 0 45 23 28 21 95 107 319 0.4

Rwanda 0 35 0 105 79 78 90 76 58 521 0.6

Sao Tome and Principe 0 0 0 1 0 0 0 4 8 13 0.0

Senegal 20 0 0 10 7 11 38 50 27 163 0.2

Seychelles 0 0 0 0 0 0 0 0 0 0 0.0

Sierra Leone 0 0 0 0 0 0 0 8 0 8 0.0

South Africa 3219 4120 5774 7429 8198 9070 7386 10085 15419 70700 84.6

Swaziland 3 0 0 110 170 190 326 332 280 1411 1.7

Togo 2 0 0 1 2 4 2 4 2 17 0.0

Uganda 17 46 0 67 26 57 93 71 89 466 0.6

United Republic of Tanzania 4 10 13 169 24 24 34 68 42 388 0.5

Zambia 37 0 50 27 56 29 0 0 80 279 0.3

Zimbabwe 0 0 0 1 1 0 17 118 149 286 0.3

Total 3501 4577 6120 9031 9751 10741 9340 12384 18129 83574 100.0

1) Benin

2) Botswana

3) Burkina Faso

4) DRC

5) Ethiopia

6) Kenya

7) Lesotho

8) Mocambique

9) Namibia

10) Nigeria

11) RSA

12) Swaziland

13) Togo

14) Uganda


14 countries have ever reported at least one case of XDR-TB by September 2013 in African Region

Progress in control efforts & remaining issues and challenges


Basic DOTS


Declining but still high burden: Case notification and estimated TB incidence rates by WHO region, 1990-2011. Regional trends in case notification rates (new, relapse cases, all forms) and estimated TB incidence rates (green). Source: Global TB Report 2012



Relatively high unfavorable treatment outcomes:

27


TB/HIV – Co-infection: High Estimated HIV prevalence in new TB cases 2012 (fuelling TB incidence)


Percentage of TB patients with known HIV status by Region, 2004-2011: Source: Global TB Report 2012

Status of core TB-HIV indicators and TB deaths African Region 2005-2011 (& 1995-2011)

Known HIV status

% HIV Pos

% on CPT

% on ART

TB deaths new cases

TB deaths Retreated

cases

0

10

20

30

40

50

60

70

80

1995 2000 2005 2009 2010 2011

Namibia: HCT Coverage and HIV prevalence among TB Patients; Namibia 2005-2012

% Tested for HIV

Testing HIV Positive

Positives on ART

Positives on CPT

10

20

30

40

50

60

70

80

90

100

2005 2006 2007 2008 2009 2010 2011 2012

Pe

rce

nta

ge

Year

Ghana: TB-HIV interventions 2006-2012

% HIV pos on CPT

% HIV pos on ART

% tested for HIV

% HIV pos

0.0

20.0

40.0

60.0

80.0

100.0

2006 2007 2008 2009 2010 2011 201211/5/2013 Ghana NTP REview

Malawi: Trend of selected Key TB-HIV indicators

With Known HIV status

Tested HIV Positive

HIV positive on CPT

HIV Positives on ART

0

20

40

60

80

100

120

2005 2008 2009 2010 2011


0102030405060708090

100

PLHIV TB Screened % TB Pos % IPT

% TB screened for HIV % TB-HIV % CPT

% on ART

Status of core tb / hiv indicators from sentinel surveillance

system. June 2011-july 2012

Zambia: Trends of key indicators

0

10

20

30

40

50

60

70

80

Teasted HIV+ CPT ART

PE

RC

EN

TAG

E

SERVICE

TRENDS OF TB/HIV SERVICES FOR 2007 - 2009

2007

2008

2009

Mozambique: Key Achievements

• Proportion of TB patients tested for HIV has risen from 24% in 2006 to approximately 86% by the end of 2009

• Proportion of HIV positive TB patients started on CPT has risen from 17% in 2006 to 89% by the end of 2009

• The proportion of eligible TB patients accessing ART is declining significantly since 2006 (46% in 2006, 33% in 2007, 30% in 2008 and 22% in 2009),


Countries in African Region with Xpert MTB-Rif technology as of May 2013. Source: WHO GLI website

Low government funding: Domestic funding as a percentage of total funding available for TB care and control, 2009-2011

11/5/2013

African Region TB Managers' meeting 2013

40



MDR-TB DIAGNOSIS TREATMENT GAP 2009-2011 AFRICAN REGION: ONLY 57% OF DIAGNOSED CASES STARTED ON TREATMENT

42

TB Laboratory services capacity, 2011


Levels of Diagnostic DST for rifampicin and isoniazid among new TB cases, by Region, 2010

0.2%

5.0%

0.6%

30.4%

0.1% 0.4% 1.8%

0%

5%

10%

15%

20%

25%

30%

35%

AFR AMR EMR EUR SEAR WPR Global

Diagnostic DST for rifampicin and isoniazid Among previously treated TB cases, by Region, 2010

2.8%

18.5%

6.3%

50.7%

0.3% 1.6%

6.4%

0%

10%

20%

30%

40%

50%

60%

AFR AMR EMR EUR SEAR WPR Global

DST coverage for second-line drugs among MDR-TB cases, 2010

0%

10%

20%

30%

40%

50%

60%

70%

AFR AMR EMR EUR SEA WPR Global

The TB Supranational Reference Laboratory (SNRL) Network



Uncertain knowledge of burden: Global coverage of drug resistance surveillance data, 2012

48

Cost issues: Summary of the available evidence on the cost effectiveness of interventions for TB care and control


Future perspectives


Basic DOTS enhancement, expansion and quality improvement


http://www.who.int/tb/publications/2010/2010/en/index.html



The New recommendations in

the new Guidelines

52

Question 1. Should new pulmonary TB patients be

treated with the 6 months or the 2 months

rifampicin regimen?

Recommendations

• New patients should receive a regimen containing 6 months of RIF: 2HRZE / 4HR.

• The treatment regimen with 2 months RIF: 2HRZE/6HE should be phased out.

Supporting evidence

• Regimens with Shorter RIF duration are significantly associated with higher Relapse rates

• Regimens with 2 months of RIF are also somewhat associated with higher Failure rates

• If there is background Isoniazid resistance – the absolute difference between 2 months RIF and 6 months RIF regimens is even greater in terms of unfavorable outcomes

Question 2. Dosing frequency: When a country

selects 2HRZE/4HR, should patients be treated

with a daily or 3 times weekly intensive phase?

Recommendations

• The optimal dosing frequency for new patients with TB is daily throughout the course of therapy (6 months)

• However, New patients may receive a daily intensive phase followed by three times weekly continuation phase

• Three times weekly dosing throughout therapy [2(HRZE)3 / 4(HR)3] is another alternative as long as:

– patient is receiving directly observed therapy of every dose, and

– patient NOT living with HIV or living in a high HIV-prevalent setting.

• New patients with TB should not receive twice weekly dosing for TB treatment for the full treatment

Question 2. Dosing frequency: When a country

selects 2HRZE/4HR, should patients be treated with

a daily or 3 times weekly intensive phase?

• Supporting evidence for the recommendations

i. There is no significant increase in failure, relapse, or acquired

drug resistance in pan-susceptible patients - when comparing

daily dosing throughout therapy with the intermittent regimens

ii. However, Patients receiving three times weekly dosing

throughout therapy had 3.3 times higher rates of acquired

drug resistance than patients who received daily treatment

iii. For patients with background INH resistance, three times

weekly intensive phase was associated with significantly

higher risk of failure and acquired drug resistance

iv. There was insufficient data to support the use of regimens that

are given two times weekly throughout therapy. On operational

grounds, missing one dose means the patient receives only

half the regimen

Question 3. What should be the continuation

phase in countries with high levels of

isoniazid resistance

Recommendations

• In populations with known (or suspected) high

levels of INH resistance, new TB patients may

receive HRE - in the continuation phase ….need

for local representative drug resistance profiles

to first line anti-TB medicines.. DRS data

• Supporting evidence

– Inadequate evidence to quantify the ability of

Ethambutol to “protect rifampicin”

– Expert opinion based

Question 4. Should intermittent regimens be used

for persons living with HIV? What should be the

duration of TB treatment in people living with HIV?

Recommendations

1) TB patients living with HIV and TB patients living in HIV

prevalent settings should receive daily TB treatment (at

least during the intensive phase)

2) For the continuation phase, the optimal dosing frequency

is also daily for these patients

3) If a daily continuation phase is not possible, three times

weekly dosing during the continuation phase is an

acceptable option

4) TB patients living with HIV should receive the same

duration of TB treatment as HIV-negative TB patients

Question 4. Should intermittent regimens be used

for persons living with HIV? What should be the

duration of TB treatment in people living with

HIV?

Supporting evidence

1. Intermittent regimen administered throughout a six

month treatment regimen was associated with at least

double the rate of failure and relapse compared with

daily regimen

2. However, there was no change in failure, relapse and

death rates if the regimen is prolonged to 9 months

3. Use of ARVs significantly reduces failure, relapse and

death rates among these patients … implications

…aim for UA to ARVs for the dually infected /

affected

Question 5. How effective is sputum monitoring

for predicting relapse, failure and pre-treatment

INH resistance?

Recommendations

• For smear positive pulmonary TB patients,

sputum smear microscopy may be performed at

completion of the intensive phase (end 2

months)

• If smear positive at the end of 2 months– repeat

smear microscopy again at the end of 3 months

• If still smear positive at the end of 3 months–

send for culture and DST

Question 5. How effective is sputum monitoring

for predicting relapse, failure and pre-treatment

INH resistance ?

Supporting evidence

1. Sputum smear at the end of 2 or 3 months of

treatment has limited utility in predicting relapse

2. Quality of evidence in most studies that

assessed failure - very low

3. Main rationale for recommending the addition of

a 3 month sputum smear is only to detect poor

response to therapy (due to DR or MDR) earlier

than 5 month

Question 6. In new patients, how effective is

treatment extension for preventing failure or

relapse?

Recommendations

• In patients treated with the regimen containing

Rifampicin for 6 months, if a positive sputum

smear is found at completion of the intensive

phase, the extension of the intensive phase is not

recommended

Question 6.

In new patients, how effective is treatment

extension for preventing failure or relapse?

Supporting evidence

• Preliminary results from 1 moderate quality study

shows only modest benefit in decreasing risk of

relapse

• Historically, when the new patient regimen

included only 2 months of RIF, the extension of the

intensive phase was meant to afford the patient an

extra month of RIF. When the recommended

regimen of 6 month of rifampicin is applied, the

justification for the extra month effectively falls

away

63

Question 7. Treating previously

treated TB cases

• Which (if any) groups of patients should receive

a retreatment regimen with first line drugs?

– What is the best regimen for previously treated

patients, so that if they have MDR, they receive

effective treatment?

The Fall and Rise phenomenon for anti-

TB drug resistance

65

Question 7. Treating previously

treated TB cases

Recommendations

1. All previously treated TB patients should

have culture and DST done before or at the

start of treatment.

2. In settings where rapid DST is available, the

results should guide the choice of regimen

66

Question 7. Previously treated cases

Recommendations 3: In settings where rapid DST results are not routinely

available, empiric treatment should be started as

follows:

i. TB patients returning after defaulting or relapsing from their first line treatment may receive the retreatment regimen containing first line drugs 2HRZES / 1HRZE / 5HRE

ii. TB patients whose treatment has failed or other patient groups with high likelihood of MDR-TB should be started on an empiric MDR regimen.

iii. As soon as DST results known – regimens should be adjusted

iv. NTPs should obtain and use their country-specific drug resistance data of failure, relapse and default patient groups to determine the levels of MDR.

67

Question 7. Previously treated cases

Supporting evidence

• Studies using WHO standard retreatment (2SHRZE/1HRZE/5HRE)

– RCT in Retreatment – None

– RCT in New cases – None

– Cohorts in Retreatment – 12 arms with 1,410

patients

D. Menzies, TDG meeting, Paris 21-23 October 2008

Question 7. Treating previously treated

cases

Supporting evidence • A few Cohort studies have been reported:

– Largest groups were pan-sensitive

– In INH resistant – Varying, but poor results

– In Mixed (most like programme conditions)

• Highly variable results, but mostly POOR

• Perhaps reflecting underlying drug resistance

– No data in Strep resistant, or Poly-drug

resistance (other than MDR)

D. Menzies, TDG meeting, Paris 21-23 October 2008


Fully implement the 2012 WHO TB/HIV policy

2012 WHO TB/HIV POLICY The 12 points policy package: What's new?

B. Decrease the burden of TB in PLHIV (Three Is for HIV/TB and earlier initiation of ART)

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

A. Establish the mechanisms for integrated TB & HIV services 1. Set up and 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

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

Section A: Establish mechanisms for integrated TB & HIV services

• Joint TB/HIV coordinating bodies including patients' groups and other line ministries

• HIV surveillance among TB patients including in anti-TB drug resistance surveys; TB surveillance among PLHIV

• Models of integrated delivery of HIV and TB services

• Harmonized indicators and R&R formats; one national M&E system

Section B: Decrease the burden of TB among PLHIV

• TB screening for all PLHIV (adults and children) at every visit using clinical algorithm (four symptoms: cough, fever, los loss of weight and haemoptysis).

• IPT provision or investigations for TB/other diseases • TB diagnosis and treatment by HIV implementers • At least 6 months of IPT; up to 36 months in HIV-

prevalent settings • TST not a requirement for initiating IPT in PLHIV • Earlier initiation of ART for TB prevention in line with

WHO guidelines

Section C: Decrease the burden of HIV in patients with presumptive and

diagnosed TB

• Routine HIV testing for all patients with presumptive and diagnosed TB

• Couple HIV testing and counselling

• Comprehensive HIV prevention methods targeting sexual, parenteral and vertical transmission

• Collaboration with harm reduction, mother and child health and PMTCT services

• ART for all TB patients living with HIV

Intensified TB Case Finding and Isoniazid Preventive Therapy for PLHIV

Summary 2010 Recommendations

TB screening Some Recommendations

Adults and adolescents living with HIV should be

screened with a clinical algorithm of five signs and

Symptoms: 1) current cough, 2) fever, 3) weight loss

4) night sweats or 5) haemoptysis

those who do not report any one of these are unlikely to have active TB and should be offered IPT.

Those with any one of these may have active TB and should

be evaluated for TB and other diseases.

(Strong recommendation, moderate quality evidence)

Inclusion criteria for studies • Collected sputum specimens from PLHIV regardless of

signs or symptoms;

• Used mycobacterial culture of at least one specimen to diagnose TB and;

• Collected data about signs and symptoms.

Top five best performing rules (1 of m) in all subjects (n = 8173)

Combination rule

Sen

(%) Spe (%)

LR-

NPV (95% CI)

5% TB prevalence

CC, F, NS, WL 79 49 0.42 97.7 (97.4-98.0)

H, F, NS, WL 76 53 0.46 97.6 (97.2-98.0)

CC, F, WL 74 54 0.48 97.5 (97.1-97.9)

CC, NS, WL 73 59 0.49 97.5 (97.1-97.8)

CC, F, NS 73 61 0.44 97.7 (97.4-98.0)

CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

Top five best performing rules (1 of m) in all subjects with abnormal CXR (n = 2805)

Combination rule

Sen

(%) Spe (%)

LR-

NPV (95% CI)

5% TB prevalence

CC, F, NS, WL, X 91 39 0.24 98.7 (97.1-99.5)

CC, F, NS, X 89 52 0.21 98.9 (97.6-99.5)

CC, F, WL, X 88 42 0.28 98.5 (96.9-99.3)

H, F, NS, WL, X 87 43 0.29 98.1 (97.3-98.6)

CC, NS, W,L X 87 45 0.29 98.6 (97.5-99.3)

CC: cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

Performance of the best rule (one of current cough, fever, night sweats or weight loss)

Setting

Sen

(%) Spe

(%) LR- (%)

NPV (95% CI)

5% TB prevalence

Community 76 61 0.39 97.3 (96.9-97.7)

Clinical 89 30 0.38 98.3 (97.5-98.8

CD4 < 200 94 22 0.29 98.9 (95.8-99.5)

CD4> 200 83 34 0.49 96.9 (95.1-98.0)

CC: cough in the last 24 hours; F: Fever; H: Hemoptysis; NS: Night sweats; WL: Weight loss

TB screening and IPT algorithm

No Yes

Not TB TB Yes No Other Dx

Screen for TB with any one of the following: Current cough; Fever, Weight loss; Night Sweats

Investigate for TB and other Diseases. Assess IPT contraindications

Person living with HIV

Treat for TB

Appropriate treatment & consider IPT

Defer IPT Give IPT Follow up & consider IPT

Screen for TB regularly, periodically

Role of Xpert MTB/RIF in TB screening among PLHIV

HIV pos HIV neg HIV neg /

unknown

P-Value

Sensitivity in C+

Smear microscopy 44.6%

(86/193)

[37.7% - 51.6%]

68.6%

(234/341)

[63.5% - 73.3%]

72.3%

(613/848)

[69.2% - 75.2%]

<.0001

Xpert MTB/RIF 82.4%

(173/210)

[76.7% - 86.9%]

90.7%

(304/335)

[87.2% - 93.4%]

92.3%

(760/823)

[90.3% - 94.0%]

0.0849

Sensitivity in S+C+

Xpert MTB/RIF

Sensitivity in S-C+

Xpert MTB/RIF

97.7%

(84/86)

[91.9% - 99.4%]

71.8%

(89/124)

[63.3% - 78.9%]

99.0%

(204/206)

[96.5% - 99.7%]

77.5%

(100/129)

[69.6% - 83.9%]

98.4%

(553/562)

[97.0% - 99.2%]

79.3%

(207/261)

[74.0% - 83.8%]

0.2167

0.8976

Specificity in Non-TB

Smear microscopy 100.0%

(660/660)

99.4%

(1054/1060)

99.4%

(3040/3058)

0.2545

Xpert MTB/RIF 99.2%

(389/392)

99.3%

(748/753)

98.9%

(2457/2484)

0.2246

Sensitivity & specificity of Xpert and smear stratified by HIV status

DON’T QUOTE -CONFIDENTIAL

Revised TB/HIV algorithms

Take home message. TB screening among PLHIV

Among PLHIV, Investigate for TB and other diseases by all available means:

Clinical algorithm (key signs and symptoms)

Sputum smear and culture

Chest x-ray

Xpert MTB/RIF

Recommendations on use of Tuberculin Test

Adults and adolescents who are living with

HIV in settings with higher TB transmission and:

have unknown or positive TST status and;

unlikely to have active TB

should receive IPT for at least 36 months

(Conditional recommendation, moderate quality

evidence)

Take home message on TST

• Tuberculin skin test is not a requirement for initiating IPT for people living with HIV

(Strong recommendation)

• Where feasible, TST can be used as people with a positive test benefit more from IPT than those with a negative test

(Strong recommendation)

Take home message on use of IPT

Providing IPT to people living with HIV does not increase the risk of developing INH resistant TB. Therefore concerns regarding the development of INH resistance should not be a barrier to providing IPT.


TB screening in children

• Children living with HIV who do not have poor weight gain*, fever or current cough are unlikely to have active tuberculosis TB.

(Strong recommendation, low quality evidence)

*Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than -3 z-scores), or underweight (weight-for-age less than -2 z-scores), or confirmed weight loss (>5%) since the last visit, or flattening growth curve

Use of IPT in children

1) Children living with HIV who have any one of poor weight gain*, fever, current cough or contact history with a TB case may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, children should be offered IPT regardless of their age.


2) Children over 12 months of age who are living with HIV and who are unlikely to have active TB on symptom based screening and have no contact with a TB case should receive 6 months of INH preventive therapy (10mg/kg)


Use of IPT in children (2)

1) Children less than 12 months of age (infants) who:

have contact with an index TB case, and

who have been evaluated for TB (using clinical investigations) and shown no evidence of active TB

Should receive IPT for 6 months

(Conditional recommendation, low quality evidence)

2) All children living with HIV who have successfully

completed treatment for TB disease should receive

INH for an additional 6 months


What is new in the guidelines for TB screening and use of IPT among PLHIV

1) Screening for TB only by using symptom based algorithm is sufficient to start IPT for PLHIV

2) CXR and TST are not mandatory requirements for starting IPT

3) Regular screening for active TB at every visit for those on IPT

4) Pregnant women, children, those on ART and those who completed TB treatment should receive IPT

5) Conditional recommendation of 36 months IPT for settings with high TB transmission among PLHIV

Acknowledgements

• Haileyesus and TB/HIV team, WHO Geneva

• Marco Vitoria & HIV Team, WHO Geneva

• TB/HIV Working Group of the STOP TB Partnership

• Members of the Policy Development Group

• Etc., etc.


Fully implement PMDT GUIDELINES…2008 & 2011

Changes in recommendations on regimen composition

between the 2008 and 2011 updates of the guidelines

Priority questions (1)

1) At what prevalence of MDR-TB in any group of TB patients is rapid drug-susceptibility testing warranted to detect resistance to rifampicin and isoniazid or rifampicin alone on all patients in the group at the time of TB diagnosis, in order to prescribe appropriate treatment at the outset ?

2) Among patients with MDR-TB receiving appropriate treatment in settings with reliable direct microscopy, is monitoring using sputum smear microscopy alone rather than sputum smear and culture, more or less likely to lead to treatment success (and other outcomes) ? 3) When designing regimens for patients with MDR-TB, is the inclusion of specific drugs (with or without documented susceptibility) more or less likely to lead to treatment success (and other outcomes) ?

Priority questions (2)

4) When designing regimens for patients with MDR-TB, is the inclusion of fewer drugs in the regimen (depending on the drug used, the patient’s history of its use and isolate susceptibility) more or less likely to lead to treatment success (and other outcomes) ? 5) In patients with MDR-TB, is shorter treatment, compared with the duration currently recommended by WHO, more or less likely to lead to treatment success (and other outcomes) ? 6) In patients with HIV infection and drug-resistant TB receiving antiretroviral therapy, is the use of drugs with overlapping and potentially additive toxicities, compared with their avoidance, more or less likely to treatment success (and other outcomes) ? 7) Among patients with MDR-TB, is ambulatory therapy, compared with inpatient treatment, more or less likely to lead to treatment success (and other outcomes) ?

Evidence Reviews

Teams based in leading academic centres assessed existent evidence for the questions using :

- Systematic reviews of literature (as per

Cochrane Handbook)

- Meta-analysis of individual patient data

- Simulations using modelling

- Cost-effectiveness analysis

The quality of evidence

Definition Quality

Further research is very unlikely to change our confidence in the estimate of effect.

High

Further research is likely to have an important impact on our confidence in the effect and may change the estimate.

Moderate

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Low

Any estimate of effect is very uncertain. Very low

Guyatt GH et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6

Implications of the strength of a

recommendation for different users

Adapted from Guyatt GH et al. GRADE Working Group. Going from evidence to recommendations. BMJ, 2008, 336(7652):1049–1051

Recommendation 1

Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB, subject to available resources (conditional recommendation / very low quality evidence)

Evidence : simulations from modelling work Rapid DST of INH & RIF at the time of diagnosis was the most cost effective testing strategy for any patient group or setting, even at very low levels of resistance among TB patients (MDR-TB in >1% and isoniazid resistance (other than MDR-TB) in >2%). Rifampicin resistance detected by Xpert MTB/RIF in patient groups in whom MDR is rare has low predictive value and results need to be confirmed by phenotypic DST or line probe assay.

Recommendation 2

The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment (conditional recommendation / very low quality evidence)

Evidence : individual patient data and simulations from modelling Monthly sputum smear microscopy and culture was the best strategy in identifying failures earlier. Sputum smear microscopy alone resulted in delayed detection of failure. Sputum smear microscopy results are of use to clinicians in identifying patients likely to fail their treatment and instituting infection control measures in a timely manner. Resource implications are important.

In the treatment of patients with MDR-TB, a fluoroquinolone should be used (strong recommendation / very low quality evidence). In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation / very low quality evidence). In the treatment of patients with MDR-TB, ethionamide (or prothionamide) should be used (strong recommendation / very low quality evidence).

Recommendations 3 to 5

In the treatment of patients with MDR-TB, four second-line anti-tuberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase (conditional recommendation / very low quality evidence). In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation / very low quality evidence).

Recommendations 6 and 7

Groups of second-line drugs

Evidence: meta-analysis of >9000 individual MDR-TB patient data from 32 published observational studies, none being randomised controlled trials (RCTs) Bias may be due to use of certain drugs for sicker patients, incomplete ascertainment of relapse, the under-representation of certain geographical regions, and missing data for some of the variables examined. Adjustments were made to try to counter these limitations but findings from this analysis may not necessarily be generalizeable to all MDR-TB cases. XDR-TB patients were excluded. Clear benefit of fluoroquinolones, particularly later-generation drugs. Among the oral bacteriostatic drugs, the association with cure was higher with ethionamide than with cycloserine, which was higher than with PAS. No particular parenteral agent was considered superior. No effect for Group 5 drugs or ethambutol.

About recommendations 3 to 7

In the treatment of patients with MDR-TB, an intensive phase of at least 8 months’ duration is recommended (conditional recommendation / very low quality evidence). In the treatment of patients with MDR-TB, a total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (conditional recommendation / very low quality evidence).

Recommendations 8 and 9

About recommendations 8 and 9

Evidence: same individual patient data meta-analysis as was used for treatment regimen composition questions (recommendations 3 to 7) Recommendation is not “pegged” to sputum conversion. Previous recommendations (2008) were to use a parenteral agent for a minimum of 6 months and at least 4 months past culture conversion, and a minimum total length of treatment of 18 months after culture conversion. Most patients may be expected to receive this length of treatment but in some it may have to be modified depending on their bacteriological status and other indicators of treatment progress

Odds of success by duration of treatment

Antiretroviral therapy is recommended for all patients with HIV and drug-resistant TB requiring second-line anti-tuberculosis drugs, irrespective of CD4 cell-count, as early as possible (within the first 8 weeks) following initiation of anti-tuberculosis treatment (strong recommendation / very low quality evidence).

Recommendation 10

Evidence: from 10 observational studies of treatment outcomes when antiretroviral therapy (ART) and second-line anti-tuberculosis drugs were used together. Available data did not allow assessment for a number of outcomes of interest, namely avoiding the additional acquisition of drug resistance, preventing TB transmission, sustaining relapse-free cure, establishing the optimal duration of MDR-TB treatment, avoiding unnecessary MDR-TB treatment, and reducing cost and improving population access to appropriate care. The strength of the recommendation is based in part on indirect evidence from its use in any patient with active TB, which shows large beneficial effects and a very high mortality when ART is not employed, particularly in very immunocompromised patients (CD4 cell-count <50 cells/mm3)

Patients with MDR-TB should be treated using mainly ambulatory care rather than models of care based principally on hospitalization (conditional recommendation / very low quality evidence

Recommendation 11

Evidence : cost-effectiveness modelled for all possible countries using a probabilistic analysis of real data from four countries (Estonia, Peru, Philippines, Russian Fed [Tomsk]). None were from RCTs. The benefit of reduced transmission can only be expected if proper infection control measures are in place in both the home and the clinic. Admission to hospitals for patients who do not warrant it may also have important social and psychological consequences which need to be taken into account. There may be important barriers to accessing clinic-based ambulatory care, including distance to travel and other costs to individual patients. Shifting costs from the service provider to the patient has to be avoided, and implementation may need to be accompanied by appropriate enablers.

Research Gaps

This update revealed important gaps in knowledge, including: - A lack of moderate or high quality evidence from randomized controlled trials for optimizing treatment regimens in patients with MDR-TB, including the best combination of drugs and treatment duration; - Lack of evidence for optimal drug regimens for treating patients with isoniazid resistance, with XDR-TB and with non-MDR-TB polydrug-resistance; - Very limited information about treatment of paediatric MDR-TB; - Identification of the most effective chemoprophylaxis for contacts of MDR-TB cases; - The therapy for symptomatic relief from adverse reactions linked to second-line anti-tuberculosis drugs.

Acknowledgements

WHO/HQ Léopold Blanc, Chris Duncombe, Dennis Falzon, Christopher Fitzpatrick, Katherine Floyd, Haileyesus Getahun Malgorzata Grzemska, Christian Gunneberg, Ernesto Jaramillo, Christian Lienhardt, Fuad Mirzayev, Paul Nunn, Mario C. Raviglione, Delphine Sculier, Marco Antonio de Avila Vitoria, Fraser Wares, Karin Weyer, Matteo Zignol Guideline Development Group Jaime Bayona, José A. Caminero, Charles L. Daley, Agnes Gebhard, Myriam Henkens, Timothy H. Holtz, Joël Keravec, Salmaan Keshavjee, Aamir J. Khan, Vaira Leimane, Andrey Mariandyshev, Carole D. Mitnick, Gloria Nwagboniwe, Domingo Palmero, Ma. Imelda Quelapio, Michael L. Rich, Sarah Royce, Sabine Rüsch-Gerdes, Archil Salakaia, Rohit Sarin, Holger Schünemann, Elena Skachkova, Francis Varaine External Review Group Samiha Baghdadi, Mercedes Becerra, Vineet Bhatia, Masoud Dara, Mirtha del Granado, Reuben Granich, Lindiwe Mvusi, Nani Nair, Norbert Ndjeka, Wilfred A.C Nkhoma, Katsunori Osuga, Hendrik Simon Schaaf, Catharina van Weezenbeek, Irina Vasilyeva, Wang Xie Xiu, Richard Zaleskis Evidence review teams Harvard University, US - Chunling Lu, Carole D. Mitnick, Richard A. White McGill University, Canada - Melissa Bauer, Richard (Dick) Menzies, Olivia Oxlade University of California (San Francisco), US - Gail Kennedy, George Rutherford, Karen Steingart University of Washington, US - Matthew Arentz, David Horne, Patricia Pavlinac, Judd L. Walson Consultant Patricia Whyte

Companion manual

Later into (perhaps in 2014), it is planned to have a manual to assist in the implementation of the principles contained in the Guidelines

(an update of the document hereunder).

Recommended models of care for DR-TB…WHO NOW RECOMMENDS AMBULATORY MODELS

…including community based care

• Hospital-based?

• Out-patient?

• Community-based?

• Mixed models ?


Hospitalization vs. outpatient care for the intensive phase of treatment

• Hospitalization

– Easier to do in some health systems

– DOT easier

– Facilitates training on clinical management

but requires:

– infection control

– guaranteed funding and bed capacity

– ethical issues addressed

• Out-patient care

– Socially acceptable

– Lower cost

– DOT more challenging

but requires:

– Access to a primary health care network

– Strong social support

– Community-based care in many cases

– Infection control


Some core aspects to consider in choosing model of care

1) Effectiveness (treatment outcomes)

2) Cost-effectiveness

3) Sustainability

Which model can handle the estimated country MDR-TB burden until the epidemic dwindles?


Factors influencing low adherence to treatment

• personal factors • poor understanding of the disease and treatment requirements, adverse

side effects to drugs),

• socioeconomic factors (i.e., stigma, poverty, lack of family and community support)

• health system factors • inadequate staffing and attitude

• poor patient-provider relations,

• inconvenient treatment arrangements,

• and erratic or insecure drug supply

• patients from marginalized groups • prisoners,

• homeless,

• drug and alcohol users

• migrants


What do patients need ?

- Psychological support (depression, affirming life in face of death, voice fears)

- Social support (involve family and community)

- Involving patient in treatment decision (willing to stop TB treatment?)

- Management of symptoms (breathlessness, pain, etc)

- Nutritional support

- Spiritual counselling whenever is requested/ demanded


Examples of patients support interventions in GLC regions

Region Food Transport

Vouchers

Hygiene

Packets

Counseling

Support

Housing

Support

Education Financial

Incentive

s

Skills-building

Workshops

AFRO 12/22 6/22 0/22 9/22 2/22 1/22 1/22 2/22

AMRO 4/16 2/16 0/16 8/16 0/16 1/16 2/16 1/16

EMRO 4/8 2/8 0/8 4/8 0/8 1/8 3/8 0/8

EURO 43/52 26/52 18/52 32/52 2/52 9/52 7/52 1/52

SEARO 4/9 3/9 0/9 4/9 2/9 0/9 1/9 1/9

WPRO 5/10 4/10 0/10 4/10 1/10 1/10 0/10 0/10

Totals 72/117 43/117 18/117 61/117 8/117 13/117 14/117 5/117


Common current flow for MDR-TB management

DR-TB Patients are diagnosed at health facilities

Referred to MDR-TB hospitals for initiation of treatment and initial hospitalization

Patients admitted and started on standard regimen

(

Patients kept for approx. 6 months or till 2 negative cultures

Then referred back to the health facility to continue treatment

Follow-up done at MDR-TB hospitals on monthly basis

11/5/2013 120

Issues associated with centralised care

Nearly half of diagnosed cases are not started on treatment

1-2 months of waiting for admission, sometimes more Long distance of transportation for admission and follow

up Negative impact on social and economic status of the

individual and family due to a long stay in hospital Risk of transmission in hospital due to inadequate

implementation of infection control measures Non-uniformity in current, sporadic efforts of

decentralized management Issues of refusal to admission and aggressive demand for

early discharge Poor outcome of DR-TB cases

11/5/2013 121

Solutions

11/5/2013 122

Solutions Advantages Challenges

Increase no. of hospitals/ beds

• Convenient to the health system

• Cost to the government/ patients • Socio-economic problems • Risk of transmission if inadequate IC • Sustainability

Decentralized management of DR-TB cases including community DOT

• Early initiation of treatment

Reduce morbidity/ mortality Reduce transmission

• Convenient for the patients •Cost effective • Improve adherence • More sustainable

• Establishment of new infrastructure • Increase training need • Other sector s/ Community involvement • Increase demand for supervision

Possible decentralized management of MDR-TB:

Principles

1. Ned for clarity of functions across all levels

2. Need for linkages to existing TB services and to the entire health system

11/5/2013 123

Requirements for the decentralized MDR-TB care

Prompt and accurate MDR-TB diagnosis

Trained multidisciplinary team with adequate and effective mentorship and supervision

Guidelines/protocols for clinical management

Uninterrupted supply of second line anti-TB drugs

Adequate infrastructure and infection control measures

Integration with local TB programme activities as well as HIV and PHC;

11/5/2013 124

Requirement for the decentralized MDR-TB care

Criteria for selection of patients to receive treatment in the community and defaulter tracing mechanism

Communication between the different levels of the health care system, including effective Advocacy, Communication and Social Mobilization.

Rigorous monitoring and evaluation: indicators to be defined

Ring fenced resources dedicated to providing specialized MDR-TB staff

11/5/2013 125

Central MDR/X-DR TB Unit /

Hospital

Decentralised (?

District) MDR-TB Unit

Satellite MDR-TB Unit

Satellite MDR-TB Unit

Mobile MDR-TB

Unit/Injection team

PHC Clinic PHC Clinic

Mobile MDR-TB

Unit/Injection team

Community DOTS Plus supporters/Households

Sample model of decentralized MDR-TB CARE

Sample proposed patient flow (1) Diagnosis at Health Care Facility

Refer to the nearest Centralized/ Decentralized DR-TB Unit

Initiation of treatment and

Hospitalization if indicated Managed on ambulatory

(smear pos, very sick, XDR, (all smear neg, stable)

side-effects)

11/5/2013 127

Sample proposed patient flow (2) Hospitalized cases

Discharged after

(smear conversion/ stable for MDR; culture conversion for XDR)

Referred to nearest health facility to continue treatment

(health facility will be prepared for DR-TB management)

Monitored on regular basis by Centralized/ Decentralized units

11/5/2013 128

Sample proposed patient flow (3) Ambulatory cases

Managed at all category of DR-TB units/ health facility/ community supporters/ mobile teams

Monitored by closest Centralized/ Decentralized units

(responsible for registering and reporting)

11/5/2013 129

DR-TB and Human Rights

1) Limitation and derogation clauses in the international

human rights instruments recognize that States at certain

times may need to limit rights. Such clauses are primarily

intended to protect the rights of individuals when States

perceive that such limitations must take place.

2) Restrictions must be in accordance with the law, in the

interest of legitimate aims, and strictly necessary for the

promotion of general welfare in a democratic society.

3) Where several types of limitations are available, the least

restrictive alternative must be adopted.

4) Even where, on grounds of protecting public health, such

limitations are basically permitted— based on a set of

principles called the Siracuse Principles—they should be of

limited duration and subject to review


The 5 Siracuse Principles 1. The restriction is provided for and carried out in

accordance with the law;

2. The restriction is in the interest of a legitimate objective of general interest;

3. The restriction is strictly necessary in a democratic society to achieve the objective;

4. There are no less intrusive and restrictive means available to reach the same goal; and

5. The restriction is not imposed arbitrarily, i.e. in an unreasonable or otherwise discriminatory manner.


Strategic action area 1 :Preventing the generation of drug-resistant TB forms – actions to close the tap

Strategic action area 2: Establishing the magnitude of DR-TB

Strategic action area 3: Promoting and supporting development and scale up of programmatic management of drug-resistant TB

Strategic action area 4: Developing / strengthening National and Regional DR-TB surveillance systems

Strategic action area 5: Addressing Health system challenges: Increased access to TB services through decentralisation, infrastructure development, initiatives to remove financial barriers to access (UHC concept), enhanced laboratory quality and networks, etc.; increased and sustained TB control financing: Health workforce capacity building; working with all providers & strategic Health information

Strategic action area 6: Operations Research 11/5/2013 African Region TB Managers' meeting 2013 132

Core strategic actions for country and regional response to DR-TB

Information on “Short course treatment regimens” for MDR-TB (1)

• Current official WHO’s guidelines for MDR-TB recommend 8 months intensive phase and a total duration of 20 months in most patients [Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update. (WHO/HTM/TB/2011.6). Geneva, World Health Organization, 2011 & Ahuja SD et al. Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients. PLoS Med. 2012, 9(8):e1001300].

• In the past few years one observational study from Bangladesh using shorter regimens (9-12 months) yielded much higher treatment success than is usually achieved with the longer regimens [Van Deun A et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. American Journal of Respiratory and Critical Care Medicine, 2010, 182(5): 684–692]. Some AFRO countries (Benin, Burundi, Cameroon, CAR and Cote D’Ivoire) have applied to conduct OR on this with WHO support.


Current WHO Position on short course regimens for MDR-TB

Until sufficient evidence is available to inform a change in policy, WHO is advising countries on a case-by-case basis to introduce short MDR-TB regimens under the following conditions: ■Treatment is delivered under operational research conditions following international standards (including Good Clinical Practice and safety monitoring), with the objective of assessing the effectiveness and safety of these regimens; ■The project is approved by a national ethics review committee with proper attention to regulatory and ethical issues, ahead of any patient enrolment; and ■The programmatic management of DR-TB and the corresponding research project are monitored by an independent monitoring board set up by, and reporting to WHO.



Source: Prof Diane Havlir. Maputo TB/HIV Meeting, April 2013

135


Core Recommendations on use of BEDAQUILINE


WHO INTERIM POLICY RECOMMENDATIONS ON USE OF BEDAQUILINE


BEDAQUILINE USE RECOMMENDATIONS


BEDAQUILINE USE RECOMMENDATIONS


DRUG RESISTANT TB DIAGNOSTIC PATHWAYS


ENHANCING COUNTRY CAPACITY TO DIAGNOSE TB: Smear, C & DST, and Molecular technologies including WHO endorsed Xpert & LPA

Countries eligible for FIND negotiated prices on Xpert MTB/RIF equipment

1. Algeria

2. Angola

3. Benin

4. Botswana

5. Burkina Faso

6. Burundi 7. Cape Verde

8. Cameroon

9. Central African Republic

10. Chad

11. Comoros

12. Congo( Brazzaville) 13. DR Congo

14. Eritrea

15. Ethiopia

16. Gabon

17. Gambia

18. Ghana

19. Guinea

20. Guinea Bissau

21. Ivory Coast 22. Kenya

23. Liberia

24. Madagascar

25. Malawi 26. Mali 27. Mauritania

28. Mozambique

29. Namibia

30. Niger

31. Nigeria

32. Rwanda

33. Senegal 34. Seychelles

35. Sierra Leone

36. South Africa

37. Tanzania

38. Togo

39. Uganda

40. Zambia

41. Zimbabwe 11/5/2013 African Region TB Managers' meeting 2013 143

Key Recommendations for

ART in Adults and

Adolescents

WHO 2013 ARV Guidelines Launch

Dr. Meg Doherty

Summary of Changes in Recommendations When to Start in Adults

TARGET POPULATION (ARV-NAIVE)

2010 ART GUIDELINES 2013 ART GUIDELINES

STRENGTH OF RECOMMENDATION

& QUALITY OF EVIDENCE

HIV+ ASYMPTOMATIC CD4 ≤350 cells/mm3

CD4 ≤500 cells/mm3 (CD4 ≤ 350 cells/mm3 as a priority)

Strong, moderate-quality evidence

HIV+ SYMPTOMATIC

WHO clinical stage 3 or 4 regardless of CD4 cell count

No change Strong, moderate-quality evidence

PREGNANT AND BREASTFEEDING WOMEN WITH HIV

CD4 ≤350 cells/mm3 or WHO clinical stage 3 or 4

Regardless of CD4 cell count or WHO clinical stage

Strong, moderate-quality evidence

HIV/TB CO-INFECTION

Presence of active TB disease, regardless of CD4 cell count

No change Strong, low-quality evidence

HIV/HBV CO-INFECTION

Evidence of chronic active HBV disease, regardless of CD4 cell count

Evidence of severe chronic HBV liver disease, regardless of CD4 cell count

Strong, low-quality evidence

HIV+ PARTNERS IN SD COUPLE

No recommendation established

Regardless of CD4 cell count or WHO clinical stage

Strong, high-quality evidence

Recommendations: CD4 Independent Conditions

INITIATE ART REGARDLESS OF CD4 COUNT OR CLINICAL STAGE

RECOMMENDATION

ADULTS WITH HIV…

…and active TB disease Strong, low-quality evidence

…and HBV co-infection with severe liver disease

Strong, low-quality evidence

…who are pregnant or breastfeeding Strong, moderate-quality of evidence

…in a HIV serodiscordant partnership

Strong, high-quality evidence

CHILDREN < 5 YEARS OLD WITH HIV

Infants diagnosed in the first year of life

Strong, moderate-quality of evidence

Children infected with HIV between one and below five years of age

Conditional, very-low-quality evidence

FIRST-LINE REGIMENS (PREFERRED ARV REGIMENS)

TARGET

POPULATION 2010 ART GUIDELINES 2013 ART GUIDELINES

STRENGTH &

QUALITY OF

EVIDENCE

HIV+ ADULTS AZT or TDF + 3TC (or

FTC) + EFV or NVP

TDF + 3TC (or FTC) + EFV

(as fixed dose

combination)

Strong,

moderate-quality

evidence

HIV+ PREGNANT

WOMEN AZT + 3TC + NVP or EFV

HIV/TB

CO-INFECTION

AZT or TDF + 3TC (or

FTC) + EFV

HIV/HBV

CO-INFECTION

TDF + 3TC (or FTC) +

EFV

Summary of Changes in Recommendations:

What to Start in Adults

1st Line ART

Adults and Adolescents (including pregnant women, TB co-infection and

HBV co-infection)

Preferred

Regimens

TDF+3TC (or FTC) + EFV

Alternative

Regimens

AZT+ 3TC + EFV (or NVP)

TDF+ 3TC (or FTC)+ NVP

Special situations

ABC +3TC+EFV (or NVP)

AZT (or ABC)+ 3TC

+ LPV/r or ATV/r

One regimen cannot fit all: preferred, alternative, special situations

Rationale: One Regimen For All

• Simplicity: regimen is very effective, well tolerated and available as a single, once-daily FDC and therefore easy to prescribe and easy to take for patients – facilitates adherence

• Harmonizes regimens across range of populations (Adults, Pregnant Women (1st trimester), Children >3 years, TB and Hepatitis B)

• Simplifies drug procurement and supply chain by reducing number of preferred regimens (phasing out d4T)

• Safety in pregnancy

• Efficacy against HBV

• EFV is preferred NNRTI for people with HIV and TB (pharmacological compatibility with TB drugs) and HIV and HBV coinfection (less risk of hepatic toxicity)

• Affordability (cost declined significantly since 2010)

Preferred 1st line regimen: TDF + 3TC (or FTC) + EFV

Managing Co-infections

TB in the 2013 Consolidated Guidelines • Synthesis of existing recommendations

http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf












Co-trimoxazole Recommendations (2006) Planned revision early 2014

AGE CRITERIA FOR INITIATION Contraindications: severe sulfa allergy, severe liver or renal disease and G6PD deficiency

HIV-EXPOSED INFANTS

Universal, starting at 4–6 weeks after birth

<1 YEAR Universal 1

1–5 YEARS WHO clinical stages 2, 3 and 4 regardless of CD4 % OR Any WHO stage and CD4 <25% OR Universal 1

≥5 YEARS, INCLUDING ADULTS

Any WHO stage and CD4 count <350 cells/mm3 2 OR WHO 3 or 4 irrespective of CD4 level OR Universal 1

1 Universal regardless of CD4 percentage or clinical stage in settings with high HIV prevalence, high infant mortality due to infectious diseases and limited health infrastructure. 2 Some countries may choose to adopt a CD4 threshold of <200 cells/mm3. 3 In settings with high prevalence of bacterial infections or malaria.

CRITERIA FOR DISCONTINUATION (Stevens-Johnson syndrome, severe liver disease, anaemia, pancytopaenia or HIV -ve status)

Until risk of HIV transmission ends HIV excluded

Until 5 years of age regardless of CD4% or clinical symptoms OR Never

Never

Never or when CD4 ≥350 cells/mm3 after 6 months of ART 3

OR CD4 ≥200 cells/mm3 after 6 months of ART

TB Screening Algorithm in Adults

Adults and adolescents living with HIV should be screened for TB with a clinical algorithm; those who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases (strong recommendation, moderate-quality evidence).

TB patients with known positive HIV status and TB patients living in HIV-prevalent settings should receive at least six months of rifampicin treatment regimen (strong recommendation, high-quality evidence).

TB Screening in Children

Children living with HIV who have any of the following symptoms of poor weight gain, fever or current cough or contact history with a TB case may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, children should be offered isoniazid preventive therapy regardless of their age (strong recommendation, low quality evidence).

Isoniazid Preventive Therapy (IPT)

IPT reduces the incidence of TB in PLHIV even if they are on ART

Offer IPT to all PLHIV who do not have TB even if they are on ART Adult and adolescents and children living with HIV should be screened with a clinical algorithm; those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT (strong recommendation, moderate-quality evidence). Children and adults living with HIV who are contacts of TB patients should be screened and evaluated for TB. Those without TB should be offered IPT (strong recommendation, very low quality of evidence)

Diagnosis of TB in PLHIV

Xpert MTB/RIF should be used as the initial diagnostic test in persons with HIV and suspected MDR-TB

(strong recommendation)

• Sputum smear microscopy has a very low

TB detection rate among PLHIV compared with sputum culture and Xpert MTB/Rif

Xpert MTB/RIF • Fully automated molecular test • Suitable for use outside laboratory • simultaneously detects TB disease and

rifampicin resistance within 2 hours • Detects 92% of culture-positive TB





TB Treatment and ART in PLHIV

• ART should be started in all TB patients living with HIV irrespective of their CD4 counts

(strong recommendation, low quality of evidence)

• Start TB treatment first using a rifampicin containing regimen

• Start ART asap within the first 8 weeks of TB treatment

(strong recommendation, moderate quality of evidence)

• Patients with CD4< 50 cells/mm3 should receive ART immediately with the first 2 weeks of initiating TB treatment

ART in PLHIV and TB Adults, adolescents and children over 3 years

Efavirenz is preferred NNRTI in patients starting ART (TDF + 3TC (or FTC) + EFV ) while on TB treatment

(strong recommendation, high-quality evidence)

Rifampicin reduces effective concentrations of PIs

If rifabutin available use standard PI regimens

If rifabutin not available provide double dose Lopinavir/ritonavir(LPV/r) (800mg/200mg or 400mg/400mg twice daily)

Preferred first-line ART regimen

Second-line ART regimen

Children and Infants Initiating TB Treatment while Receiving ART

If on a standard NNRTI-based regimen (two NRTIs + EFV or NVP)

continue NVP (ensure dose is 200 mg/m2) OR Triple NRTI (AZT + 3TC + ABC)

If on standard PI-based regimen (two NRTIs + LPV/r)

Triple NRTI (AZT + 3TC + ABC) OR Substitute NVP for LPV/r (ensure dose is 200 mg/m2) OR Continue LPV/r (consider adding RTV to achieve the full therapeutic dose)

Interactions between rifampicin and LPV/r or NVP mean that TBHIV co-treatment in children under three years needs ART modification

Once TB therapy has been completed, this regimen should be stopped and the original regimen should be restarted (strong recommendation, moderate-quality evidence)

SUMMARY : Pertinent DR-TB control issues in the Region & barriers to scale up

1) High burden of TB & TB/HIV co-infection

2) Very high preventable unfavorable programme performance indicators

3) Sub-optimal political & programmatic strategic policy environment for PMDT leading to significant diagnosis / treatment gap

4) Inadequate laboratory diagnostic capacity and networks for DR-TB diagnosis and follow up

5) Limited availability of SLDs

6) Health system challenges: access to health services; Infrastructure; HRH; funding; surveillance systems; etc, etc


Thank you for your attention

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Status of Drug Resistant TB and efforts for its control in the … · STATUS OF DRUG RESISTANT TB IN THE AFRICAN REGION: BURDEN, CONTROL EFFORTS, CHALLENGES AND FUTURE PERSPECTIVES

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