dots plus in developing countries experiences & implications dr. nirmal kumar jain md, dnb(rm)...

DOTS PLUS IN DEVELOPING COUNTRIESEXPERIENCES & IMPLICATIONS

Dr. Nirmal Kumar JainMD, DNB(RM)

Professor & Head and

Medical Superintendent

Hospital for Chest Disease & Tuberculosis

SMS Medical College, Jaipur

DOTS PLUS

• A case management strategy under development, designed to manage MDR-TB using second line drugs within the DOTS strategy in low – and middle – income countries.

To prevent further development and spread of MDR-TB.

DOTS-PLUS PREREQUISITES

• The potential DOTS-Plus pilot project site should :

– DOTS strategy is in place and is functioning well.

– Government commitment and adequate funding.

– Co-ordinated project management plan.

– Adequate laboratory services.

– Rational treatment strategy.

– Adequate information (data) management system.

DOTS REFERALS Name of Medical College

2000 2001 2002 2003 2004 Total

Jaipur 3238 4066 4371 4936 5147 21758

Udaipur 513 2719 2554 2227 2536 10549

Bikaner - 424 716 972 1449 3561

Jodhpur - - - 1191 1107 2298

Ajmer 614 604 910 1631 1286 5045

Kota - - - - - -

Total 4365 7813 8551 10957 11525 43211

PATIENT PUT ON MDR-TB TREATMENT MONTH YEAR-2002 YEAR-2003 YEAR-2004

January 109 214 157

February 125 190 144

March 150 173 154

April 151 178 147

May 159 186 137

June 138 192 213

July 160 119 220

August 175 236 211

September 159 159 225

October 181 145 189

November 92 145 187

December 209 120 190

Total : 1808 2057 2174

FACTORS RESPONSIBLE FOR TREATMENT FAILURE AMONG PATIENTS ON DOTS REGIMEN

BYDr. N.K. Jain

Dr. Himanshu Garg

Dr. Shubhranshu

Dr. S.P. Agnihotri

Dr. N. Joshi

Dr. S. Koolwal

Deptt. of Chest Diseases & Tuberculosis,

SMS Medical College, Jaipur.

DISTRIBUTION OF PATIENTS ACCORDING TO CATEGORY OF TREATMENT

S.No. Category No. %

1. Cat. I Failure 48 32.88

2. Cat. II Failure 98 67.12

Total : 146 100

MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY I FAILURE PATIENTS

S.No. Pattern No. %1. Smear Positive Culture Negative 10 20.832. Sensitive to all drugs 16 33.343. HR resistance 12 254. HER resistance 3 6.255. SHR resistance 3 6.256. HRQ 3 6.257. Resistance to all drugs

Atypical Mycobacteria1 2.08

Total : 48 100

H= Isoniazid, R= Rifampicin, E= Ethambutol, S= Streptomycin, Q= Quinolones

DISTRIBUTION OF CATEGORY II FAILURE PATIENTS ACCORDING TO HISTORY OF CHEMOTHERAPY

S.No. Group After Cat. I Treatment

After Conventional

Chemotherapy

Total

No. % No. % No. %

1. Relapses 9 25 12 21.43 21 21.432. Defaulters 17 47.22 26 46.43 43 43.883. Failures 10 27.78 18 32.14 28 28.574. Fresh cases

(Wrongly Categorized)

-- -- -- -- 6 6.12

Total : 36 100 56 100 98 100

MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY II FAILURE PATIENTS

S.No. Pattern No. %1. Smear Positive Culture Negative 8 8.162. Sensitive to all drugs 17 17.353. HR resistance 25 25.514. SHR resistance 24 24.495. SHER resistance 9 9.186. SHR Ed P T resistance 3 3.067. SHER T Q 3 3.068. HE 3 3.069. SH resistance 2 2.04

10. HRQ 2 2.0411. Resistance to all drugs Atypical

Mycobacteria2 2.04

Total : 98 100

Ed=Ethionamide, T=Thioaceteazone, P=Para Amino Salicylic Acid

DRUGS FOR MDR-TBRESERVE ANTI-TUBERCULOSIS DRUGS.

• Aminoglycosides.

Amikacin. 7.5mg/kg Hearing loss, ataxia,

b.i.d. Nystagmus,Azotemia, Protein urea etc.

Kanamycin 15 mg/kg --do--

Capreomycin 15 mg/kg --do--

• Others.

PAS 200 mg/kg Nausea, Vomiting, Diarrhea, Hepatitis

Ethionamide 15 mg/kg Nausea, Vomiting, Hepatitis

Prothionamide 15 mg/kg --do--

Cycloserine 15 mg/kg Neurotoxicity, Heart failure

Newer Anti-tuberculosis Drugs.

• Quinolones.

Ciprofloxacin. 1000-1500 mg/day Nausea, Vomiting,

Ofloxacin. 200-800 mg/day Diarrhoea, Insomnia,

Pefloxacin. 400-800 mg/day Headache, Skin Rash,

Lomefloxacin. 400-800 mg/day Tremulous,

Sparfloxacin. 200-400 mg/day Drug Interactions.

Levofloxacin. 500 mg/day -

Gatifloxacin. 400 mg/day -

Moxifloxacin. 400 mg/day -

Newer and ExperimentalAnti-tuberculosis Drugs.

• Macrolides. Roxithromycin. 300 mg/day G.I. Disturbances, Nausea,

Diarrhoea, Dyspepsia & Pain

Clarithromycin . 500-2000mg/day Abdomen, Dysphoria, Enzyme (High

Dose).

Azithromycin. 500 mg/day

• Rifamycin Derivatives. Rifabutin. 300 mg/day Nausea, Vomiting,

Hepatitis, Flulike, Syndrome, Renal failure,

Rifabutin. 600 mg/day Thrombocytopenia,

Haemolytic anemia.

Rifalazil. - -

Newer and ExperimentalAnti-tuberculosis Drugs.

• B-Lactamase Inhibitors.

Amoxycillin + 500+125 (625mg)/ Skin rash, Anaphylaxis,

Clavulanate. 750 to 2gm Diarrhea, Candidiasis,

PM, Collitis, Hepatitis

Ticarcillin + - & Cholstatic Jaundice.

Clavulanate.

• Immunophenazine Derivatives. Clofazemine 100-200 mg/day. Skin pigmentation,

GI upset.

• Oxazolidinones. - -

• Nitroimidazopyrans. - -

Management of Multi Drug Resistant Tuberculosis.

1. Retreat with at least 3 or 4 new drugs for first 3 to

6 months (Total 5 to 7 drugs).

2. Continue chemotherapy with 2 to 3 new drugs.

3. Previously used drugs may be used in addition.

4. Use combinations with little potential of cross resistance.

5. A single drug should never be added.

Management of Multi Drug Resistant Tuberculosis.

6. Start with small dosage, increase to maximum.

7. Treatment should be initiated in hospital/directly supervised.

8. Careful bacteriological monitoring essential.

9. Surgery/ Immunotherapy should be considered in patients poorly responding to medical treatment.

10. All measures – not to stop treatment.

11. Intermittent therapy usually not effective.

12. Optimal duration, 18-to-24 months after culture conversion.

MDR TB treatment regimensResistance profile Initial phase Continuation phase

drugs months drugs months

Isoniazid Aminoglycoside 3-6 Ethambutol 18-24

+rifampicin Ethambutol ± pyrazinamide (ASCC)

± streptomycin Pyrazinamide Quinolone

Quinolone Ethionamide Ethionamide

Comments• Aminoglycoside not previously used as injectable drug for 3 to 6

months

• ETB dose may be increased to 25 mg/kg

• PZA in the continuation phase may add to response rate

• Inclusion of ETB & PZA – associated with favourable outcome

• Consider surgery if no conversion after 6 months



Isoniazid Aminoglycoside 3-6 ± pyrazinamide 18-24

+ rifampicin Pyrazinamide Quinolone (ASCC)

+ ethambutol Quinolone Ethionamide

± streptomycin Ethionamide PAS/Cycloserine

PAS/ Cycloserine

Comments

• Aminoglycoside not previously used as injectable drug for 3 to 6 months

• PZA in the continuation phase may add to response rate

• Consider surgery if no conversion after 6 months



Isoniazid Aminoglycoside 3-6 Ethambutol 18-24

+ rifampicin Ethambutol Quinolone (ASCC)

+ pyrazinamide Quinolone Ethionamide

± streptomycin Ethionamide PAS/Cycloserine

PAS/ Cycloserine

Comments• Aminoglycoside not previously used as injectable drug for 3 to 6

months• ETB dose may be increased to 25 mg/kg with careful monitoring for

retrobulbar neuritis• PZA in the continuation phase may add to response rate• Consider surgery if no conversion after 6 months

MDR TB treatment regimens

Resistance profile Initial phase Continuation phase


Isoniazid Aminoglycoside 3-6 Quinolone 18-24

+ rifampicin Quinolone Ethionamide (ASCC)

+ ethambutol Ethionamide PAS

+ pyrazinamide PAS Cycloserine

± streptomycin Cycloserine

Comments

• Aminoglycoside not previously used as injectable drug for 3 to 6 months

Potential Regimen for Patients with Multi Drug Resistant Tuberculosis.

Resistance. Suggested Duration.Regimens.

HR (+ S)* AEZQ 24 months.HER (+ S)* AZQ+2 24 months. ASCHRZ (+ S)* AEQ+2 24 months. ASCHRZ (+ S)* AQ+3 24 months. ASC

A=Aminoglycoside - SM/KM/CM/AM Q=Quinolones - Cipro/Oflo/Spar/Levo/Gati + = 2 or 3 drugs among ETH/PTH/PAS/CYC/Macrolides/-lactaminhibitor/Others.

* = Surgery may be considered.

PRIORITY RESEARCH AGENDA FOR DOTS-PLUS FOR MDR-TB

• Primary topics– Identify optimal standardised protocols to treat MDR-TB.– Identify optimal protocols for diagnostic testing.– Identify the minimum requirement for constructing and

implementing DOTS-Plus.

• Secondary topics– Identify threshold indicators for implementing DOTS-Plus.– Other operational issues.

EFFICACY OF DIFFERENT REGIMENS IN TREATMENT OF DOTS CATEGORY II FAILURE OF

PULMONARY TUBERCULOSIS

BY

Dr. N.K. Jain

Dr. Shubhranshu

Deptt. of Chest Diseases & Tuberculosis,

SMS Medical College, Jaipur.

RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 6 MONTHS

Group Total no. of cases

Sputum Status*

Radiological Response*

Clinical Response*

-Ve +Ve Imp. Stat.Quo.

Det. Imp. No Imp.

Det.

I-KHEZQP 28 23(82.14%)

5(17.85%)

22(78.57%)

6(21.43%)

- 25(89.28%)

3(10.71%)

-

II-KHEZQEd. 27 21(77.78%)

6(22.22%)

1970.37%)

8(29.63%)

- 21(77.78%)

6(22.22%)

-

III-KHEZQPEd. 27 22(81.48%)

5(18.51%)

22(81.48%)

5(18.51%)

- 24(88.89%)

3(11.11%)

-

*Percentages from total no. of cases in each group.

IMP=Improvement, Stat.= Status, Det.= Deterioration.


Group & Total No. of Cases

Deaths* Drug Toxicity*

Remaining Cases

Sputum Status*

-Ve +Ve

I-KHEZQP/HEZQP(28)

- - 28 24(85.47%)

414.20%)

II-KHEZQEd./ HEZQEd (27)

1(3.7%)

- 26 22(81.48%)

4(14.82%)

III-KHEZQPEd./ HEZQPEd. (27)

- 1(3.7%)

26 21(77.78%)

5(18.52%)

*Percentages from total no. of cases in each group. IMP=Improvement,

Stat.= Status, Det.= Deterioration.

Contd…


*Percentages from total no. of cases in each group. IMP=Improvement,

Stat.= Status, Det.= Deterioration.


Remaining Cases

Radiological Response* Clinical Response*Imp. Stat.

QuoDet. Imp. No

Imp.Det.

I-KHEZQP/ HEZQP (28)

28 18(64.29%)

4(14.20%)

2(7.14%)

24(85.47%)

2(7.14%)

2(7.14%)


26 22(81.48%)

2(7.4%)

2(7.4%)

22(81.48%)

2(7.4%)

2(7.4%)


26 21(77.78%)

1(3.7%)

4(14.82%)

21(77.78%)

1(3.7%)

4(14.82%)



Deaths* Drug Toxicity*

Remaining Cases

Sputum Status*-Ve +Ve

I-KHEZQP/HEZQP (28)

2(7.14%)

2(7.14%)

24 17(60.71%)

7(25%)


2(7.4%)

3(11.11%)

22 16(59.26%)

6(22.22%)


1(3.7%)

4(14.82%)

22 18(66.67%)

4(14.82%)



Contd…





Remaining Cases

Radiological Response* Clinical Response*Imp. Stat.

QuoDet. Imp. No

Imp.Det.

I-KHEZQP/ HEZQP (28)

24 17(60.71%)

3(10.71%)

4(14.29%)

17(60.71%)

2(7.14%)

5(17.86%)


22 16(59.26%)

- 6(22.22%)

16(59.26%)

- 6(22.22%)


22 18(66.67%)

- 4(14.82%)

18(66.67%)

2(7.4%)

2(7.4%)

COMPARISON OF OVERALL RESPONSE OF DOTS CATEGORY II FAILURE ON DIFFERENT REGIMEN

AT THE END OF 18 MONTHS

Group & Regimen

No. of Cases

Favorable Response

Unfavorable Response

Cases Exclude

from Response

I-KHEZQP/HEZQP 28 17

(60.71%)

8

(28.57%)

3

(10.71%)

II-KHEZQEd./ HEZQEd.

27 16

(59.26%)

8

(29.63%)

3

(11.11%)

III-KHEZQPEd./ HEZQPEd.

27 18

(66.67%)

5

(18.51%)

4

(14.81%)

TOTAL : 82 51

(62.2%)

21

(25.6%)

10

(12.2%)

ISSUES DOTS MDR-TB

TB Suspects -H/O cough for 3 weeks -Failure of RNTCP Cat.II(Chronic case) or more duration -Patients receiving inappropriate,

incomplete, irregular teratment, 2 or more time against NTCP policy.

Diagnostic -3 sputum examination -Direct microscopy modalities (Spot-Early Morning-Spot) 0,2,3,4,5,6,9,12,15,18,21,24

- Early Morning-Spot - Myco C/S test

Cat.I 2,4,6 0,3,6,9, ---

Cat.II 3,5,8 -X-ray

Cat.III 2,6 0,3,6,9,12,15,18,24

Outcome -Cure rate in new smear +ve -40-60% cases=85% or more

-Cure rate in re-treatment cases=70% or more

ISSUES DOTS MDR-TB

Management -IP: 3/7 (Thrice a week on alternate day) -IP: 7/7 (Daily)

-CP: 1/7 (Thrice a week on alternate day, -CP: 7/7 (Daily) one dose supervised)

Cost on

Investigation -Rs. 0-100/- -10,000/-

Cost -Cat. I 2(HRZE)3/ 4(HR)3 Rs.600/- - KHEZQEd/HEZQEd Rs.21688

-Catt.II 2(SHRZE)3/ 1(HRZE)3/ - KHEZQP/HEZQP Rs.28996

5(HRE)3 Rs.760.78/- - KHEZQPEd/HEZQPEd Rs.37096

-Cat.III 2(HRZ)3/ 4(HR)3 Rs.411.90/-

DRAFT POLICY SUGGESTIONS1. Emphasis should be given to prevent MDR-TB by wider use of DOTS by

medical professionals and to achieve cure rate of more than 85% in new sputum positive cases and more then 70% in retreatment cases.

2. Wider community participation by identifying their strengths.

3. II line drugs should be used only when resistance to I line drugs exists or patients fails on WHO Category II regimen.

4. Drugs under EDL should be used on priority basis, as these are effective, less toxic, affordable and well tolerated by patients. Kanamycin and Ethionamide be included in EDL.

5. Treatment of MDR-TB should be supervised and drugs should be made available for not more than 15 days.

Treatment should be supervised by the nearest DOT provider and empty strip/blister packs be deposited fortnightly.

6. In intensive phase: 1 injectable & 3-4 oral drugs may be administered for 3 to 6 months.

In continuation phase: 3 oral drugs preferably those not used in past may be administered for 18 months.

Contd. …

DRAFT POLICY SUGGESTIONS

7. II line drugs should be guaranteed available in specialized units attached with laboratories having culture & sensitivity facility.

8. II line drugs should be available on prescription of highly skilled specialist (Prof./Ass.Prof. of TB & Chest Hospitals).

9. MDR-TB prescription can be scrutinized by EDL committee made for rational use on Anti-TB drugs.

10. EDL committee be asked to submit report on rational use of II line drug in terms of combination, intermittency and length of time, cost incurred, cost effectiveness and prohibitory cost.

11. Since MDR-TB treatment is a last crusade against TB for survival, as per WHO recommendations, II line drugs need to be administered under strict supervision of a personnel who is highly skilled.

DOTS PLUS IN DEVELOPING COUNTRIES

1. Ensure effective DOTS – No further MDR-TB.

2. Early diagnosis of MDR-TB

High index suspicion - smear +ve at 3rd month

Mycobacterial C/S - continuation of DOTS

3. Standardized treatment regimens possible

I-KHEZQP/HEZQP

II-KHEZQEd./ HEZQEd.

III-KHEZQPEd./ HEZQPEd.

4. Reliable supply of high quality II line anti-TB drugs

5. All measures of strict adherence to therapy

6. Rigorous quality assurance, monitoring & evaluation

Most cost effectiveAccording to pattern of local resistance.

dots plus in developing countries experiences & implications dr. nirmal kumar jain md, dnb(rm)...

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