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Standard Treatment for INH-Resistant Tuberculosis

By Arturo Eligan | 29 Dec, 2016

My name is Arturo Eligan. I am working in Kabul, Afghanistan as an Intergovernmental panel physician. I have diagnosed a case of INH-only resistant TB case through Culture and Sensitivity. In compliance with WHO and ATS / CDC Guidelines (Not to treat MDR TB in Stand-alone DOTS clinics) I referred this patient to a JICA-supported regional reference MDR TB clinic. This patient came to me the other day and I was surprised with the medicines she is taking : She is on PO- Ethionamide, Rifampicin, PZA, Ethambutol, LevoFloxacin and IM -Amikacin. I went back to the WHO Guidelines and didn't see these regimen as the recommended for INH-only resistant TB. Practically this is an MDR regimen minus the Rifampicin. I will appreciate if you guys who have experience with INH-resistant cases could shed light on this. Thank you.



Tamirirashe Mahwire Replied at 1:37 AM, 29 Dec 2016

thank you for the case. Youre definitely correct. The regimen your patient is on is OVERKILL. in our program if a patient has mono-resistance to INH we give them rifafour (RHZE)for 12 months. please stop the mDR regimen and give first line drugs .

Haluk Çalışır Replied at 7:38 AM, 29 Dec 2016

Dear Dr. Eligan,

I agree with Dr. Mahwire to stop MDRTB regimen for your INH resistant case.
RHZE regimen seems the most reliable solution.
Best regards.
Haluk Çalışır M.D. Assoc. Prof.
on Pulmonary Diseases
Acibadem University, Istanbul

2016-12-29 9:38 GMT+03:00 Tamirirashe Mahwire via GHDonline <

Dr. Saswata Dutt Replied at 9:30 AM, 29 Dec 2016

Dr. Eligan,

Thank you for the discussion generated. Though not reliable & reproducible,
the DST for ethambutol & pyrazinamide becomes important in cases of
isoniazid resistance (as many laboratories in developing countries faces
challenges to do DST for these drugs), as treatment regimen will differ
accordingly. Though we all know, I have attached WHO guidelines here.

Follow-up with geneXpert MTB/RIF test is also quite important in such

Thanks & regards.

HAIDER AL-DARRAJI Replied at 9:46 AM, 29 Dec 2016

Dear Dr Eligan
Such conditions still require further investigation.
Yes, this case might have been overtreated (although I suggest contacting the clinic for further clarification), but WHO recommended treatment for initial TB cases might not work here. Recent data showed higher rates of failure, relapse and progression to MDR-TB (attached)

Attached resource:

Tamirirashe Mahwire Replied at 11:21 AM, 29 Dec 2016

I think we should look at country specific guidelines which are based on context. This context will include if drug resistance surveillance has been conducted in the country. While there is need for further culture and DST to ascertain resistance to other first line drugs these may be very expensive in high burden low resource settings. The systematic review alluded to 11% failure . As a public health approach it maybe necessary t continue first line medication for the 89% who will benefit from it. The few failing treatment based on clinical or sputum deterioration would then need 2nd line medication. Starting Injectables using second line drugs on all mono resistant isoniazid cases is not cost effective. Unfortunately the systematic review did not download well . I would have wanted to see the funnel plot to check for publication bias. I would also want to know if any conflicts of interest exist with authors. i would have further wanted to know if cohort studies were combined with RCTs and if systematic review was conducted according to Cochrane guidelines before i accept the findings.

Dr. Saswata Dutt Replied at 11:29 AM, 31 Dec 2016

Dear Dr. Eligan,

Here is another recent interesting study on isoniazid mono-resistance &
treatment outcome. And why treatment of it is bit challenging.

Thanks & regards.

Tom Yates Replied at 3:37 PM, 2 Jan 2017

There's some correspondence about the treatment of INH resistant TB in this
month's IJTLD. I have copied a section from a nice letter by Rieder and Van
Deun below.

Happy new year,

*'Isoniazid resistance that is solely attributable to mutations in the inhA
gene does not usually even require a high dose of isoniazid: even the upper
end ofminimum inhibitory concentration distributions associated with inhA
mutations is generally by far exceeded by the serum concentrations
achievable with a normal dose of 5 mg/kg body weight of isoniazid. At the
other end of the spectrum, a combination of mutations in both the inhA and
katG genes confers an unassailable level of isoniazid resistance. A high
dose of isoniazid (10 mg/kg body weight) covers the middle ground, and is
precisely given to overcome resistance-conferring mutations in the katG
gene. The very frequent katG mutation 315Thr is special in the sense that
it gives highly variable resistance levels. Some are so high that they are
non-responsive even to high-dose isoniazid, but the majority of these
strains show moderate resistance levels around the peak serum concentration
of a normal dose of isoniazid. High-dose isoniazid will thus be
bactericidal for the majority of strains with the most frequent resistance
mutation. Knowing whether isoniazid resistance is due to a mutation in the
katG gene is thus in itself an insufficient basis for a decision to
withhold isoniazid. Moreover, it would in some instances unnecessarily be
depriving a patient of an effective and well-tolerated drug.'*

Arturo Eligan Replied at 6:41 PM, 2 Jan 2017

Thank you Tom Yates for this excerpt. I wish IULATD, WHO and CDC/ATS will come up with evidence-based guidelines on INH mono resistant TB because apparently many clinicians are confused on its proper management. Even doctors on designated MDR Referral clinics have different take on INH Resistant TB. Even  if you look into the literature including WHO, there are those who say that the doubling the time for the first line drugs (12 month of RHZE) works while it seems that the 9 months HZE with Qinolones (Levofloxacin) is the other more popular option. But which regimen really work? Which one is least detrimental to the patient?
Being a patient advocate, I am really worried about the injectables (aminoglycosides) because I have personally witnessed patients with disastrous outcomes because of long time use of these drugs like hearing loss and kidney failure.

Dylan Tierney Moderator Emeritus Replied at 4:01 PM, 6 Jan 2017

There are not enough is not enough controlled evidence to be able to make strong statements about the best regimen for the management of INH mono-resistant TB.

It is important to thoroughly consider the possibility that there may be more resistance than initially appreciated. As already noted, resistance testing for ethambutol and pyrazinamide is prone to error.

A very careful clinical history should be taken, with a focus on determining whether the patient has a previous history of TB and, if so, which treatments have been provided in the past. The possibility of contact with a source patient should also be explored.

Prescriptions errors for mono- or poly-resistant TB are a common pathway for the amplification of resistance so, if there is low confidence in the diagnosis, it may make sense to opt for a regimen that includes more likely effective drugs rather than fewer.

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