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Treatment of drug resistant TB – Shorter, longer (conventional) regimens

Treatment of drug resistant TB

The treatment of drug resistant TB has always been more difficult than the treatment of drug susceptible TB. It has required the use of “second line” or reserve drugs that are more costly and cause more side effects. Also the drugs must be taken for up to two years. The following is the type of problem that patients taking the drugs were faced with.

“These drugs are so horrible to eat every day. After nearly a year and a half, I thought it was just too much; I couldn’t keep taking all those pills. I thought it would be OK if I stopped taking them. But they told me if I didn’t keep going I might get sick again and then I would have to start again from the beginning with all the injections. So I kept going with the pills and now I am cured. It was such a long time.”
Drug resistant TB patient1Keshavjee, S., Farmer, P.E. “Time to put boots on the ground: making universal access to MDR-TB treatment a reality”, Int J Tuberc Lung Dis, 14(10), October 2010, 1222-1225 http://www.ingentaconnect.com

And so the search began for shorter regimens for the treatment of drug resistant TB, that were also easier to take.

This led to the development of the Bangladesh regimen which appears to have much higher cure rates and the drugs only need to be taken for eight or nine months. There are also other shorter regimens that are now being tested. There have however, been no randomised control trials of these new regimens. Some people were very unenthusiastic about the new shorter regimens.

In India Dr Zarir Udwadia in Mumbai said:

“This has as much chance of working successfully in India as the proverbial snowflake in hell”.2“WHO’s shorter treatment for multi-drug resistant tuberculosis, city may not gain”, NYOOZ, 2016, www.nyoooz.com/mumbai/ He said that most patients in Mumbai are already resistant to three to four components of the “one size fits all” regimen given to all MDR-TB patients by the government run RNTCP.

There is more about drug resistant TB in India.

Eligibility for treatment with a shorter regimen

Not all patients with drug resistant TB are eligible for treatment with a shorter regimen. A shorter regimen is usually considered suitable for patients with rifampicin resistant or multi drug resistant TB who have not been previously treated with second line drugs and in whom resistance to fluoroquinolones and second line injectables has been excluded or is considered highly unlikely.

Fewer drugs may be needed when the treatment of drug resistant TB is with a shorter TB drug regimen

Fewer drugs are needed when the treatment of drug resistant TB is with a shorter TB drug regimen.

There needs to be a careful selection of patients to be enrolled in any shorter regimen. There also needs to be effective patient support to enable full adherence to treatment. It is recommended that patients are tested for susceptibility or resistance to fluoroquinolones and to the second line injectable agents used in the regimen before starting on a shorter MDR-TB regimen. Patients with strains resistant to any of the two groups of medicines should be transferred to treatment with a conventional MDR-TB regimen.

The availability of rapid and reliable TB tests can be very valuable in deciding within a few days which patients are eligible for shorter MDR TB regimens. It can also provide information about what modifications to conventional MDR-TB regimens are necessary based on the resistance detected. The Line Probe Assay test can be used as an initial direct test, rather than tests such as the culture test to detect resistance to fluoroquinolones and to the second line injectable drugs.

In settings where laboratory capacity for drug susceptibility testing (DST) for fluoroquinolones and injectable agents is not yet available, treatment decisions need to be guided by the likelihood of resistance to these medicines. This needs to take into account the patient’s clinical history and recent surveillance data.

WHO recommendations on treatment of drug resistant TB

In 2016 WHO changed their recommendations on the drugs to be used for the treatment of drug resistant TB.3“Rapid diagnostic test and shorter, cheaper treatment signal new hope for multidrug-resistant tuberculosis patients”, WHO, Geneva, 2016 www.who.int/mediacentre/news/releases/2016/multidrug-resistant-tuberculosis/en/ For details of the drugs recommended before 2016 see the page on TB drugs. The drugs to be used as the treatment for drug resistant TB after 2016 are as follows.

TB drugs used to treat rifampicin resistant and multi drug resistant TB after May 2016
Group A : Fluoroquinolones Group B : Second line injectable agents Group C : Other core second line Agents Group D : Add-on agents (not part of the core MDR-TB regimen)
Levofloxacin (Lfx) Amikacin (Am) Ethionamide/Prothionamide (Eto/Pto) D1 Pyrazinamide
Moxifloxacin (Mfx) Capreomycin (Cm) Cycloserine / Terizidone (Cs Trd) D1 Ethambutol (E)
Gatifloxacin (Gfx) Kanamycin (Km) Linezolid (Lzd) D1 High-dose isoniazid (Hh)
(Streptomycin) Clofazimine (Cfz) D2 Bedaquiline (Bdq)
D2 Delamanid (Dlm)
D3 p-aminosalicylic acid PAS)
D3 lmipenem-cilastatin (lpm)
D3 Meropenem (Mpm)
D3 Amoxicillin-clavulanate (Amx-Clv)
D3 Thioacetazone (T)

This regrouping is intended to guide the design of conventional length regimens. For shorter regimens of eight or nine months the drug regimen is usually standardized. Medicines in Groups A and C are shown by decreasing order of usual preference for use. The carbapenems (which include meropenem and imipenem and ertapenem) and clavulanate are meant to be used together. Clavulanate is only available in formulations combined with amoxicillin. HIV status must be tested and confirmed to be negative before thioacetazone is started.

Conventional treatment regimens for rifampicin resistant TB

A conventional treatment regimen for any patient with rifampicin resistant TB, is always going to be complex. A number of different drugs need to be used on the basis of which drugs the patient is already known, or likely to be resistant to.

These recommendations cover rifampicin resistant forms of TB, including patients with strains susceptible to isoniazid, or with additional resistance to isoniazid (i.e. multi drug resistant TB; MDR-TB), or also resistant to other medicines from the first line group (poly-resistant) or from the second-line group (e.g. extremely drug resistant TB (XDR-TB).

In patients with rifampicin resistant or multi drug resistant TB, a regimen with at least five effective TB medicines is recommended during the intensive phase. This includes pyrazinamide and four core second line medicines, one chosen from Group A, one from Group B, and at least two from Group C. If the minimum of effective TB medicines cannot be composed, an agent from Group D2 and other agents from D3 may be added to bring the total to five.

In patients with rifampicin-resistant or multi-drug resistant TB, it is recommended that the regimen be further strengthened with high dose isoniazid and/or ethambutol.

Fluoroquinolones

Treatment with later generation fluoroquinolones (defined here as high dose levofloxacin, moxifloxacin, and gatifloxacin) has been shown to significantly improve treatment outcomes in adults with rifampicin resistant or multi drug resistant TB. This group of drugs is therefore considered to be the most important component of the core MDR-TB regimen. The benefits from their use outweighs the potential risks. So they should always be included unless there is an absolute contra-indication for their use.

The order of preference for the inclusion of the later generation fluoroquinolones in MDR-TB regimens is:

  • high-dose levofloxacin
  • moxifloxacin
  • & gatifloxacin

It is recommended that ofloxacin is phased out from MDR-TB regimens and that ciprofloxacin is never used due to the limited evidence for their effectiveness.

Second line injectable agents

Adults with rifampicin resistant or multi drug resistant TB should always receive a second line injectable agent as part of their regimen, unless there is an important reason for not doing so. The choice of which of the three standard agents to use, amikacin, capreomycin or kanamycin should be determined by the likelihood of effectiveness and by implementation considerations. Adverse effects need to be carefully monitored for, while using second line injectable agents. Hearing loss and nephrotoxicity are among the most frequent and most severe.

Other core second line agents

Two or more of the following four medicines should be included. Ethionamide (or prothionamide) cycloserine (or terizidone) linezolid and clofazimine. Group C agents are included to bring the total of effective second line TB medicines in the core regimen to at least four during the intensive phase of the regimen.

Add on agents

Group D1 consists of pyrazinamide, ethambutol and high dose isoniazid. These agents are usually added to the core second line medications unless the risks from confirmed resistance, pill burden, intolerance or drug drug interactions outweigh the potential benefits.

Group D2 is made up of bedaquiline and delamanid. These are two new TB drugs. The previous recommendations for their use haven’t changed.

Group D3 consists of p-aminosalicylic acid (PAS), imipenem-cilastatin, meropenem, clavulanate and thioacetazone. These drugs are only to be used when an MDR-TB regimen with at least 5 effective drugs ( i.e. primarily 4 core second line medicines plus pyrazinamide) cannot otherwise be composed.

You can read more about:

Drug resistant TB in South Africa

or TB & HIV in South Africa

or Drug resistant TB

Major Source

WHO treatment guidelines for drug resistant tuberculosis 2016 update  http://apps.who.int/iris/handle/10665/250125/

References

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1. Keshavjee, S., Farmer, P.E. “Time to put boots on the ground: making universal access to MDR-TB treatment a reality”, Int J Tuberc Lung Dis, 14(10), October 2010, 1222-1225 http://www.ingentaconnect.com
2. “WHO’s shorter treatment for multi-drug resistant tuberculosis, city may not gain”, NYOOZ, 2016, www.nyoooz.com/mumbai/
3. “Rapid diagnostic test and shorter, cheaper treatment signal new hope for multidrug-resistant tuberculosis patients”, WHO, Geneva, 2016 www.who.int/mediacentre/news/releases/2016/multidrug-resistant-tuberculosis/en/