HOW TO DESIGN APPROPRIATE REGIMEN FOR MDR, PRE XDR AND XDR

Priyanti Z Soepandi
Department of Respiratory Medicine Faculty of Medicine, University of Indonesia,
Persahabatan Hospital Jakarta

ABSTRACT
Multidrug-resistant (MDR) tuberculosis, defined as tuberculosis resistant to at least
rifampicin and isoniazid, is an increasing worldwide threat. In 2015, there were an
estimated 480 000 new cases of multidrug-resistant TB (MDR-TB) and an additional
100 000 people with rifampicin-resistant TB (RR-TB) who were also newly eligible for
MDR-TB treatment. India, China and the Russian Federation accounted for 45% of the
combined total of 580 000 cases.

The crisis of MDR-TB detection and treatment continues. In 2015, of the estimated 580
000 people newly eligible for MDR-TB treatment, only 125 000 (20%) were enrolled.
Five countries accounted for more than 60% of the gap: India, China, the Russian
Federation, Indonesia and Nigeria. Globally, the MDR-TB treatment success rate was
52% in 2013.

Treatment of MDR-TB requires longer regimens – at least 20 months – with lower

success rates compared to the treatment of drug sensitive TB (DS-TB). These longer
regimens, along with a need for enhanced laboratory testing and hospitalization,
increase the cost and complexity of MDR-TB treatment. The impact of these differences
is particularly profound in high-burden countries such as South Africa. Drug resistant TB
also threatens the lives of healthcare workers in high-burden countries . The current
MDR-TB regimen is suboptimal for many reasons: it is based on poor evidence of
efficacy , is too long and toxic, includes injectable drugs that add cost and discomfort,
and does not reflect evolving drug resistance patterns.

One of the biggest barriers to scaling up MDR tuberculosis programmes is the treatment
regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. The
current WHO-recommended regimen for treating MDR tuberculosis requires daily
injections for a minimum of 8 months and has a total duration of at least 20 months.

The guidelines update WHO 2016, the previous evidence-informed recommendations

on the treatment of drug-resistant tuberculosis issued by the World Health Organization
(WHO) in 2011. The current priorities in the management of drug-resistant tuberculosis
have been reflected in the scope of the current guidance which differs from that of the
2011 version in a number of ways. For the 2016 update, the Guidelines Development

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Group convened to update the guidelines proposed priority questions focused on the
composition of treatment regimens for rifampicin-resistant and multidrug-resistant
tuberculosis (MDR-TB), the effectiveness and safety of shorter MDR-TB regimens, the
treatment of isoniazid-resistant tuberculosis, the role of surgery, and the impact of
delays in starting treatment for rifampicin-resistant tuberculosis.

The main changes in the 2016 recommendations are as follows:

 A shorter MDR-TB treatment regimen is recommended under specific conditions

 Medicines used in the design of conventional MDR-TB treatment regimens are
now regrouped differently based upon current evidence on their effectiveness
and safety. Clofazimine and linezolid are now recommended as core second-line
medicines in the MDR-TB regimen while p-aminosalicylic acid is an Add-on
agent
 MDR-TB treatment is recommended for all patients with rifampicin-resistant
tuberculosis, regardless if isoniazid resistance is confirmed or not
 Specific recommendations are made on the treatment of children with rifampicin-
resistant or MDR-TB
 Clarithromycin and other macrolides are no longer included among the
medicines to be used for the treatment of MDR-TB
 Evidence-informed recommendations on the role of surgery are now included

It is recognized that some drug-resistant TB programmes may have to design strategies

based on limited data, as treatment for many patients cannot wait until full assessment
DRS and other information are available

In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines
during the intensive phase is recommended, including pyrazinamide and four core
second-line TB medicines – one chosen from Group A ( fluroquinolons ), one from
Group B ( second line injectable agents ) , and at least two from Group C other core
second line agents ( ethionamide or protheonamide, cycloserin or terizidone, linezolid,
clofazimine. If the minimum number of effective TB medicines cannot be composed as
given above, an agent from Group D2 ( and other agents from Group D3 may be added
to bring the total to five

In patients with RR-TB or MDR-TB, it is recommended that the regimen be further

strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation,
very low certainty in the evidence).
The intensive phase of MDR-TB treatment should consist of at least four second-line
anti-TB drugs that are likely to be effective (including an injectable anti-TB drug), as
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well as pyrazinamide (conditional recommendation, very low quality evidence). In this
phase consists of five drugs and lasts for eight months in most patients second line
injectabe is given six days a week and all other drugs are given seven days a week. In
continous phase without the injectable continues all the oral agents for a minimum of 12
months, for a total minimum treatment of at least 20 months

Conclusion : One of the biggest barriers to scaling up MDR tuberculosis programmes

is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and
expensive. Some drug-resistant TB programmes may have to design strategies based
on limited data, as treatment for many patients cannot wait until full assessment DRS
and other information are available. The intensive phase of MDR-TB treatment should
consist of at least four second-line anti-TB drugs that are likely to be effective for
minimal eight months. In continous phase without the injectable continues all the oral
agents for a minimum of 12 months, for a total minimum treatment of at least 20
months.

Keywords :MDR-TB, Regimen