Treatment of drug resistant TB - Shorter TB 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 reserve or second line 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 and indeed still are 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 patient 1Keshavjee, 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

Shorter TB regimens

And so the search began for shorter regimens for the treatment of drug resistant TB. Shorter regimens would also be easier to take.

This led to the development of the Bangladesh regimen which appears to have much higher TB 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. The results of randomised control trials of these new regimens, are only just now starting to be available.

Change in WHO recommendations

In May 2016 the WHO changed their recommendations on the use of TB drugs for the treatment of drug resistant TB.2"WHO treatment guidelines for drug-resistant tuberculosis (2016 update)", jQuery("#footnote_plugin_tooltip_2").tooltip({ tip: "#footnote_plugin_tooltip_text_2", tipClass: "footnote_tooltip", effect: "fade", fadeOutSpeed: 100, predelay: 400, position: "bottom center", relative: true, offset: [10, 10] });"> This was partly because of the Bangladesh regimen, which appeared to show that a shorter regimen could be just as successful as a longer regimen. 3Van Deun, A "Short, highly effective and inexpensive standardized treatment of multidrug-resistant tuberculosis", Am J Respir Crit Care Med 2010; 182:684-692 There had also been a number of other studies which had shown a similar result. There had however been no randomized control trial, but WHO decided that the treatment of MDR-TB was too important for there not to be new recommendations.

The recommendations also covered the use of bedaquiline and delamanid which are starting to be used for the treatment of drug resistant TB.

Injectable drugs

Even when patients can take the Bangladesh regimen it does not solve all the problems. It still requires patients to have injections as part of their TB treatment. For some patients these can be extremely painful and difficult as Zolelwa Sifumba explains below.

“The injection was like nothing I’d ever felt before. It burns from the second it starts - it is quite a thick serum so you can’t inject it in fast. It takes some time. The pain went down my legs and up to my back. It is so painful. No injection should be that painful. It is intense pain that never stops.”
The pain lasts after the patient walks out of the doctor’s room.
“It is painful to get up. It is painful to go shower. It is painful to eat. It is painful to go to school. Everything is so difficult all day. And the next day when you go for your injection, you’re still in pain from the last injection”4“Frightening injection sends never-ending pain throughout your body”,

Not every patient will suffer in this way, but the fact that some do, means that the search must continue for TB treatments for the treatment of drug resistant TB that don’t involve this type of injectable drug.

Treatment Outcomes

Although they are improving globally and in some countries, the treatment success rates for drug resistant TB are considered by the World Health Organisation to be unacceptably low.

In their latest strategic plan, the South African government has set the very ambitious target that the treatment of drug resistant TB in South Africa should be 75% successful.

Eligibility for treatment with a shorter TB regimen

Fewer drugs are 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.

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. They also need to be patients in whom resistance to the fluoroquinolones group of drugs and second line injectable drugs has been excluded or is considered highly unlikely.

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. This is to ensure that patients are not being treated with drugs that they are already resistant to.

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 drug susceptibility testing (DST) for fluoroquinolones and injectable drugs 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.

Conventional treatment regimens for rifampicin resistant TB

Complicated regimens for the treatment of drug resistant TB

A conventional treatment regimen for any patient with rifampicin resistant TB, is always going to be complicated. A number of different second line drugs need to be used on the basis of the drugs that 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). It also includes patients with strains 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. See the second line drugs for the drugs in each group.

Group D2 consists of the drugs bedaquiline and delamanid. WHO has produced a “best practice” statement on the use of these two drugs.5“WHO best practice statement on the off-label use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis”, WHO, 2017,

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.

Surgical interventions for the treatment of drug resistant TB

Surgery for the treatment of drug resistant TB is now recommended in some circumstances. In patients with RR-TB or MDR-TB elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen.

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