XDR TB- Newer medications to the rescue

Chaitalee Ghosalkar

 Business analyst, Sun Pharma

Adaptation has never seemed as scary as it does when it comes to diseases. Over the course of the last few years, XDR TB, a rare form of multi-drug resistant tuberculosis that is resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin), is on the rise.

To help combat this resistant strain of bacterium, two drugs have been introduced in the past few years: Bedaquiline and Delamanid.

Bedaquiline[1][2], sold by trade name Sirturo, is the first drug to be approved for TB after 40 years. While it received approval in the US in 2012, approval in India and other developing countries followed soon after in 2015.

The drug works by blocking an enzyme inside the Mycobacterium tuberculosis bacteria called ATP synthase. This enzyme is used by the bacteria to generate energy. Without the ability to generate energy, the TB bacteria die and the patient’s condition can start to improve

A major instruction for use of this drug is that it should be administered in combination with at least 3 other TB drugs which drug susceptibility testing has shown that the patient is susceptible to. If drug susceptibility testing is not available, then bedaquiline should be used with at least 4 other drugs to which the patient is likely to be susceptible. Contraindications for the drug include:

  • Latent TB infections due to Mycobacterium tuberculosis
  • Drug sensitive tuberculosis
  • Extra-pulmonary tuberculosis
  • Infections caused by non-tuberculosis mycobacteria

The recommended dose of Bedaquiline is 400 mg a day for two weeks and then 200 mg taken three times a week (with at least 48 hours between doses) for the next 22 weeks. The drug is available as 100 mg tablets, and the tablets should be swallowed whole with water and taken with food.

Although limited number of clinical trials have been conducted with the drug, the results have been significant. The earlier study showed that after 24 weeks 79% of the patients given bedaquiline were sputum smear negative, compared with 58% of patients given placebo. A more recent Phase 3 trial was conducted to compare the efficacy of nine-month and twenty-month regimen of bedaquiline. Both the regimens were close in terms of efficacy; thereby, the results would align with WHO guidelines that recommend a shorter duration of therapy.

Delamanid[3], known by its trade name of Deltyba is a nitroimidazole. It acts by inhibiting the synthesis of mycobacterial cell wall components, methoxy mycolic acid and ketomycolic acid.

Like bedaquiline, this drug is used together with other standard medicines and should not be taken on its own. Available as 50mg tablets, the recommended dose is two tablets taken twice a day with food. The drug needs to be taken for six months.

Clinical trials of delamanid haven’t been as promising. Culture conversion at six months in the delamanid arm was 87.6% vs 86.1% in the control arm. 24 month outcomes and all-cause mortality in the two arms were very similar.

Way forward:

Companies like Orient Pharma (HUEXC 030), AstraZeneca (preclinical drug), Sequella (SQ 109, Sutezolid, SQ609) are developing drugs for the disease. There have been attempts in the past to eradicate the disease through development of vaccines, but trials have been discontinued midway.

Government initiatives[4]:

Revised National TB Control Program (RNTCP) was started in 1997. This program uses the World Health Organisation (WHO) recommended Directly Observed Treatment Short Course (DOTS) strategy. Also, there have been a number of five year National Strategic Plans (NSP)s since the start of the RNTCP. The NSP 2012 – 2017 had the aim of achieving universal access to quality diagnosis and treatment.

Certain improvements made by the government through this duration of the NSP are

  1. Complete geographical coverage (achieved in 2013)
  2. Notification by the private sector (done with the aim of improving collection of patient information)
  3. Banning of sero-diagnostic tests (believed to have saved countless inaccurate results)
  4. Development of Nikshay (A central case based and web based system
  5. Standards for TB care in India (developed in 2014)

These implementations and the ones proposed in NSP 2017-2025 have helped standardize procedures to help detect and keep TB in check. While additional steps will be developed and modified in the future, measures should be taken to curtail the evolution from basic form of TB to drug susceptible or drug resistant one.

These efforts cannot just be made by the government. It is essential for patient and alert citizens to seek medical treatment when they encounter a case that is suspected to be of tuberculosis. The risk of developing XDR TB increases when a patient does not take TB medicine regularly, or does not take all the prescribed medicines.

With contribution from both the people and the government, it is possible to keep XDR TB in check, if not eradicate it completely.

References:

1 https://www.theunion.org/news-centre/news/stream-clinical-trial-results-provide-vital-insight-into-nine-month-treatment-regimen-for-multidrug-resistant-tuberculosis

2 https://www.tbfacts.org/bedaquiline/

3 https://www.tbfacts.org/delamanid/

4 https://www.tbfacts.org/rntcp/

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