New options for fighting the global disease of tuberculosis

Tuberculosis (TB) is a global health problem. The Centers for Disease Control and Prevention (CDC) estimates that one third of the world’s population is infected with TB, and the World Health Organization (WHO) estimates 9 million new cases each year worldwide. Of these new cases, one million are in people who are positive for the human immunodeficiency virus (HIV), and 500,000 of the new cases are multidrug resistant at time of diagnosis. The burden of multidrug resistant TB (MDR-TB) is not shared equally. Twenty-seven countries contain 85% of people with MDR-TB. Two thirds of the 10,000 people diagnosed yearly in the United States are foreign born.

One of the authors of this article is a Fulbright Scholar currently serving in Kigali, Rwanda (Donaghy) and the other (Ugirase) works at the University of Rwanda-Kigali College of Medicine and Health Sciences, School of Nursing and Midwifery. We want to share with you efforts in Rwanda and Sub-Saharan Africa to control TB and to discuss a new diagnostic test for TB and two new medications for the treatment of MDR-TB. (If you need a refresher as to terminology, please refer to the list of definitions at the end of this article.)

TB in Rwanda

In 2011, Ugirase and colleagues conducted a research study delineating the characteristics of patients being treated at a local hospital in Rwanda in the multidrug resistant unit. The sample consisted of 35 clients. Findings were consistent with other research on people living with TB; our patients were young, males outnumbered females, and about 37% did not adhere to previously prescribed treatment. Factors contributing to the spread of TB and the increase in multidrug resistant cases include delayed diagnosis, reporting, and treatment as well as delayed determination of drug susceptibility. Other risk factors include living in poverty in overcrowded conditions; concomitant HIV infection; other comorbid infections such as hepatitis B, hepatitis C, and diabetes mellitus; and drug and alcohol abuse.

With support from global partners, Rwanda has been successful in reducing both the prevalence of TB and deaths from TB by 50% from baselines established in 1990. The current goals include reducing the incidence of TB from 86 per 100,000 to 67 per 100,000 and reducing the number of deaths from 10 per 100,000 to 6.3 per 100,000. Continued global financial support combined with implementation of new diagnostic and treatment modalities will aid this effort.

A new diagnostic test

Approved in 2013, the Xpert MTB/RIF (MDR-TB/ rifampin-resistance mutations) may dramatically reduce the time to diagnosis, reporting, and identification of drug susceptibility to TB. The test is a real-time polymer chain reaction assay for Mycobacterium tuberculosis that simultaneously tests for Rifampin resistance. Results are available in less than 2 hours, a vast improvement over liquid cultures that take 16 days and solid cultures, which average 30 days. (See Xpert MTB/RIF and microscopy.) The Xpert MTB/RIF’s ability to detect drug resistance in a matter of hours compares to 20 days using a line probe assay and 106 days for phenotyping drug susceptibility.

Xpert MTB/RIF vs microscopy

The Xpert MTB/RIF is superior to microscopy of sputum cultures because they take 1 day to process and have a very high false negative rate leading to delayed treatment pending culture confirmation of TB infection. Other drawbacks to microscopy include the need for raw sputum, which increases the risk of healthcare worker exposure, the fact that only a few specimens can be run at a time at a high cost, and lower sensitivity of infection in patients with HIV, which means that those with TB go undetected.


In a multicenter trial in settings of intended use, rather than the ideal reference laboratory research setting, the Xpert MTB/RIF test was used for testing on 6,648 participants during a 10-month period beginning in August 2009. The assay correctly detected TB in more than 90% of patients with positive cultures, compared to a 67% detection rate by microscopy. A meta-analysis conducted by Chang and colleagues confirmed that when Xpert MTB/RIF is used, the sensitivity or number of true positive diagnoses is not lower in people who are HIV positive, as is the case with microscopy.

The Foundation for Innovative New Diagnostics (FIND), a nonprofit organization, negotiated with Cepheid, the manufacturer of the Xpert MTB/RIF, to make the tests available to TB endemic countries for the cost of $9.98 per cartridge. The cost of the testing machine is $1,750 with a laptop computer or $1,700 with a desktop computer. Testing uses a closed system, eliminating contamination as well as the need for biosafety facilities. Training on Xpert MTB/RIF testing takes 1 to 2 days and was even done online for two of the sites in the multicenter trial during Phase 2 testing.

As of October 2014, 16 facilities in Rwanda had purchased and were using the Xpert MTB/RIF with no reported problems. The Bill and Melinda Gates Foundation funded the distribution of this new technology to many developing countries. This affordable, accurate rapid diagnosis test for both TB and TB drug resistance has the potential to change the face of TB by reducing the incidence of drug resistance through early diagnosis and treatment.

New pharmacologic agents

Two medications with novel mechanisms of action were recently approved for use as part of a regimen in the treatment of MDR-TB. The WHO has issued interim guidelines for the use of both medications. The purpose of these guidelines is to ensure appropriate patient selection with informed consent as well as adherence to WHO guidelines in administration including treatment monitoring, pharmacovigilance and reporting of adverse events.

Bedaquiline
Bedaquiline (Sirturo) was approved in December 2012 by the U.S. Food and Drug Administration (FDA) for the treatment of MDR-TB. It is the first drug with a novel mechanism of action approved for TB in more than 40 years.

Bedaquiline is a diarylquinolone. It inhibits mycobacterial ATP, an enzyme essential for the generation of energy in Mycobacterium tuberculosis. It’s effective against both replicating and dormant organisms. Sputum conversion, a measurement by which a patient is no longer infectious, averaged 12 weeks in the bedaquiline group compared to 18 week with placebo. The rates of conversion at 24 weeks were 79% in the bedaquiline group and 58% in the placebo group. For ethical reasons, the placebo group was treated with other second-line antitubercular medications.

Bedaquiline is only approved for pulmonary MDR- TB. It must be taken with four other antitubercular medications for a period of 24 weeks. This is a much shorter timeframe then the typical 20-month regimen for treating MDR-TB.

Dosing for bedaquiline starts at 400 mg/ daily for the first 2 weeks followed by 200 mg three times per week for an additional 22 weeks. The medication should be taken with food to increase absorption.

In a Phase Two study that compared the drug to placebo, nausea was the only significant adverse effect. However, there was an increased risk of death; 11.4% for the bedaquiline group as compared to 2.5% for the placebo group. Adverse effects noted in other studies included prolonged QT rate on ECG, elevated liver enzymes, and accumulation of phospholipids in cells. Patient monitoring of liver function and cardiac status is needed during treatment and for a minimum of 6 months after treatment due to the long half-life (173 hours) of the drug.

Although bedaquiline has a high-risk profile for adverse effects and increased death it should be noted that other second-line drugs used in the management of MDR-TB also have high adverse risk profiles. In addition, these medications, developed many years ago, did not undergo the rigorous testing that bedaquiline was subjected to. Researchers have speculated that some of these other second-line drugs might not have received approval if subjected to today’s more stringent standards.

Delamanid
Another new medication with a novel mechanism of action approved for use in 2014 is Delamanid (Deltyba) a dihydro-nitroimidazooxazole derivative. It acts by inhibiting the synthesis of mycobacterial cell wall components of methoxy mycolic acid and ketomycolic acid. Delamanid received approval for use from the European Medicines Agency in 2014. It is not currently FDA approved.

Delamanid is typically dosed for 24 weeks at 100 mg twice per day with food. Serious side effects requiring monitoring include prolonged QT on ECG and hyperkalemia.

Both bedaquiline and delamanid are only for use in patients with MDR-TB as part of a multidrug regimen. It’s recommended that approval be obtained from the country’s TB advisory board before initiation. Ideally, all regimens for treatment of MDR-TB should be administered under direct observational therapy (DOT), as adherence is crucial for successful treatment.

Case study

A simulated case will illustrate how a patient might be managed with the new diagnostic test and drugs.

Emmanuel is a 38-year-old male who lives in Kibagabaga Kigali Province, Rwanda with his wife and five children in a three-room rented house. He works 6 days a week as a security guard. Emmanuel went to the hospital after 18 days of coughing, fever, weight loss, and night sweats. An Xpert MDR/RIF test confirmed the diagnosis of MDR-TB, but tests for HIV and hepatitis were negative. All members of Emmanuel’s family and close contacts were evaluated for latent TB infection and found to be negative.

After obtaining a baseline ECG and lab work, all of which was normal, Emmanuel was started on a 24-week five-drug regimen that included bedaquiline. A community health worker provided patient education for TB and medications used in achieving cure and served as the observer for DOT in medication administration. Text messages were used as a supplement to DOT to remind Emmanuel when to take his medications and when to have follow-up laboratory testing.

Twelve weeks after diagnosis Emmanuel and his family were retested. Emmanuel’s sputum was negative and his family members remained free of TB infection. He continued his medications for the 24-week duration and remained sputum negative. Although his liver enzymes did elevate during treatment they gradually receded to pretreatment levels.

Looking to the future

Adequate funding to ensure the worldwide availability of faster and more accurate diagnosis tools and early implementation, adherence, and monitoring of drug therapy according to guidelines is essential to reduce the incidence of TB and the spread of MDR-TB.

The Xpert MDR/RIF is a low-cost, simple test capable of diagnosing both TB and drug resistance in less than 2 hours. Efforts need to continue to make this test available in all TB endemic areas. Bedaquiline and delamanid, in combination with other medications, have the potential to successfully treat MDR-TB in a shorter time frame than previously used regimens that require up to 2 years of treatment. Further research is needed on these medications.

The potential development of other medications in this class combined with early diagnosis and treatment may make TB a disease of the past.

Definitions related to tuberculosis (TB)

Directly observed therapy (DOT) — a healthcare worker visually observes the patient taking each dose of prescribed medication.
Drug-susceptible TB — no resistance identified to first-line drugs (Isoniazid, Rifampin)
Drug-resistant TB — resistant to one first-line drug
Multidrug resistant TB (MDR-TB) — resistant to both Isoniazid and Rifampin
Extensively drug resistant (XDR-TB) — resistant to Isoniazid, Rifampin, fluoroquinolones, and injectable second line agents
Primary-drug resistance — drug resistance in newly diagnosed cases of TB
Secondary (or acquired) drug-resistance — drug resistance in a previously treated case of TB

Selected references

Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet 2011;377(9776):1495–505.

Centers for Disease Control and Prevention. Reported Tuberculosis in the United States, 2012. 2014 www.cdc.gov/tb/statistics/reports/2012/default.htm

Centers for Disease Control and Prevention Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis. MMWR. 2013;62(9). www.cdc.gov/mmwr/pdf/rr/rr6209.pdf. Errata at www.cdc.gov/mmwr/preview/mmwrhtml/mm6245a10.htm?s_cid=mm6245a10_w

Chang K, Lu W, Wang J, et al. Rapid and effective diagnosis of tuberculosis and rifampicin resistance with Xpert MTB/RIF assay: a meta-analysis. J Infect. 2012;64(6):580-8.

Global Tuberculosis Report 2014. www.who.int/tb/publications/global_report/en/.

Goel D. Bedaquiline: a novel drug to combat multiple drug‑resistant tuberculosis. J Pharmacol Pharmacother. 2014;5(1):76-8.

Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011;378(9785):57-72.

Mingote LR, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities. Lancet 2014; http://dx.doi.org/10.1016/S0140-6736(14)60523-7.

Skripconoka V, Danilovits M, Pehme L, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Euro Respir J. 2013;41(6):1393-400.

Umubyeyi AN, Vandebriel G, Gasana M, et al. Results of a national survey on drug resistance among pulmonary tuberculosis patients in Rwanda. Int J Tuberc Lung Dis. 2007;11(2)189-94.

WHO/HTM/TB/2014.23, Geneva, WHO, 2014. The use of delamanid in the treatment of multidrug-resistant tuberculosis. Inerim policy guidance. http://apps.who.int/iris/bitstream/10665/137334/1/WHO_HTM_TB_2014.23_eng.pdf?ua=1&ua=1

Xavier AS, Lakshmanan M. Delamanid: A new armor in combating drug-resistant tuberculosis. J Pharmacol Pharmacother. 2014;5(3):222-24.

Additional resources
www.gatesfoundation.org/What-We-Do/Global-Health/Tuberculosis.

www.cdc.gov/tb/publications/factsheets/treatment/bedaquiline.htm. 2013

www.cdc.gov/tb/topic/globaltb/Rwanda.htm. 2012

www.finddiagnostics.org/about/what_we_do/successes/find-negotiated-prices/xpert_mtb_rif.html. 2013

www.stoptb.org/wg/gli/assets/documents/map/2/Pdf_files/RWA.pdf. 2013

Mwiseneza MJ, Rugema J, Ugirase S, et al. Factors associated with multi-drug resistant tuberculosis in Kibagabaga Hospital. Unpublished manuscript Kigali Health Institute 2011; 1-44.

Claire P. Donaghy is a professor in the nursing department at William Paterson University in Wayne, New Jersey. Sibylle Ugirase is a tutorial assistant at the University of Rwanda-Kigali College of Medicine and Health Sciences, School of Nursing and Midwifery, where Dr. Donaghy is currently serving as a Fulbright Scholar.

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